Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years

Abstract

Background-Cigarette smoke contains compounds that may damage DNA, and the repair of damage may be impaired in women with germline mutations in BRCA1 or BRCA2. However, the effect of cigarette smoking on breast cancer risk in mutation carriers is the subject of conflicting reports. We have examined the relation between smoking and breast cancer risk in non-Hispanic white women under the age of 50 years who carry a deleterious mutation in BRCA1 or BRCA2.Methods-We conducted a case-control study using data from carriers of mutations in BRCA1 (195 cases and 302 controls) and BRCA2 (128 cases and 179 controls). Personal information, including smoking history, was collected using a common structured questionnaire by eight recruitment sites in four countries. Odds-ratios (OR) for breast cancer risk according to smoking were adjusted for age, family history, parity, alcohol use, and recruitment site. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptResults-Compared to non-smokers, the OR for risk of breast cancer for women with five or more pack-years of smoking was 2.3 (95% confidence interval 1.6-3.5) for BRCA1 carriers and 2.6 (1.8-3.9) for BRCA2 carriers. Risk increased 7% per pack-year (p < 0.001) in both groups. The epidemiological evidence on the association of smoking with risk of breast cancer is contradictory. Terry and Rohan in 2002 reviewed the published evidence and concluded that smoking probably did not decrease, and may increase, risk of breast cancer [6]. A combined re-analysis of 53 epidemiological studies, however, did not show smoking to be associated with an increased risk of breast cancer after alcohol use was taken into account [7]. In a meta-analysis in 2005, Johnson found that both active and passive smoking were associated with an increased risk of premenopausal breast cancer [8]. Conclusions-TheseThe biological effects of smoking suggest that genetic variations in acetylation, oxidative damage, and DNA repair, may influence risk of disease. For example, high levels of reactive oxygen species may cause single and double strand breaks. BRCA1 and BRCA2 genes are involved in the repair of such breaks [9], and mutations in these genes may impair the ability of carriers to repair any defects caused by smoking.Lifetime risks of breast cancer among carriers of deleterious mutations in BRCA1 and BRCA2 have been estimated at 40-80% [10][11][12]. Because 20-60% of carriers live to an advanced age, and do not develop breast cancer, there are likely to be other genetic or environmental factors that modify risk. The purpose of the present study was to examine the effects of cigarette smoking on breast cancer risk in a large number of affected (cases) and unaffected (controls) members of families segregating mutations in the BRCA1 or BRCA2 genes.et al.

Cigarette smoking and postmenopausal breast cancer risk in a prospective cohort

“…Two other studies did not find interaction between smoking and family history ( Cui et al , 2006 ; Gaudet et al , 2013 ), but stratified estimates were not shown; therefore, it is unknown whether the estimates were consistent with our findings. In women at high risk of a specific type of familial breast cancer, BRCA1/BRCA2 mutation carriers, current smoking was not associated with increased risk ( Ghadirian et al , 2004 ; Nkondjock et al , 2006 ; Ginsburg et al , 2009 ), which is consistent with our finding of no smoking-associated risk among women with a family history, although smoking was associated with increased risk among mutation carriers in one study ( Breast Cancer Family Registry et al , 2008 ). The potential mechanism that would result in smoking-associated risk only among those without a family history of breast cancer is unknown.…”

Smoking and risk of breast cancer in the Generations Study cohort

“…In three studies, researchers reported significant interactions, with one showing increased breast cancer risk with smoking only among those with a positive family history [ 39 ], whereas two demonstrated that breast cancer risk was raised only among those with no family history [ 15 , 18 ]. Increased risk of breast cancer with smoking has also been seen in some [ 40 , 41 ], but not all ( see review [ 1 ] and a large meta-analysis [ 41 ]), studies of BRCA1/2 carriers (or by proxy, women with three or more first-degree relatives with breast or ovarian cancer [ 42 ]). There are also reports of significant interactions with smoking and polymorphisms in carcinogen metabolism genes NAT2 [ 43 ] and CYP1A1 [ 44 , 45 ] as well as breast cancer susceptibility single-nucleotide polymorphisms [ 46 , 47 ].…”

BRCA Mutations and Breast Cancer Prevention

“…A recent meta-analysis of the prospective studies conducted in the general population suggested a 13% increased risk of breast cancer (95% CI 1.09–1.17) for current smokers, compared to never smokers [39]. Regarding whether cigarette smoking is a risk factor for cancer in BRCA mutation carriers within this high-risk population, a number of earlier reports, including two from our group, have yielded inconclusive results, and have been limited by small sample sizes and retrospective study designs, which are vulnerable to selection bias and information bias [40,41,42,43,44,45]. In a recent prospective analysis of BRCA mutation carriers that included 26,711 person-years of follow-up and 700 incident cancers (428 breast cancers, 109 ovarian cancers), tobacco smoking was a risk factor for BRCA -associated cancer in general, including cancers of the breast and ovary [46].…”