We did not observe strong associations between PAH-DNA adducts and all-cause or breast cancer mortality among the LIBCSP cases. There was little evidence for effect modification of these associations by age at diagnosis, hormone receptor status, menopausal status, BMI, cigarette smoke or alcohol consumption. Associations were modified by treatment, however, with more than a doubling in risk of mortality associated with detectable PAH-DNA adducts among the subgroup who received radiation therapy, but a lower mortality risk due to adducts among hormone therapy users.
Important predictors of breast cancer survival reported in the literature include stage at diagnosis and treatment (American Cancer Society, 2004
; Chu et al. 1996
), with consistent associations also found for BMI (Tretli et al., 1990
; Zhang et al., 1995
). To our knowledge, this is the first study to look at the association between PAH-DNA adducts and mortality among breast cancer cases. Studies of diet (Zhang et al., 1995
; Holmes et al., 1999
; Newman et al., 1986
), exogenous hormone use (Holmberg et al., 1994
; Reeves et al. 2000
), reproductive history (Daling et al., 2002
; Whiteman et al., 2004
), physical activity (Holmes et al., 2005
; Rohan et al., 1995
) and alcohol consumption (Ewertz et al., 1994; McDonald et al., 2002
) are less conclusive. Though there has been concern that cigarette smoking among women with breast cancer is associated with survival (Ewertz et al., 1994; Manjer et al., 2000
; Vatten et al., 1991
; Yu et al., 1997
), we did not find this to be the case in our study (Sagiv et al., 2007
). A significant strength of the current study is that exposure was based on PAH-DNA adducts, a biomarker of exposure, rather exposure based on self-report, as is the case with cigarette smoking. Adduct levels reflect not only exposure dose but the body’s response to the exposure and is therefore a better measure of body burden (Santella et al. 1999
). Further, in a previous report of the Long Island Breast Cancer Study (Shantakumar et al. 2005
), we found that women with higher adduct levels were more likely to be current or past smokers (OR=1.50, 95% CI=1.00, 2.24; OR=1.46, 95% CI=1.05, 2.02, respectively) and to have donated blood in summer and fall (OR=2.65, 95% C =1.69, 4.17; OR=1.59, 95% CI=1.08, 2.32, respectively). However, PAH from other sources, including food (estimated using a food frequency questionnaire and self-reports about intake of grilled and smoked foods) and vehicular traffic (estimated using geographic modeling techniques) were not associated with PAH-DNA adducts in these data.
The biologic mechanism for the association between PAH-DNA adducts and breast cancer mortality and the critical window for exposure to factors that lead to PAH-DNA adduct formation is unclear. PAHs, such as benzo(a)pyrene (BaP) and 7,12-dimethylbenz(a)anthracene (DMBA), are well known complete carcinogens, capable of both tumor initiation via genotoxic actions on DNA as well as tumor promotion through non-genotoxic signaling pathways (Luch, 2005
). Thus, it is plausible that PAH exposure could act as a tumor promoter of cancer cells that eluded eradication during treatment, to increase the risk of tumor progression and hence mortality among breast cancer survivors.
Care was also taken to draw blood prior to treatment. The LIBCSP is the largest, most comprehensive study to date to investigate PAH-DNA adducts and breast cancer. Despite the large sample size, however, this study still had limited power to study mortality, most likely due to the small number of deaths that occurred over the study period. This was a particular problem when investigating effect modification as cell sizes were quite small. Treatment data were available for only a subset of breast cancer cases. This limited study power but probably did not result in a selection bias since the DNA-PAH adduct-mortality associations remained the same for the subgroup. Despite power limitations, if a true association between PAH-DNA adducts and mortality does exist, it is unlikely that this association is strong. Further investigation is warranted among a larger population with more outcomes, however, particularly among premenopausal women where PAH-related mortality may be higher.
In contrast to several other investigations (Ford et al., 2003
; Neugut et al., 1994
), we previously reported little evidence for an interaction between radiation treatment and smoking on mortality among women with breast cancer (Sagiv et al., 2007
). The current analysis detected a two- to six-fold increase in mortality for the interaction between radiation therapy and detectable PAH-DNA adducts. Because the PAH biomarker is a measure of exposure as well as the inherent individual variability in response to the exposure (Santella et al., 1999
), our biomarker results may identify those who are particularly susceptible to the dual effects of both PAH and radiation. Another explanation for this finding is that treatment is a reflection of disease stage, which in turn is a major predictor of survival. Thus, this potential interaction requires further evaluation in biomarker studies that include larger numbers of breast cancer survivors with information of stage over a longer period of follow-up.
In summary, these data do not support a strong association between PAH-DNA adducts and all cause or breast cancer mortality, though effect modification by treatment was observed. Investigation of modifiable environmental risk factors for breast cancer incidence and mortality remains a public health priority.