P-1 Study Design, Participant Eligibility, Risk Assessment, and Analysis

Women at increased risk for breast cancer were randomly assigned to receive either placebo or tamoxifen (20 mg/day) for 5 years. Women were considered to be at increased risk if they were 60 years of age or older, were between 35 and 59 years of age with a 5-year predicted risk for breast cancer of at least 1.66%, or had a history of LCIS.

By September 30, 1997, after 13,388 women aged 35 years and older had been randomly assigned in the trial, participant entry was terminated. The first report of the P-1 findings was published on September 16, 1998 with a follow-up in 1999.^{302, 312}

The Gail model was used to estimate of the probability (risk) of breast cancer over time.This considered a woman's age, race, number of first-degree relatives with breast cancer, nulliparity or age at first live birth, number of breast biopsies, pathologic diagnosis of atypical hyperplasia, and age at menarche. The mean time on the study for the 13,175 participants who were included in the analysis was 47.7 months; 73.9% had a follow-up exceeding 36 months; 67.0% were followed for more than 48 months; and 36.8% had follow-up exceeding 60 months. The median follow-up time was 54.6 months.

Participant Characteristics

Of the 13,175 participants included in the analysis, 39% were 35 to 49 years old at randomization, 31% were aged 50 to 59 years, and 30% were 60 years of age or older (Table 121-28) The distribution of participants among the placebo and tamoxifen groups relative to these and other characteristics was similar.

Table 121-28

Characteristics at Time of Randomization for P-1 Participants Included in the Analyses.

Almost one-quarter (24%) of the participants had no first-degree relatives with breast cancer, more than one-half (57%) had one first-degree relative with the disease, 16% had two, and 3% had three or more. About one-quarter of the women had a 5-year predicted breast cancer risk of 2.00% or less. Almost three-fifths (58%) had a 5-year risk of between 2.01% and 5.00%, and 17% had a risk of more than 5.00%.

The Benefit from Tamoxifen

Reduction in Breast Cancer Risk

There was a highly significant reduction in the incidence of invasive and noninvasive breast cancer as a result of tamoxifen administration. There was a 49% reduction in the cumulative incidence of invasive breast cancer through 69 months of follow-up—43 versus 22 per 1,000 women in the placebo and tamoxifen groups, respectively (p < .00001). The reduction in risk was 50% (p < .002) for noninvasive breast cancer related to a decrease in the incidence of both DCIS and LCIS. No survival differences were observed. Nine deaths were attributed to breast cancer (ie, six in the group that received placebo and three in the tamoxifen group).

To assess the consistency of tamoxifen across the population, rates of invasive cancer were calculated for various subgroups of women (Table 121-29). When the rate of invasive breast cancer was examined according to age, a decrease was observed in all age groups after tamoxifen administration. Of particular interest was the observation of a similar reduction in the rate of breast cancer at all levels of family histories. Women with no first-degree relatives with the disease had a reduction of 54%; in women with three or more, the reduction was 49%. The same reduction in risk was observed in women with any category of predicted 5-year risk. There was a 63% reduction in women with a 5-year predicted risk ≤2.00% and a 66% reduction in those with a risk ≥ 5.01. In women with a history of either atypical hyperplasia or LCIS, the risk of invasive cancer was reduced by 86% and 56%, respectively.

Table 121-29

Rates for Invasive Breast Cancer by Age, 5-Year Predicted Breast Cancer Risk, Number of First-Degree Relatives with Breast Cancer, History of Lobular Carcinoma in Situ (LCIS), or History of Atypical Hyperplasia.

Additional evidence of the effectiveness of the drug was provided by the observation that during each of the first 6 years of follow-up, tamoxifen administration resulted in a significant reduction in the risk of invasive cancer. The rates of decrease in years 1 through 6 were 35%, 55%, 39%, 49%, 69%, and 55%, respectively.

When invasive breast cancers that occurred were examined relative to selected tumor characteristics, particularly important was the finding that a 69% reduction was noted in the rate of ER-positive tumors in the group that received tamoxifen. No such reduction was observed, however, in the rate of breast cancers that were ER negative. Similarly, the rate of invasive breast cancer among women in the tamoxifen group was less than that among women in the placebo group in all categories independent of tumor size. The greatest difference was noted in the occurrence of tumors that were 2.0 cm or less in size at the time of diagnosis. The rate of occurrence of tumors 1.0 cm or smaller was reduced by 42% as a result of tamoxifen administration; the rate of tumors 1.1 to 2.0 cm was reduced by 62%. Similar reductions (ie, 50% and 57%, respectively) were observed in the rates of breast cancer in women who had either no nodal involvement or one to three nodes involved with tumor.

Adverse Effects from Tamoxifen

There was considerable concern, both before and during the conduct of the P-1 study, about the dangers of liver damage, hepatoma, colon cancer, and retinal toxicity that might be associated with tamoxifen. However, no liver cancers have been observed in either the placebo or tamoxifen groups of P-1, and although posterior subcapsular opacities were more frequently observed in the eyes of women who received tamoxifen, there has been no evidence of either macular degeneration or vision-threatening toxicity in that group.³¹³ There have been too few ophthalmic toxicities from tamoxifen administration in the P-1 trial to warrant making a recommendation that the drug be withheld from women such as those who participated in that study.

Even greater concern was expressed about the risks to postmenopausal women of endometrial cancer and vascular-related toxic events. The issue has been raised, primarily in the lay press, about whether the benefit that was achieved by a reduction in the incidence of breast cancer was sufficiently great to justify the use of tamoxifen as a chemopreventive agent in the face of the risk of those events. About 7 per 1,000 women, or less than 1 woman per 100 (0.7%), in the tamoxifen group developed endometrial cancer over a 5-year period. This is a 4-fold increase in risk for a 5-year duration of tamoxifen therapy. The findings that all invasive endometrial cancers were Stage 1 and that no deaths from endometrial cancer were reported were findings of major importance. In other studies, a small number of uterine sarcomas have been reported. Although no data are currently available to indicate that women who take tamoxifen should have regular endometrial biopsies or undergo vaginal ultrasound examination, all those who take the drug should be advised to undergo an annual gynecologic evaluation and to report any abnormalities that might be evident.

Over a 5-year period, 0.2 to 0.3% of women experienced a stroke, about 0.2% had a pulmonary embolism, and between 0.2 and 0.3% exhibited a deep-vein thrombosis. Those events occurred less frequently in women ≤49 years of age but were somewhat more frequent in women aged ≥50 years. In the latter group, the rate of endometrial cancer was about 1% over 5 years; for each of the vascular-related events, it was less than 1%.

When P-1 participants were evaluated with regard to undesirable events from tamoxifen that could have an effect on their quality of life (Table 121-30), 12% more women in the tamoxifen than in the placebo group experienced some degree of hot flashes, and 20% more reported vaginal discharge. Of those women who had hot flashes, only about 8% more women in the tamoxifen group than in the placebo group reported that their hot flashes were extremely bothersome; about 2% more described their vaginal discharge in the same manner.

Table 121-30

Distribution of P-1 Participants in the Placebo and Tamoxifen Groups by Highest Percentage of Hot Flashes, Vaginal Discharge, and Depression Reported.

A report on the health-related quality-of-life component of the P-1 trial provided information to indicate that weight gain and depression (see Table 121-30), two clinical problems anecdotally associated with tamoxifen treatment, were not significantly different from women who received placebo in the study.³¹⁴ Moreover, overall rates of sexual activity remained similar for women in both the placebo and tamoxifen groups.

Relationship Between the Beneficial and Harmful Effects of Tamoxifen

Although the benefits from tamoxifen are impressive and the toxicity risks are low, the issue arises as to how best to convey to a woman what her net benefit from taking tamoxifen is likely to be. The issue is a complex one. The higher a woman's risk for breast cancer, the more likely it is that tamoxifen will confer a substantial benefit. Assessing the extent of a benefit when nondrug primary or secondary prevention strategies are employed is relatively straightforward. In such a circumstance, the number of events expected minus the number of events prevented indicates the net benefit. In chemoprevention, the net benefit is confounded by the side effects that result from the agent employed, in this case, tamoxifen. However, to consider an endometrial cancer or a DVT as observed in the P-1 study, to be “equivalent” to a breast cancer and to conclude that the prevention study merely “exchanged one event for another” is not justifiable. To subtract an undesirable event from a beneficial one is inappropriate because the two are not of equal value. For example, endometrial cancer has a mortality rate that is far less than that from a breast cancer. Furthermore, the morbidity and mortality rates from a hysterectomy for a possible endometrial cancer are likely to be less than those resulting from surgery, radiation therapy, and chemotherapy for a breast cancer, which might have occurred in the absence of tamoxifen administration.

Candidates for Tamoxifen

Who should take tamoxifen to decrease the risk of developing breast cancer? Women younger than 50 years of age who meet the eligibility requirements of the P-1 trial are likely to be considered highly eligible for tamoxifen because their risk of a serious adverse event is practically nil and because the reduction in the incidence of breast cancer is still reduced by almost one half. Moreover, the greater the risk, the greater the benefit.

Postmenopausal women who have had a hysterectomy are also favorable candidates for tamoxifen because they cannot develop endometrial cancer. Women with a history of LCIS or atypical hyperplasia are at particularly high risk for breast cancer and because tamoxifen reduces that risk dramatically, the level of benefit achieved markedly outweighs the adverse effects that might result from tamoxifen administration. In addition, because the risk of future invasive breast cancer in women with localized DCIS is at least as high as that for women with a history of LCIS or atypical hyperplasia, they would also benefit from tamoxifen insofar as reducing their rate of invasive breast cancer is concerned. The benefit is likely to eclipse the consequences of any adverse effects from the drug.

The decision to prescribe tamoxifen for women 50 years of age or older who have stopped menstruating, have not had a hysterectomy, and have no history of LCIS, DCIS, or atypical hyperplasia is less clear. Because the incidence of adverse events remains constant regardless of the breast cancer risk in these women, it is evident that the greater the risk, the less controversial the issue. The greater the mortality and morbidity associated with the breast cancers that have been prevented by tamoxifen, the greater the benefit from the drug when the benefit is balanced against potential adverse events. A precise level of risk above and below which a woman should or should not be considered a candidate for tamoxifen has not yet been determined and is likely to be difficult to agree upon. The probability that an adverse event from tamoxifen will occur in women 50 years of age or older requires careful consideration of the risk-benefit equation but should not necessarily prevent the use of tamoxifen in this age group. It must be emphasized, however, that, before a woman is advised to begin taking tamoxifen, her overall clinical status must be evaluated. Her physical well-being must be assessed to ensure that she does not have comorbid conditions that make the administration of tamoxifen not only undesirable but also inappropriate. Moreover, the task of recommending tamoxifen for women at increased risk for breast cancer should be undertaken by only those individuals who possess complete and accurate information about breast disease, know how to determine a woman's risk for breast cancer, and are adept at counseling her about her individual course of action.

The Meaning of Prevention

The use of the term prevention to describe the P-1 findings has prompted a great deal of debate. When the study was designed, that term was used to indicate a reduction in the incidence (risk) of invasive breast cancer that occurred over the period of the trial. Whether the benefit achieved from tamoxifen in the P-1 study was due to the drug's interference with the initiation (genetic changes in normal cells resulting from carcinogenic agents), promotion (clonal expression and genetic changes resulting in the progression of preneoplastic lesions to noninvasive and malignant tumors), or to hindrance in the growth of (phenotypically expressed) occult tumors is unknown. Because it is likely that a broad spectrum of molecular-biologic and pathologic changes in breast tissue existed among participants at the time of their entry into the trial, it might be assumed that all of the mechanisms may have been involved.

Considered at face value, these changes constitute the first evidence that the administration of a systemic agent can change the natural history of seemingly healthy women who are at increased risk for developing invasive or noninvasive breast cancer.

Future Steps: The MORE Trial, Raloxifene, and the STAR Trial

Approximately half of the invasive and noninvasive breast cancers in the P-1 trial were prevented, in all age groups, by the administration of tamoxifen. Although more studies are needed to address the issues that have arisen as a result of the P-1 findings, on the basis of the data from that trial it seems highly appropriate to offer tamoxifen to women similar to those who participated in that study. It could be said that this would be best done in a research setting to further advance our knowledge. To that end, the new NSABP P-2 chemoprevention trial (STAR) evaluates postmenopausal women at increased risk for breast cancer who are similar to P-1 participants. In P-2, the toxicity, risks, and benefits of the SERM raloxifene are compared with those of tamoxifen.

Raloxifene is a SERM with many actions similar to Tamoxifen. In a large randomized study of raloxifene, with a primary aim of preventing or slowing osteoporosis in postmenopausal women, there was a significant reduction of breast cancer incidence. The overall reduction was 76%—seemingly better than the P-1 results, but the two populations differed significantly; breast cancer risk was not evaluated among the MORE participants. It is reasonable to assume that it was probably less than average, since participants were chosen for their increased risk of osteoporosis. Many of these women have less bone mineralization because of a lower serum estrogen level, and this could lower their risk of breast cancer. The rate of endometrial cancer was not different in the raloxifene group compared to the placebo group. Thus, a direct comparison between the two active SERMS that have been shown to decrease the incidence of breast cancer is necessary. The STAR (Study of Tamoxifen And Raloxifene) trial will compare breast cancer risk reduction and endometrial cancer risk amongst women selected because of a high breast cancer risk profile.

Although raloxifene has been shown to prevent osteoporosis, its value in reducing the rate of breast cancer without increasing the risk of endometrial cancer has yet to be established. The issues are too complex to permit predictions with regard to future directions for breast cancer research, but the findings from P-1 clearly indicate that much of such research must be related to prevention. Agents that have the ability to prevent the occurrence of ER-negative tumors must be discovered and evaluated, and new, more effective SERMs with different mechanisms of action must be developed. Despite the fact that scientists have failed to eradicate breast cancer, the twentieth century can be viewed, in retrospect, as a period during which progress was made in the understanding, treatment, and prevention of the disease.