Cigarette Smoking, N-Acetyltransferase 2 Genotypes, and Breast Cancer Risk: Pooled Analysis and Meta-analysis

Abstract

Approximately 10 years ago, it was noted that smoking increased risk of breast cancer among women with Nacetyltransferase 2 (NAT2) slow acetylation genotypes. This report was followed by a number of studies to address this question. We pooled data from 10 existing studies and also conducted a meta-analysis of 13 studies published from 1996 to October 2006 that were conducted among women, were published in English, and had adequate information on smoking and NAT2 genotyping. Raw data were requested from authors. Unconditional logistic regression was done for pooled analysis, and random effect models was done for metaanalysis. Study heterogeneity was assessed, and sensitivity tests were done when subgroups were excluded from the analysis. In the pooled analysis, there was a significant interaction between smoking, NAT2 genotype, and risk of breast cancer [pack-years (continuous variable, P interaction = 0.03)], with higher pack-years significantly associated with an increased risk of breast cancer among women with NAT2 slow genotypes (pooled analysis relative risk, 1.49; 95% confidence interval, 1.08-2.04). These findings were supported by the meta-analysis including all studies; pack-years were significantly associated with risk among slow acetylators in a dose-dependent fashion (meta-analysis relative risk, 1.44; 95% confidence interval, 1.23-1.68 for z20 pack-years versus never smokers), but not among rapid acetylators. Similar relationships were noted for smoking status (ever, never) and duration of smoking. Our results show that cigarette smoking is associated with an increase in breast cancer risk among women with NAT2 slow acetylation genotypes. Because slow NAT2 genotypes are present in 50% to 60% of Caucasian populations, smoking is likely to play an important role in breast cancer etiology. (Cancer Epidemiol Biomarkers Prev 2008;17(1):15 -26)

A Multilevel Model of Postmenopausal Breast Cancer Incidence

“…However, the model suggests that the greatest impact in 2000 would be from reductions in HT use and an increase in the age at menarche followed by reductions in excess BMI. Reductions in alcohol or tobacco use have only small effects as would be expected from the levels of attributable risk estimated from prospective cohort studies (70,90). Interestingly, if the age at menarche, which has been dropping over the last century (144,145), were to be reversed (by a year or 18 months), breast cancer incidence would be reduced by 5.5% overall.…”

Active and passive cigarette smoking and breast cancer risk: Results from the EPIC cohort

“…42 For example, smokers with the NAT2 (N-acetyltransferase 2, an enzyme that detoxifies aromatic amines contained in tobacco smoke) slow acetylator genetically determined phenotype might be at a higher risk of breast cancer than those with intermediate or high acetylation phenotype. 45,46 Biological mechanisms that could explain the similarity of the risk among passive and active smokers still have to be identified. Differences in the composition of mainstream and sidestream smoke have been observed 25 and the faster absorption in blood of vapor-phase components (predominant in sidestream smoke) than particulate-phase components supports a role of passive smoking on breast cancer.…”

Smoking and Breast Cancer: Is There Really a Link?

“…If the population was unstratified, no effect was observed. Eleven years on, these researchers have conducted pooled and metaanalyses using the 13 studies that have addressed the same issue (12). Both analytic approaches lead to the same conclusion: NAT2 slow acetylators have increased risk of breast cancer from smoking.…”

“…A recent study suggests that BRCA1 and BRCA2 mutation carriers who smoke have 2.3-fold (95% confidence interval, 1.6-3.5) and 2.6-fold (95% confidence interval, 1.8-3.9), respectively, higher risk of breast cancers than carriers who do not (20). The Ambrosone paper on breast cancer, smoking, and NAT2 genotype is another important step (12).…”