Results from this study provide evidence that higher serum estrogen concentrations contribute to risk for recurrence in women who have been diagnosed and treated for early-stage breast cancer. In a nested case-control cohort of women who were matched on key factors such as cancer stage and age at diagnosis, average concentrations of total, bioavailable, and free estradiol were more than double in the women who recurred compared with the nonrecurred women and were independently directly associated with likelihood of recurrence. Given the proliferative effect of estrogens on human mammary cells and the hypothesized DNA-damaging effects of estrogen and related metabolites on these cells (1
), this association between estrogen status and progression of breast cancer is consistent with expectations. Further, these results are consistent with a prior WHEL Study finding suggesting that the presence of hot flashes was associated with reduced risk for recurrence (25
). In this sample, women reporting hot flashes had significantly lower serum concentrations of total, bio-available, and free estradiol. Contrary to expectations, we did not observe a relationship between serum testosterone concentrations and risk for recurrence. Although SHBG concentrations defined the estrogen fractions that we examined, which allowed the demonstration that higher levels of fractions that can affect peripheral tissues were associated with recurrence, this hormonal factor was not independently associated with recurrence.
The relationship between estrogen and breast carcinogenesis is complex (1
). Reproductive steroid hormones are biochemically related, so teasing out independent associations from a group of compounds that are readily interconverted may not be an appropriate goal. More importantly, genetic polymorphisms in the synthesis and metabolic pathways for steroid hormones likely influence the relationship between circulating hormone concentrations and actual tissue exposure and responsiveness. Further, the interpretation of observational data (epidemiologic or clinical) is constrained by the inherent limitations in these investigations, such as timing of blood collections, laboratory measurement capabilities, and influencing factors such as lifestyle factors and various treatment modalities.
Studies of serum reproductive hormones and risk for primary breast cancer in postmenopausal women have linked higher levels of estrogens and androgens, and lower level of SHBG (which determines the pool of estrogens that can enter cells), with increased risk for primary breast cancer (6
). For example, in a pooled analysis of data from nine prospective studies involving 663 postmenopausal women who developed breast cancer and 1,765 women who did not, risk increased significantly with increasing concentrations of total, bioavailable, and free estradiol; estrone, estrone sulfate; and androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone (4
). In that pooled analysis, the relative risks were at least 2-fold greater in the highest versus the lowest quintile for estradiol and testosterone concentrations, and a 34% increased risk was observed in the lowest versus highest quintile for SHBG. In participants in the National Surgical Adjuvant Breast and Bowel Project Cancer Prevention Trial, who are at particularly high risk of breast cancer, circulating levels of estradiol, testosterone, and SHBG were not predictive of risk for primary breast cancer or responsiveness to tamoxifen (28
). That finding illustrates that other risk factors and physiologic, biochemical, and genetic factors that characterize the individual course of breast carcinogenesis and cellular activities can affect the effect of estrogen status on risk for breast cancer.
Data on the relationship between serum reproductive hormones and progression or survival following the diagnosis of breast cancer are limited. Serum concentrations of testosterone, estradiol, and SHBG and risk for recurrence were examined in 110 women who had been diagnosed and treated for breast cancer and had participated in the Diet and Androgens Trial-2 (13
), another diet intervention study. Over a follow-up period of 5.5 years, 31 participants in that study experienced a new breast cancer event (contralateral breast cancer, distant metastasis, or local relapse). The HRs (95% CIs) were 1.8 (0.5−6.3) for the middle tertile and 7.2 (2.4−21.4) for the upper tertile of baseline testosterone concentration. Although serum concentration of estradiol also was higher in recurred women compared with women who did not recur, an independent effect was not observed when adjusted for testosterone levels. In 107 of those participants, an analysis of hormone levels measured at 1 year post-enrollment suggested that women who exhibited a reduction in testosterone concentration from above to below the median had a reduced risk of recurrence (HR, 0.15; 95% CI, 0.03−0.71) compared with women whose testosterone levels remained high at follow-up. In another more recent investigation (29
), higher plasma testosterone concentration was observed to predict poorer prognosis in a cohort of 194 postmenopausal women diagnosed with early-stage breast cancer who participated in a randomized fenretinide trial as untreated controls. Notably, estrogen concentrations were not examined in that study. In contrast with these two small previous studies, testosterone concentrations were not significantly associated with recurrence-free survival in the present study, although the point estimates were lower in controls compared with cases. Differences in some characteristics of the study participants may explain the conflicting findings relating to testosterone and prognosis; for example, the women in the other more recent investigation never received chemotherapy or hormonal therapy (28
Genetic polymorphisms that affect synthesis and metabolism of reproductive steroid hormones would be expected to influence circulating levels of these hormones, peripheral tissue concentrations, and, potentially, risk for recurrence (1
). In the Health, Eating, Activity and Lifestyle Study, associations between the CYP17
, and SHBG
polymorphisms and serum sex hormone concentrations were examined in 366 postmenopausal breast cancer survivors (27
). In that study, no associations between any of the genotypes examined and sex hormone concentrations were observed when analyzing for main effects, although CYP17
variants were associated with a few differences in androgen, estradiol, and SHBG levels in small subsets of those participants. Whether these polymorphisms affect peripheral tissue concentrations or overall survival, within the context of potentially multiple polymorphisms and other influencing factors, such as diet, physical activity, treatment modalities, and other characteristics that contribute to risk, is unknown and will be challenging to disentangle.
As reported previously (15
), the WHEL Study diet intervention (high in vegetables, fruit, and fiber and low in fat) did not have an overall effect on recurrence or survival. However, we have observed previously that the diet intervention was associated with an average 32% reduction in serum bioavailable estradiol concentration at 1 year following enrollment in a subset of study participants (19
). That analysis, other populations (20
), and laboratory animal studies (31
) have identified dietary fiber as one dietary component that feasibly could modulate estrogen status by interfering with enterohepatic circulation. In the present analysis, we did not observe a difference in dietary fiber intake in women who recurred compared with women who did not recur.
This study has several limitations. The nested case-control design is a statistically powerful approach, and the number of participants in this study exceeds that examined in other analyses of serum reproductive hormone concentrations and risk for recurrence in breast cancer survivors; this is still a relatively small study, particularly in view of the heterogeneous nature of human breast carcinogenesis. Further, we recognize that numerous genetic and other factors, including diurnal variation, may influence serum hormone concentrations and their effect on risk for recurrence, which likely explains why a significant association with serum estrogen (and not testosterone or SHBG) concentration was identified in spite of using a powerful study design. Also, we examined blood samples from only one time point for this hormone analysis. In the general population, the within-person correlations between measurements of reproductive hormone concentrations collected at least 1 year apart are moderately high for estrogen and somewhat higher for testosterone and SHBG (6
). However, women who have been diagnosed and treated for breast cancer may have greater variability in reproductive hormone concentrations, so characterizing status based on one measurement may be considered a limitation. The mean interval between diagnosis and WHEL Study enrollment was ~2 years (14
), and chemotherapy and tamoxifen usage was similar in the recurred and nonrecurred women in the cohort analyzed in the present study, so effects of treatment were unlikely to bias the analysis. Follow-up data on hormonal response to the diet intervention were also not available for this analysis, and we would expect those data, in addition to characterizing genetic polymorphisms, could provide additional insights.
In summary, this study found significant independent associations between serum concentrations of total, bioavailable, and free estradiol and risk for recurrence in a nested case-control study design involving 153 case-control pairs of women diagnosed and treated for early-stage breast cancer. Although genetic and metabolic factors likely modulate the relationship between circulating sex hormones and risk, results from this study provide evidence that higher serum estrogen concentration contributes to risk for recurrence in this population.