In the interpretation of the above findings, we should consider the limitations of our study. First, we were unable to interview 15% of the women eligible for the original case-control studies on which this population-based cohort study was based. At five years, 43.5% of the non-interviewed cases and 14.5% of the interviewed cases were deceased. To the extent that non-interviewed cases differ from interviewed cases on the basis of their alcohol consumption, our results may be biased. Because this differential was greatest for women in the earliest years of the cohort (due to a lag in interviewing), we assessed its potential impact through a subset analysis limited to women diagnosed after 1986. The absence of any change in results suggests that our results may be generalizable to the entire spectrum of breast cancer cases. A second potential limitation was the possibility of confounding. Despite the breadth of data available to us to assess potential confounding influences, including comprehensive treatment data and other lifestyle variables, we could not exclude the possibility of unmeasured or residual confounding that accounts for our findings. Additionally, this study did not collect information on dietary factors, and as a result, we were unable to examine whether dietary factors may modify the effect of alcohol consumption on risk of death. Also, since this study was performed in a sample of predominantly white women, reflecting to a great extent the underlying racial distribution of the Seattle-Puget Sound area, we cannot be sure these results are generalizable to non-white populations. Lastly, the ascertainment of alcohol exposure relied on self-reported drinking history. The interviewer-guided questionnaires were developed to chart the pattern of exposure beginning with the age at which alcohol consumption began and document the changes in this pattern over time. Overall, the quantity/frequency method for ascertaining alcohol exposure is a reliable approach to estimate alcohol use and the accompanying strategy of using a lifetime calendar with milestones noted further facilitated recall.7
In our analysis, we found an effect achieved by any intake of alcohol and the magnitude of this association did not vary further according to levels of alcohol consumption, and thus misclassification within different categories of use would have minimal impact on the interpretation of our results. Because any misclassification resulting from this is likely to be non-differential, misclassification in this case would lead to an attenuation of the real effect of alcohol in our results.
The strengths of this study are also worth noting, including the population-based design which heightens the generalizability of the results, the large sample size, particularly the large numbers of very young cases, and the centralized pathological review and lab analyses performed on tissue samples.
Our results indicate that young women who consumed alcohol prior to a diagnosis of breast carcinoma were at a decreased risk of mortality compared to women who consumed no alcohol. There was some suggestion that the decreased risk of death was limited to wine consumption. This reduction in risk of dying does not appear to be due to differences in mammography screening history, tumor characteristics, treatment, or other exposures.
Little research has been focused on the association between alcohol and risk of dying after a breast cancer diagnosis, particularly among young women. A number of studies have found results broadly similar to ours in terms of the direction and magnitude of effects although in general these studies represent an older demographic than ours. In Saxe, et al, while the risk of death among premenopausal breast cancer cases associated with alcohol consumption did not reach statistical significance (HR = 0.41 [0.01–16.35] per 2 drinks/day), the magnitude of the observed effect was consistent with our findings. Their sample of 149 breast cancer patients consisted of 51 (34.2%) premenopausal and 98 (65.8%) postmenopausal women with a median age of 57.8 (in our study, 92.5% were premenopausal). Similarly, Holmes, et al, observed a decreased risk of death among breast cancer cases in relation to prior alcohol consumption in the Nurses’ Health Study. However, these results also failed to reach statistical significance (HR=0.79 [0.61–1.02], 0.86 [0.63–1.16], and 0.92 [0.66–1.27] for the second, third, and fourth quartiles, respectively, compared to the first quartile of alcohol consumption).15
While this study had a generous sample size of 1,982 women with invasive breast cancer, it reflected a wider age spectrum and older age group than ours, with a mean age of 54 years (versus our study’s 37.7). Lastly, Zhang, et al, observed a non-statistically significant reduction in risk of death for women consuming 4 grams or more of alcohol per day (risk of death 0.7 [0.3–1.5]) in a dataset of 698 breast cancer patients aged 55–69 years at baseline.40
Some studies with results which conflict with ours include Hebert, et al, who observed in their hospital-based cohort of 546 early-stage breast cancer cases that beer (but not wine or liquor) consumption was related to an increased risk of breast cancer mortality among pre-menopausal women.14
McDonald, et al, in a hospital-based cohort of 125 post-menopausal African American breast cancer cases, found pre-diagnostic consumption of at least one drink per week was associated with a 2.7 times greater risk of all-cause mortality.25
The inconsistencies in these epidemiologic studies, as a whole, potentially reflect the heterogeneity of alcohol as an exposure and the relatively small samples of breast cancer patients that have been studied in many of these analyses. Additionally, there is reason to believe that pre-menopausal and post-menopausal breast cancer development differs,27
and thus potentially alcohol’s impact on tumorigenesis differs among pre- and post-menopausal women which would create inconsistencies across studies with different age ranges.
Previous studies have not investigated the role of pre-diagnostic alcohol use on tumor characteristics in young women. Our data indicate that alcohol’s role in decreasing the risk of death among breast cancer death may be through its effect on reducing the risk of p53 positive tumors and tumors with high necrosis levels, both of which are associated with decreased survival. However, adjusting for these factors did not fully explain the association of alcohol with improved mortality, particularly in moderate and heavy drinkers.
A potential mechanism involving alcohol consumption in breast cancer survival includes the role of genes involved in metabolism of drugs and other toxins, such as the cytochrome P450 and glutathione S-transferase enzymes. Some of the women who chose not to drink may have a deficiency in their metabolism of alcohol causing their bodies to react unfavorably to the ingestion of alcohol; this same subset of women could also experience poor metabolism of chemotherapeutic agents based on poor drug metabolism, resulting in higher toxicity to typical doses. This mechanism would require the genes involved in alcohol metabolism to be the same genes involved in chemotherapy metabolism. Some support for the hypothesis that chemotherapy and alcohol metabolism operate in a shared pathway is the observation that alcohol and certain chemotherapeutic agents, including methotrexate and 5-fluorouracil, are involved in the folate pathway.8;37;41
Interestingly, several studies have shown an interaction between folate and alcohol in breast cancer, indicating that the effect of alcohol on breast cancer incidence may be reduced by dietary folate.31;41
The role of folate in breast cancer development is complex with indications that folate has a dual nature in tumorigenesis involving mechanisms that are anti- and pro- carcinogenic depending on the timing and dose of folate.18–20
In breast cancer development, a hypothesis involving folate and alcohol could include folate’s anti-carcinogenic (e.g. DNA repair capabilities) properties being diminished by alcohol consumption which is compatible with the increased breast cancer risk associated with low folate levels occurring only among regular alcohol drinkers.31
However, with regard to survival from breast cancer, it is less clear how folate and alcohol would interact. Perhaps, alcohol diminishes the amount of folate available, and thus the pro-carcinogenic properties (e.g. increased proliferation) of folate that are proposed to occur later in tumor development are diminished, which is consistent with the timing of alcohol’s effects as suggested to occur later in tumorigenesis. This would be compatible with the finding in our data that alcohol consumption did not lead to tumors with high proliferation, as indicated by the Ki-67 index, however, we were unable to directly test a mechanism involving folate because our study did not collect information on dietary factors.
Current hypotheses regarding alcohol’s role in breast cancer etiology include the effect of alcohol on circulating hormone levels.33
Recent findings from the Epic Cohort showed that levels of dehydroepiandrosterone (DHEAS), free testosterone, and estrone increase as alcohol consumption increases in pre- and post-menopausal women. However no statistically significant increase was observed for estradiol, free estradiol, or sex hormone binding globulin (SHBG) in response to increasing alcohol consumption in premenopausal women.28
Additionally, alcohol has been shown to increase proliferation in ER+, but not ER−, breast cancer cell lines.32
Our data did not provide support for the role of alcohol in breast cancer survival to involve hormones in that there were no clear associations with hormone-related tumor markers. This would make sense if alcohol acts later in tumorigenesis when some of the tumor features, such as ER/PR status, have already been established.
Additionally, a hypothesis involving insulin-like growth factor (IGF) has been developed to explain the increased risk of breast cancer associated with alcohol consumption.9
In response to the observation that breast cancer risk did not increase further within the highest level of alcohol consumption,34;41
Hu hypothesized that IGF levels decrease as a result of impaired liver function due to high consumption of alcohol.39;41
With the observation that breast cancer risk was associated with high serum levels of IGF in pre-menopausal women,13
Jones and Clemmons put forth a mechanism for IGF’s role in carcinogenesis involving IGF’s mitogenic effects and suppression of apoptosis, which counteracts the role of wildtype p53 protein.16
It is possible that plasma IGF levels, as mediated by alcohol, are reduced and thus, the role of the wildtype p53 protein is more pronounced in tumorigenesis among women who consume alcohol; therefore, (and as our data suggests) variant p53 would play a greater role proportionately in the tumors of alcohol drinkers.
Also, with the suggestion in our results that wine, but not beer or liquor, may reduce the risk of death among breast cancer patients, we speculate that components of wine such as polyphenols, (e.g. reservatrol and cinnamic acid) could be contributory factors. Several long-term epidemiologic cohort studies have demonstrated that wine is associated with a decreased overall mortality, and that the effect is not as strong or not observed at all in drinkers of beer or liquor.26
Research investigating the protective effects of wine has mostly centered around mechanisms involved in cardiovascular disease, including the antioxidant effects of polyphenols.3;10
In cancer it is possible that the antioxidant properties of wine’s components have a role in decreasing the process of tumorigenesis, although their role in survival would be less clear. Perhaps in breast cancer, the pathway leading to p53-negative tumors and low necrosis levels in tumors are mediated by polyphenol’s antioxidant effects.
While alcohol may increase the risk of developing breast cancer in young women, 2;17;22;42
an age group where tumors tend to be aggressive and mortality is high, it does not appear to have an adverse effect on progression. The results from this study suggest that women who consume alcohol prior to a diagnosis of breast cancer have improved survival compared to non-drinkers which does not appear to be attributable to differences in stage, screening, treatment or other confounders. Our results do not exclude the possibility that abstainers are at an increased risk of death due to the potential clustering of confounders for which we were unable to adjust, and may be separate from the biologic pathways, such as inability to metabolize alcohol adequately, we discussed above. The findings presented here need to be replicated in similar study populations with an emphasis on elucidating mechanisms.