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Originally published as JCO Early Release 10.1200/JCO.2009.24.4517 on September 8 2009 © 2009 American Society of Clinical Oncology.
Could Modification of Lifestyle Factors Prevent Second Primary Breast Cancers?Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA Modifiable factors have increasingly been associated with breast cancer. Studies have long suggested a link between modifiable factors, such as weight, physical activity, and alcohol use, and the risk of developing a primary breast cancer.1–4 Dozens of case-control and prospective cohort studies have demonstrated up to a two-fold increase in risk of breast cancer in overweight and obese postmenopausal women.3 Inactivity1 and regular consumption of alcohol4 have similarly been consistently shown to be associated with higher rates of primary breast cancer. Recent data also suggest that modifiable factors could impact breast cancer prognosis; observational data demonstrate that obesity5 and inactivity6,7 are associated with increased risk of cancer recurrence, while data from randomized trials suggest that dietary modification may decrease the risk of breast cancer recurrence, at least in some patient subsets.8–10 Much less is known regarding the relationship between modifiable factors and risk of a second primary breast cancer. A few recent reports have begun to evaluate the relationship between weight, alcohol intake, and smoking and the incidence of second primary breast cancers. In a prospective cohort of 10,953 women with newly diagnosed breast cancer, Trentham-Dietz et al11 found that women with a greater body mass index and those who had gained a significant amount of weight in adulthood were at increased risk of second primary breast cancer (P = .003 and P = .02, respectively), but did not find an increase risk of second breast cancer based on alcohol use or smoking history. Li et al reported an increased risk of second breast cancer in obese women diagnosed with breast cancer before age 45 (odds ratio [OR], 2.6; 95% CI, 1.1 to 5.9), but did not see any relationship between alcohol intake and risk of contralateral breast cancer in this group.12 Digham et al reported an increased risk of second breast cancers associated with obesity in both women with estrogen receptor (ER)–positive cancers assigned to tamoxifen or placebo in the National Surgical Adjuvant Breast and Bowel Program B-14 study,13 and in women with ER-negative tumors in a variety of National Surgical Adjuvant Breast and Bowel Program trials.14 Finally, Knight et al15 found a marginally significant relationship between ever drinking and risk of second primary breast cancer (risk ratio, 1.3; 95% CI, 1.0 to 1.6) in a case control study of 708 women with asynchronous contralateral breast cancers, as compared with 1,399 women with unilateral breast cancer. No relationship between smoking and risk of second breast cancer was seen.
In this issue, Li et al16 report an increased risk of second primary breast cancers associated with obesity, regular alcohol use and smoking. The authors compared weight and alcohol and smoking behaviors in 365 cases diagnosed with an ER-positive breast cancer and a subsequent contralateral breast cancer, and in 726 controls diagnosed only with a primary ER-positive breast cancer. Women who were overweight at the time of their first breast cancer diagnosis were 50% more likely to develop a second breast cancer as compared with women who had a body mass index lower than 25 kg/m2 (OR, 1.5; 95% CI, 1.0 to 2.1). Women who consumed more than seven drinks/week after their first breast cancer diagnosis had a 70% increase in the risk of a contralateral breast cancer as compared with nondrinkers (OR, 1.9; 95% CI, 1.1 to 3.2), and women who smoked after breast cancer diagnosis had more than a two-fold increase in their risk of second breast cancer as compared with nonsmokers (OR, 2.2; 95% CI, 1.2 to 4.0). Alcohol use and smoking appeared to be synergistically associated with an increased risk of second breast cancer, with individuals who both smoked and drank So does this mean that women should be advised to lose weight and avoid alcohol and smoking after breast cancer diagnosis in order to reduce the risk of a second primary breast cancer? Excess weight and smoking are certainly associated with other adverse health outcomes, and the finding that obesity is associated with increased risk of second breast cancer is consistent with most other reports on this topic.11,13,14 Conversely, although regular alcohol intake has been linked to risk of primary breast cancer, moderate alcohol intake may actually have beneficial health effects, such as lowering the risk of heart disease. Given the inconsistencies regarding the relationship between moderate alcohol use and adverse outcomes in patients with breast cancer, it would be premature to counsel survivors to avoid all alcohol, based on current evidence. In addition, it is important to recognize that identification of relationships between potentially modifiable risk factors such as weight and alcohol use and risk of second primary breast cancers does not mean that modification of these factors after primary breast cancer diagnosis will reduce rates of second cancers. Although an exploratory analysis by Li et al showed that current smoking appeared to confer a greater risk of second breast cancer than past smoking, many studies suggest that risk of breast cancer may be more strongly affected by exposures earlier in life. There is almost no data demonstrating that behavioral change for a few years later in life will impact breast cancer risk. Given that Li et al surmise in their report that the mechanisms through which weight and alcohol likely increase the risk of contralateral cancer involve modification of estrogen levels, it is striking that in this study, 39% of cases and 30% of controls, never received any hormonal therapy after their initial cancer diagnosis, and only 14.5% of cases and 18.5% of controls completed the recommended 5-year course of adjuvant hormonal therapy treatment. Studies have demonstrated an approximately 50% decrease in the risk of subsequent breast cancers in women treated with tamoxifen,17 and recent work suggests that the aromatase inhibitors may be even more efficacious in preventing second primary breast cancers.18 Digham et al13 reported that the efficacy of tamoxifen in improving disease-free survival, a composite end point encompassing both recurrence events and second primary breast cancers, was similar in obese and nonobese women. Due to a small number of events, they were not able to ascertain whether tamoxifen specifically lowered rates of contralateral breast cancers in obese women. In the report by Li et al in this issue, as well as in the study by Knight et al,15 hormonal therapy use was significantly lower in cases with a second primary breast cancer than in controls with unilateral cancers. In fact, in the three published reports looking at risk factors for second primary breast cancers that reported on rates of hormonal therapy use, use of these drugs was uniformly low among individuals with contralateral primary breast cancers.12,15 There are several potential explanations for the low rates of hormonal therapy use in this study: many of the cases were enrolled in the early and mid-1990s, when the value of tamoxifen was not well established for premenopausal women, and a significant proportion of patients had tumors smaller than 1 cm. The authors acknowledge the low levels of hormonal therapy use in the manuscript, and they performed multivariate analysis in an attempt to adjust for any bias this might have introduced. However, given the relatively limited sample size, they were not able to test for interactions between study variables and hormonal therapy use due to power limitations. Given this, it seems likely that the most efficient way that oncologists could intervene to reduce rates of second primary breast cancers would be to encourage adherence to hormonal therapy in patients with hormone receptor–positive breast cancers. Where does this leave us? The report by Li et al in this issue adds to the growing body of data suggesting that modifiable factors may influence the risk of breast cancer risk and prognosis. However, given low rates of hormonal therapy use in this population of patients with ER-positive breast cancers, it is reasonable to ask whether the relationship between weight and alcohol use seen in this study would be maintained in women with ER-positive tumors treated according to current adjuvant therapy guidelines. Thus, further work is needed to define the impact of modifiable factors on the risk of second primary breast cancers from modern observational data sets including women treated with modern hormonal therapy regimens. Finally, although obesity and smoking may pose other health risks for breast cancer survivors, weight loss and smoking cessation are difficult for many patients to achieve. Data from randomized trials of weight loss and other behavioral interventions after breast cancer diagnosis is needed to determine whether changes in potentially modifiable risk factors in the years after breast cancer diagnosis could help lower risk of second primary breast cancer and other adverse events in breast cancer survivors. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES See accompanying article on page 5312 REFERENCES
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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7 alcohol beverages per week having a seven-fold increase in risk as compared to individuals who did neither. Of note, control patients were significantly more likely to have been treated with hormonal therapy after their primary breast cancer (P < .0001), and cases were numerically, but not statistically, more likely to have had a first-degree relative with breast cancer (29.5% v 25.5%; P = .29). Other treatment and tumor characteristics were distributed similarly between cases and controls. 
