1.1. The global burden of breast cancer: incidence, mortality, survival, and prevalence

1.1.1. Global burden

Breast cancer is the most commonly diagnosed cancer in women and the most common cause of cancer death in women worldwide. Globally, it is estimated that in 2012 there were 1.68 million new diagnoses (25% of all new cancer diagnoses in women) and 0.52 million deaths (15% of all cancer deaths in women) from invasive breast cancer, corresponding to age-standardized incidence and mortality rates of 43.3 and 12.9 per 100 000, respectively (Ferlay et al., 2013, 2014a). Unless otherwise stated, all further references in Section 1 to breast cancer refer to invasive breast cancer in women.

Before age 75 years, 1 in 22 women will be diagnosed with breast cancer and 1 in 73 women will die from breast cancer, worldwide. Breast cancer in men is a very rare disease, with incidence rates of about 1% of those for women and with little evidence for changes over time (Ly et al., 2013). Male breast cancer is not considered further in this Handbook.

The estimated global incidence of breast cancer in 2012 was 3 times that of the next most common types of cancer in women: cancers of the colorectum (0.61 million new cases, 14.3 per 100 000), lung (0.58 million, 13.6 per 100 000), and cervix (0.53 million, 14.0 per 100 000) (Fig. 1.1; Ferlay et al., 2013, 2014a). Mortality from breast cancer was broadly similar to that from lung cancer in women (0.49 million deaths, 11.1 per 100 000) and substantially greater than that from the next most common causes of cancer death in women: cancers of the colorectum (0.32 million, 6.9 per 100 000) and cervix (0.27 million, 6.8 per 100 000) (Fig. 1.1; Ferlay et al., 2013, 2014a).

Fig. 1.1

Estimated age-standardized (World) cancer incidence and mortality rates (ASR) per 100 000, for 10 major sites, in men and women, 2012

About one quarter of the breast cancer cases and deaths in the world in 2012 occurred in Europe, and approximately 15% of the cases and 9% of the deaths occurred in North America (Fig. 1.2; Ferlay et al., 2013, 2014a). However, the largest contributor to the global burden was East and Central Asia, where 36.3% of the cases and 41.5% of the deaths occurred. Within East and Central Asia, China and India contributed substantially to the global burden, with 11.2% and 8.6% of the cases, respectively, and 9.2% and 13.5% of the deaths, respectively. Latin America and the Caribbean contributed 9.1% of the cases and 8.3% of the deaths, whereas sub-Saharan Africa was estimated to contribute 5.6% of the cases and 9.1% of the deaths (Fig. 1.2).

Fig. 1.2

Estimated global number of new cases and deaths with proportions by major world regions for breast cancer in women, 2012

For women diagnosed in 2005–2009, 5-year net survival rates from breast cancer generally exceeded 80% in Europe (excluding eastern Europe), in Australia and New Zealand, and in some countries in South America and Asia, and reached almost 90% in the USA (Allemani et al., 2014). High 10-year relative survival rates have also been reported in the more-developed regions of the world, such as 71.0% in Europe (Fig. 1.3; Allemani et al., 2013) and 82.7% in the USA (SEER, 2014a). A combination of this level of survival with high incidence rates results in a high global prevalence of breast cancer. Thus, in 2012 there were an estimated 6.3 million women alive who had had a diagnosis of breast cancer in the previous 5 years (Ferlay et al., 2013). This represents more than one third (36.4%) of all 5-year prevalent cancer cases in women and almost one fifth (19.2%) of those in both sexes combined. There are many more women living with a history of breast cancer than there are people living with a history of any other type of cancer (excluding non-melanoma skin cancer); the next highest estimated 5-year prevalence rates are for prostate cancer (3.9 million) and colorectal cancer (3.5 million in both sexes combined) (Fig. 1.4; Ferlay et al., 2013).

Fig. 1.3

10-Year age-standardized relative survival (age at diagnosis, 0–89 years) for breast cancer in Nordic countries, 1964–2011

Fig. 1.4

Estimated global number of 5-year prevalent cancer cases in the adult population (total: 32 544 633 for all sites combined) with proportions by major sites for both sexes, 2012

Similarly to most cancer types, both incidence and mortality rates of breast cancer increase with increasing age (Fig. 1.5), although (in the absence of screening) not as rapidly as for most other cancers; the majority of breast cancer cases and deaths occur in women older than 50 years. Of the worldwide burden of 1.68 million incident cases in 2012, 0.55 million (33%) were estimated to occur in women younger than 50 years, 0.91 million (54%) in women aged 50–74 years, and 0.22 million (13%) in women aged 75 years and older. Of the 0.52 million deaths in 2012, 0.13 million (25%) were estimated to occur in women younger than 50 years, 0.27 million (52%) in women aged 50–74 years, and 0.12 million (23%) in women aged 75 years and older (Ferlay et al., 2013).

Fig. 1.5

Age-specific incidence rates per 100 000 for breast cancer in women in selected cancer registry populations, 2003–2007

1.1.2. International variation

Breast cancer was the most frequently diagnosed cancer among women in 140 (76%) of the 184 major countries included in the GLOBOCAN database (Ferlay et al., 2013). In most of the remaining countries, breast cancer was the second most frequently diagnosed cancer, after cervical cancer. However, there are substantial regional variations in breast cancer incidence rates worldwide (Fig. 1.6). In 2012, more than a 3-fold variation in the age-standardized breast cancer incidence rates was recorded between North America and western Europe (rates > 90 per 100 000) and Central Africa and East and South-Central Asia (rates < 30 per 100 000) (Fig. 1.7).

Fig. 1.6

Global distribution of estimated age-standardized (World) incidence rates (ASR) per 100 000 for breast cancer in women, 2012

Fig. 1.7

Estimated age-standardized incidence and mortality rates (ASR) per 100 000 for breast cancer in women, for major world regions, 2012

At the country level, data from Volume X of Cancer Incidence in Five Continents for 2003–2007 showed an approximately 5-fold variation in risk, which can reach 10-fold at the extremes (Fig. 1.8; Forman et al., 2013). In populations with incidence rates higher than 90 per 100 000, such as USA SEER, US Non-Hispanic White (92.5), the Netherlands (93.5), and Belgium (110.8), the risk of a woman being diagnosed with breast cancer before age 75 years is about 1 in 10, whereas in populations with rates lower than 20 per 100 000, such as Thailand, Khon Kaen (18.6), Malawi, Blantyre (14.3), and India, Dindigul (12.0), this risk is less than 1 in 50. Between these extremes, a gradient in risk is observed, including within the same continent. For example, within Europe, rates per 100 000 in Latvia (48.4), Bulgaria (52.7), and Spain, Granada (54.8) were less than half those in Belgium (110.8); similarly, within South America, rates in Ecuador, Quito (38.0) were about half those in Argentina, Córdoba (78.1).

Fig. 1.8

Age-standardized incidence rates (ASR) per 100 000 for breast cancer in women, in selected cancer registry populations, 2003–2007

The general shape of the age–incidence curve (Fig. 1.5) – a rapid rate of increase before age 50 years and a general flattening in later years – is observed in many populations. However, there is some variation between countries in the shape after age 50 years. Some populations show a plateau (e.g. Tunisia, North), whereas others show a decline (e.g. Thailand, Khon Kaen), which may be due to an increasing risk of occurrence in successive generations rather than to a real decline in risk with age (Moolgavkar et al., 1979). In less-developed countries, which are characterized by both a generally young age structure and a flat age–incidence curve, the increasing occurrence translates to a considerably lower mean age at diagnosis compared with more-developed countries. Although it has been suggested that this indicates different biological characteristics of breast cancer in women in less-developed countries, the evidence does not generally support such an interpretation (McCormack et al., 2013). Nevertheless, the existing variations in mean age at diagnosis can have important implications for early detection strategies (Harford, 2011; Corbex et al., 2012).

International variation in breast cancer mortality is also evident, although considerably less so than for incidence (Fig. 1.9). Regions with the highest age-standardized mortality rates (> 17 per 100 000) were Melanesia, North Africa, and West Africa; the lowest rates (< 10 per 100 000) were seen in East Asia and Central America (Fig. 1.10). At the country level, selected results from the World Health Organization (WHO) Mortality Database for the period 2003–2007 showed the highest age-standardized mortality rates (~20 per 100 000) in Denmark (21.6), the Netherlands (20.8), Argentina (19.3), and the United Kingdom (19.3); the lowest rates (≤ 6 per 100 000) were seen in Ecuador (6.0), Egypt (5.6), and the Republic of Korea (4.9) (Fig. 1.11; WHO, 2014).

Fig. 1.9

Global distribution of estimated age-standardized mortality rates (ASR) per 100 000 for breast cancer in women, 2012

Fig. 1.10

Age-standardized mortality rates (ASR) per 100 000 for breast cancer in women, in selected populations, 2003–2007

Fig. 1.11

Age-standardized incidence rates per 100 000 by year in selected populations for breast cancer in women of all ages

This observed smaller variation in mortality rates than in incidence rates is mainly a consequence of the relatively improved survival and lower case fatality rates that are seen in high-incidence, high-income countries and are not generally seen in lower-incidence, lower-income countries. Thus, as stated above, whereas the 5-year survival rate is usually more than 80% in high-income countries, it is about 60% in countries such as Algeria and India (Allemani et al., 2014). Within Europe, 5-year survival ranges from 71% in Latvia to 87% in Finland (Allemani et al., 2014), and 10-year survival ranges from 54% in eastern Europe to 75% in northern Europe (Allemani et al., 2013). In another international comparative study, of women mainly diagnosed in the mid-1990s, the 5-year relative survival rate varied from 82% in China to 47% in the Philippines, 46% in Uganda, and 12% in The Gambia (Sankaranarayanan et al., 2010). Lower relative survival rates are explained largely by lower proportions of women presenting with localized disease, within both high-resource settings (Walters et al., 2013a) and low-resource settings (Sankaranarayanan et al., 2010). Comparable differences can also be observed within countries, among different socioeconomic, racial, or ethnic groups. For example, within the USA in 2011, White women had a slightly higher age-standardized breast cancer incidence rate compared with Black women (127.2 vs 122.7 per 100 000, respectively) and a lower age-standardized mortality rate (20.9 vs 30.2 per 100 000, respectively) (SEER, 2014a). This finding reflects substantially different survival rates (90.0% vs 77.3% at 5 years and 84.3% vs 68.4% at 10 years, respectively) (SEER, 2014a).

1.1.3. Incidence and mortality in relation to level of development

Table 1.1 compares incidence and mortality estimates for breast cancer among countries aggregated according to four different levels of the Human Development Index (HDI) in 2012 (UNDP, 2012). The HDI is a composite index based on life expectancy at birth, adult literacy rate, education enrolment rate, and gross domestic product (GDP) per capita. In 2012, almost half of the global breast cancer burden (45%; 0.75 million cases) and one third of the breast cancer deaths (33%; 0.17 million) occurred in countries with very high HDI. A substantial number of cases (29%; 0.49 million) and deaths (35%; 0.18 million) occurred in countries with medium HDI, although this includes the highly populous countries of China and India. Whereas age-standardized incidence rates broadly increased with increasing HDI (from 32.6 per 100 000 in countries with low HDI to 79.0 per 100 000 in countries with very high HDI), mortality rates had no equivalent relationship with HDI and were highest in countries with low HDI (17.0 per 100 000), largely in sub-Saharan Africa. The net effect of this is that the ratio of the number of deaths to the number of cases (a crude indicator of survival), by HDI category, increases from 23% for very high HDI to 36% for high HDI, 37% for medium HDI, and 47% for low HDI. Breast cancer was the most commonly diagnosed cancer within all four HDI levels, the most common cause of cancer death within the very high and low HDI levels, and the second most common cause of cancer death (after lung cancer) within the high and medium HDI levels.

Table 1.1

Breast cancer in women: estimated annual number of cases, age-standardized incidence rate, number of deaths, age-standardized mortality rate, and number of deaths as a percentage of number of cases, by HDI ranking and for the world, in 2012.

1.1.4. Time trends

Figs. 1.11–1.14 show the annual age-standardized breast cancer incidence and mortality trends by year, for all ages and for the age group 50–74 years (which is the age group most likely to have received breast cancer screening), for several representative populations.

The incidence graphs make use of data provided by population-based cancer registries and published in successive volumes of Cancer Incidence in Five Continents (Ferlay et al., 2014b). Registries have been selected that represent different world regions and for which comparatively long time series were available. In general, all-age incidence rates, although variable between populations, have consistently increased over the five decades considered, although without ever exceeding 100 per 100 000. There are signs of the rate of increase slowing down and the incidence rates reaching a plateau since the late 1990s, noticeably in the higher-incidence countries (Australia, Denmark, Finland, Israel, the United Kingdom, and the USA), whereas the lower-incidence countries tend to show ongoing increases and less of an evident plateau effect in the most recent 10 years (Fig. 1.11). A detailed study from India shows that the recent increase in female breast cancer incidence rates is one of the most important secular trends in the overall pattern of cancer applying to both urban and rural populations (Badwe et al., 2014). Incidence trends for the age group 50–74 years are broadly similar to those for all ages, with some evidence of a downtrend beginning in the late 1990s to early 2000s in the higher-incidence countries (Fig. 1.12).

Fig. 1.12

Age-standardized incidence rates per 100 000 by year in selected populations for breast cancer in women aged 50–74 years

The mortality data are from the WHO Mortality Database (WHO, 2014), and countries were selected according to the same criteria as for the incidence graphs (different world regions and comparatively long time series). All-age mortality rates increased modestly in most populations until the mid-1980s and have since declined in the higher-mortality countries (Fig. 1.13). Data from Japan singularly show a consistent increase since the mid-1960s. The highest mortality rates were observed in Denmark and the United Kingdom, where they approached 30 per 100 000 in the early 1980s (Fig. 1.13). Mortality trends for the age group 50–74 years are, overall, similar to those for all ages, with a decline in mortality rates over the most recent two decades especially notable in the higher-mortality countries (Fig. 1.14). The start of the period of decline in mortality rates varies between countries (the mid-1980s in the United Kingdom and the USA, the early to mid-1990s in Australia, Denmark, and Israel, and the early 2000s in Estonia).

Fig. 1.13

Age-standardized mortality rates per 100 000 by year in selected populations for breast cancer in women of all ages

Fig. 1.14

Age-standardized mortality rates per 100 000 by year in selected populations for breast cancer in women aged 50–74 years

1.1.5. Time trends by age

Using the same sources as for Figs. 1.11–1.14, a more detailed consideration of time trends for selected individual countries is provided in Fig. 1.15 and Fig. 1.16. Each graph shows time trends for age-standardized breast cancer incidence and mortality, within the age groups 25–49 years, 50–74 years, and 75 years and older. Where possible, these figures are based entirely on national data, but for some (Japan and the USA), regional cancer registry data for incidence and national data for mortality were used. For each country, an indication is provided (by shading) of the period within which population-based breast screening programmes were operational within the age group offered screening (usually the age group 50–69 years) (see Section 3.2). It should be noted that before the implementation of a programme, opportunistic screening would usually have been taking place for subsets of the population, and that after a screening service became operational, full roll-out to eligible women may have taken at least 10 years. In addition, due to the relatively high breast cancer survival rates, several years are required before the impact of a service screening programme becomes discernible in routine cancer statistics. Thus, the time trends shown here are presented to provide context for the incidence and mortality trends, but they do not allow conclusions to be drawn about the impact of breast cancer screening programmes (see Section 5.2.1c for further discussion).

Fig. 1.15

Age-standardized incidence rates (solid lines) and mortality rates (dashed lines) per 100 000 by year in selected countries for breast cancer in women

Fig. 1.16

Age-standardized incidence rates (solid lines) and mortality rates (dashed lines) per 100 000 by year in selected countries for breast cancer in women

Fig. 1.15 shows trends in countries where national or regional mammography screening services were introduced during the 1980s or the 1990s. An increase in incidence rates in the two younger age groups (25–49 years and 50–74 years) was evident before the introduction of screening; in general, this increase continued after the introduction of screening, but the rate of increase was greater in the age group 50–74 years. Such an increase was generally less evident in the age group 75 years and older, and in Sweden and New Zealand it was hardly evident at all. The introduction of screening tended to coincide with (or to just follow) the beginning of a period of decline in mortality rates in all three age groups. In Denmark, no such decline was apparent in the age group 75 years and older.

Fig. 1.16 shows trends in countries where screening services were introduced after 2000 or have never been introduced. In all of these countries, incidence rates increased consistently over time in each of the three age groups. In the Czech Republic, Ireland, Slovakia, and Slovenia, mortality rates declined in the two younger age groups; this decline started before the onset of screening and was less apparent in the age group 75 years and older. In Bulgaria, Costa Rica, Japan, and Singapore, there is evidence of a decline in mortality rates, although this is confined to the age group 25–49 years. In Bulgaria, Japan, and Singapore, mortality rates continued to increase in the two older age groups, whereas in Costa Rica mortality rates increased in the age group 75 years and older but remained stable for the age group 50–74 years.

Overall, Fig. 1.15 and Fig. 1.16 show a general increase in incidence and a general decrease in mortality in all three age groups starting before the introduction of screening programmes. In those countries where screening services were introduced in the 1980s or the 1990s (Fig. 1.15), the increase in incidence was most rapid in the age group 50–74 years. In Bulgaria, Costa Rica, Japan, and Singapore, no decrease in mortality rates was seen in women older than 50 years. It is noteworthy that breast cancer incidence and mortality rates have been changing in different ways during the recent decades, during which national mammography screening programmes have been established.

1.1.6. Projection to 2025

Table 1.2 shows the estimated global burden of incidence and mortality from breast cancer in 2012 projected to 2025, overall and by HDI category. Overall, a 30% increase in the estimated number of new cases (from 1.68 million to 2.19 million) and a 33% increase in the number of deaths (from 0.52 million to 0.69 million) is projected by 2025. Because of differential population growth levels among different HDI categories, the numbers of cases and deaths are projected to increase most rapidly in countries with low HDI. The number of deaths is also projected to increase more rapidly in countries with medium HDI.

Table 1.2

Breast cancer in women: estimated annual number of cases and deaths, by HDI ranking and for the world, 2012 and 2025 projection.

It is important to note that these projections only take account of global demographic changes in population structure and growth based on United Nations estimates (United Nations, 2012). The risk of developing or of dying from breast cancer is assumed to remain constant at 2012 levels, and no allowance is made for changes in screening intensity. At least in more-developed countries, the projections in Table 1.2 may well underestimate incidence and overestimate mortality.

1.2. Classification and natural history

Several guidelines on breast disease classification and on diagnostic criteria with respect to mammography screening are available (NHSBSP, 2005; Perry et al., 2006; Lakhani et al., 2012; Table 1.3). This section highlights areas of relevance to the different forms of breast screening, i.e. all forms of imaging and of palpation. The section on benign breast disease (Section 1.2.1) describes common breast conditions that may be indistinguishable from invasive ones by palpation and/or imaging, and lesions that may exhibit microcalcifications similar to those seen in some forms of carcinoma in situ. The section on breast carcinoma in situ (Section 1.2.2) provides an overview of those lesions that are found at a higher frequency in mammography screen-detected breast cancers than in symptomatic breast cancers, and may thus contribute to overdiagnosis and overtreatment. The section on invasive breast carcinoma (Section 1.2.3) provides a concise summary of the detailed classification and current understanding of the underlying molecular genetic basis (provided in detail elsewhere; Dixon & Sainsbury, 1998; Lakhani et al., 2012). Section 1.2.4 provides an overview of hereditary and somatic mutations in breast cancers.

Table 1.3

Benign and malignant breast tumours recognized in the current WHO classification of tumours of the breast.

1.3. Risk factors

Although it would be ideal to identify a subset of the population from which most cases would arise on the basis of established breast cancer risk factors, simulations of risk-based screening have not confirmed the validity of this approach. Screening of 17 543 women led to the conclusion that more than 50% of the cases would not have been detected if only women with either a previous breast biopsy or a family history of breast cancer had been screened, and that more than 40% of the cases would have been missed if women had been selected for screening on the basis of other established breast cancer risk factors (Solin et al., 1984). An analysis of the Edinburgh randomized trial similarly reported that if women had been selected for screening based on a previous biopsy or on a history of breast cancer in a mother or sister, only 19.8% of the first-round cancers would have been detected (Alexander et al., 1987). When menopausal status and nulliparity or first birth after age 30 years were included as high-risk factors, the proportion of first-round cases that would have been detected increased to 55.6%. Consequently, restricting screening to women with the most established risk factors would fail to identify the majority of prevalent cancers in an asymptomatic population. Madigan et al. reported population attributable risk estimates for breast cancer derived using data from the United States National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study (Madigan et al., 1995). Well-established risk factors, such as later age at first live birth, nulliparity, higher family income, and family history of breast cancer in first-degree relatives, were associated with approximately 41% of the breast cancer cases in the USA. In the Netherlands, retrospective evaluation of a breast cancer screening programme showed that only 63% of the breast cancer cases would have been identified if the programme had screened only women with at least one established risk factor, representing only 37% of the study group (De Waard et al., 1988). The authors concluded that the “relevance of the high-risk group concept in screening for breast cancer is small”. Finally, data from a large multicentre case–control study in Italy indicated that it would be necessary to screen 87% of the population in order to detect 95% of the cases (Paci et al., 1988). The authors concluded that breast cancer risk factors discriminated poorly for selective screening.

In each of these studies, the overall conclusion was that breast screening on the basis of selected breast cancer risk factors, individually or in combination, fails to identify a subset of women from which the majority of cases of breast cancer are expected to arise. It should also be stressed that the greater the complexity of the risk-based strategy, the greater the need for a regular risk assessment programme to ensure that as risk profiles change, women are cycled in and out of the programme. This necessity not only adds complexity and costs but also adds the potential for misspecification. From a public health standpoint, it appears that the single best strategy for breast cancer screening is a simple one, based on age-related invitation.

Breast cancer in women, as is the case for most cancers, is a multifactorial disease. Its risk factors strongly reflect the hormonal etiology; among the relevant biological exposures are levels of sex steroids, other hormones, and growth factors, including estrogens, androgens, prolactin, and insulin-like growth factors. Life-course reproductive, anthropometric, and lifestyle factors, many of which are prevalent in high-incidence countries, are well-established risk factors: early menarche, late menopause, later age at first pregnancy, nulliparity and low parity, little or no breastfeeding, higher body mass index (BMI) at postmenopausal ages, and tall stature. Lifestyle factors associated with increased risk include low physical activity levels, alcohol consumption, certain exogenous hormone therapies, and exposure to ionizing radiation. Breast density, history of benign breast disease, and family history of cancer are also linked to an increased risk of breast cancer. Also, a small proportion of breast cancers are hereditary, and specific genetic mutations have been identified.

In the following sections, breast cancer risk factors are broadly grouped into: hormonal and reproductive factors (Section 1.3.1), lifestyle factors and environmental exposures (Section 1.3.2), and risk factors that are not modifiable (Section 1.3.3). Exposure to ionizing radiation is described in Section 1.3.4, and genetic factors are described in Section 1.3.5. Population attributable fractions to known risk factors in different settings are summarized in Section 1.3.6. Table 1.4 presents the magnitude of relative risks for breast cancer associated with these risk factors.

Table 1.4

Magnitude of relative risk for breast cancer associated with established risk factors.

1.3.3. Non-modifiable risk factors

(a) Height

Overall, there is abundant and consistent evidence of a clear exposure–response relationship and of plausible mechanisms in humans of the association between height and breast cancer risk. The World Cancer Research Fund reported that factors leading to greater adult attained height are associated with an increased risk of breast cancer in both premenopausal and postmenopausal women (RR, 1.03; 95% CI, 1.01–1.04 per 5 cm increase in height) (WCRF/AICR, 2010).

(b) Age

In many populations, breast cancer incidence rates appear to increase rapidly before age 50 years and generally flatten in later years (see Section 1.1). Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the United States National Cancer Institute show that at postmenopausal ages, incidence rates of ER-positive breast cancer continue to increase, whereas those for more-aggressive, earlier-onset ER-negative breast cancer reach a plateau or decline (Anderson et al., 2006). Breast cancer shows an age–incidence pattern for ER expression, and relative risks compared with women younger than 50 years increase 6-fold at ages 50–59 years and up to 10-fold at ages 70 years and older (Anderson et al., 2006).

(c) Benign breast disease

The majority of benign breast conditions are non-proliferative lesions with no associated increased risk of subsequent development to breast cancer. However, usual epithelial hyperplasia is associated with a 1.5–2.0-fold increased risk, and atypical hyperplasia, both ductal and lobular, with a 2.5–4.0-fold increased risk (London et al., 1992; Dupont et al., 1993; Fitzgibbons et al., 1998; Colditz et al., 2000; Lakhani et al., 2012).

(d) Breast density

Breast density, commonly referred to as “mammographic density”, is the relative composition of mammary collagen-rich stromal tissues in the breast, as opposed to the lower-density adipose tissue. The American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) has visually estimated and classified breast density into the following categories of increasing area density: category 1, < 25% (almost entirely fatty); category 2, 25–50% (scattered fibroglandular densities); category 3, 51–75% (heterogeneously dense); category 4, > 75% (extremely dense) (see Table 1.5 for the distribution of breast density by age group and cancer status; Lazarus et al., 2006; Kerlikowske et al., 2007). These categories serve during the routine interpretation of mammography and are measured on a mammogram as the percentage of the projected breast area that is radiodense (radiopaque), known as “percent mammographic density” (Boyd et al., 2005; McCormack & dos Santos Silva, 2006; Boyd et al., 2007; Chiu et al., 2010; Pike & Pearce, 2013).

Table 1.5

Distribution of breast density on first and last screening mammography, by age group, for women without and with breast cancer diagnosed after the most recent or last screening mammography.

Mammographic density appears to be correlated with several other breast cancer risk factors, including genetic predisposition (Becker & Kaaks, 2009; Boyd et al., 2009) and genetic polymorphisms (Dumas & Diorio, 2010; Lindström et al., 2011; Peng et al., 2011). Although after adjusting for other risk factors, mammographic density appears to remain independently associated with breast cancer risk (Pettersson et al., 2014), at present it has not proven to be a valuable component for modelling and predicting breast cancer risk (Barlow et al., 2006; Tice et al., 2008).

An important effect of mammographic density is the risk of a false-negative mammography finding due to the masking effect of dense tissue (Boyd et al., 2007). The effect of density on the sensitivity of mammographic screening is discussed and quantified in Section 2.1.9.

1.3.4. Ionizing radiation

Exposure to ionizing radiation is a well-established risk factor for breast cancer, as concluded by several international committees (National Research Council, 2006; INSERM, 2008; UNSCEAR, 2010, 2013; IARC, 2012c). Knowledge about radiation-related risk of breast cancer in women is derived mainly from studies of atomic bomb survivors, women exposed to diagnostic radiation, and patients exposed during therapy for benign disease or for cancer, mainly during childhood. Other useful information about the radiation-related risk of the general population derives from studies of occupationally exposed workers, such as medical workers (Table 1.6). The huge amount of evidence of an exposure–risk relationship comes from epidemiological studies of various populations, age groups, and exposure conditions (Ronckers et al., 2005; Telle-Lamberton, 2008). In summary, the majority of studies indicate that breast cancer may be induced after radiation exposure of women younger than 40 years. Studies of atomic bomb survivors or of patients medically exposed show very low or no risk from exposure after that age.

Table 1.6

Epidemiological studies on radiation exposure and risk of breast cancer in women.

(a) Atomic bomb survivors

Regularly updated analyses of incidence and mortality in the Life Span Study of Japanese atomic bomb survivors have enabled detailed studies of the consequences of exposure received at one time and at a high exposure rate over a population exposed at various ages (Land et al., 2003; Preston et al., 2007; Ozasa et al., 2012). The dose–response for breast cancer risk is significant, is among the highest compared with other cancer sites, and is consistent with a statistical model in which the excess risk of breast cancer is proportional to the radiation dose received (the so-called linear, no-threshold model). An important and significant effect of age at exposure is observed, with a higher risk for women exposed before age 20 years, a less-increased risk for women exposed after age 40 years, and a not measurably increased risk for women exposed after age 50 years. Although it is challenging to separate the role of age at exposure from the role of attained age (or age at observation for risk), it is necessary to calculate the radiation-associated breast cancer risk, and this has enabled the identification of an early-onset group of women at high risk (before age 35 years). The general conclusions are similar whether based on incidence or on mortality studies.

(b) Women exposed for medical monitoring

Other informative studies are from women exposed for diagnostic purposes, as during fluoroscopic examinations of pulmonary tuberculosis. An incidence study was conducted in the USA (Boice et al., 1991) and a mortality study was conducted in Canada (Howe & McLaughlin, 1996). The doses to the breast were moderate but fractionated at a high dose rate and received at a mean age of 25 years, resulting in significant dose–response relationships. The estimated excess risks observed in studies of women undergoing multiple radiological examinations for spine deformities were similarly high and suggested a higher carcinogenic effect of radiation among women with a family history of breast cancer (Doody et al., 2000; Ronckers et al., 2008, 2010). The modifying effect of stage of reproductive development at exposure was not found to be significant. Overall, the excess risk of fractionated exposure is similar to the excess risk of acute exposure, such as that received by atomic bomb survivors.

(c) Women irradiated for benign disease

The risk of breast cancer after radiotherapy for treatment of benign diseases has been estimated mainly among women treated for postpartum mastitis (Shore et al., 1986) or for benign breast disease (Mattsson et al., 1993, 1995), and among children treated for thymus hypertrophy (Hildreth et al., 1989; Adams et al., 2010) or for skin haemangioma (Lundell et al., 1999; Eidemüller et al., 2009). The doses were low to moderate but were received at a fractionated high dose rate, except for the skin haemangioma study. All these studies overall reported significant excess risks of breast cancer. The mean age at exposure of women treated for postpartum mastitis was 26 years and for benign breast disease was 40 years, but in these two studies no effect of age at exposure was observed. Infants treated for thymus hypertrophy were exposed mainly before age 1 year, and an excess risk of breast cancer was still observed after a mean follow-up of 57 years (Adams et al., 2010). In children treated for haemangioma, who were exposed at low doses and at a low dose rate, the estimated dose–response was lower but significant (Eidemüller et al., 2009).

(d) Women irradiated for breast cancer

Two studies were conducted on the risk of contralateral cancer associated with radiotherapy for breast cancer (Boice et al., 1992; Storm et al., 1992). The study in Denmark was mostly of perimenopausal or postmenopausal women and reported little evidence of radiation-induced contralateral breast cancer at low doses (Storm et al., 1992). The study in the USA reported an excess risk that was significant only for women treated before age 45 years (Boice et al., 1992). These two studies concluded that radiotherapy for breast cancer, at average radiation doses of 2.8 Gy and after age 45 years, contributes little, if at all, to the risk of a second cancer in the opposite breast.

(e) Survivors of childhood cancer

Cohorts of survivors of childhood cancer in the United Kingdom and the USA who were treated by X-ray radiotherapy with moderate to very high doses of chest radiation, targeted to mantle and modified mantle fields, mediastinum, lung, and chest (Henderson et al., 2010) exhibit a much higher risk of developing breast cancer compared with the general population (Kenney et al., 2004; Friedman et al., 2010; Reulen et al., 2011). The excess risk of breast cancer was consistently higher among survivors of Hodgkin lymphoma, mainly because they received higher exposure (Henderson et al., 2010). Two pooled studies (Guibout et al., 2005; Moskowitz et al., 2014) reported similar increased risks and gave detailed results either by radiation field or by radiation dose. A significant increase in risk of breast cancer was observed in the pooled cohort from France and the United Kingdom, with each Gray unit received by any breast increasing the excess relative risk by 0.13 (95% CI, < 0.0–0.75) (Guibout et al., 2005). Higher risks for mantle-field therapy (very high doses) and whole-lung-field therapy (large volume of radiation) were reported among women in Canada and the USA treated for cancer during childhood (Moskowitz et al., 2014). Female survivors of Wilms tumour who had been treated with chest radiotherapy had a high risk of developing early breast cancer (Lange et al., 2014). A study of women treated for Hodgkin lymphoma during childhood focused on a good reconstruction of radiation dosimetry and reported a significant dose–response relationship that still increased at very high doses and remained significant with increasing time since therapy (Travis et al., 2003). An analysis of modifying factors in that study was not conclusive (Hill et al., 2005). Similarly, in another study, in the Netherlands, the risk of breast cancer increased significantly with radiation dose, and the relationship was still observed at high doses (van Leeuwen et al., 2000, 2003). In that study, the risk seemed to decrease in women treated after age 30 years (compared with ≤ 20 years) and in women who received additional chemotherapy, partly due to the effect of chemotherapy on an earlier age at menopause.

(f) Women undergoing mammography

The risk of breast cancer induced by mammography is dependent on the dose received by the glandular tissue, as well as many other parameters, including age at exposure, dose rate, type of radiation, and dose–response relationship at low or high dose. Historical estimated doses to glandular breast tissue received from a single mammography view are presented in Fig. 1.17 (Thierry-Chef et al., 2012). Since the late 1990s, the dose received is about 2 mGy, about one sixth of the dose level in the 1960s and well below the dose level of most other exposures, apart from that received by radiation workers (see Table 1.6). Nevertheless, the detailed screening modalities (age range, frequency of screening, number of examinations at each screening, etc.) are necessary to accurately estimate the cumulative dose received by women during their entire participation in a screening programme. The risk of mammography-induced breast cancer is discussed in more detail in Section 5.3.4.

Fig. 1.17

Population estimates (mean, minimum, maximum) of glandular tissue dose (mGy) from mammography, by time period and CBT

(g) Pooled analysis of non-occupational exposures

A very informative pooled analysis of eight cohort studies, of atomic bomb survivors, women with tuberculosis, women with postpartum mastitis, women with benign breast disease, infants treated for thymus hypertrophy, and children treated for skin hemangioma, included women from Japan, Sweden, and the USA exposed to a wide range of radiation doses at different ages (Preston et al., 2002). This study supports the linearity of the dose–response relationship for breast cancer, with evidence of a flattening at high doses. It highlights the independent modifying effect of age at exposure and attained age. Some heterogeneity of the dose–response relationship was observed across studies; this is partly explained by modifying factors such as family history of breast cancer. The study also suggests a similarity in dose–response for acute and fractionated high-dose-rate exposure.

(h) Women exposed occupationally

Incidence and mortality data on radiological technologists are available from large cohorts in Canada, the USA, Europe, and China (Mohan et al., 2002; Sigurdson et al., 2003; Doody et al., 2006). Doses received were elevated before 1940 and then decreased gradually; accordingly, current results show higher risks of breast cancer for women in their earlier years of employment. Other cohort studies of medical workers occupationally exposed to radiation are currently under way and may provide interesting results on breast cancer risk among women in the general population. Studies of nuclear workers are another important source of information on cancer risk at low doses and low-dose-rate exposure, but to date they have included too few women to be informative (Cardis et al., 2007). An incidence and mortality study from the United Kingdom National Registry for Radiation Workers showed no significant dose–response relationship for breast cancer (Muirhead et al., 2009). A case–control study in Australia found a low and non-significant excess risk of breast cancer among exposed women (Buitenhuis et al., 2013). Airline flight crews, composed mainly of women, are exposed to doses of cosmic radiation of up to 6 mSv per year. The most recent updated mortality study of an international joint analysis of cohorts of flight crews from 10 countries showed a breast cancer mortality rate similar to that of the general population, whereas a deficit was observed for almost all other cancer sites (Hammer et al., 2010).

(i) Increased radiosensitivity

Due to the involvement of BRCA1/2 in the repair of DNA double-strand breaks, which can be caused by radiation, BRCA1/2 mutation carriers show increased radiosensitivity (Nieuwenhuis et al., 2002; Venkitaraman, 2002; Powell & Kachnic, 2003; Yoshida & Miki, 2004; Boulton, 2006). In addition to the DNA repair mechanisms described in the above-mentioned studies, very recently a DNA damage-induced BRCA1 protein complex was described as part of the mRNA-splicing machinery. Mutations in BRCA1 and several proteins found within this complex lead to increased sensitivity to DNA damage (Savage et al., 2014).

It has been shown that female BRCA1/2 mutation carriers have a higher risk of developing a radiation-induced breast cancer compared with non-carriers, and particularly before age 40 years (Broeks et al., 2007). A meta-analysis based on six case–control studies and one cohort study showed a non-significantly increased risk of breast cancer due to exposure to low-dose radiation (OR, 1.3; 95% CI, 0.9–1.8) among women with a familial or genetic predisposition (Jansen-van der Weide et al., 2010). The risk became significant at increasing cumulative doses compared with no or minimal radiation exposure (OR, 1.8; 95% CI, 1.1–3.0) and for exposure occurring before age 20 years (OR, 2.0; 95% CI, 1.3–3.1) (Jansen-van der Weide et al., 2010). Similarly, female BRCA1/2 mutation carriers showed an increased risk of breast cancer before age 20–30 years associated with increasing cumulative doses of (low-dose) diagnostic radiation, and sensitivity analysis showed that this was not confounded by family history in this population (Pijpe et al., 2012).

1.3.5. Women at high genetic risk of breast cancer

Among the established risk factors for breast cancer (Mahoney et al., 2008), genetic factors are of particular importance. The current implementation of high-throughput technology has enabled the detection of hereditary alterations and related oncogenic pathways and of driver somatic mutations in mammary tumours, to characterize the phenotypic subtypes of pathologically heterogeneous breast tumours (Stephens et al., 2012).

As in other malignant tumours, the development of breast cancer is driven predominantly by the gradual and lifelong accumulation of acquired (somatic) mutations, but also by epigenetic changes in mammary cells and their progenitors (Polyak, 2007). Breast cancer is a highly pleomorphic disease, and numerous driver mutations (guiding the process of tumorigenesis) (Stratton et al., 2009) have been described by next-generation sequencing studies (Stephens et al., 2012). These mutations usually affect genes that code for key proteins regulating the maintenance of normal tissue homeostasis. A schematic distribution of breast cancer incidence according to genetic risk is given in Fig. 1.18. (See Section 5.6 for a discussion of the screening of women at an increased risk.)

Fig. 1.18

Schematic distribution of breast cancer incidence according to genetic risk

(a) Hereditary breast cancer

Hereditary breast cancer is caused by germline mutations in highly penetrant breast cancer susceptibility genes, most commonly the BRCA1/2 genes (Lichtenstein et al., 2000; Rahman, 2014a). Breast cancers attributable to heritable factors represent 5–10% of all breast cancer cases, which is a small but important proportion. Overall, the presence of breast cancer in any first-degree female relative nearly doubles the risk for a proband, and the inherited risk increases gradually with the number of affected relatives (Collaborative Group on Hormonal Factors in Breast Cancer, 2001). When risk is conferred through the mother, it increases gradually if the mother was diagnosed at a young age or had multiple diagnoses of breast or ovarian cancer (Anderson et al., 2000). For example, the presence of breast cancer in at least one first-degree relative accounts for 13% of cases (Collaborative Group on Hormonal Factors in Breast Cancer, 2001). Also, the early onset of breast cancer and other cancers in mutation carriers increases the probability of recurrence.

Other high- or moderate-penetrance breast cancer susceptibility genes that contribute to the hereditary breast cancer spectrum include CHEK2, PTEN, TP53, ATM, STK11/LKB1, CDH1, NBS1, RAD50, BRIP1, and PALB2, although none of them is comparable in frequency and clinical importance to BRCA1/2 (Antoniou et al., 2014; Couch et al., 2014). Several common features of hereditary breast cancer, documented in both affected families and individuals, characterize this high-risk population.

(b) Penetrance of breast cancer susceptibility genes

Breast cancer susceptibility genes are usually categorized as high-penetrance, moderate-penetrance, or low-penetrance genes, reflecting the relative risk of breast cancer development in mutation carriers.

Mutations in high-penetrance genes (BRCA1, BRCA2, PALB2, TP53, PTEN, STK11, and CDH1) increase breast cancer risk more than 5-fold (Collaborative Group on Hormonal Factors in Breast Cancer, 2001). Within this group, the major breast cancer susceptibility genes BRCA1 and BRCA2 account for approximately 3–5% of all breast cancer cases and approximately 20–50% of all hereditary breast cancer cases (Rahman, 2014b).

Mutations in moderate- or intermediate-penetrance genes (such as CHEK2, ATM, BRIP1, NBS1, RAD51C, and XRCC2) increase breast cancer risk 2–5-fold. The identification of breast cancer-predisposing mutations in genes is of great clinical importance for both patients and unaffected relatives carrying a pathogenic variant. Analysis of these moderate-penetrance genes has been recommended in individuals with a high familial risk who are found to be negative for the presence of mutations in the major breast cancer susceptibility genes. Signs suggesting the presence of a germline mutation in a breast cancer susceptibility gene are: (i) unusual breast cancer appearance (early disease onset; tumour recurrence; bilateral tumour development; male breast cancer development; presence of rare or minor histopathological diagnoses [triple-negative, medullary, or atypical medullary type]; ER-negative); (ii) clustering of breast cancer in affected families; and (iii) cancer multiplicity (development of breast and other cancer types, including ovarian cancer, colorectal cancer, and melanoma).

Mutations in low-penetrance genes increase breast cancer risk less than 2-fold and have no clinical utility at present (Michailidou et al., 2013). However, the categorization of penetrance is not optimal and sometimes could be rather misleading, due to a limited understanding of the true phenotypic characteristics. Even the major breast cancer susceptibility genes exhibit polymorphisms that increase breast cancer risk only mildly (although with high statistical significance); examples are the BRCA1 missense mutation R1699Q and the BRCA2 truncating mutation c.K3326* (Michailidou et al., 2013). Deep sequencing analyses revealed that approximately 20% of triple-negative cancers have potentially druggable aberrations, which include BRAF V600E, EGFR amplifications, and ERBB2/ERBB3 mutations (Shah et al., 2012). The incomplete knowledge of the disease characteristics and response to treatment in patients harbouring mutations in breast cancer susceptibility genes limits the clinical potential of dozens of recently characterized variants, making the assessment of cancer risk in this high-risk population uncertain (Kean, 2014).

The clinical utility of specific variants in the breast cancer susceptibility genes depends not only on their penetrance but also on the population-specific prevalence, which is inversely correlated with the risk of breast cancer development (John et al., 2007; Karami & Mehdipour, 2013). Mutations in breast cancer-predisposing genes other than BRCA1/2 are usually not frequent and have large population variability. For example, the most common pathogenic variant in the CHEK2 gene, c.1100delC (Bell et al., 1999), has a frequency of more than 1% in populations in northern Europe, whereas its frequency is lower in central Europe, extremely low in southern Europe, and practically null in Asian populations (Kleibl et al., 2005).

The large majority of breast cancer susceptibility genes code for tumour suppressor proteins that are involved in key DNA repair pathways (except for PTEN, STK11, and CDH1) and could thus represent a critical anticancer barrier; however, the molecular mechanisms through which hereditary alterations trigger the development of breast cancer remain to be elucidated (Bartek et al., 2007).

(c) BRCA1 and BRCA2 mutation carriers

The BRCA1 and BRCA2 proteins are coded by the most important breast cancer susceptibility genes responsible for the development of familial breast and ovarian cancer syndromes 1 and 2 (Online Mendelian Inheritance in Man [OMIM] #604370 and #612555; OMIM, 2015). The BRCA1 and BRCA2 proteins are structurally unrelated and form part of large multiprotein complexes involved in the repair of DNA double-strand breaks (Li & Greenberg, 2012). Currently, the Breast Cancer Information Core database (BIC, 2015) describes more than 1700 distinct variants in the BRCA1 gene and more than 1900 in the BRCA2 gene. The mutation frequency in both genes varies worldwide; it is highest in the Ashkenazi Jewish population, in which 2.5% of women are carriers (Warner et al., 1999; Karami & Mehdipour, 2013).

Among BRCA1 and BRCA2 mutation carriers, the cumulative risk to age 80 years was shown to reach 90% and 41%, respectively, for breast cancer and 24% and 8.4%, respectively, for ovarian cancer (Offit, 2006). Overall, the risk of mutations in either gene is comparable in patients from hereditary breast cancer-only families, is particularly increased in families with breast and/or ovarian cancer cases, and is inversely correlated with the age at onset (see above).

Carriers of mutations in either gene are also at increased risk of cancer at other anatomical sites. BRCA1 mutations in women predispose to the development of fallopian tube and peritoneal cancers, and to a 5-fold increased risk of early-onset colorectal cancer in women younger than 50 years (Sopik et al., 2014).

It has been suggested that several lifestyle factors may modulate the risk of breast cancer in BRCA1/2 mutation carriers, including breastfeeding, the use of oral contraceptives (associated with a reduced risk in BRCA1/2 mutation carriers), and smoking (associated with an increased risk in BRCA2 mutation carriers) (Friebel et al., 2014).

(d) Putative BRCA3 candidate: PALB2

The PALB2 (partner and localizer of BRCA2) gene codes for a protein that serves as a scaffold for the BRCA1/2 proteins during the DNA double-strand break repair process. PALB2 mutations have been associated with an increased risk of hereditary breast cancer and pancreatic cancer. A recent study estimated the cumulative risk to age 70 years of developing breast cancer to be 47.5% for carriers of PALB2 loss-of-function mutations (Antoniou et al., 2014). Therefore, the risk is similar to that ascertained in BRCA2 mutation carriers, although PALB2 mutations are less frequent. The clinical management of PALB2 mutation carriers should be similar to that of BRCA2 mutation carriers.

(e) Other high-penetrance breast cancer susceptibility genes

Hereditary mutations in other high-penetrance genes conferring a high risk of breast cancer are very rare. Previously, they were usually analysed in cases with the clinical and histopathological characteristics of the associated genetic syndromes (Walsh et al., 2006). This practice has changed with the implementation of next-generation sequencing analyses in high-risk individuals (Couch et al., 2014; Tung et al., 2014). Interestingly, somatic mutations in these genes represent frequent driver mutations in sporadic breast cancer (Stephens et al., 2012).

Breast cancer is the most common cancer diagnosed in women affected by Li–Fraumeni syndrome (LFS; OMIM #151623; OMIM, 2015), mostly as ductal carcinoma or DCIS with ER and PR positivity and/or HER2/neu positivity (Masciari et al., 2012). LFS is a hereditary cancer predisposition syndrome caused by a TP53 mutation (Gonzalez et al., 2009), which confers a cumulative risk of 49% of developing breast cancer by age 60 years. The probability of carrying a TP53 mutation is increased in breast cancer patients younger than 30 years with a first- or second-degree relative with typical LFS-associated cancers at any age, and is almost null in patients diagnosed with breast cancer at age 30–49 years and with no family history of LFS-associated cancers (Gonzalez et al., 2009).

Female carriers of CDH1 (human epithelial cadherin) mutations have a cumulative breast cancer risk to age 75 years of 52% (Kaurah et al., 2007), and the breast cancer is frequently of lobular type in patients older than 45 years (Schrader et al., 2011).

Hereditary heterozygous mutations in the PTEN (phosphatase and tensin homologue) gene, which codes for a phosphatase targeting phosphatidylinositol (3,4,5)-triphosphate, were characterized in individuals with Cowden syndrome (OMIM #158350; OMIM, 2015). Cowden syndrome is a rare, multisystem disease with an increased lifetime risk of developing breast cancer of 25–50% (Pilarski et al., 2013); higher lifetime risks of breast cancer (67%) and development of other cancer types (e.g. dysplastic cerebellar gangliocytoma) are also reported (Nieuwenhuis et al., 2014).

Mutations in the STK11 (serine/threonine-protein kinase) gene have been associated with Peutz–Jeghers syndrome (OMIM #175200; OMIM, 2015), a rare disorder characterized by an increased risk of various neoplasms, including an increased risk of 45% of developing ductal breast cancer by age 70 years (Hearle et al., 2006).

(f) Moderate-penetrance breast cancer susceptibility genes

A representative of this group is the CHEK2 (checkpoint kinase 2) gene, which codes for a regulatory serine/threonine kinase that phosphorylates various protein substrates (including p53 and BRCA1) in response to DNA damage. Mutations in CHEK2 variants could be dispersed over the entire coding sequence, but only a few studies have analysed these in breast cancer patients (Desrichard et al., 2011). The most common variant, c.1100delC, increases breast cancer risk, with odds ratios of 2.7 for unselected breast cancer, 2.6 for early-onset breast cancer, and 4.8 for familial breast cancer (Weischer et al., 2008) and a hazard ratio of 3.5 and worsened survival for contralateral breast cancer (Weischer et al., 2012), in high-risk individuals not carrying BRCA1/2 mutations (Meijers-Heijboer et al., 2002). The cumulative risk for patients with familial breast cancer and who are heterozygous carriers was estimated at 37% (Weischer et al., 2008). Breast tumours arising in c.1100delC mutation carriers are frequently of luminal type and express ER and/or PR (Nagel et al., 2012; Kriege et al., 2014), and do not occur at a particularly young age (Narod, 2010). CHEK2 variants are highly population-specific, and four other variants were found to be associated with increased risk of multiple cancers, including cancers of the breast, colorectum, prostate, and thyroid (Cybulski et al., 2004). The p.I157T variant has been associated with a significantly increased breast cancer risk (OR, 4.2 for lobular breast cancer) (Liu et al., 2012a, b).

The upstream signalling activator of the CHEK2 protein is the large ATM (ataxia telangiectasia mutated) kinase. The frequency of hereditary variants of the ATM gene is estimated to be 0.3–1% in the general population (Prokopcova et al., 2007), and these variants have been associated with an increased relative risk of breast cancer of 2.4 (Renwick et al., 2006). Several studies led to the identification of only a limited number of mutation carriers in high-risk patients, characterized by a 2–3-fold increased breast cancer risk (Damiola et al., 2014).

Several other breast cancer susceptibility genes have been reported. BRIP1 (also known as BACH1) is a BRCA1-binding helicase associated with breast cancer. Three genes – MRE11, RAD50, and NBN (NBS1) – that code for a protein complex (MRE11–RAD50–NBS1) required for DNA strand processing during the repair of DNA double-strand breaks have also been identified in breast cancer patients. Recent studies also indicate that mutations in non-canonical breast cancer susceptibility genes (e.g. mismatch repair genes, including MLH1, MLH2, and PMS6, which are associated with hereditary colorectal cancer) may contribute to the increased risk in patients with hereditary breast cancer (Castéra et al., 2014; Tung et al., 2014).

1.3.6. Attributable burden to known risk factors

Overall, established breast cancer risk factors are common across female populations worldwide and explain a large proportion of the 10-fold international variations in breast cancer incidence rates, as well as the increases seen in migrant studies. It has been estimated that the cumulative incidence of breast cancer to age 70 years in developed countries would drop from 6.3% to 2.7% if women had just two reproductive factors (parity and lifetime breastfeeding) similar to those of women in less-developed countries at the time (Collaborative Group on Hormonal Factors in Breast Cancer, 2002; see Table 1.7); in lower-incidence countries, such as those in Africa and Asia, the cumulative risks to age 70 years were 1–2%. International differences in age at first full-term pregnancy and age at menarche are likely to contribute further. Similarly, in the Million Women Study in the United Kingdom, lower breast cancer incidence rates in South Asian women (unadjusted RR, 0.82) and Black women (RR, 0.85) compared with White women were almost entirely attributed to eight reproductive and lifestyle risk factors (Gathani et al., 2014).

Table 1.7

Population attributable fraction for breast cancer incidence associated with lifestyle factors in selected populations.

Within the same population, non-modifiable risk factors and family history appear to account for population attributable fractions of 40–50%, but most results are from higher-incidence countries. In terms of immediately modifiable risk factors, the 2005 Global Burden of Disease study estimated that 5% of deaths from breast cancer worldwide were attributable to alcohol consumption, 9% to overweight/obesity, and 10% to physical inactivity (with 21% attributable to their joint hazard) (Danaei et al., 2005). Joint population attributable fractions were considerably lower (18%) in low- and middle-income countries (LMICs) than in high-income countries (27%), largely due to lower alcohol consumption and lower prevalence of overweight/obesity in LMICs. [Note that this analysis did not include breastfeeding.]

1.4. Stage at diagnosis, survival, and management

The diagnosis and management of breast cancer developed significantly during the late 1990s and early 2000s. Staging describes the size of a carcinoma and whether it has spread regionally to lymph nodes or metastasized to distant organs. Accurate staging provides key prognostic information, helps to tailor treatment protocols, and contributes to the planning and implementation of specific public health interventions, such as screening programmes, aiming to improve the detection of lesions at an early stage and to decrease overall cancer mortality rates.

The staging system routinely used for breast cancer is the tumour–node–metastasis (TNM) classification. It describes localized disease as stages I and II, regional disease as stage III, and distant disease as stage IV, mostly based on the anatomical extent of the primary tumour and the presence of spread to regional lymph nodes and of distant metastases (Table 1.8 and Table 1.9; UICC, 2010). This classification was first developed in 1940 and is periodically revised and updated by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) (Edge et al., 2010). Although the coding schema has evolved considerably over time, a good correlation has always been maintained between old and new classifications, especially for stages 0, I, II, and IV (Kwan et al., 2012; Walters et al., 2013b). The sixth edition of the TNM staging system was officially adopted by tumour registries in January 2003. The heterogeneity of small tumours was reflected in more subcategories in the lower levels of the staging system, and additional issues were assessed, including metastatic lesions detected by molecular biology techniques and/or immunohistochemical staining of sentinel node specimens and the clinical importance of the total number of positive axillary lymph nodes (Singletary & Greene, 2003). The most recent, seventh edition (Table 1.8 and Table 1.9) was published in 2010 and includes the use of specific imaging modalities and of circulating tumour cells detectable in blood or bone marrow to better estimate clinical tumour size (Edge et al., 2010; Murthy & Chamberlain, 2011). The eighth edition will be published in late 2016 and will incorporate further advances in cancer research, staging, diagnosis, and treatment (AJCC, 2014).

Table 1.8

Tumour–node–metastasis (TNM) clinical classification of breast cancer.

Table 1.9

Tumour–node–metastasis (TNM) stage grouping of breast cancer.

Although the TNM classification system is accepted worldwide, there is great variability in the process of stage recording, due to different technological advances in diagnostic procedures across the globe. Therefore, estimates of survival based on stage at diagnosis may be misleading, and survival by stage at diagnosis may appear to have improved while overall survival does not change (Feinstein et al., 1985). International comparisons of survival by stage at diagnosis should take into consideration the variations in clinical classification and coding among cancer registries, which reflect the source of stage data, the time frame after the diagnosis within which the stage was recorded, whether the classification was defined clinically or pathologically, and whether tumour size was recorded before or after neo-adjuvant therapy (Walters et al., 2013a). The TNM system has become extremely complex and may be too complicated for use in developing countries. A much simpler system, such as the one used by the United States National Cancer Institute, could be a better option. The SEER staging, based on the widely accepted theory of cancer development, is the most basic staging system applicable to all anatomical sites (solid tumours). The five main categories of summary staging (in situ, localized, regional, distant, and unknown) are developed based on information available in the medical, clinical, and pathological records. However, although this system is frequently used by tumour registries, is not always properly understood by physicians (SEER, 2014b).

1.4.1. Stage at diagnosis and survival

Population-based cancer registries (PBCRs) provide information on the cancer burden in communities around the world, including incidence, mortality, stage at diagnosis, and survival. Currently, there are more than 700 PBCRs worldwide, although the quality and data coverage of registries differ substantially between developed and developing countries. PBCRs are especially valuable in LMICs, where the available population-based cancer data are few; poorly developed and inaccessible health services result in inconsistencies in early diagnosis, adequate treatment, and follow-up care, with a profound negative effect on cancer survival (Sankaranarayanan et al., 2010; Bray et al., 2014). A standardized minimum data set of variables with coding based on international systems like the TNM classification is required to facilitate the analysis of data and to enable comparison of results among registries (Bray et al., 2014).

(a) Stage at diagnosis

In developing countries, an estimated 75% (range, 30–98%) of breast cancer cases are diagnosed at late clinical stages, such as stage III or IV (Sloan & Gelband, 2007; Coughlin & Ekwueme, 2009).

In African countries, retrospective studies have reported that 70–90% of breast cancers are diagnosed at stage III or IV (Fregene & Newman, 2005). A PBCR that covers the Gharbiah Governorate in Egypt reported an increase in the percentage of localized breast tumours from 14.8% in 1999 to 21.4% in 2008 (Hirko et al., 2013).

In India, more than 70% of patients are diagnosed with clinically advanced disease (stage III or IV) (Okonkwo et al., 2008).

In China, findings from a multicentre nationwide screening study showed a tendency towards higher cancer stages for disadvantaged women, with the majority of cases diagnosed at stage II (44.9% of cases) or stage III (18.7% of cases) (Li et al., 2011; Fan et al., 2014).

The proportion of breast cancer cases that are clinically advanced at diagnosis (stages III and IV) is reported as approximately 30–40% in Mexico and less than 20% in Uruguay, although in Uruguay the data come from a single institution. In Brazil, women are diagnosed earlier in the wealthier regions of the country; generally percentages of advanced disease (25–40%) are similar to those in Chile (30%) in 2003 (Justo et al., 2013).

Data from high-income countries for 2000–2007 reported the proportion of stage III or IV disease to be 8% in Sweden and 22% in Denmark and the proportion of localized disease to be 61–62% in Australia, Canada, Denmark, Norway, Sweden, and the United Kingdom (Walters et al., 2013a). For Norway in 2008–2012, the proportion was 0.7% for stage 0, 40.8% for stage I, 38.0% for stage II, 5.9% for stage III, and 3.5% for stage IV (Cancer Registry of Norway, 2014).

In British Columbia, Canada, a population-based cohort study of participants in the Screening Mammography Program reported that the majority of cases were detected at localized stages (38% at stage I and 32% at stage II) (Davidson et al., 2013). Similarly, in the USA in 1999–2005, 61% of cases were detected at localized stages (stages I and II), 32% at a regionally advanced stage (stage III), and only 5% at a distant-metastatic stage (stage IV) (Shulman et al., 2010). However, the proportion of cases diagnosed beyond the local stage and the 5-year cause-specific probability of death were higher among Black women than among White women (Harper et al., 2009). Data for 2003–2009 for all races showed that 61% of breast cancers were localized (among African-American women, only 52%), 32% were regional, and 5% were distant (Siegel et al., 2014).

(b) Survival

Worldwide, survival differences that persist after adjustment for tumour stage at diagnosis are likely to reflect differences in treatment, accuracy of staging, or tumour biology (Sant et al., 2003; Walters et al., 2013a). Overall, 5-year survival rates are consistently lower in LMICs compared with upper-middle- and high-income countries (Table 1.10; Anderson et al., 2011). Differences in 5-year survival between more- and less-developed health services for both localized and regional breast cancer are shown in Fig. 1.19.

Table 1.10

5-Year age-standardized breast cancer relative survival, by country/region.

Fig. 1.19

Absolute survival for breast cancer, localized and regional extent of disease, by level of development of health services

A population-based study on breast cancer survival in countries in Africa, Asia, and Central America reported 5-year relative survival rates of 12% in The Gambia, 46% in Uganda, 52% in India, 82% in China, and 63% in Thailand. Rates in upper-middle- and high-income countries were 70% in Costa Rica, 77% in Turkey, 79% in the Republic of Korea, and 76% in Singapore (Sankaranarayanan et al., 2010). In Latin America, reported 5-year survival rates were 79% in Suriname, 72% in Chile, and 75% in Brazil (Mendonça et al., 2004; Navarrete Montalvo et al., 2008; van Leeuwaarde et al., 2011). In the industrialized city of Shanghai, China, 5-year survival was 78% in 1992–1995, whereas in a rural neighbouring area, Qidong, it was only 58% in 1992–2000 (Fan et al., 2014).

Data from PBCRs in Canada (Alberta, British Columbia, Ontario, and Manitoba) showed a slight increase in 5-year survival rates over time, from 85.3% in 1995–2000 to 86.3% in 2005–2007 (Coleman et al., 2011) and to 88% in 2006–2008 (Canadian Cancer Society, 2014).

In the USA, the 5-year survival increased from 75% in 1975 to 89% in 2010, and was 98% for localized disease, 85% for regional disease, and 25% for distant disease (SEER, 2014a). A meta-analysis among African-American and White American breast cancer patients revealed that African-American ethnicity was associated with a 20% excess of mortality in 1980–2005 (Newman et al., 2006).

In Finland, the 5-year survival for breast cancer (all malignant neoplasms) of patients diagnosed in 2005–2010 and observed in 2010–2012 was 90% (Finnish Cancer Registry, 2015).

The largest cooperative study of population-based cancer survival in Europe (EUROCARE) shows a mean breast cancer survival rate of about 82% for breast cancer diagnosed in 2000–2007 (De Angelis et al., 2014). Geographical differences were reported, with higher survival in northern (84.7%), southern (83.6%), and central Europe (83.9%) and lower survival in the United Kingdom and Ireland (79.2%) and eastern Europe (73.7%). For most countries, the 5-year survival rate for breast cancer was fairly close to the European mean. Overall, survival rates in Europe increased over time, from 78.4% in 1999–2001 to 82.4% in 2005–2007. This increase was the most marked in eastern Europe and the United Kingdom and Ireland, so the survival gap between these countries and the rest of Europe decreased. Predictions of 10-year survival exceed 70% in most regions, with the highest value in northern Europe (74.9%) and the lowest in eastern Europe (54.2%), although 10-year survival is about 10% lower than 5-year survival in almost all European regions (Allemani et al., 2013). See Sections 1.5 and 1.6 and Section 4.1 for further details on the interpretation of survival findings with regard to mammographic screening.

1.4.2. Management

Breast cancer care has improved dramatically over the past 50 years, thanks to advances in multidisciplinary management, diagnosis, and treatment, including adjuvant treatments. Biological markers of prognosis have been identified, as well as biomarkers for targeted therapies, such as aromatase inhibitors for hormone receptor-positive breast cancers and anti-HER2 therapy for HER2/neu-overexpressing breast cancers.

The management of breast cancer often requires multimodality treatment involving surgery, radiotherapy, systemic treatment with chemotherapy, and/or hormone therapy and targeted therapy. Neo-adjuvant therapy may be given before surgery to shrink the tumour and after surgery to treat micrometastases.

(a) Surgery

Surgical treatment for breast cancer has been used for centuries. Radical mastectomy became the standard surgical approach towards the end of the 19th century and was popular until the 1980s, when randomized trials showed that it had a limited beneficial effect on survival. Modified radical mastectomy, simple mastectomy, and the evaluation of breast-conserving surgery were then introduced. Surgical interventions such as oophorectomies and adrenalectomies were relatively popular in the 20th century (Ahmed et al., 2011; American College of Surgeons, 2014). Nowadays, surgical treatment for the primary tumour may involve breast-conserving surgery plus radiotherapy, modified radical mastectomy, or simple mastectomy, depending on the size and location of the tumour, the suitability of breast-conserving surgery, and, in developing countries, the availability of radiotherapy.

Assessing the axillary lymph nodes is critical in staging and to determine prognosis and therapeutic options. Nowadays, axillary lymph node dissection as a staging procedure has largely been replaced by the less-invasive sentinel lymph node biopsy. Local surgical treatments have improved greatly without compromising locoregional control in breast cancer management (McWhirter, 1948; Lythgoe et al., 1978; Langlands et al., 1980; Fisher et al., 1981; Maddox et al., 1983).

(b) Radiotherapy

Radiotherapy is regularly indicated for locoregional treatment after breast-conserving surgery and in post-mastectomy patients to eradicate residual disease, thus reducing local recurrence. In women with axillary lymph node dissection and with up to three positive lymph nodes or with four or more positive nodes, radiotherapy reduced locoregional recurrence and overall recurrence (RR, 0.68; 95% CI, 0.57–0.82 versus RR, 0.79; 95% CI, 0.69–0.90) and reduced cancer mortality (RR, 0.80; 95% CI, 0.67–0.95 versus RR, 0.87; 95% CI, 0.77–0.99) (McGale et al., 2014). In women with no positive nodes, radiotherapy had no statistically significant effect on locoregional recurrence, overall recurrence, or cancer mortality, although it increased overall mortality (RR, 1.23; 95% CI, 1.02–1.49). Results were similar in the subset of trials in which women received systemic therapy (McGale et al., 2014). Women who receive breast-conserving surgery without radiotherapy have a risk of recurrence in the conserved breast of greater than 20% even when axillary lymph nodes are absent. It has been shown that radiotherapy to the conserved breast reduces the 10-year risk of any recurrence from 35.0% to 19.3% and the 15-year risk of mortality from 25.2% to 21.4%. The mortality reduction differed significantly between patients with node-positive and node-negative disease (Darby et al., 2011).

(c) Chemotherapy and adjuvant therapy

Chemotherapy was introduced into clinical cancer practice in the middle of the 20th century, and targeted therapy was introduced towards the end of the 20th century, whereas hormone therapy was already in use by the end of the 19th century (American College of Surgeons, 2014). The need for and the choice of adjuvant systemic treatment are determined by the stage and the molecular features of the disease. The side-effects must be considered before starting any treatment, as they can be immediate (appearing during treatment) or long-term (appearing weeks, months, or years after the treatment ends) and may be associated both with the patient’s clinical conditions and stage at diagnosis and with the treatment (type and intensity).

Patients with ER-positive and/or PR-positive tumours, which account for 50–80% of breast cancers, usually receive hormone therapy, and patients with HER2-overexpressing tumours receive adjuvant anti-HER2 therapy in combination with chemotherapeutic agents, which may reduce mortality by one third and the risk of recurrence by 40% (Moja et al., 2012; Pinto et al., 2013). When neither HER2 overexpression nor hormone receptors are present, adjuvant therapy relies on chemotherapeutic regimens. It has been shown that 2 years of adjuvant anti-HER2 therapy is not more effective than 1 year of treatment for patients with HER2-positive early breast cancer, and thus 1 year of treatment remains the standard of care (Gianni et al., 2011; Goldhirsch et al., 2013), although cardiac toxicity is still a concern.

The classic adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (Bonadonna et al., 1976) was shown to improve survival in both node-positive and node-negative patients. Chemotherapy regimens such as 6 months of anthracycline as well as the addition of taxanes led to an additional decline in recurrence and mortality. A few years after its introduction in routine adjuvant practice, CMF was replaced by more-effective “third-generation” regimens containing anthracyclines and taxanes (Munzone et al., 2012). A meta-analysis showed that six cycles of anthracycline-based polychemotherapy, such as combination of 5-fluorouracil, doxorubicin, and cyclophosphamide or 5-fluorouracil, epirubicin, and cyclophosphamide, reduced the annual breast cancer death rate by about 38% in women younger than 50 years and by about 20% in women aged 50–69 years, irrespective of the use of tamoxifen and of ER status, nodal status, or other tumour characteristics (EBCTCG, 2005). The addition of four separate cycles of a taxane to such anthracycline-based regimens and the extension of treatment duration further reduced breast cancer mortality (RR, 0.86) (Peto et al., 2012).

It has been clearly demonstrated that neo-adjuvant chemotherapy such as tamoxifen reduces breast cancer mortality (RR, 0.71) and recurrence (RR, 0.68) in both node-positive and node-negative ER-positive breast cancers (Davies et al., 2011). Recent findings suggest that tamoxifen treatment is more beneficial for 10 years rather than for 5 years in women at high risk of recurrence (Davies et al., 2013). Studies have shown that the aromatase inhibitors offer an incremental improvement in survival and lower toxicity for postmenopausal women requiring hormone therapy. Pooled analyses of radiotherapy and systemic treatments reported a clinically significant improvement for both local and systemic therapy and provided evidence of modest but consistent effects of treatment.

As an example, the milestones of breast cancer treatment in the USA and their relationship with time trends in incidence, survival, and mortality are shown in Fig. 1.20.

Fig. 1.20

Milestones of breast cancer therapy in the USA

(i) Access to care and treatment in high-income countries

In high-income countries and in populations where sufficient resources are available, access to optimal cancer treatment is promoted by well-developed infrastructures, due to the spending of 6–16% of gross domestic product (GDP) on health care (Coleman, 2010). The variations observed in survival trends mainly reflect later diagnosis or differences in treatment (Coleman et al., 2011), particularly among women in eastern European countries and non-Hispanic Black women in the USA (Kingsmore et al., 2004; Mikeljevic et al., 2004).

Expenditure on cancer therapy in Europe rose from €840 million in 1993 to €6.2 billion in 2004, and is likely to increase further with the advent of targeted chemotherapy (Sullivan et al., 2011). Variations in breast cancer care across European countries are apparent (Allemani et al., 2010). Data from EUROCARE-3 show that 55% of women diagnosed with T1N0M0 breast cancers received breast-conserving surgery plus radiotherapy, ranging from 9% in Estonia to 78% in France. Of node-positive patients, chemotherapy was received by 52.1% of postmenopausal women and by 90.7% of premenopausal women, with marked variations among countries, particularly for postmenopausal women. For patients with ER-positive tumours, which constituted 45.3% of total cases, marked variations across countries in the availability of endocrine therapy were noted (Allemani et al., 2010).

Breast cancers are generally less advanced at diagnosis in the USA than in Europe, but the overall frequency of metastatic tumours is similar, at about 5–6% (Allemani et al., 2013). Currently, about 60% of cancer patients in the USA are treated with highly modern radiotherapy (Sullivan et al., 2011). Lymphadenectomy was reported in 86% of women in Europe and in 81% of women in the USA; surgical treatment was received by 91% of women in Europe and by 96% of women in the USA. Among women with early node-negative disease, 55% in Europe and 49% in the USA received breast-conserving surgery plus radiotherapy. Among women with node-positive tumours, 58% in Europe and 69% in the USA received chemotherapy. Compared with women aged 15–49 years, the proportion of women aged 50–99 years who received chemotherapy was higher in the USA (60%) than in Europe (46%), as was access to endocrine treatment for ER-positive tumours (62% in the USA and 55% in Europe) (Allemani et al., 2013).

(ii) Access to care and treatment in low- and middle-income countries

In many LMICs, major treatments (surgery, chemotherapy, and radiotherapy) are delivered within inadequate health services infrastructures. Rural areas, in particular, lack infusion equipment or other supplies, skilled oncology surgeons, and proper equipment; radiotherapy facilities are scarce (available to about 15% of patients) or non-existent, and access to chemotherapy and hormone therapy is limited (Anderson at al., 2011; Cesario, 2012).

In Latin America, the WHO Medical Devices Database reports inadequate cancer care due to limited physical and technological resources. The supply of radiotherapy units may vary, from 6 per 100 000 people in Bolivia and Paraguay to 57 per 100 000 people in Uruguay (Goss et al., 2013). In most Latin American countries, oncology services are concentrated in major cities, whereas rural regions often lack or have limited cancer care services. In Brazil, anti-HER2 targeted therapy for HER2-positive early breast cancer became available only in 2012. The situation is similar in other Latin American countries, such as Mexico, Argentina, and Colombia (Goss et al., 2013).

In sub-Saharan Africa, delayed presentation of breast cancer is common. Although mastectomy is not always culturally accepted in this region, it is the most widely used procedure for breast cancer treatment, due to the poor availability of adjuvant radiotherapy, chemotherapy, and resources for the assessment of sentinel lymph nodes. In a hospital in Uganda in 1996–2000, 75% of patients underwent surgery (58% of surgeries were modified radical mastectomy), 76% received radiotherapy, 60% received hormone therapy, and 29% received chemotherapy (Kingham et al., 2013). Locally advanced breast cancers are frequently treated with neo-adjuvant therapy; however, the frequencies of response and positive outcomes are not as high as those in high-income countries (Kingham et al., 2013).

In China, important disparities in access and timely care for breast cancer are reported. Although breast-conserving surgery has become the recommended surgical treatment since the 1990s, mastectomy still accounts for almost 89% of primary breast cancer surgery (Li et al., 2011; Fan et al., 2014). Even in developed urban areas, breast-conserving surgeries represented only 12.1% of surgeries in 2005 and 24.3% of surgeries in 2008. In Beijing in 2008, complete axillary lymph node dissection was performed for 84.1% of the patients. There is poor availability of radiotherapy as well as linear accelerator equipment, trained radiation oncologists, and technologists. Among patients who underwent breast-conserving surgery, 16.3% did not receive radiotherapy as per standard guidelines, and only 27% of patients nationwide received radiotherapy as part of their primary treatment. Access to systemic therapy is relatively frequent in China. About 81.4% of all patients with invasive breast cancer received adjuvant chemotherapy, and 80.2% of patients with HER2-positive tumours received adjuvant targeted therapy. Unfortunately, for many drugs the costs are not reimbursed by insurance, and the lack of access to new drugs also limits systemic treatment options for metastatic disease. For example, despite the approval of anti-HER2 therapy in 2002, in Beijing only 20.6% of patients with HER2-positive disease received targeted therapy (Fan et al., 2014).

Although cancer control programmes are becoming a higher priority and adequate multidisciplinary breast cancer treatment services generally exist, socioeconomic, geographical, or ethnic barriers are reflected in the inequity of cancer treatment. As the economies of middle-resource countries strengthen, higher breast cancer survival rates are reported, due to earlier detection and better treatment options (Anderson at al., 2011). Identifying what can be done to diagnose and treat cancers more effectively at each level of the health system will require a global public health approach (Anderson et al., 2010). Recommended breast cancer treatment resources for low-resource countries from the Breast Health Global Initiative are shown in Table 1.11.

Table 1.11

Recommended breast cancer treatment resources for low-resource countries.

1.5. Breast awareness, early detection and diagnosis, and screening

Early detection of breast cancer aims to reduce mortality and other serious consequences of advanced disease through the early clinical diagnosis of symptomatic breast cancer or by screening asymptomatic women (Sankaranarayanan, 2000). When earlier treatments are available for detected cases, life expectancy, locoregional control of disease, and quality of life are much improved. In turn, early detection relies on access to prompt and effective diagnostic and treatment services (von Karsa et al., 2014a).

Early cancer detection is part of a cancer control strategy, which also should include: health education; breast cancer awareness; health-care providers with sufficient clinical skills, particularly at the primary care level; availability of accessible, affordable, and efficient health services with adequate infrastructure, human resources, and information systems; prompt diagnosis, staging, and treatment; and follow-up care (Richards et al., 1999; Norsa’adah et al., 2011; Ermiah et al., 2012; Caplan, 2014; Poum et al., 2014; Unger-Saldaña, 2014).

1.5.3. Screening asymptomatic women

Screening asymptomatic women, as part of early detection, includes both performing mammography screening at specified intervals and referring those women with positive screening findings for further diagnostic investigations and possibly treatment. Screening programmes may be either organized or unorganized (opportunistic) programmes (von Karsa et al., 2014a).

The main objective of screening asymptomatic women of appropriate age and average risk is to enable adequate treatment before the cancer poses a more serious threat to the individual woman (Fig. 1.21; Wilson & Jungner, 1968; Duffy et al., 2003; Perry et al., 2006, 2008; de Koning, 2009). As in any form of early detection, access to prompt and effective diagnosis and treatment is key to achieving the potential benefit of breast cancer screening (von Karsa et al., 2014a). In practice, less than one third of the breast cancers detected by mammography screening would also be detectable by clinical examination (Friedman et al., 2013). Also, some subtypes of breast cancer are more frequently detected at a more advanced stage, irrespectively of whether through screening or symptomatically (Tabár et al., 2014).

Fig. 1.21

Early detection of breast cancer through screening asymptomatic women or early diagnosis of symptomatic women

(a) Appropriate balance of benefits and harms

In recent decades, the principles of screening established by WHO in 1968 have been extended through experience gained from the implementation of population-based cancer screening programmes (WHO, 2007, 2013a, b). The careful consideration of the harm–benefit balance associated with the implementation of a cancer screening programme is particularly important in breast cancer screening, given the large number of women potentially involved.

The principal benefits of screening are the avoidance of death due to breast cancer (IARC, 2002; see Section 5.2), or of other serious consequences, such as advanced-stage breast cancer (Taplin et al., 2004; Norman et al., 2006; Malmgren et al., 2014; Fig. 1.21). The primary harms of screening include the morbidity and mortality from the procedures for detection and diagnosis, false-positive tests, overdiagnosis, and the side-effects of treatment (Sections 5.3.1–5.3.4). Another reported harm is anxiety, particularly when further investigation is required after a mammogram (see Section 5.3.5).

Exposure to these risks in the absence of any direct health benefit is of particular concern.

(b) Organized, population-based programmes

Organized programmes are characterized by centralized screening invitations to a well-defined target population, systematic call and recall for screening, delivery of test results, investigations, treatment and follow-up care, centralized quality assurance, and a programme database with linkages to other information systems, such as cancer registration systems and death registration systems, for monitoring and evaluation of the programme. Implementation of organized and opportunistic screening programmes is presented in Section 3.2, by WHO regions.

Most breast cancer screening programmes offer mammography to normal-risk women beginning at age 40–50 years and ending at age 69–74 years, typically at 2-year intervals (von Karsa et al., 2014b). The screening policy of an organized programme defines at least the screening protocol, the repeat interval, and the determinants of eligibility for screening. Effective communications should also be supported (Giordano et al., 2006; Webster & Austoker, 2006; Robb et al., 2010), enabling women to make an informed decision about whether to participate (Giordano et al., 2006, 2012; von Karsa et al., 2014a). In addition, organized programmes include an administrative structure, which is responsible for service delivery, including follow-up of detected lesions, quality assurance, and evaluation. Organized screening programmes generally include a national or regional implementation team, which is responsible for coordinating the delivery of the screening services, maintaining the requisite quality, reporting on performance and results, and defining standard operating procedures. In addition, information about all new cases and deaths from breast cancer occurring in the defined population served by the screening programme enables an estimate to be made of the impact of the programme on breast cancer mortality (IARC, 2002). Ideally, this can be achieved through linkage of individual data from a PBCR and a screening registry, if available (von Karsa & Arrossi, 2013; Anttila et al., 2014).

(c) Opportunistic programmes

Opportunistic programmes are not tailored to a predetermined eligible population and provide screening tests on request or at the time of routine health examinations. These programmes are less amenable to quality assurance than population-based screening, due, among other things, to the lack of administrative and organization infrastructure (de Gelder et al., 2009). They rely on the initiative of individual health-care providers to offer screening or to encourage participation in a screening programme or outside the context of any programme (so-called wild screening). Organized breast screening programmes reach women who have not participated in opportunistic screening (Chamot et al., 2007; Gorini et al., 2014).

(d) Quality assurance of screening programmes

Quality assurance in breast cancer screening programmes goes beyond the need to ensure that any medical intervention is performed adequately, efficiently, and with minimum risk and maximum benefit. Screening involves a complex sequence of events and interrelated activities (see Fig. 1.22 for a summary of the process). To achieve maximum benefits with minimum risk, quality must be optimal at every step of the screening process (Perry et al., 2006, 2008; von Karsa & Arrossi, 2013). This can be achieved by a coordinated approach to programme planning and management, and by the availability of adequate human, financial, and technical resources. Overall, in Europe, the proportion of expenditure devoted to quality assurance should be no less than 10–20%, depending on the scale of the programme (Perry et al., 2013b; von Karsa et al., 2013, 2014a).

Fig. 1.22

The process of cancer screening

Numerous countries have adopted regulations, guidelines, and recommendations covering different aspects of quality assurance of mammography screening (Sibbering et al., 2009; Ellis, 2011; Gemeinsamen Bundesausschuss, 2011; Tonelli et al., 2011; Smith et al., 2012; BMV-Ä/EKV, 2014). The European Commission has published comprehensive multidisciplinary European guidelines for quality assurance in breast cancer screening and diagnosis (Perry et al., 2006, 2008, 2013a), and for establishing a population-based cancer screening programme (Lynge et al., 2012; Perry et al., 2013b; von Karsa & Arrossi, 2013; von Karsa et al., 2013) (see Section 3.2 for further information by country/region). In the USA, the Mammography Quality Standards Act (MQSA) made accreditation of mammography facilities mandatory (FDA, 2014). Professional and scientific societies provide additional guidance and standards, and training and technical support for the achievement of the standards, such as in preparation for accreditation, including comprehensive audits of professional and organizational performance (D’Orsi et al., 2013; American College of Surgeons, 2014; Canadian Association of Radiologists, 2014).

It may take several years to implement a population-based cancer screening programme, from the beginning of planning to completion of roll-out across an entire country or region. Sustainable institutional capacity is useful for programme management; computerized information systems, registration of breast cancer cases in the population, in screening registries and other data repositories and institutions are needed to collaborate in monitoring and evaluation, for regular audits of programme performance, and to assure the technical quality of equipment and services.

International collaboration can compensate for a local shortage of expertise in any given country, to facilitate process evaluation and avoid unnecessary delays in establishing fully functional screening programmes (von Karsa et al., 2014a).

(e) Denominators

As pointed out in the Working Procedures of this Handbook, the evaluation of the efficacy and effectiveness of breast cancer screening should measure the impact of a specific intervention, procedure, regimen, or service (Porta, 2008). The terms “breast cancer screening” and “mammography screening” are ambiguous; they may refer either to the invitation of women intended to be screened or to their actual participation by undergoing a screening mammogram. It is crucial to properly differentiate between the two concepts in order to evaluate breast cancer screening and to accurately interpret published reports.

The number of women, invited or participating, provides the denominator when the results of a screening programme are presented as rates or proportions. Results on women invited to screening are of particular interest to public health authorities when considering the potential benefits and harms to the population served by the programme. Participation in screening is fundamental to estimate the actual benefit of breast screening programmes and make informed decisions about whether to participate. In this Handbook, mammography screening programmes are examined using the number of women invited as the denominator, and the effects of participation in the screening programme are examined using the number of women participating as the denominator. Due consideration is given to the fact that the difference between the effect of invitation and the effect of attendance will depend on the proportion of women participating and so will not be generalizable from programme to programme.

References

• Abdel-Fatah TM, Powe DG, Hodi Z, Reis-Filho JS, Lee AH, Ellis IO. Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family. Am J Surg Pathol. 2008;32(4):513–23. [PubMed: 18223478] [CrossRef]
• Adams MJ, Dozier A, Shore RE, Lipshultz SE, Schwartz RG, Constine LS, et al. Breast cancer risk 55+ years after irradiation for an enlarged thymus and its implications for early childhood medical irradiation today. Cancer Epidemiol Biomarkers Prev. 2010;19(1):48–58. [PMC free article: PMC2939494] [PubMed: 20056622] [CrossRef]
• Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, et al. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32(25):2794–803. [PubMed: 25049332] [CrossRef]
• Ahmed MI, Youssef M, Carr M. Breast Cancer Care: A Historical Review. Pak J Surg. 2011;27(2):135–9.
• AJCC (2014). AJCC cancer staging manual, 8th edition updates. Chicago (IL), USA: American Joint Committee on Cancer. Available from: http:​//cancerstaging​.org/About/Pages/8th-Edition.aspx.
• Alexander FE, Roberts MM, Huggins A. Risk factors for breast cancer with applications to selection for the prevalence screen. J Epidemiol Community Health. 1987;41(2):101–6. [PMC free article: PMC1052592] [PubMed: 3498783] [CrossRef]
• Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2002;2(2):101–12. [PubMed: 12635173] [CrossRef]
• Allemani C, Minicozzi P, Berrino F, Bastiaannet E, Gavin A, Galceran J, et al. EUROCARE Working Group. Predictions of survival up to 10 years after diagnosis for European women with breast cancer in 2000–2002. Int J Cancer. 2013;132(10):2404–12. [PubMed: 23047687] [CrossRef]
• Allemani C, Storm H, Voogd AC, Holli K, Izarzugaza I, Torrella-Ramos A, et al. Variation in ‘standard care’ for breast cancer across Europe: a EUROCARE-3 high resolution study. Eur J Cancer. 2010;46(9):1528–36. [PubMed: 20299206] [CrossRef]
• Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. CONCORD Working Group. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 2014 [PMC free article: PMC4588097] [PubMed: 25467588] [CrossRef]
• Allen NE, Beral V, Casabonne D, Kan SW, Reeves GK, Brown A, et al. Million Women Study Collaborators. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst. 2009;101(5):296–305. [PubMed: 19244173] [CrossRef]
• American College of Surgeons (2014). National Accreditation Program for Breast Centers. Available from: https://www​.facs.org​/quality%20programs/napbc.
• Anderson B, Ballieu M, Bradley C, Elzawawy A, Cazap E, Enio A, et al. (2010). Access to cancer treatment in low- and middle-income countries – an essential part of global cancer control. Working Paper. CanTreat International.
• Anderson BO, Cazap E, El Saghir NS, Yip CH, Khaled HM, Otero IV, et al. Optimisation of breast cancer management in low-resource and middle-resource countries: executive summary of the Breast Health Global Initiative consensus, 2010. Lancet Oncol. 2011;12(4):387–98. [PubMed: 21463833] [CrossRef]
• Anderson H, Bladström A, Olsson H, Möller TR. Familial breast and ovarian cancer: a Swedish population-based register study. Am J Epidemiol. 2000;152(12):1154–63. [PubMed: 11130621] [CrossRef]
• Anderson TJ, Lamb J, Donnan P, Alexander FE, Huggins A, Muir BB, et al. Comparative pathology of breast cancer in a randomised trial of screening. Br J Cancer. 1991;64(1):108–13. [PMC free article: PMC1977297] [PubMed: 1854609] [CrossRef]
• Anderson WF, Pfeiffer RM, Dores GM, Sherman ME. Comparison of age distribution patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1899–905. [PubMed: 17035397] [CrossRef]
• Anderson BO, Yip CH, Smith RA, Shyyan R, Sener SF, Eniu A, et al. Guideline implementation for breast healthcare in low-income and middle-income countries: overview of the Breast Health Global Initiative Global Summit 2007. Cancer. 2008;113 (8 Suppl):2221–43. [PubMed: 18816619] [CrossRef]
• Andre F, Pusztai L. Molecular classification of breast cancer: implications for selection of adjuvant chemotherapy. Nat Clin Pract Oncol. 2006;3(11):621–32. [PubMed: 17080180] [CrossRef]
• Antoine C, Ameye L, Paesmans M, Rozenberg S. Systematic review about breast cancer incidence in relation to hormone replacement therapy use. Climacteric. 2014;17(2):116–32. [PubMed: 23909434] [CrossRef]
• Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497–506. [PMC free article: PMC4157599] [PubMed: 25099575] [CrossRef]
• Anttila A, Lönnberg S, Ponti A, Suonio E, Villain P, Coebergh JW, et al. Towards better implementation of cancer screening in Europe through improved monitoring and evaluation and greater engagement of cancer registries. Eur J Cancer. 2014;51(2):241–51. [PubMed: 25483785] [CrossRef]
• Arnold M, Pandeya N, Byrnes G, Renehan AG, Stevens GA, Ezzati M, et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. Lancet Oncol. 2015;16(1):36–46. [PMC free article: PMC4314462] [PubMed: 25467404] [CrossRef]
• ASCO (2014). American Society of Clinical Oncology. Data available at: http:​//cancerprogress​.net/timeline/breast-cancer, accessed May 2011.
• Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, et al. Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26(26):4282–8. [PMC free article: PMC6366335] [PubMed: 18779615] [CrossRef]
• Badwe RA, Dikshit R, Laversanne M, Bray F. Cancer incidence trends in India. Jpn J Clin Oncol. 2014;44(5):401–7. [PubMed: 24755545] [CrossRef]
• Badwe RA, Mittra I, Havaldar R. Timing of surgery with regard to the menstrual cycle in women with primary breast cancer. Surg Clin North Am. 1999;79(5):1047–59. [PubMed: 10572550] [CrossRef]
• Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, et al. Light alcohol drinking and cancer: a meta-analysis. Ann Oncol. 2013;24(2):301–8. [PubMed: 22910838] [CrossRef]
• Balko JM, Stricker TP, Arteaga CL. The genomic map of breast cancer: which roads lead to better targeted therapies? Breast Cancer Res. 2013;15(4):209. [PMC free article: PMC3979080] [PubMed: 23905624] [CrossRef]
• Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol. 2003;21(10):1973–9. [PubMed: 12743151] [CrossRef]
• Barlow WE, White E, Ballard-Barbash R, Vacek PM, Titus-Ernstoff L, Carney PA, et al. Prospective breast cancer risk prediction model for women undergoing screening mammography. J Natl Cancer Inst. 2006;98(17):1204–14. [PubMed: 16954473] [CrossRef]
• Bartek J, Bartkova J, Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene. 2007;26(56):7773–9. [PubMed: 18066090] [CrossRef]
• Baum M. Modern concepts of the natural history of breast cancer: a guide to the design and publication of trials of the treatment of breast cancer. Eur J Cancer. 2013;49(1):60–4. [PubMed: 22884336] [CrossRef]
• Becker S, Kaaks R. Exogenous and endogenous hormones, mammographic density and breast cancer risk: can mammographic density be considered an intermediate marker of risk? Recent Results Cancer Res. 2009;181:135–57. [PubMed: 19213565] [CrossRef]
• Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286(5449):2528–31. [PubMed: 10617473] [CrossRef]
• Beral V, Reeves G, Banks E. Current evidence about the effect of hormone replacement therapy on the incidence of major conditions in postmenopausal women. BJOG. 2005;112(6):692–5. [PubMed: 15924521] [CrossRef]
• Berlin L. Point: Mammography, breast cancer, and overdiagnosis: the truth versus the whole truth versus nothing but the truth. J Am Coll Radiol. 2014;11(7):642–7. [PubMed: 24794764] [CrossRef]
• BIC (2015). Breast Cancer Information Core database. Bethesda (MD), USA: National Human Genome Research Institute. Available from: http://research​.nhgri.nih.gov/bic/.
• Bijker N, Peterse JL, Duchateau L, Julien JP, Fentiman IS, Duval C, et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol. 2001a;19(8):2263–71. [PubMed: 11304780]
• Bijker N, Peterse JL, Duchateau L, Robanus-Maandag EC, Bosch CA, Duval C, et al. Histological type and marker expression of the primary tumour compared with its local recurrence after breast-conserving therapy for ductal carcinoma in situ. Br J Cancer. 2001b;84(4):539–44. [PMC free article: PMC2363778] [PubMed: 11207051] [CrossRef]
• Bloom HJ, Richardson WW. Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957;11(3):359–77. [PMC free article: PMC2073885] [PubMed: 13499785] [CrossRef]
• BMV-Ä/EKV (2014). Provision of care in the Programme for Early Detection of Breast Cancer by Mammography Screening. Federal Collective Agreement – Physician fee schedule of the substitute funds, Annex 9.2, version 16 June 2014, valid from 1 July 2014 [in German]. Legal documents compendium of the German National Association of Statutory Health Insurance Physicians. Available from: http://www​.kbv.de/media/sp/09​.2_Mammographie.pdf.
• Boice JD Jr, Harvey EB, Blettner M, Stovall M, Flannery JT. Cancer in the contralateral breast after radiotherapy for breast cancer. N Engl J Med. 1992;326(12):781–5. [PubMed: 1538720] [CrossRef]
• Boice JD Jr, Morin MM, Glass AG, Friedman GD, Stovall M, Hoover RN, et al. Diagnostic x-ray procedures and risk of leukemia, lymphoma, and multiple myeloma. JAMA. 1991;265(10):1290–4. [PubMed: 2053936] [CrossRef]
• Bombonati A, Sgroi DC. The molecular pathology of breast cancer progression. J Pathol. 2011;223(2):308–17. [PMC free article: PMC3069504] [PubMed: 21125683] [CrossRef]
• Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, et al. Combination Chemotherapy as an Adjuvant Treatment in Operable Breast Cancer. N Engl J Med. 1976;294(8):405–10. [PubMed: 1246307] [CrossRef]
• Boulton SJ. Cellular functions of the BRCA tumour-suppressor proteins. Biochem Soc Trans. 2006;34(5):633–45. [PubMed: 17052168] [CrossRef]
• Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007;356(3):227–36. [PubMed: 17229950] [CrossRef]
• Boyd NF, Martin LJ, Rommens JM, Paterson AD, Minkin S, Yaffe MJ, et al. Mammographic density: a heritable risk factor for breast cancer. Methods Mol Biol. 2009;472:343–60. [PubMed: 19107441] [CrossRef]
• Boyd NF, Rommens JM, Vogt K, Lee V, Hopper JL, Yaffe MJ, et al. Mammographic breast density as an intermediate phenotype for breast cancer. Lancet Oncol. 2005;6(10):798–808. [PubMed: 16198986] [CrossRef]
• Bray F, Znaor A, Cueva P, Korir A, Swaminathan R, Ullrich A, et al. (2014). Planning and developing population-based cancer registration in low- and middle-income settings. Lyon: International Agency for Research on Cancer (IARC Technical Publication Series, No. 43). Available from: http://www​.iarc.fr/en​/publications/pdfs-online​/treport-pub/treport-pub43/index​.php. [PubMed: 33502836]
• Brewster AM, Hortobagyi GN, Broglio KR, Kau SW, Santa-Maria CA, Arun B, et al. Residual risk of breast cancer recurrence 5 years after adjuvant therapy. J Natl Cancer Inst. 2008;100(16):1179–83. [PMC free article: PMC6592411] [PubMed: 18695137] [CrossRef]
• Brinkley D, Haybrittle JL. The curability of breast cancer. Lancet. 1975;306(7925):95–7. [PubMed: 49738] [CrossRef]
• Broeks A, Braaf LM, Huseinovic A, Nooijen A, Urbanus J, Hogervorst FB, et al. Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study. Breast Cancer Res. 2007;9(2):R26. [PMC free article: PMC1868917] [PubMed: 17428320] [CrossRef]
• Bruzzi P, Green SB, Byar DP, Brinton LA, Schairer C. Estimating the population attributable risk for multiple risk factors using case-control data. Am J Epidemiol. 1985;122(5):904–14. [PubMed: 4050778]
• Buerger H, Otterbach F, Simon R, Poremba C, Diallo R, Decker T, et al. Comparative genomic hybridization of ductal carcinoma in situ of the breast-evidence of multiple genetic pathways. J Pathol. 1999;187(4):396–402. [PubMed: 10398097] [CrossRef]
• Buitenhuis W, Fritschi L, Thomson A, Glass D, Heyworth J, Peters S. Occupational exposure to ionizing radiation and risk of breast cancer in Western Australia. J Occup Environ Med. 2013;55(12):1431–5. [PubMed: 24270294] [CrossRef]
• Bundred NJ. Prognostic and predictive factors in breast cancer. Cancer Treat Rev. 2001;27(3):137–42. [PubMed: 11417963] [CrossRef]
• Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501(7467):338–45. [PubMed: 24048066] [CrossRef]
• Byrne C, Harris A.(1996). Cancer rates and risks, 4th edition. Bethesda (MD), USA: US Department of Health and Human Services, National Institute of Health.
• Cadman BA, Ostrowski JL, Quinn CM. Invasive ductal carcinoma accompanied by ductal carcinoma in situ(DCIS): comparison of DCIS grade with grade of invasive component. Breast. 1997;6(3):132–7. [CrossRef]
• Canadian Association of Radiologists (2014). Mammography Accreditation Program (MAP). Canadian Association of Radiologists. Available from: http://www​.car.ca/en/accreditation/map​.aspx.
• Canadian Cancer Society. (2014). Breast Cancer Statistics. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2014. Toronto: Canadian Cancer Society.
• Cancer Genome Atlas Network. (2012). Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. 10.1038/nature11412. [PMC free article: PMC3465532] [PubMed: 23000897] [CrossRef]
• Cancer Registry of Norway. (2014). Cancer in Norway 2012 – Cancer incidence, mortality, survival and prevalence in Norway. Oslo: Cancer Registry of Norway. Available from: http://www.kreftregisteret.no/global/cancer in norway/2012/cin_2012.pdf.
• Caplan L. Delay in breast cancer: implications for stage at diagnosis and survival. Front Public Health. 2014;2:87. [PMC free article: PMC4114209] [PubMed: 25121080] [CrossRef]
• Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, et al. The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: estimates of radiation-related cancer risks. Radiat Res. 2007;167(4):396–416. [PubMed: 17388693] [CrossRef]
• Castéra L, Krieger S, Rousselin A, Legros A, Baumann JJ, Bruet O, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014;22(11):1305–13. [PMC free article: PMC4200427] [PubMed: 24549055] [CrossRef]
• Cesario SK. Global inequalities in the care of women with cancer. Nurs Womens Health. 2012;16(5):372–85. [PubMed: 23067282] [CrossRef]
• Chamot E, Charvet AI, Perneger TV. Who gets screened, and where: a comparison of organised and opportunistic mammography screening in Geneva, Switzerland. Eur J Cancer. 2007;43(3):576–84. [PubMed: 17223542] [CrossRef]
• Chappuis PO, Nethercot V, Foulkes WD. Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. Semin Surg Oncol. 2000;18(4):287–95. [PubMed: 10805950] [CrossRef]
• Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736–50. [PMC free article: PMC2684553] [PubMed: 19436038] [CrossRef]
• Chen L, Zhou WB, Zhao Y, Liu XA, Ding Q, Zha XM, et al. Bloody nipple discharge is a predictor of breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2012;132(1):9–14. [PubMed: 21947751] [CrossRef]
• Chiu SY, Duffy S, Yen AM, Tabár L, Smith RA, Chen HH. Effect of baseline breast density on breast cancer incidence, stage, mortality, and screening parameters: 25-year follow-up of a Swedish mammographic screening. Cancer Epidemiol Biomarkers Prev. 2010;19(5):1219–28. [PubMed: 20406961] [CrossRef]
• Chlebowski RT. Nutrition and physical activity influence on breast cancer incidence and outcome. Breast. 2013;22 (Suppl 2):S30–7. [PubMed: 24074789] [CrossRef]
• Chlebowski RT, Manson JE, Anderson GL, Cauley JA, Aragaki AK, Stefanick ML, et al. Estrogen plus progestin and breast cancer incidence and mortality in the Women’s Health Initiative Observational Study. J Natl Cancer Inst. 2013;105(8):526–35. [PMC free article: PMC3691942] [PubMed: 23543779] [CrossRef]
• Chuaqui RF, Zhuang Z, Emmert-Buck MR, Liotta LA, Merino MJ. Analysis of loss of heterozygosity on chromosome 11q13 in atypical ductal hyperplasia and in situ carcinoma of the breast. Am J Pathol. 1997;150(1):297–303. [PMC free article: PMC1858529] [PubMed: 9006344]
• Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17(9):2639–48. [PubMed: 10561337]
• Colditz GA, Atwood KA, Emmons K, Monson RR, Willett WC, Trichopoulos D, et al. Harvard report on cancer prevention volume 4: Harvard Cancer Risk Index. Risk Index Working Group, Harvard Center for Cancer Prevention. Cancer Causes Control. 2000;11(6):477–88. [PubMed: 10880030] [CrossRef]
• Colditz GA, Rosner B. Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses’ Health Study. Am J Epidemiol. 2000;152(10):950–64. [PubMed: 11092437] [CrossRef]
• Coleman MP. Cancer survival in the developing world. Lancet Oncol. 2010;11(2):110–1. [PubMed: 20005176] [CrossRef]
• Coleman MP, Forman D, Bryant H, Butler J, Rachet B, Maringe C, et al. ICBP Module 1 Working Group. Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995–2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. Lancet. 2011;377(9760):127–38. [PMC free article: PMC3018568] [PubMed: 21183212] [CrossRef]
• Coleman MP, Quaresma M, Berrino F, Lutz JM, De Angelis R, Capocaccia R, et al. CONCORD Working Group. Cancer survival in five continents: a worldwide population-based study (CONCORD). Lancet Oncol. 2008;9(8):730–56. [PubMed: 18639491] [CrossRef]
• Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347(9017):1713–27. [PubMed: 8656904] [CrossRef]
• Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet. 1997;350(9084):1047–59. [PubMed: 10213546] [CrossRef]
• Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet. 2001;358(9291):1389–99. [PubMed: 11705483] [CrossRef]
• Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet. 2002;360(9328):187–95. [PubMed: 12133652] [CrossRef]
• Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13(11):1141–51. [PMC free article: PMC3488186] [PubMed: 23084519] [CrossRef]
• Collins LC, Tamimi RM, Baer HJ, Connolly JL, Colditz GA, Schnitt SJ. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: results from the Nurses’ Health Study. Cancer. 2005;103(9):1778–84. [PubMed: 15770688] [CrossRef]
• Corbex M, Burton R, Sancho-Garnier H. Breast cancer early detection methods for low and middle income countries, a review of the evidence. Breast. 2012;21(4):428–34. [PubMed: 22289154] [CrossRef]
• Couch FJ, Nathanson KL, Offit K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science. 2014;343(6178):1466–70. [PMC free article: PMC4074902] [PubMed: 24675953] [CrossRef]
• Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer Epidemiol. 2009;33(5):315–8. [PubMed: 19896917] [CrossRef]
• Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, et al. METABRIC Group. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 2012;486(7403):346–52. [PMC free article: PMC3440846] [PubMed: 22522925]
• Cuzick J. Epidemiology of breast cancer – selected highlights. Breast. 2003;12(6):405–11. [PubMed: 14659113] [CrossRef]
• Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al. ATAC/LATTE investigators. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010;11(12):1135–41. [PubMed: 21087898] [CrossRef]
• Cybulski C, Górski B, Huzarski T, Masojć B, Mierzejewski M, Debniak T, et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75(6):1131–5. [PMC free article: PMC1182149] [PubMed: 15492928] [CrossRef]
• D’Orsi CJ, Sickles EA, Mendelson EB, Morris EA, et al. (2013). ACR BI-RADS^® Atlas, Breast Imaging Reporting and Data System. Reston (VA), USA: American College of Radiology.
• Dalton LW, Page DL, Dupont WD. Histologic grading of breast carcinoma. A reproducibility study. Cancer. 1994;73(11):2765–70. [PubMed: 8194018] [CrossRef]
• Damiola F, Pertesi M, Oliver J, Le Calvez-Kelm F, Voegele C, Young EL, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast Cancer Res. 2014;16(3):R58. [PMC free article: PMC4229874] [PubMed: 24894818] [CrossRef]
• Danaei G, Vander Hoorn S, Lopez AD, Murray CJ, Ezzati M., Comparative Risk Assessment collaborating group (Cancers). Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005;366(9499):1784–93. [PubMed: 16298215] [CrossRef]
• Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707–16. [PMC free article: PMC3254252] [PubMed: 22019144] [CrossRef]
• Davidson A, Chia S, Olson R, Nichol A, Speers C, Coldman AJ, et al. Stage, treatment and outcomes for patients with breast cancer in British Columbia in 2002: a population-based cohort study. CMAJ Open. 2013;1(4):E134–41. [PMC free article: PMC3985980] [PubMed: 25077115] [CrossRef]
• Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84. [PMC free article: PMC3163848] [PubMed: 21802721] [CrossRef]
• Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, et al. Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805–16. [PMC free article: PMC3596060] [PubMed: 23219286] [CrossRef]
• Dawson SJ, Rueda OM, Aparicio S, Caldas C. A new genome-driven integrated classification of breast cancer and its implications. EMBO J. 2013;32(5):617–28. [PMC free article: PMC3590990] [PubMed: 23395906] [CrossRef]
• De Angelis R, Sant M, Coleman MP, Francisci S, Baili P, Pierannunzio D, et al. EUROCARE-5 Working Group. Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5 – a population-based study. Lancet Oncol. 2014;15(1):23–34. [PubMed: 24314615] [CrossRef]
• de Gelder R, Bulliard JL, de Wolf C, Fracheboud J, Draisma G, Schopper D, et al. Cost-effectiveness of opportunistic versus organised mammography screening in Switzerland. Eur J Cancer. 2009;45(1):127–38. [PubMed: 19038540] [CrossRef]
• de Koning HJ (2009). The mysterious mass(es). [Inaugural address, Professor of Screening Evaluation.] Rotterdam, Netherlands: Erasmus MC. Available from: http://repub​.eur.nl/res​/pub/30689/oratie.pdf.
• de Villiers TJ, Gass ML, Haines CJ, Hall JE, Lobo RA, Pierroz DD, et al. Global consensus statement on menopausal hormone therapy. Climacteric. 2013a;16(2):203–4. [PubMed: 23488524] [CrossRef]
• de Villiers TJ, Pines A, Panay N, Gambacciani M, Archer DF, Baber RJ, et al. International Menopause Society. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric. 2013b;16(3):316–37. [PubMed: 23672656] [CrossRef]
• De Waard F, Collette HJ, Rombach JJ, Collette C. Breast cancer screening, with particular reference to the concept of ‘high risk’ groups. Breast Cancer Res Treat. 1988;11(2):125–32. [PubMed: 3401604] [CrossRef]
• Dean L, Geshchicter CF. Comedo carcinoma of the breast. Arch Surg. 1938;36(2):225–34. [CrossRef]
• Desrichard A, Bidet Y, Uhrhammer N, Bignon YJ. CHEK2 contribution to hereditary breast cancer in non-BRCA families. Breast Cancer Res. 2011;13(6):R119. [PMC free article: PMC3326561] [PubMed: 22114986] [CrossRef]
• Dixon JM, Sainsbury JRC.(1998). Handbook of diseases of the breast, 2nd edition. Edinburgh, UK: Churchill Livingstone.
• Dolan RT, Butler JS, Kell MR, Gorey TF, Stokes MA. Nipple discharge and the efficacy of duct cytology in evaluating breast cancer risk. Surgeon. 2010;8(5):252–8. [PubMed: 20709281] [CrossRef]
• Donker M, Litière S, Werutsky G, Julien JP, Fentiman IS, Agresti R, et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma in situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol. 2013;31(32):4054–9. [PubMed: 24043739] [CrossRef]
• Doody MM, Freedman DM, Alexander BH, Hauptmann M, Miller JS, Rao RS, et al. Breast cancer incidence in U.S. radiologic technologists. Cancer. 2006;106(12):2707–15. [PubMed: 16639729] [CrossRef]
• Doody MM, Lonstein JE, Stovall M, Hacker DG, Luckyanov N, Land CE. Breast cancer mortality after diagnostic radiography: findings from the U.S. Scoliosis Cohort Study. Spine. 2000;25(16):2052–63. [PubMed: 10954636] [CrossRef]
• Douglas-Jones AG, Gupta SK, Attanoos RL, Morgan JM, Mansel RE. A critical appraisal of six modern classifications of ductal carcinoma in situ of the breast (DCIS): correlation with grade of associated invasive carcinoma. Histopathology. 1996;29(5):397–409. [PubMed: 8951484] [CrossRef]
• Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J, et al. International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656–64. [PMC free article: PMC3216967] [PubMed: 21960707] [CrossRef]
• Duffy SW, Tabár L, Vitak B, Day NE, Smith RA, Chen HH, et al. The relative contributions of screen-detected in situ and invasive breast carcinomas in reducing mortality from the disease. Eur J Cancer. 2003;39(12):1755–60. [PubMed: 12888371] [CrossRef]
• Dumas I, Diorio C. Polymorphisms in genes involved in the estrogen pathway and mammographic density. BMC Cancer. 2010;10(1):636. [PMC free article: PMC3000407] [PubMed: 21092186] [CrossRef]
• Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA, et al. Breast cancer risk associated with proliferative breast disease and atypical hyperplasia. Cancer. 1993;71(4):1258–65. [PubMed: 8435803] [CrossRef]
• EBCTCG. Early Breast Cancer Trialists’ Collaborative Group. 2001Tamoxifen for early breast cancer. Cochrane Database Syst Rev 1CD000486. [PubMed: 11279694]
• EBCTCG. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–717. [PubMed: 15894097] [CrossRef]
• Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors (2010). AJCC cancer staging manuals. Preface, 7th edition. With CD-ROM.
• Eidemüller M, Holmberg E, Jacob P, Lundell M, Karlsson P. Breast cancer risk among Swedish hemangioma patients and possible consequences of radiation-induced genomic instability. Mutat Res. 2009;669(1–2):48–55. [PubMed: 19416732] [CrossRef]
• El Saghir NS, Adebamowo CA, Anderson BO, Carlson RW, Bird PA, Corbex M, et al. Breast cancer management in low resource countries (LRCs): consensus statement from the Breast Health Global Initiative. Breast. 2011;20 (Suppl 2):S3–11. [PubMed: 21392996] [CrossRef]
• Ellis I, editor (2011). Quality assurance guidelines for breast pathology services, 2nd edition. NHSBSP Publication No. 2. Sheffield, UK: NHS Cancer Screening Programmes.
• Ellis IO, Coleman D, Wells C, Kodikara S, Paish EM, Moss S, et al. Impact of a national external quality assessment scheme for breast pathology in the UK. J Clin Pathol. 2006;59(2):138–45. [PMC free article: PMC1860326] [PubMed: 16443727] [CrossRef]
• Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW. Pathological prognostic factors in breast cancer. II. Histological type. Relationship with survival in a large study with long-term follow-up. Histopathology. 1992;20(6):479–89. [PubMed: 1607149] [CrossRef]
• Ellis IO, Galea MH, Locker A, Roebuck EJ, Elston CW, Blamey RW, et al. Early experience in breast cancer screening: emphasis on development of protocols for triple assessment. Breast. 1993;2(3):148–53. [CrossRef]
• Elshof LE, Tryfonidis K, Slaets L, van Leeuwen-Stok AE, Skinner VP, Dif N, et al. Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ - The LORD study. Eur J Cancer. 2015;51(12):1497–510. [PubMed: 26025767] [CrossRef]
• Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–10. [PubMed: 1757079] [CrossRef]
• Engholm G, Ferlay J, Christensen N, Kejs AMT, Johannesen TB, Khan S, et al. (2014). NORDCAN: Cancer incidence, mortality, prevalence and survival in the Nordic countries, Version 7.0 (17.12.2014). Association of the Nordic Cancer Registries. Danish Cancer Society. Available from: http://www​.ancr.nu, accessed 5 December 2014.
• Erbas B, Provenzano E, Armes J, Gertig D. The natural history of ductal carcinoma in situ of the breast: a review. Breast Cancer Res Treat. 2006;97(2):135–44. [PubMed: 16319971] [CrossRef]
• Ermiah E, Abdalla F, Buhmeida A, Larbesh E, Pyrhönen S, Collan Y. Diagnosis delay in Libyan female breast cancer. BMC Res Notes. 2012;5(1):452. [PMC free article: PMC3542159] [PubMed: 22909280] [CrossRef]
• Ewertz M, Duffy SW, Adami HO, Kvåle G, Lund E, Meirik O, et al. Age at first birth, parity and risk of breast cancer: a meta-analysis of 8 studies from the Nordic countries. Int J Cancer. 1990;46(4):597–603. [PubMed: 2145231] [CrossRef]
• Fan L, Strasser-Weippl K, Li JJ, St Louis J, Finkelstein DM, Yu KD, et al. Breast cancer in China. Lancet Oncol. 2014;15(7):e279–89. [PubMed: 24872111] [CrossRef]
• Faulder C. Breast awareness: what do we really mean? Eur J Cancer. 1992;28(10):1595–6. [PubMed: 1389471] [CrossRef]
• FDA (2014). Mammography Quality Standards Act and Program. US Food and Drug Administration. Available from: http://www​.fda.gov/Radiation-EmittingProducts​/MammographyQualityStandardsActandProgram/default.htm.
• Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med. 1985;312(25):1604–8. [PubMed: 4000199] [CrossRef]
• Ferlay J, Bray F, Steliarova-Foucher E, Forman D.(2014b). Cancer Incidence in Five Continents, CI5plus: IARC CancerBase No. 9 [Internet]. Lyon, France: International Agency for Research on Cancer. Available from: http://ci5​.iarc.fr.
• Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. (2014a). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136(5):E359–86. 10.1002/ijc.29210. [PubMed: 25220842] [CrossRef]
• Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. (2013). GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer. Available from: http://globocan​.iarc.fr, accessed 15 September 2014.
• Finnish Cancer Registry (2015). Survival ratios of cancer patients in Finland. Institute for Statistical and Epidemiological Cancer Research. Available from: http://www​.cancer.fi​/syoparekisteri/en/statistics​/survival-ratios-of-cancer-patien/
• Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233–41. [PubMed: 12393820] [CrossRef]
• Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28(4):400–18. [PubMed: 11498833] [CrossRef]
• Fisher B, Wolmark N, Redmond C, Deutsch M, Fisher ER. Findings from NSABP Protocol No. B-04: comparison of radical mastectomy with alternative treatments. II. The clinical and biologic significance of medial-central breast cancers. Cancer. 1981;48(8):1863–72. [PubMed: 7284980] [CrossRef]
• Fisher ER, Dignam J, Tan-Chiu E, Costantino J, Fisher B, Paik S, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer. 1999;86(3):429–38. [PubMed: 10430251] [CrossRef]
• Fisher ER, Land SR, Fisher B, Mamounas E, Gilarski L, Wolmark N. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer. 2004;100(2):238–44. [PubMed: 14716756] [CrossRef]
• Fitzgibbons PL, Henson DE, Hutter RV., Cancer Committee of the College of American Pathologists. Benign breast changes and the risk for subsequent breast cancer: an update of the 1985 consensus statement. Arch Pathol Lab Med. 1998;122(12):1053–5. [PubMed: 9870852]
• Forman D, Bray F, Brewster DH, Gombe Mbalawa C, Kohler B, Piñeros M, et al. (2013). Cancer Incidence in Five Continents, Volume X (electronic version). Lyon, France: International Agency for Research on Cancer. Available from: http://ci5​.iarc.fr.
• Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448–54. [PubMed: 15551359] [CrossRef]
• Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F. Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks? J Clin Oncol. 2009;27(31):5138–43. [PMC free article: PMC6413836] [PubMed: 19752341] [CrossRef]
• Fournier A, Mesrine S, Dossus L, Boutron-Ruault MC, Clavel-Chapelon F, Chabbert-Buffet N. Risk of breast cancer after stopping menopausal hormone therapy in the E3N cohort. Breast Cancer Res Treat. 2014;145(2):535–43. [PMC free article: PMC5924370] [PubMed: 24781971] [CrossRef]
• Fregene A, Newman LA. Breast cancer in sub-Saharan Africa: how does it relate to breast cancer in African-American women? Cancer. 2005;103(8):1540–50. [PubMed: 15768434] [CrossRef]
• Friebel TM, Domchek SM, Rebbeck TR. 2014Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst 106(6)dju091. 10.1093/jnci/dju091. [PMC free article: PMC4081625] [PubMed: 24824314] [CrossRef]
• Friedenreich CM, Neilson HK, Lynch BM. State of the epidemiological evidence on physical activity and cancer prevention. Eur J Cancer. 2010;46(14):2593–604. [PubMed: 20843488] [CrossRef]
• Friedman DL, Whitton J, Leisenring W, Mertens AC, Hammond S, Stovall M, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102(14):1083–95. [PMC free article: PMC2907408] [PubMed: 20634481] [CrossRef]
• Friedman EB, Chun J, Schnabel F, Schwartz S, Law S, Billig J, et al. Screening prior to breast cancer diagnosis: the more things change, the more they stay the same. Int J Breast Cancer. 2013;2013:1. [PMC free article: PMC3789493] [PubMed: 24159387] [CrossRef]
• Frierson HF Jr, Wolber RA, Berean KW, Franquemont DW, Gaffey MJ, Boyd JC, et al. Interobserver reproducibility of the Nottingham modification of the Bloom and Richardson histologic grading scheme for infiltrating ductal carcinoma. Am J Clin Pathol. 1995;103(2):195–8. [PubMed: 7856562]
• Fujii H, Szumel R, Marsh C, Zhou W, Gabrielson E. Genetic progression, histological grade, and allelic loss in ductal carcinoma in situ of the breast. Cancer Res. 1996;56(22):5260–5. [PubMed: 8912866]
• Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst. 1989;81(24):1879–86. [PubMed: 2593165] [CrossRef]
• Gathani T, Ali R, Balkwill A, Green J, Reeves G, Beral V, et al. Million Women Study Collaborators. Ethnic differences in breast cancer incidence in England are due to differences in known risk factors for the disease: prospective study. Br J Cancer. 2014;110(1):224–9. [PMC free article: PMC3887283] [PubMed: 24169349] [CrossRef]
• Gemeinsamen Bundesausschuss. (2011). Regulation of the Joint Committee on Cancer Screening (cancer screening regulation/KFE-RL) [in German]Bundesanzeiger. 34S.8641–5.
• Ghiasvand R, Bahmanyar S, Zendehdel K, Tahmasebi S, Talei A, Adami HO, et al. Postmenopausal breast cancer in Iran; risk factors and their population attributable fractions. BMC Cancer. 2012;12(1):414. [PMC free article: PMC3517420] [PubMed: 22992276] [CrossRef]
• Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, et al. Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011;12(3):236–44. [PubMed: 21354370] [CrossRef]
• Giess CS, Keating DM, Osborne MP, Ng YY, Rosenblatt R. Retroareolar breast carcinoma: clinical, imaging, and histopathologic features. Radiology. 1998;207(3):669–73. [PubMed: 9609889] [CrossRef]
• Giordano L, Cogo C, Patnick J, Paci E., Euroscreen Working Group. Communicating the balance sheet in breast cancer screening. J Med Screen. 2012;19 (Suppl 1):67–71. [PubMed: 22972812] [CrossRef]
• Giordano L, Webster P, Segnan N, Austoker J.(2006). Guidance on breast screening communication. In: Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L, et al., editors. European guidelines for quality assurance in breast cancer screening and diagnosis. 4th ed. Luxembourg: European Commission, Office for Official Publications of the European Communities; pp. 379–94.
• Go EM, Tsang JY, Ni YB, Yu AM, Mendoza P, Chan SK, et al. Relationship between columnar cell changes and low-grade carcinoma in situ of the breast–a cytogenetic study. Hum Pathol. 2012;43(11):1924–31. [PubMed: 22542249] [CrossRef]
• Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, et al. Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013;382(9897):1021–8. [PubMed: 23871490] [CrossRef]
• Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY, Nguyen VQ, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009;27(8):1250–6. [PubMed: 19204208] [CrossRef]
• Goodwin PJ, Phillips KA, West DW, Ennis M, Hopper JL, John EM, et al. Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol. 2012;30(1):19–26. [PubMed: 22147742] [CrossRef]
• Gorini G, Zappa M, Cortini B, Martini A, Mantellini P, Ventura L, et al. Breast cancer mortality trends in Italy by region and screening programme, 1980–2008. J Med Screen. 2014;21(4):189–93. [PubMed: 25186117] [CrossRef]
• Goss PE, Lee BL, Badovinac-Crnjevic T, Strasser-Weippl K, Chavarri-Guerra Y, St Louis J, et al. Planning cancer control in Latin America and the Caribbean. Lancet Oncol. 2013;14(5):391–436. [PubMed: 23628188] [CrossRef]
• Guibout C, Adjadj E, Rubino C, Shamsaldin A, Grimaud E, Hawkins M, et al. Malignant breast tumors after radiotherapy for a first cancer during childhood. J Clin Oncol. 2005;23(1):197–204. [PubMed: 15625374] [CrossRef]
• Haagensen CD.(1986). Diseases of the breast. Philadelphia (PA), USA: Saunders.
• Halsted WS. The results of operations for the cure of cancer of the breast performed at The Johns Hopkins Hospital from June 1889 to January 1894. Ann Surg. 1894;20(5):497–555. [PMC free article: PMC1493925] [PubMed: 17860107] [CrossRef]
• Hammer GP, Auvinen A, De Stavola BL, Grajewski B, Gundestrup M, Haldorsen T, et al. Mortality from cancer and other causes in commercial airline crews: a joint analysis of cohorts from 10 countries. Occup Environ Med. 2014;71(5):313–22. [PubMed: 24389960] [CrossRef]
• Hammer GP, Seidenbusch MC, Schneider K, Regulla D, Zeeb H, Spix C, et al. Cancer incidence rate after diagnostic X-ray exposure in 1976–2003 among patients of a university children’s hospital [in German] Rofo. 2010;182(5):404–14. [PubMed: 20234999] [CrossRef]
• Harford JB. Breast-cancer early detection in low-income and middle-income countries: do what you can versus one size fits all. Lancet Oncol. 2011;12(3):306–12. [PubMed: 21376292] [CrossRef]
• Harper S, Lynch J, Meersman SC, Breen N, Davis WW, Reichman MC. Trends in area-socioeconomic and race-ethnic disparities in breast cancer incidence, stage at diagnosis, screening, mortality, and survival among women ages 50 years and over (1987–2005). Cancer Epidemiol Biomarkers Prev. 2009;18(1):121–31. [PubMed: 19124489] [CrossRef]
• Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer. N Engl J Med. 1992;327(5):319–28. [PubMed: 1620171] [CrossRef]
• Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006;12(10):3209–15. [PubMed: 16707622] [CrossRef]
• Henderson TO, Amsterdam A, Bhatia S, Hudson MM, Meadows AT, Neglia JP, et al. Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med. 2010;152(7):444–55, W144–54. [PMC free article: PMC2857928] [PubMed: 20368650] [CrossRef]
• Hildreth NG, Shore RE, Dvoretsky PM. The risk of breast cancer after irradiation of the thymus in infancy. N Engl J Med. 1989;321(19):1281–4. [PubMed: 2797100] [CrossRef]
• Hill DA, Gilbert E, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E, et al. Breast cancer risk following radiotherapy for Hodgkin lymphoma: modification by other risk factors. Blood. 2005;106(10):3358–65. [PMC free article: PMC1895063] [PubMed: 16051739] [CrossRef]
• Hirko KA, Soliman AS, Hablas A, Seifeldin IA, Ramadan M, Banerjee M, et al. Trends in breast cancer incidence rates by age and stage at diagnosis in Gharbiah, Egypt, over 10 years (1999–2008). J Cancer Epidemiol. 2013;2013:1. [PMC free article: PMC3824336] [PubMed: 24282410] [CrossRef]
• Honrado E, Benítez J, Palacios J. Histopathology of BRCA1- and BRCA2-associated breast cancer. Crit Rev Oncol Hematol. 2006;59(1):27–39. [PubMed: 16530420] [CrossRef]
• Howe GR, McLaughlin J. Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study. Radiat Res. 1996;145(6):694–707. [PubMed: 8643829] [CrossRef]
• Hsieh CC, Trichopoulos D, Katsouyanni K, Yuasa S. Age at menarche, age at menopause, height and obesity as risk factors for breast cancer: associations and interactions in an international case-control study. Int J Cancer. 1990;46(5):796–800. [PubMed: 2228308] [CrossRef]
• Hukkinen K, Kivisaari L, Heikkilä PS, Von Smitten K, Leidenius M. Unsuccessful preoperative biopsies, fine needle aspiration cytology or core needle biopsy, lead to increased costs in the diagnostic workup in breast cancer. Acta Oncol. 2008;47(6):1037–45. [PubMed: 18607862] [CrossRef]
• Hwang ES, DeVries S, Chew KL, Moore DH 2nd, Kerlikowske K, Thor A, et al. Patterns of chromosomal alterations in breast ductal carcinoma in situ. Clin Cancer Res. 2004;10(15):5160–7. [PubMed: 15297420] [CrossRef]
• IARC. (2002). Breast cancer screening. IARC Handb Cancer Prev, 7:1–229. Available from: http://www​.iarc.fr/en​/publications/pdfs-online​/prev/handbook7/Handbook7_Breast​.pdf.
• IARC. (2012a). Pharmaceuticals. IARC Monogr Eval Carcinog Risks Hum. 100A:1–437. Available from: http://monographs​.iarc​.fr/ENG/Monographs/vol100A/index.php. [PMC free article: PMC4781347] [PubMed: 23189749]
• IARC. (2012b). Personal habits and indoor combustions. IARC Monogr Eval Carcinog Risks Hum. 100E:1–575. Available from: http://monographs​.iarc​.fr/ENG/Monographs/vol100E/index.php. [PMC free article: PMC4781577] [PubMed: 23193840]
• IARC. (2012c). Radiation. IARC Monogr Eval Carcinog Risks Hum. 100D:1–437. Available from: http://monographs​.iarc​.fr/ENG/Monographs/vol100D/index.php.
• Inoue M, Sawada N, Matsuda T, Iwasaki M, Sasazuki S, Shimazu T, et al. Attributable causes of cancer in Japan in 2005 – systematic assessment to estimate current burden of cancer attributable to known preventable risk factors in Japan. Ann Oncol. 2012;23(5):1362–9. [PubMed: 22048150] [CrossRef]
• INSERM (2008). Cancer et environnement. Rapport. Institut national de la santé et de la recherche médicale. Paris, France: Les éditions INSERM.
• Isaacs C, Stearns V, Hayes DF. New prognostic factors for breast cancer recurrence. Semin Oncol. 2001;28(1):53–67. [PubMed: 11254867] [CrossRef]
• Isola J, Saijonkari M, Kataja V, Lundin J, Hytönen M, Isojärvi J, et al. (2013). Gene profiling assays for planning breast cancer treatment. [in Finnish]. Suomen Lääkärilehti. 6850–523321–7ö. English summary available from: http://www​.thl.fi/attachments​/halo/summaries​/SLL_2013_GeeniprofilointitestienMerkitysRintasyovanHoidonValinnassa_eng.pdf.
• ISRCTN registry. (2014). Surgery versus active monitoring for low risk ductal carcinoma in situ (DCIS). Available from: http://www​.isrctn.com/ISRCTN27544579.
• Iwasaki M, Otani T, Inoue M, Sasazuki S, Tsugane S., Japan Public Health Center-based Prospective Study Group. Role and impact of menstrual and reproductive factors on breast cancer risk in Japan. Eur J Cancer Prev. 2007;16(2):116–23. [PubMed: 17297387] [CrossRef]
• Iwasaki M, Tsugane S. Risk factors for breast cancer: epidemiological evidence from Japanese studies. Cancer Sci. 2011;102(9):1607–14. [PubMed: 21624009] [CrossRef]
• Jain AN, Chin K, Børresen-Dale AL, Erikstein BK, Eynstein Lonning P, Kaaresen R, et al. Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival. Proc Natl Acad Sci USA. 2001;98(14):7952–7. [PMC free article: PMC35449] [PubMed: 11438741] [CrossRef]
• Jansen-van der Weide MC, Greuter MJ, Jansen L, Oosterwijk JCW, Pijnappel RM, de Bock GH. Exposure to low-dose radiation and the risk of breast cancer among women with a familial or genetic predisposition: a meta-analysis. Eur Radiol. 2010;20(11):2547–56. [PubMed: 20582702] [CrossRef]
• John EM, Miron A, Gong G, Phipps AI, Felberg A, Li FP, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007;298(24):2869–76. [PubMed: 18159056] [CrossRef]
• Justo N, Wilking N, Jönsson B, Luciani S, Cazap E. A review of breast cancer care and outcomes in Latin America. Oncologist. 2013;18(3):248–56. [PMC free article: PMC3607519] [PubMed: 23442305] [CrossRef]
• Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C, et al. Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer. 2005;12(4):1071–82. [PubMed: 16322344] [CrossRef]
• Kaplan RM, Porzsolt F. The natural history of breast cancer. Arch Intern Med. 2008;168(21):2302–3. [PubMed: 19029491] [CrossRef]
• Karami F, Mehdipour P. A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. BioMed Res Int. 2013;2013:1. [PMC free article: PMC3838820] [PubMed: 24312913] [CrossRef]
• Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297(21):2360–72. [PubMed: 17545690] [CrossRef]
• Kean S. Breast cancer. The ‘other’ breast cancer genes. Science. 2014;343(6178):1457–9. [PubMed: 24675950] [CrossRef]
• Kelsey JL, Bernstein L. Epidemiology and prevention of breast cancer. Annu Rev Public Health. 1996;17(1):47–67. [PubMed: 8724215] [CrossRef]
• Kenney LB, Yasui Y, Inskip PD, Hammond S, Neglia JP, Mertens AC, et al. Breast cancer after childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med. 2004;141(8):590–7. [PubMed: 15492338] [CrossRef]
• Kerlikowske K, Ichikawa L, Miglioretti DL, Buist DS, Vacek PM, Smith-Bindman R, et al. National Institutes of Health Breast Cancer Surveillance Consortium. Longitudinal measurement of clinical mammographic breast density to improve estimation of breast cancer risk. J Natl Cancer Inst. 2007;99(5):386–95. [PubMed: 17341730] [CrossRef]
• Key T, Appleby P, Barnes I, Reeves G., Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94(8):606–16. [PubMed: 11959894] [CrossRef]
• Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, et al. Endogenous Hormones Breast Cancer Collaborative Group. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95(16):1218–26. [PubMed: 12928347] [CrossRef]
• Key TJ, Appleby PN, Reeves GK, Roddam AW., Endogenous Hormones and Breast Cancer Collaborative Group. Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol. 2010;11(6):530–42. [PMC free article: PMC3113287] [PubMed: 20472501] [CrossRef]
• Key TJ, Appleby PN, Reeves GK, Travis RC, Alberg AJ, Barricarte A, et al. Endogenous Hormones and Breast Cancer Collaborative Group. Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies. Lancet Oncol. 2013;14(10):1009–19. [PMC free article: PMC4056766] [PubMed: 23890780] [CrossRef]
• Kingham TP, Alatise OI, Vanderpuye V, Casper C, Abantanga FA, Kamara TB, et al. Treatment of cancer in sub-Saharan Africa. Lancet Oncol. 2013;14(4):e158–67. [PubMed: 23561747] [CrossRef]
• Kingsmore D, Hole D, Gillis C. Why does specialist treatment of breast cancer improve survival? The role of surgical management. Br J Cancer. 2004;90(10):1920–5. [PMC free article: PMC2409479] [PubMed: 15138472] [CrossRef]
• Kleibl Z, Novotny J, Bezdickova D, Malik R, Kleiblova P, Foretova L, et al. The CHEK2 c.1100delC germline mutation rarely contributes to breast cancer development in the Czech Republic. Breast Cancer Res Treat. 2005;90(2):165–7. [PubMed: 15803363] [CrossRef]
• Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009;9(4):302–12. [PubMed: 19308069] [CrossRef]
• Kobayashi S, Sugiura H, Ando Y, Shiraki N, Yanagi T, Yamashita H, et al. Reproductive history and breast cancer risk. Breast Cancer. 2012;19(4):302–8. [PMC free article: PMC3479376] [PubMed: 22711317] [CrossRef]
• Kopans DB, Smith RA, Duffy SW. Mammographic screening and “overdiagnosis”. Radiology. 2011;260(3):616–20. [PubMed: 21846757] [CrossRef]
• Kriege M, Hollestelle A, Jager A, Huijts PE, Berns EM, Sieuwerts AM, et al. Survival and contralateral breast cancer in CHEK2 1100delC breast cancer patients: impact of adjuvant chemotherapy. Br J Cancer. 2014;111(5):1004–13. [PMC free article: PMC4150261] [PubMed: 24918820] [CrossRef]
• Kristensen VN, Vaske CJ, Ursini-Siegel J, Van Loo P, Nordgard SH, Sachidanandam R, et al. Integrated molecular profiles of invasive breast tumors and ductal carcinoma in situ (DCIS) reveal differential vascular and interleukin signaling. Proc Natl Acad Sci USA. 2012;109(8):2802–7. [PMC free article: PMC3286992] [PubMed: 21908711] [CrossRef]
• Kwan ML, Haque R, Lee VS, Joanie Chung WL, Avila CC, Clancy HA, et al. Validation of AJCC TNM staging for breast tumors diagnosed before 2004 in cancer registries. Cancer Causes Control. 2012;23(9):1587–91. [PMC free article: PMC3418812] [PubMed: 22798182] [CrossRef]
• Lakhani SR, Collins N, Stratton MR, Sloane JP. Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p. J Clin Pathol. 1995;48(7):611–5. [PMC free article: PMC502709] [PubMed: 7560165] [CrossRef]
• Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ, editors. (2012). WHO classification of tumours of the breast. 4th ed. Lyon, France: International Agency for Research on Cancer.
• Lakhani SR, Jacquemier J, Sloane JP, Gusterson BA, Anderson TJ, van de Vijver MJ, et al. Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst. 1998;90(15):1138–45. [PubMed: 9701363] [CrossRef]
• Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20(9):2310–8. [PubMed: 11981002] [CrossRef]
• Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO. Transient increase in the risk of breast cancer after giving birth. N Engl J Med. 1994;331(1):5–9. [PubMed: 8202106] [CrossRef]
• Lampejo OT, Barnes DM, Smith P, Millis RR. Evaluation of infiltrating ductal carcinomas with a DCIS component: correlation of the histologic type of the in situ component with grade of the infiltrating component. Semin Diagn Pathol. 1994;11(3):215–22. [PubMed: 7831533]
• Land CE, Tokunaga M, Koyama K, Soda M, Preston DL, Nishimori I, et al. Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950–1990. Radiat Res. 2003;160(6):707–17. [PubMed: 14640793] [CrossRef]
• Lange JM, Takashima JR, Peterson SM, Kalapurakal JA, Green DM, Breslow NE. Breast cancer in female survivors of Wilms tumor: a report from the national Wilms tumor late effects study. Cancer. 2014;120(23):3722–30. [PMC free article: PMC4239191] [PubMed: 25348097] [CrossRef]
• Langlands AO, Prescott RJ, Hamilton T. A clinical trial in the management of operable cancer of the breast. Br J Surg. 1980;67(3):170–4. [PubMed: 6988032] [CrossRef]
• Larsen SU, Rose C. Spontaneous remission of breast cancer. A literature review [in Danish] Ugeskr Laeger. 1999;161(26):4001–4. [PubMed: 10402936]
• Lazarus E, Mainiero MB, Schepps B, Koelliker SL, Livingston LS. BI-RADS lexicon for US and mammography: interobserver variability and positive predictive value. Radiology. 2006;239(2):385–91. [PubMed: 16569780] [CrossRef]
• Lee SA, Ross RK, Pike MC. An overview of menopausal oestrogen-progestin hormone therapy and breast cancer risk. Br J Cancer. 2005;92(11):2049–58. [PMC free article: PMC2361783] [PubMed: 15900297] [CrossRef]
• Li J, Zhang BN, Fan JH, Pang Y, Zhang P, Wang SL, et al. A nation-wide multicenter 10-year (1999–2008) retrospective clinical epidemiological study of female breast cancer in China. BMC Cancer. 2011;11(1):364. [PMC free article: PMC3178543] [PubMed: 21859480] [CrossRef]
• Li L, Ji J, Wang JB, Niyazi M, Qiao YL, Boffetta P. Attributable causes of breast cancer and ovarian cancer in China: reproductive factors, oral contraceptives and hormone replacement therapy. Chin J Cancer Res. 2012;24(1):9–17. [PMC free article: PMC3555252] [PubMed: 23359757] [CrossRef]
• Li ML, Greenberg RA. Links between genome integrity and BRCA1 tumor suppression. Trends Biochem Sci. 2012;37(10):418–24. [PMC free article: PMC3459146] [PubMed: 22836122] [CrossRef]
• Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer – analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343(2):78–85. [PubMed: 10891514] [CrossRef]
• Lindström S, Vachon CM, Li J, Varghese J, Thompson D, Warren R, et al. Common variants in ZNF365 are associated with both mammographic density and breast cancer risk. Nat Genet. 2011;43(3):185–7. [PMC free article: PMC3076615] [PubMed: 21278746] [CrossRef]
• Liu C, Wang QS, Wang YJ. The CHEK2 I157T variant and colorectal cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2012a;13(5):2051–5. [PubMed: 22901170] [CrossRef]
• Liu C, Wang Y, Wang QS, Wang YJ. The CHEK2 I157T variant and breast cancer susceptibility: a systematic review and meta-analysis. Asian Pac J Cancer Prev. 2012b;13(4):1355–60. [PubMed: 22799331] [CrossRef]
• Liu JJ, Freedman DM, Little MP, Doody MM, Alexander BH, Kitahara CM, et al. Work history and mortality risks in 90,268 US radiological technologists. Occup Environ Med. 2014;71(12):819–35. [PubMed: 24852760] [CrossRef]
• London SJ, Connolly JL, Schnitt SJ, Colditz GA. A prospective study of benign breast disease and the risk of breast cancer. JAMA. 1992;267(7):941–4. [PubMed: 1734106] [CrossRef]
• Lopez-Garcia MA, Geyer FC, Lacroix-Triki M, Marchió C, Reis-Filho JS. Breast cancer precursors revisited: molecular features and progression pathways. Histopathology. 2010;57(2):171–92. [PubMed: 20500230] [CrossRef]
• Lu YJ, Osin P, Lakhani SR, Di Palma S, Gusterson BA, Shipley JM. Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia. Cancer Res. 1998;58(20):4721–7. [PubMed: 9788628]
• Lundell M, Mattsson A, Karlsson P, Holmberg E, Gustafsson A, Holm LE. Breast cancer risk after radiotherapy in infancy: a pooled analysis of two Swedish cohorts of 17,202 infants. Radiat Res. 1999;151(5):626–32. [PubMed: 10319736] [CrossRef]
• Ly D, Forman D, Ferlay J, Brinton LA, Cook MB. An international comparison of male and female breast cancer incidence rates. Int J Cancer. 2013;132(8):1918–26. [PMC free article: PMC3553266] [PubMed: 22987302] [CrossRef]
• Lynge E, Törnberg S, von Karsa L, Segnan N, van Delden JJ. Determinants of successful implementation of population-based cancer screening programmes. Eur J Cancer. 2012;48(5):743–8. [PubMed: 21788130] [CrossRef]
• Lythgoe JP, Leck I, Swindell R. Manchester regional breast study. Preliminary results. Lancet. 1978;1(8067):744–7. [PubMed: 76750] [CrossRef]
• Mac Bride MB, Pruthi S, Bevers T. The evolution of breast self-examination to breast awareness. Breast J. 2012;18(6):641–3. [PubMed: 23009674] [CrossRef]
• MacMahon B, Cole P, Brown J. Etiology of human breast cancer: a review. J Natl Cancer Inst. 1973;50(1):21–42. [PubMed: 4571238]
• Maddox WA, Carpenter JT Jr, Laws HL, Soong SJ, Cloud G, Urist MM, et al. A randomized prospective trial of radical (Halsted) mastectomy versus modified radical mastectomy in 311 breast cancer patients. Ann Surg. 1983;198(2):207–12. [PMC free article: PMC1353081] [PubMed: 6870379] [CrossRef]
• Madigan MP, Ziegler RG, Benichou J, Byrne C, Hoover RN. Proportion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst. 1995;87(22):1681–5. [PubMed: 7473816] [CrossRef]
• Mahoney L, Csima A. Efficiency of palpation in clinical detection of breast cancer. Can Med Assoc J. 1982;127(8):729–30. [PMC free article: PMC1862403] [PubMed: 7139488]
• Mahoney MC, Bevers T, Linos E, Willett WC. Opportunities and strategies for breast cancer prevention through risk reduction. CA Cancer J Clin. 2008;58(6):347–71. [PubMed: 18981297] [CrossRef]
• Malmgren JA, Parikh J, Atwood MK, Kaplan HG. Improved prognosis of women aged 75 and older with mammography-detected breast cancer. Radiology. 2014;273(3):686–94. [PubMed: 25093690] [CrossRef]
• Mark K, Temkin SM, Terplan M. Breast self-awareness: the evidence behind the euphemism. Obstet Gynecol. 2014;123(4):734–6. [PubMed: 24785598] [CrossRef]
• Masannat YA, Bains SK, Pinder SE, Purushotham AD. Challenges in the management of pleomorphic lobular carcinoma in situ of the breast. Breast. 2013;22(2):194–6. [PubMed: 23357705] [CrossRef]
• Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J, et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012;133(3):1125–30. [PMC free article: PMC3709568] [PubMed: 22392042] [CrossRef]
• Mattsson A, Rudén BI, Hall P, Wilking N, Rutqvist LE. Radiation-induced breast cancer: long-term follow-up of radiation therapy for benign breast disease. J Natl Cancer Inst. 1993;85(20):1679–85. [PubMed: 8411245] [CrossRef]
• Mattsson A, Rudén BI, Palmgren J, Rutqvist LE. Dose- and time-response for breast cancer risk after radiation therapy for benign breast disease. Br J Cancer. 1995;72(4):1054–61. [PMC free article: PMC2034025] [PubMed: 7547222] [CrossRef]
• Mavaddat N, Barrowdale D, Andrulis IL, Domchek SM, Eccles D, Nevanlinna H, et al. HEBON. EMBRACE. GEMO Study Collaborators. kConFab Investigators. SWE-BRCA Collaborators. Consortium of Investigators of Modifiers of BRCA1/2. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomarkers Prev. 2012;21(1):134–47. [PMC free article: PMC3272407] [PubMed: 22144499] [CrossRef]
• McCormack VA, dos Santos Silva I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2006;15(6):1159–69. [PubMed: 16775176] [CrossRef]
• McCormack VA, Joffe M, van den Berg E, Broeze N, Silva IS, Romieu I, et al. Breast cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in Soweto, South Africa: a case series. Breast Cancer Res. 2013;15(5):R84. [PMC free article: PMC3978918] [PubMed: 24041225] [CrossRef]
• McCready T, Littlewood D, Jenkinson J. Breast self-examination and breast awareness: a literature review. J Clin Nurs. 2005;14(5):570–8. [PubMed: 15840071] [CrossRef]
• McGale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127–35. [PMC free article: PMC5015598] [PubMed: 24656685] [CrossRef]
• McWhirter R. The value of simple mastectomy and radiotherapy in the treatment of cancer of the breast. Br J Radiol. 1948;21(252):599–610. [PubMed: 18099752] [CrossRef]
• Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, et al. CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet. 2002;31(1):55–9. [PubMed: 11967536] [CrossRef]
• Mendonça GA, Silva AM, Caula WM. Tumor characteristics and five-year survival in breast cancer patients at the National Cancer Institute, Rio de Janeiro, Brazil [in Portuguese]. Cad Saude Publica. 2004;20(5):1232–9. [PubMed: 15486666]
• Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, et al. Breast and Ovarian Cancer Susceptibility Collaboration. Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON). kConFab Investigators. Australian Ovarian Cancer Study Group. GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network. Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet. 2013;45(4):353–61, e1–2. [PMC free article: PMC3771688] [PubMed: 23535729] [CrossRef]
• Mikeljevic JS, Haward R, Johnston C, Crellin A, Dodwell D, Jones A, et al. Trends in postoperative radiotherapy delay and the effect on survival in breast cancer patients treated with conservation surgery. Br J Cancer. 2004;90(7):1343–8. [PMC free article: PMC2409668] [PubMed: 15054452] [CrossRef]
• Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst. 2004;96(24):1856–65. [PubMed: 15601642] [CrossRef]
• Mittra I, Mishra GA, Singh S, Aranke S, Notani P, Badwe R, et al. A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening. Int J Cancer. 2010;126(4):976–84. [PubMed: 19697326]
• Moelans CB, de Wegers RA, Monsuurs HN, Maess AH, van Diest PJ. Molecular differences between ductal carcinoma in situ and adjacent invasive breast carcinoma: a multiplex ligation-dependent probe amplification study. Cell Oncol (Dordr). 2011;34(5):475–82. [PMC free article: PMC3219861] [PubMed: 21547576] [CrossRef]
• Mohan AK, Hauptmann M, Linet MS, Ron E, Lubin JH, Freedman DM, et al. Breast cancer mortality among female radiologic technologists in the United States. J Natl Cancer Inst. 2002;94(12):943–8. [PubMed: 12072548] [CrossRef]
• Moinfar F, Man YG, Bratthauer GL, Ratschek M, Tavassoli FA. Genetic abnormalities in mammary ductal intraepithelial neoplasia-flat type (“clinging ductal carcinoma in situ”): a simulator of normal mammary epithelium. Cancer. 2000;88(9):2072–81. [PubMed: 10813719] [CrossRef]
• Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4:CD006243. [PMC free article: PMC6718210] [PubMed: 22513938] [CrossRef]
• Moolgavkar SH, Stevens RG, Lee JA. Effect of age on incidence of breast cancer in females. J Natl Cancer Inst. 1979;62(3):493–501. [PubMed: 283278]
• Moskowitz CS, Chou JF, Wolden SL, Bernstein JL, Malhotra J, Novetsky Friedman D, et al. Breast cancer after chest radiation therapy for childhood cancer. J Clin Oncol. 2014;32(21):2217–23. [PMC free article: PMC4100937] [PubMed: 24752044] [CrossRef]
• Muirhead CR, O’Hagan JA, Haylock RG, Phillipson MA, Willcock T, Berridge GL, et al. Mortality and cancer incidence following occupational radiation exposure: third analysis of the National Registry for Radiation Workers. Br J Cancer. 2009;100(1):206–12. [PMC free article: PMC2634664] [PubMed: 19127272] [CrossRef]
• Munzone E, Curigliano G, Burstein HJ, Winer EP, Goldhirsch A. CMF revisited in the 21st century. Ann Oncol. 2012;23(2):305–11. [PubMed: 21715566] [CrossRef]
• Murthy V, Chamberlain RS. Recommendation to revise the AJCC/UICC breast cancer staging system for inclusion of proven prognostic factors: ER/PR receptor status and HER2 neu. Clin Breast Cancer. 2011;11(5):346–7. [PubMed: 21820971] [CrossRef]
• Nagata C, Hu YH, Shimizu H. Effects of menstrual and reproductive factors on the risk of breast cancer: meta-analysis of the case-control studies in Japan. Jpn J Cancer Res. 1995;86(10):910–5. [PMC free article: PMC5920604] [PubMed: 7493908] [CrossRef]
• Nagel JH, Peeters JK, Smid M, Sieuwerts AM, Wasielewski M, de Weerd V, et al. Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes. Breast Cancer Res Treat. 2012;132(2):439–48. [PubMed: 21614566] [CrossRef]
• Narod SA. Testing for CHEK2 in the cancer genetics clinic: ready for prime time? Clin Genet. 2010;78(1):1–7. [PubMed: 20597917] [CrossRef]
• National Research Council. (2006). Health risks from exposure to low levels of ionizing radiation: BEIR VII Phase 2. Washington (DC), USA: National Academies Press.
• Navarrete Montalvo D, González M N, Montalvo V MT, Jiménez A A, Echiburú-Chau C, Calaf GM. Patterns of recurrence and survival in breast cancer. Oncol Rep. 2008;20(3):531–5. [PubMed: 18695902]
• Newman LA, Griffith KA, Jatoi I, Simon MS, Crowe JP, Colditz GA. Meta-analysis of survival in African American and white American patients with breast cancer: ethnicity compared with socioeconomic status. J Clin Oncol. 2006;24(9):1342–9. [PubMed: 16549828] [CrossRef]
• NHSBSP (2005). Pathology reporting of breast disease: a joint document incorporating the third edition of the NHS Breast Screening Programme’s Guidelines for Pathology Reporting in Breast Cancer Screening and the second edition of The Royal College of Pathologists’ Minimum Dataset for Breast Cancer Histopathology. NHSBSP Publication No. 58. Sheffield, UK: NHS Cancer Screening Programmes and The Royal College of Pathologists.
• NHSBSP (2006). Be breast aware. NHS Cancer Screening Programmes information leaflet. London, UK: Department of Health. Available from: https://www​.gov.uk/government​/publications​/nhs-breast-screening-awareness-leaflet.
• NICE (2013). Gene expression profiling and expanded immunohistochemistry tests for guiding adjuvant chemotherapy decisions in early breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat. NICE diagnostics guidance [DG10]. London, UK: National Institute for Health and Care Excellence. Available from: http://www​.nice.org.uk/guidance/dg10/.
• Nieuwenhuis B, Van Assen-Bolt AJ, Van Waarde-Verhagen MA, Sijmons RH, Van der Hout AH, Bauch T, et al. BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage. Int J Radiat Biol. 2002;78(4):285–95. [PubMed: 12020440] [CrossRef]
• Nieuwenhuis MH, Kets CM, Murphy-Ryan M, Yntema HG, Evans DG, Colas C, et al. Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome. Fam Cancer. 2014;13(1):57–63. [PubMed: 23934601] [CrossRef]
• Norman SA, Localio AR, Zhou L, Weber AL, Coates RJ, Malone KE, et al. Benefit of screening mammography in reducing the rate of late-stage breast cancer diagnoses (United States). Cancer Causes Control. 2006;17(7):921–9. [PubMed: 16841259] [CrossRef]
• Norsa’adah B, Rampal KG, Rahmah MA, Naing NN, Biswal BM. Diagnosis delay of breast cancer and its associated factors in Malaysian women. BMC Cancer. 2011;11(1):141. [PMC free article: PMC3101177] [PubMed: 21496310] [CrossRef]
• Norum JH, Andersen K, Sørlie T. Lessons learned from the intrinsic subtypes of breast cancer in the quest for precision therapy. Br J Surg. 2014;101(8):925–38. [PubMed: 24849143] [CrossRef]
• Offit K. BRCA mutation frequency and penetrance: new data, old debate. J Natl Cancer Inst. 2006;98(23):1675–7. [PubMed: 17148764] [CrossRef]
• Ohene-Yeboah M, Amaning E. Spectrum of complaints presented at a specialist breast clinic in Kumasi, Ghana. Ghana Med J. 2008;42(3):110–3. [PMC free article: PMC2643436] [PubMed: 19274109]
• Okonkwo QL, Draisma G, der Kinderen A, Brown ML, de Koning HJ. Breast cancer screening policies in developing countries: a cost-effectiveness analysis for India. J Natl Cancer Inst. 2008;100(18):1290–300. [PubMed: 18780864] [CrossRef]
• OMIM (2015). Online Mendelian Inheritance in Man database. Baltimore (MD), USA: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. Available from: www​.omim.org.
• Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998;339(22):1609–18. [PubMed: 9828250] [CrossRef]
• Ozasa K, Shimizu Y, Suyama A, Kasagi F, Soda M, Grant EJ, et al. Studies of the mortality of atomic bomb survivors, Report 14, 1950–2003: an overview of cancer and noncancer diseases. Radiat Res. 2012;177(3):229–43. [PubMed: 22171960] [CrossRef]
• Paci E, Del Turco MR, Palli D, Buiatti E, Bruzzi P, Piffanelli A. Selection of high-risk groups for breast cancer screening. Evidence from an Italian multicentric case control study. Tumori. 1988;74(6):675–9. [PubMed: 3068864]
• Page DL, Dupont WD, Rogers LW, Jensen RA, Schuyler PA. Continued local recurrence of carcinoma 15–25 years after a diagnosis of low grade ductal carcinoma in situ of the breast treated only by biopsy. Cancer. 1995;76(7):1197–200. [PubMed: 8630897] [CrossRef]
• Palacios J, Robles-Frías MJ, Castilla MA, López-García MA, Benítez J. The molecular pathology of hereditary breast cancer. Pathobiology. 2008;75(2):85–94. [PubMed: 18544963] [CrossRef]
• Park S, Kim Y, Shin HR, Lee B, Shin A, Jung KW, et al. Population-attributable causes of cancer in Korea: obesity and physical inactivity. PLoS ONE. 2014;9(4):e90871. [PMC free article: PMC3982956] [PubMed: 24722008] [CrossRef]
• Patey DH, Scarff RW. The position of histology in the prognosis of carcinoma of the breast. Lancet. 1928;211(5460):801–4. [CrossRef]
• Peng S, Lü B, Ruan W, Zhu Y, Sheng H, Lai M. Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies. Breast Cancer Res Treat. 2011;127(2):309–24. [PubMed: 21445572] [CrossRef]
• Pereira H, Pinder SE, Sibbering DM, Galea MH, Elston CW, Blamey RW, et al. Pathological prognostic factors in breast cancer. IV: Should you be a typer or a grader? A comparative study of two histological prognostic features in operable breast carcinoma. Histopathology. 1995;27(3):219–26. [PubMed: 8522285] [CrossRef]
• Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011;29(25):3366–73. [PMC free article: PMC3164242] [PubMed: 21768458] [CrossRef]
• Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52. [PubMed: 10963602] [CrossRef]
• Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L, et al., editors (2006). European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition. Luxembourg: European Commission, Office for Official Publications of the European Communities; pp. 15–56. Available from: http://ec​.europa.eu/health​/ph_projects/2002​/cancer/cancer_2002_01_en.htm.
• Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L. European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition–summary document. Ann Oncol. 2008;19(4):614–22. [PubMed: 18024988] [CrossRef]
• Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L (2013a). European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition, Supplements. Luxembourg: European Commission, Office for Official Publications of the European Union.
• Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L (2013b). Executive summary. In: Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L, editors. European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition, Supplements. Luxembourg: European Commission, Office for Official Publications of the European Union; pp. XIV–XX.
• Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432–44. [PMC free article: PMC3273723] [PubMed: 22152853] [CrossRef]
• Pettersson A, Graff RE, Ursin G, Santos Silva ID, McCormack V, Baglietto L, et al. Mammographic density phenotypes and risk of breast cancer: a meta-analysis. J Natl Cancer Inst. 2014;106(5):dju078. [PMC free article: PMC4568991] [PubMed: 24816206] [CrossRef]
• Pieri A, Harvey J, Bundred N. Pleomorphic lobular carcinoma in situ of the breast: can the evidence guide practice? World J Clin Oncol. 2014;5(3):546–53. [PMC free article: PMC4127624] [PubMed: 25114868] [CrossRef]
• Pijpe A, Andrieu N, Easton DF, Kesminiene A, Cardis E, Noguès C, et al. GENEPSO. EMBRACE. HEBON. Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK). BMJ. 2012;345:e5660. [PMC free article: PMC3435441] [PubMed: 22956590] [CrossRef]
• Pike MC, Pearce CL. Mammographic density, MRI background parenchymal enhancement and breast cancer risk. Ann Oncol. 2013;24 (Suppl 8):viii37––41. [PMC free article: PMC3894109] [PubMed: 24131968] [CrossRef]
• Pike MC, Wu AH, Spicer DV, Lee S, Pearce CL. 2007). Estrogens, progestins, and risk of breast cancer. Ernst Schering Found Symp Proc. (1):127–50. [PubMed: 18540571]
• Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013;105(21):1607–16. [PubMed: 24136893] [CrossRef]
• Pinto AC, Ades F, de Azambuja E, Piccart-Gebhart M. Trastuzumab for patients with HER2 positive breast cancer: delivery, duration and combination therapies. Breast. 2013;22 (Suppl 2):S152–5. [PubMed: 24074778] [CrossRef]
• Polyak K. Breast cancer: origins and evolution. J Clin Invest. 2007;117(11):3155–63. [PMC free article: PMC2045618] [PubMed: 17975657] [CrossRef]
• Porta M.(2008). A dictionary of epidemiology, 5th edition. Oxford, UK: Oxford University Press.
• Porter PL, El-Bastawissi AY, Mandelson MT, Lin MG, Khalid N, Watney EA, et al. Breast tumor characteristics as predictors of mammographic detection: comparison of interval- and screen-detected cancers. J Natl Cancer Inst. 1999;91(23):2020–8. [PubMed: 10580027] [CrossRef]
• Poum A, Promthet S, Duffy SW, Parkin DM. Factors associated with delayed diagnosis of breast cancer in northeast Thailand. J Epidemiol. 2014;24(2):102–8. [PMC free article: PMC3983282] [PubMed: 24335087] [CrossRef]
• Powell SN, Kachnic LA. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. 2003;22(37):5784–91. [PubMed: 12947386] [CrossRef]
• Pradhan M, Dhakal HP. Study of breast lump of 2246 cases by fine needle aspiration. JNMA J Nepal Med Assoc. 2008;47(172):205–9. [PubMed: 19079396]
• Preston DL, Mattsson A, Holmberg E, Shore R, Hildreth NG, Boice JD Jr. Radiation effects on breast cancer risk: a pooled analysis of eight cohorts. Radiat Res. 2002;158(2):220–35. [PubMed: 12105993] [CrossRef]
• Preston DL, Ron E, Tokuoka S, Funamoto S, Nishi N, Soda M, et al. Solid cancer incidence in atomic bomb survivors: 1958–1998. Radiat Res. 2007;168(1):1–64. [PubMed: 17722996] [CrossRef]
• Prokopcova J, Kleibl Z, Banwell CM, Pohlreich P. The role of ATM in breast cancer development. Breast Cancer Res Treat. 2007;104(2):121–8. [PubMed: 17061036] [CrossRef]
• Puliti D, Duffy SW, Miccinesi G, de Koning H, Lynge E, Zappa M, et al. EUROSCREEN Working Group. Overdiagnosis in mammographic screening for breast cancer in Europe: a literature review. J Med Screen. 2012;19 (Suppl 1):42–56. [PubMed: 22972810] [CrossRef]
• Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014a;505(7483):302–8. [PMC free article: PMC4975511] [PubMed: 24429628] [CrossRef]
• Rahman N. Mainstreaming genetic testing of cancer predisposition genes. Clin Med. 2014b;14(4):436–9. [PMC free article: PMC4312836] [PubMed: 25099850] [CrossRef]
• Rakha EA, Lee AH, Evans AJ, Menon S, Assad NY, Hodi Z, et al. Tubular carcinoma of the breast: further evidence to support its excellent prognosis. J Clin Oncol. 2010b;28(1):99–104. [PubMed: 19917872] [CrossRef]
• Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, et al. Breast Cancer Susceptibility Collaboration (UK). ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38(8):873–5. [PubMed: 16832357] [CrossRef]
• Retsky MW, Demicheli R, Hrushesky WJ, Baum M, Gukas ID. Dormancy and surgery-driven escape from dormancy help explain some clinical features of breast cancer. APMIS. 2008;116(7–8):730–41. [PubMed: 18834415] [CrossRef]
• Reulen RC, Frobisher C, Winter DL, Kelly J, Lancashire ER, Stiller CA, et al. British Childhood Cancer Survivor Study Steering Group. Long-term risks of subsequent primary neoplasms among survivors of childhood cancer. JAMA. 2011;305(22):2311–9. [PubMed: 21642683] [CrossRef]
• Richards MA, Westcombe AM, Love SB, Littlejohns P, Ramirez AJ. Influence of delay on survival in patients with breast cancer: a systematic review. Lancet. 1999;353(9159):1119–26. [PubMed: 10209974] [CrossRef]
• Robb K, Wardle J, Stubbings S, Ramirez A, Austoker J, Macleod U, et al. Ethnic disparities in knowledge of cancer screening programmes in the UK. J Med Screen. 2010;17(3):125–31. [PMC free article: PMC4116226] [PubMed: 20956722] [CrossRef]
• Robbins P, Pinder S, de Klerk N, Dawkins H, Harvey J, Sterrett G, et al. Histological grading of breast carcinomas: a study of interobserver agreement. Hum Pathol. 1995;26(8):873–9. [PubMed: 7635449] [CrossRef]
• Ronckers CM, Doody MM, Lonstein JE, Stovall M, Land CE. Multiple diagnostic X-rays for spine deformities and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(3):605–13. [PubMed: 18349278] [CrossRef]
• Ronckers CM, Erdmann CA, Land CE. Radiation and breast cancer: a review of current evidence. Breast Cancer Res. 2005;7(1):21–32. [PMC free article: PMC1064116] [PubMed: 15642178] [CrossRef]
• Ronckers CM, Land CE, Miller JS, Stovall M, Lonstein JE, Doody MM. Cancer mortality among women frequently exposed to radiographic examinations for spinal disorders. Radiat Res. 2010;174(1):83–90. [PMC free article: PMC3982592] [PubMed: 20681802] [CrossRef]
• Sanders ME, Schuyler PA, Dupont WD, Page DL. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer. 2005;103(12):2481–4. [PubMed: 15884091] [CrossRef]
• Sankaranarayanan R. Integration of cost-effective early detection programs into the health services of developing countries. Cancer. 2000;89(3):475–81. [PubMed: 10931445] [CrossRef]
• Sankaranarayanan R, Ramadas K, Thara S, Muwonge R, Prabhakar J, Augustine P, et al. Clinical breast examination: preliminary results from a cluster randomized controlled trial in India. J Natl Cancer Inst. 2011;103(19):1476–80. [PubMed: 21862730] [CrossRef]
• Sankaranarayanan R, Swaminathan R. Cancer survival in Africa, Asia, the Caribbean and Central America. Introduction. IARC Sci Publ. 2011;162(162):1–5. [PubMed: 21675400]
• Sankaranarayanan R, Swaminathan R, Brenner H, Chen K, Chia KS, Chen JG, et al. Cancer survival in Africa, Asia, and Central America: a population-based study. Lancet Oncol. 2010;11(2):165–73. [PubMed: 20005175] [CrossRef]
• Sant M, Allemani C, Capocaccia R, Hakulinen T, Aareleid T, Coebergh JW, et al. EUROCARE Working Group. Stage at diagnosis is a key explanation of differences in breast cancer survival across Europe. Int J Cancer. 2003;106(3):416–22. [PubMed: 12845683] [CrossRef]
• Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol. 1996;14(10):2738–46. [PubMed: 8874335]
• Savage KI, Gorski JJ, Barros EM, Irwin GW, Manti L, Powell AJ, et al. Identification of a BRCA1-mRNA splicing complex required for efficient DNA repair and maintenance of genomic stability. Mol Cell. 2014;54(3):445–59. [PMC free article: PMC4017265] [PubMed: 24746700] [CrossRef]
• Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci USA. 2003;100(13):7737–42. [PMC free article: PMC164657] [PubMed: 12808139] [CrossRef]
• Schrader KA, Masciari S, Boyd N, Salamanca C, Senz J, Saunders DN, et al. kConFab. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011;48(1):64–8. [PMC free article: PMC3003879] [PubMed: 20921021] [CrossRef]
• Scoccianti C, Lauby-Secretan B, Bello PY, Chajes V, Romieu I. Female breast cancer and alcohol consumption: a review of the literature. Am J Prev Med. 2014;46(3) Suppl 1:S16–25. [PubMed: 24512927] [CrossRef]
• Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi F, Bouvard V, et al. WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens – Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 2009;10(11):1033–4. [PubMed: 19891056] [CrossRef]
• SEER (2014a). Cancer statistics fact sheets: female breast cancer. Bethesda (MD), USA: Surveillance, Epidemiology, and End Results Program, US National Cancer Institute. Available from: http://seer​.cancer.gov​/statfacts/html/breast.html.
• SEER (2014b). Staging a cancer case. Bethesda (MD), USA: Surveillance, Epidemiology, and End Results Program, US National Cancer Institute. Available from: http://training​.seer.cancer.gov/staging/, accessed 24 September 2014.
• Seitz HK, Pelucchi C, Bagnardi V, La Vecchia C. Epidemiology and pathophysiology of alcohol and breast cancer: update 2012. Alcohol Alcohol. 2012;47(3):204–12. [PubMed: 22459019] [CrossRef]
• Shah NR, Borenstein J, Dubois RW. Postmenopausal hormone therapy and breast cancer: a systematic review and meta-analysis. Menopause. 2005;12(6):668–78. [PMC free article: PMC1781058] [PubMed: 16278609] [CrossRef]
• Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395–9. [PMC free article: PMC3863681] [PubMed: 22495314]
• Shore RE, Hildreth N, Woodard E, Dvoretsky P, Hempelmann L, Pasternack B. Breast cancer among women given X-ray therapy for acute postpartum mastitis. J Natl Cancer Inst. 1986;77(3):689–96. [PubMed: 3462410]
• Shulman LN, Willett W, Sievers A, Knaul FM. Breast cancer in developing countries: opportunities for improved survival. J Oncol. 2010;2010:1. [PMC free article: PMC3021855] [PubMed: 21253541] [CrossRef]
• Sibbering M, Watkins R, Winstanley J, Patnick J, editors (2009). Quality assurance guidelines for surgeons in breast cancer screening, 4th edition. NHSBSP Publication No. 20. Sheffield, UK: NHS Cancer Screening Programmes.
• Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. [PubMed: 24399786] [CrossRef]
• Sigurdson AJ, Doody MM, Rao RS, Freedman DM, Alexander BH, Hauptmann M, et al. Cancer incidence in the US radiologic technologists health study, 1983–1998. Cancer. 2003;97(12):3080–9. [PubMed: 12784345] [CrossRef]
• Silverstein MJ, Lagios MD, Craig PH, Waisman JR, Lewinsky BS, Colburn WJ, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer. 1996;77(11):2267–74. [PubMed: 8635094] [CrossRef]
• Silverstein MJ, Poller DN, Waisman JR, Colburn WJ, Barth A, Gierson ED, et al. Prognostic classification of breast ductal carcinoma-in-situ. Lancet. 1995;345(8958):1154–7. [PubMed: 7723550] [CrossRef]
• Simpson PT, Gale T, Fulford LG, Reis-Filho JS, Lakhani SR. The diagnosis and management of pre-invasive breast disease: pathology of atypical lobular hyperplasia and lobular carcinoma in situ. Breast Cancer Res. 2003;5(5):258–62. [PMC free article: PMC314428] [PubMed: 12927036] [CrossRef]
• Simpson PT, Gale T, Reis-Filho JS, Jones C, Parry S, Sloane JP, et al. Columnar cell lesions of the breast: the missing link in breast cancer progression? A morphological and molecular analysis. Am J Surg Pathol. 2005;29(6):734–46. [PubMed: 15897740] [CrossRef]
• Singh D, Malila N, Pokhrel A, Anttila A. Association of symptoms and breast cancer in population-based mammography screening in Finland. Int J Cancer. 2015;136(6):E630–7. [PMC free article: PMC4312922] [PubMed: 25160029] [CrossRef]
• Singletary SE, Greene FL., Breast Task Force. Revision of breast cancer staging: the 6th edition of the TNM classification. Semin Surg Oncol. 2003;21(1):53–9. [PubMed: 12923916] [CrossRef]
• Sinn P, Aulmann S, Wirtz R, Schott S, Marmé F, Varga Z, et al. Multigene assays for classification, prognosis, and prediction in breast cancer: a critical review on the background and clinical utility. Geburtshilfe Frauenheilkd. 2013;73(9):932–40. [PMC free article: PMC3859151] [PubMed: 24771945] [CrossRef]
• Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–82. [PubMed: 3798106] [CrossRef]
• Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92. [PubMed: 11248153] [CrossRef]
• Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, Goodwin PJ, Wolff AC. Past, present, and future challenges in breast cancer treatment. J Clin Oncol. 2014;32(19):1979–86. [PMC free article: PMC4879690] [PubMed: 24888802] [CrossRef]
• Sloan FA, Gelband H, editors. (2007). Cancer control opportunities in low- and middle-income countries. Washington (DC), USA: Institute of Medicine of the National Academies. [PubMed: 21595106]
• Smith E, Heaney E, Dooher P (2012). Interim quality assurance guidelines for clinical nurse specialists in breast cancer screening, 5th edition. NHSBSP Publication No. 29. Sheffield, UK: NHS Cancer Screening Programmes.
• Solin L, Schwartz G, Feig S, Shaber G, Patchefsky A.(1984). Risk factors as criteria for inclusion in breast cancer screening programs. In: Ames F, Blumenschein G, Montague E, editors. Current controversies in breast cancer. Austin (TX), USA: University of Texas Press; pp. 565–73.
• Solin LJ, Yeh IT, Kurtz J, Fourquet A, Recht A, Kuske R, et al. Ductal carcinoma in situ (intraductal carcinoma) of the breast treated with breast-conserving surgery and definitive irradiation. Correlation of pathologic parameters with outcome of treatment. Cancer. 1993;71(8):2532–42. [PubMed: 8384070] [CrossRef]
• Sopik V, Phelan C, Cybulski C, Narod S. BRCA1 and BRCA2 mutations and the risk for colorectal cancer. Clin Genet. 2014;87(5):411–8. [PubMed: 25195694] [CrossRef]
• Sørlie T. Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer. 2004;40(18):2667–75. [PubMed: 15571950] [CrossRef]
• Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98(19):10869–74. [PMC free article: PMC58566] [PubMed: 11553815] [CrossRef]
• Sotiriou C, Pusztai L. Gene-expression signatures in breast cancer. N Engl J Med. 2009;360(8):790–800. [PubMed: 19228622] [CrossRef]
• Soumian S, Verghese ET, Booth M, Sharma N, Chaudhri S, Bradley S, et al. Concordance between vacuum assisted biopsy and postoperative histology: implications for the proposed Low Risk DCIS Trial (LORIS). Eur J Surg Oncol. 2013;39(12):1337–40. [PubMed: 24209431] [CrossRef]
• Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, et al. WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647–57. [PubMed: 16609086] [CrossRef]
• Stephens PJ, Tarpey PS, Davies H, Van Loo P, Greenman C, Wedge DC, et al. Oslo Breast Cancer Consortium (OSBREAC). The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486(7403):400–4. [PMC free article: PMC3428862] [PubMed: 22722201]
• Storm HH, Andersson M, Boice JD Jr, Blettner M, Stovall M, Mouridsen HT, et al. Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst. 1992;84(16):1245–50. [PubMed: 1640483] [CrossRef]
• Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458(7239):719–24. [PMC free article: PMC2821689] [PubMed: 19360079] [CrossRef]
• Stratton MR, Collins N, Lakhani SR, Sloane JP. Loss of heterozygosity in ductal carcinoma in situ of the breast. J Pathol. 1995;175(2):195–201. [PubMed: 7738715] [CrossRef]
• Stuart-Harris R, Caldas C, Pinder SE, Pharoah P. Proliferation markers and survival in early breast cancer: a systematic review and meta-analysis of 85 studies in 32,825 patients. Breast. 2008;17(4):323–34. [PubMed: 18455396] [CrossRef]
• Sullivan R, Peppercorn J, Sikora K, Zalcberg J, Meropol NJ, Amir E, et al. Delivering affordable cancer care in high-income countries. Lancet Oncol. 2011;12(10):933–80. [PubMed: 21958503] [CrossRef]
• Tabár L, Dean PB, Chen SL, Chen HH, Yen AM, Fann JC, et al. Invasive lobular carcinoma of the breast: the use of radiological appearance to classify tumor subtypes for better prediction of long-term outcome. J Clin Exp Pathol. 2014;4(4)
• Tabár L, Dean PB, Péntek Z. Galactography: the diagnostic procedure of choice for nipple discharge. Radiology. 1983;149(1):31–8. [PubMed: 6611939] [CrossRef]
• Tabár L, Fagerberg G, Day NE, Duffy SW, Kitchin RM. Breast cancer treatment and natural history: new insights from results of screening. Lancet. 1992;339(8790):412–4. [PubMed: 1346670] [CrossRef]
• Tamakoshi K, Yatsuya H, Wakai K, Suzuki S, Nishio K, Lin Y, et al. JACC Study Group. Impact of menstrual and reproductive factors on breast cancer risk in Japan: results of the JACC study. Cancer Sci. 2005;96(1):57–62. [PubMed: 15649257] [CrossRef]
• Taplin SH, Ichikawa L, Buist DS, Seger D, White E. Evaluating organized breast cancer screening implementation: the prevention of late-stage disease? Cancer Epidemiol Biomarkers Prev. 2004;13(2):225–34. [PubMed: 14973097] [CrossRef]
• Taylor R, Davis P, Boyages J. Long-term survival of women with breast cancer in New South Wales. Eur J Cancer. 2003;39(2):215–22. [PubMed: 12509954] [CrossRef]
• Telle-Lamberton M. Epidemiologic data on radiation-induced breast cancer [in French] Rev Epidemiol Sante Publique. 2008;56(4):235–43. [PubMed: 18672338] [CrossRef]
• Thierry-Chef I, Simon SL, Weinstock RM, Kwon D, Linet MS. Reconstruction of absorbed doses to fibroglandular tissue of the breast of women undergoing mammography (1960 to the present). Radiat Res. 2012;177(1):92–108. [PMC free article: PMC3876279] [PubMed: 21988547] [CrossRef]
• Thornton H, Pillarisetti RR. ‘Breast awareness’ and ‘breast self-examination’ are not the same. What do these terms mean? Why are they confused? What can we do? Eur J Cancer. 2008;44(15):2118–21. [PubMed: 18805689] [CrossRef]
• Tice JA, Cummings SR, Smith-Bindman R, Ichikawa L, Barlow WE, Kerlikowske K. Using clinical factors and mammographic breast density to estimate breast cancer risk: development and validation of a new predictive model. Ann Intern Med. 2008;148(5):337–47. [PMC free article: PMC2674327] [PubMed: 18316752] [CrossRef]
• Tikk K, Sookthai D, Johnson T, Rinaldi S, Romieu I, Tjønneland A, et al. Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the EPIC cohort. Ann Oncol. 2014;25(7):1422–8. [PubMed: 24718887] [CrossRef]
• Tonelli M, Connor Gorber S, Joffres M, Dickinson J, Singh H, Lewin G, et al. Canadian Task Force on Preventive Health Care. Recommendations on screening for breast cancer in average-risk women aged 40–74 years. CMAJ. 2011;183(17):1991–2001. [PMC free article: PMC3225421] [PubMed: 22106103] [CrossRef]
• Travis LB, Hill DA, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E, et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA. 2003;290(4):465–75. [PubMed: 12876089] [CrossRef]
• Trichopoulos D, Hsieh CC, MacMahon B, Lin TM, Lowe CR, Mirra AP, et al. Age at any birth and breast cancer risk. Int J Cancer. 1983;31(6):701–4. [PubMed: 6862681] [CrossRef]
• Tryggvadóttir L, Gislum M, Bray F, Klint A, Hakulinen T, Storm HH, et al. Trends in the survival of patients diagnosed with breast cancer in the Nordic countries 1964–2003 followed up to the end of 2006. Acta Oncol. 2010;49(5):624–31. [PubMed: 20429724] [CrossRef]
• Tubiana M, Koscielny S. Natural history of human breast cancer: recent data and clinical implications. Breast Cancer Res Treat. 1991;18(3):125–40. [PubMed: 1756255] [CrossRef]
• Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2014;121(1):25–33. [PubMed: 25186627] [CrossRef]
• Tworoger SS, Eliassen AH, Zhang X, Qian J, Sluss PM, Rosner BA, et al. A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Res. 2013;73(15):4810–9. [PMC free article: PMC3738582] [PubMed: 23783576] [CrossRef]
• UICC (2010). TNM classification of breast cancer [in French]. UICC stage, 7th edition. Geneva, Switzerland: Union for International Cancer Control. Available from: http://www​.canceraquitaine​.org/sites/default​/files/documents​/INFOS-PRO/surveillance-sein​/kit/base-documentaire/TNM.pdf.
• UNDP (2012). Human development reports. United Nations Development Programme. Available from: http://hdr​.undp.org/en​/content/table-1-human-development-index-and-its-components.
• Unger-Saldaña K. Challenges to the early diagnosis and treatment of breast cancer in developing countries. World J Clin Oncol. 2014;5(3):465–77. [PMC free article: PMC4127616] [PubMed: 25114860] [CrossRef]
• United Nations (2012). World population prospects (demographic data). Available from: http://www​.un.org/esa/population/unpop​.htm.
• UNSCEAR (2010). Sources and effects of ionizing radiation, UNSCEAR 2008 Report, Volume I: Sources - Report to the General Assembly Scientific Annexes A and B. New York (NY), USA: United Nations Scientific Committee on the Effects of Atomic Radiation. Available from: http://www​.unscear.org​/unscear/en/publications/2008_1.html.
• UNSCEAR (2013). Sources, effects and risks of ionizing radiation, UNSCEAR 2013 Report, Volume II: Scientific Annex B: Effects of radiation exposure of children. New York (NY), USA: United Nations Scientific Committee on the Effects of Atomic Radiation. Available from: www​.unscear.org/docs​/reports/2013/UNSCEAR2013Report​_AnnexB_Children​_13-87320_Ebook_web.pdf.
• van der Groep P, van der Wall E, van Diest PJ. Pathology of hereditary breast cancer. Cell Oncol (Dordr). 2011;34(2):71–88. [PMC free article: PMC3063560] [PubMed: 21336636] [CrossRef]
• van Dongen JA, Fentiman IS, Harris JR, Holland R, Peterse JL, Salvadori B, et al. In-situ breast cancer: the EORTC consensus meeting. Lancet. 1989;2(8653):25–7. [PubMed: 2567800] [CrossRef]
• van Leeuwaarde RS, Vrede MA, Henar F, Does R, Issa P, Burke E, et al. A nationwide analysis of incidence and outcome of breast cancer in the country of Surinam, during 1994–2003. Breast Cancer Res Treat. 2011;128(3):873–81. [PubMed: 21340478] [CrossRef]
• van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, van’t Veer MB, Noordijk EM, et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin’s disease. J Natl Cancer Inst. 2003;95(13):971–80. [PubMed: 12837833] [CrossRef]
• van Leeuwen FE, Klokman WJ, Veer MB, Hagenbeek A, Krol AD, Vetter UA, et al. Long-term risk of second malignancy in survivors of Hodgkin’s disease treated during adolescence or young adulthood. J Clin Oncol. 2000;18(3):487–97. [PubMed: 10653864]
• Vargas AC, Reis-Filho JS, Lakhani SR. Phenotype-genotype correlation in familial breast cancer. J Mammary Gland Biol Neoplasia. 2011;16(1):27–40. [PubMed: 21400086] [CrossRef]
• Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108(2):171–82. [PubMed: 11832208] [CrossRef]
• Vincent-Salomon A, Lucchesi C, Gruel N, Raynal V, Pierron G, Goudefroye R, et al. Breast cancer study group of the Institut Curie. Integrated genomic and transcriptomic analysis of ductal carcinoma in situ of the breast. Clin Cancer Res. 2008;14(7):1956–65. [PubMed: 18381933] [CrossRef]
• von Karsa L. (1995). Mammography screening – comprehensive, population-based quality assurance is required! [in German]. Z Allgemeinmed. 71:1863–7.
• von Karsa L, Anttila A, Primic Žakelj M, de Wolf C, Bielska-Lasota M, Törnberg S, et al. (2013). Stockholm statement on successful implementation of population-based cancer screening programmes. Annex 1a. In: Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L, editors. European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition, Supplements. Luxembourg: European Commission, Office for Official Publications of the European Union; pp. 123–8.
• von Karsa L, Arrossi S. Development and implementation of guidelines for quality assurance in breast cancer screening: the European experience. Salud Publica Mex. 2013;55(3):318–28. [PubMed: 23912545]
• von Karsa L, Dean PB, Arrossi S, Sankaranarayanan R. (2014a). Screening – principles. In: Stewart BW, Wild CP, editors. World cancer report 2014. Lyon, France: International Agency for Research on Cancer; pp. 322–9.
• von Karsa L, Qiao Y-L, Ramadas K, Keita N, Arrossi S, Dean PB, et al. (2014b). Screening – implementation. In: Stewart BW, Wild CP, editors. World cancer report 2014. Lyon, France: International Agency for Research on Cancer; pp. 330–6.
• Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006;295(12):1379–88. [PubMed: 16551709] [CrossRef]
• Walters S, Maringe C, Butler J, Brierley JD, Rachet B, Coleman MP. Comparability of stage data in cancer registries in six countries: lessons from the International Cancer Benchmarking Partnership. Int J Cancer. 2013b;132(3):676–85. [PubMed: 22623157] [CrossRef]
• Walters S, Maringe C, Butler J, Rachet B, Barrett-Lee P, Bergh J, et al. ICBP Module 1 Working Group. Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000–2007: a population-based study. Br J Cancer. 2013a;108(5):1195–208. [PMC free article: PMC3619080] [PubMed: 23449362] [CrossRef]
• Warner E, Foulkes W, Goodwin P, Meschino W, Blondal J, Paterson C, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. J Natl Cancer Inst. 1999;91(14):1241–7. [PubMed: 10413426] [CrossRef]
• Warren GW, Alberg AJ, Kraft AS, Cummings KM. The 2014 Surgeon General’s report: “The health consequences of smoking – 50 years of progress”: a paradigm shift in cancer care. Cancer. 2014;120(13):1914–6. [PMC free article: PMC5928784] [PubMed: 24687615] [CrossRef]
• Washbrook E. Risk factors and epidemiology of breast cancer. Women’s Health Med. 2006;3(1):8–14. [CrossRef]
• WCRF/AICR. (2007). Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington (DC), USA: World Cancer Research Fund and American Institute for Cancer Research.
• WCRF/AICR. (2009). Ministério da Saúde, Instituto Nacional de Câncer, Políticas e ações para prevenção do câncer no Brasil: alimentação, nutrição e atividade física. Rio de Janeiro, Brazil: World Cancer Research Fund and American Institute for Cancer Research.
• WCRF/AICR. (2010). Continuous Update Project Report. Food, nutrition, physical activity, and the prevention of breast cancer World Cancer Research Fund and American Institute for Cancer Research. Available from: http://www​.dietandcancerreport​.org/cancer_resource_center​/downloads​/cu/Breast-Cancer-2010-Report.pdf.
• Webster P, Austoker J. Women’s knowledge about breast cancer risk and their views of the purpose and implications of breast screening–a questionnaire survey. J Public Health (Oxf). 2006;28(3):197–202. [PubMed: 16902075] [CrossRef]
• Weischer M, Bojesen SE, Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol. 2008;26(4):542–8. [PubMed: 18172190] [CrossRef]
• Weischer M, Nordestgaard BG, Pharoah P, Bolla MK, Nevanlinna H, Van’t Veer LJ, et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol. 2012;30(35):4308–16. [PMC free article: PMC3515767] [PubMed: 23109706] [CrossRef]
• Welch HG, Black WC. Using autopsy series to estimate the disease “reservoir” for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med. 1997;127(11):1023–8. [PubMed: 9412284] [CrossRef]
• WHO (2007). Cancer control: Knowledge into action. WHO guide for effective programmes. Module 3: Early detection. Geneva, Switzerland: World Health Organization. Available from: http://www​.who.int/cancer​/publications/cancer​_control_detection/en/index.html. [PubMed: 24716262]
• WHO (2013a). WHO guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. Geneva, Switzerland: World Health Organization. Available from: http://www​.who.int/reproductivehealth​/publications​/cancers/screening​_and_treatment​_of_precancerous_lesions/en/. [PubMed: 24716265]
• WHO (2013b). Implementation tools: Package of Essential Noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva, Switzerland: World Health Organization. Available from: http://apps​.who.int/iris​/bitstream/10665​/133525/1/9789241506557_eng​.pdf?ua=1&ua=1.
• WHO (2014). World Health Organization Cancer Mortality Database. Available from: http://www-dep​.iarc.fr/WHOdb/WHOdb.htm.
• Wilson JMG, Jungner G (1968). Principles and practice of screening for disease. Geneva, Switzerland: World Health Organization. Public Health Papers No. 34. Available from: http://whqlibdoc​.who​.int/php/WHO_PHP_34.pdf.
• Wohlfahrt J, Melbye M. Age at any birth is associated with breast cancer risk. Epidemiology. 2001;12(1):68–73. [PubMed: 11138822] [CrossRef]
• Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. American Society of Clinical Oncology. College of American Pathologists. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013. [PubMed: 24101045] [CrossRef]
• Wu Y, Zhang D, Kang S. Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Res Treat. 2013;137(3):869–82. [PubMed: 23274845] [CrossRef]
• Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11(2):174–83. [PubMed: 20152769] [CrossRef]
• Yip CH, Smith RA, Anderson BO, Miller AB, Thomas DB.Ang ES, et al. Breast Health Global Initiative Early Detection Panel (2008) Guideline implementation for breast healthcare in low- and middle-income countries: early detection resource allocation. Cancer. 113(8 Suppl)2244–56. 10.1002/cncr.23842. [PubMed: 18837017] [CrossRef]
• Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 2004;95(11):866–71. [PubMed: 15546503] [CrossRef]
• Zahl PH, Maehlen J, Welch HG. The natural history of invasive breast cancers detected by screening mammography. Arch Intern Med. 2008;168(21):2311–6. [PubMed: 19029493] [CrossRef]