How Smoking Causes Cancer

Cigarette smoke contains more than 7,000 compounds, at least 60 of which are known carcinogens, said Pechacek and Graham Warren, a clinical radiation oncologist who treats cancer patients and director of the Tobacco Assessment and Cessation Program at Roswell Park Cancer Institute (HHS, 2010b). Approximately 600 compounds are added to tobacco to enhance flavor or nicotine absorption. Inhaling this mix of chemicals through smoke induces tissue injury and changes in the cellular environment that foster proliferation and transformation into cancer cells (HHS, 2004, 2010b).

Fadlo Khuri, professor and chair of hematology and medical oncology at Emory University, deputy director for the Winship Cancer Institute, and Roberto C. Goizueta Distinguished Chair in Cancer Research, showed the major pathways by which cigarette smoke causes cancer, including the ability of carcinogens in tobacco smoke to latch onto DNA, leading to mutations in critical genes. This results in a loss of normal growth control mechanisms, precancerous tumor growth, and the accumulation of additional mutations that cause those cells to become malignant (see Figure 3). Khuri said several environmental factors, including tobacco smoke, and specific genetic mutations are linked to carcinogenesis, from precancerous abnormal growth of cells to metastatic lung cancer (HHS, 2010b). He pointed out that compounds in tobacco smoke can also silence tumor suppressor genes that normally prevent tumor growth. Khuri added that there is a strong correlation with lifetime cigarette consumption and the genetic changes that are a signature for the loss of this critical tumor suppressor mechanism (Takeshima et al., 1993). “We now have the imprint of tobacco on DNA showing carcinogenesis,” he said.

FIGURE 3

Link between cigarette smoking and cancer through carcinogens in tobacco smoke. SOURCES: Khuri presentation (June 12, 2012) and HHS (2010b).

Even after a cell becomes malignant, “tobacco is able to turn on a symphony of bad actors in a very organized manner,” Khuri said, including changes in the activity of many genes that are targeted by new cancer treatments. Mutations in these genes are known as driver mutations because tumor growth depends on them.

Nicotine and activation of systemic nicotinic acetylcholine receptors by various products in tobacco can trigger cell survival pathways that prevent the death of mutated cells. Warren noted several studies demonstrating that nicotine can increase cancer proliferation, angiogenesis, migration, and invasion, and decrease the effectiveness of conventional cancer treatments such as chemotherapy and/or radiotherapy (Warren et al., 2008, 2012c).

Khuri also stressed that “tobacco-related carcinogenesis is something of a race because you have multiple tumors emerging so even if you treat one, another will emerge to take its place. Continuation of smoking enhances the likelihood of second primary tumors.” Such tumors are likely to emerge in part because of the overexpression of some genes, such as cyclooxygenase-2, that don't directly cause tumors, but regulate other genes that do, Khuri added.

Khuri noted that the 2010 Surgeon General's report “put to bed any lingering doubt as to whether tobacco had left its fingerprints all over these diseases” (HHS, 2010b). This report also concluded that tobacco cessation is the only proven strategy for reducing the pathogenic processes leading to cancer. There is insufficient evidence that modifying tobacco products can reduce cancer risk, the report clearly stated.

Impact of Smoking on Cancer Incidence and Treatment Outcomes

The impact of smoking on cancer is substantial. Smoking accounts for at least 30 percent of all cancer deaths and 80 percent of lung cancer deaths (ACS, 2012). Lung cancer, for which smoking is the primary risk factor, is the leading cause of cancer death in both men and women (ACS, 2012). However, smoking heightens the risk of up to 18 types of cancers, including head and neck cancers, leukemia, and cancers of the esophagus, bladder, pancreas, kidney, liver, stomach, colorectum, cervix, uterus, and ovaries (ACS, 2012; HHS, 2004; Secretan et al., 2009).

Smoking not only raises the risk of developing various cancers, but it worsens cancer outcomes (NCI, 2012b). Worse survival among patients who smoked or continue to smoke is seen not only among patients with cancers strongly linked to smoking (lung, esophageal, or head and neck), but also in patients with breast, prostate, and other cancers (Warren et al., 2012a). Warren highlighted more than 100 studies demonstrating that cancer patients who are or were smokers were also more likely to have decreased therapeutic responses, increased cancer recurrences, and increased cancer treatment complications, including problems with wound healing, infections, cardiovascular complications, and the development of a secondary malignancy.

The risk of developing secondary malignancies in cancer patients who smoke is very high, Warren said. He noted studies demonstrating that smoking substantially increased the risk of developing lung cancer in patients with breast cancer or Hodgkin's disease treated with radiotherapy and/or chemotherapy (Kaufman et al., 2008; Lorigan et al., 2005; Travis et al., 2002). In addition, smoking substantially increased the risk of bladder cancer in patients treated with radiotherapy (Boorjian et al., 2007). The increased risk of developing a second malignancy provides strong support for the synergistic tumorigenic activities of tobacco with conventional cancer treatments.

Warren pointed out that the difference in survival outcomes between patients who do not smoke and those who do can be much greater than the difference in survival associated with various treatment regimens. For example, there is about a 15 percent improvement in survival in breast cancer patients who are nonsmokers as compared with those who smoke (Warren et al., 2012a), but there is a less than 4 percent difference in survival between breast cancer patients who are treated with cyclophosphamide and doxorubicin versus cyclophosphamide, methotrexate, and fluorouracil chemotherapies (Breast Cancer Trialists Group, 1998). This 4 percent improvement led to a change in treatment guidelines for breast cancer. Unfortunately, current nationally funded actively accruing cooperative group clinical trials do not capture information on tobacco use or cessation. A new study demonstrates that only 29.4 percent of cooperative group trials assess any form of tobacco use at study entry, only 4.5 percent assess tobacco at follow up, and no trials offer cessation support (Peters et al., 2012). “We are changing our standard [of care] recommendations for a treatment modality for breast cancer, yet we are ignoring tobacco,” Warren said.

Warren, Cummings, Toll, and others noted that one significant limitation to accurately understanding the effects of tobacco on cancer treatment is the lack of well-defined tobacco assessments in clinical practice. In order to fully understand the effects of tobacco on cancer treatment, we must ask about former and current tobacco use prior to diagnosis, during treatment, and during follow-up. In addition, mandatory cessation efforts should be implemented and tracked to understand the effects of cessation as well as to identify risks of continued tobacco use in cancer patients. Warren further discussed biologic models showing that exposure to tobacco products [nicotine] specifically during the time of cancer treatment is the primary determinant of changes in therapeutic response (Warren et al., 2012c). “This is the reason that it is critically important for cancer patients to stop using tobacco as soon as possible to get the most benefit from cancer treatment,” Warren said.

Warren stressed that encouraging cancer patients to quit smoking may have a marked effect on their survival, as some studies have indicated for head, neck, and lung cancers (Browman et al., 1993; Herbst et al., 2005; Thatcher et al., 2005). “If you have a current smoker, you might still be able to help them,” he said. Data demonstrate that having quit tobacco use within the past year results in a significant improvement in survival for head and neck as well as lung cancer, suggesting that some of the effects of tobacco on survival may be reversible (Warren et al., 2012a). Pechacek pointed out that inhaled smoke is particularly damaging to health and, as Warren noted, inhaling even secondhand smoke can increase the risk of lung cancer, as was seen in nearly 37 studies of spouses of people who smoke (Hackshaw et al., 1997). Pechacek stressed that the duration of smoking is more important for cancer risk than level of exposure (Flanders et al., 2003). He added that cancer risk increases much more for each additional year of smoking than it does for higher average number of cigarettes smoked.

Pechacek also pointed out that among people who currently smoke, about 70 percent smoke 10 to 30 cigarettes per day (CDC, 2011d), which makes them well within the intensity levels needed to boost their cancer risk. He added that “people are far from understanding that infrequent, but still regular, exposure, is very risky to health, particularly to cardiovascular health. Over half of tobacco-related health effects are likely to be maintained at low levels of cigarette use,” Pechacek said. In light of these risks, Abrams expressed concern that noncombustible tobacco products merely lower the number of cigarettes smoked and deter people from quitting smoking completely. “Substantial population risks may be associated with any product that delays complete cessation among people who smoke,” Pechacek added.