Lifetime exposure to estrogen that is related to reproductive factors including early menarche, late menopause and parity have a well-established impact on breast cancer risk . While the increased risk is more prominent for ER positive disease rather than ER negative disease, few studies address the effect of reproductive factors on other tumor characteristics and outcomes. Here, we investigated the influence of endogenous estrogen exposure on early-stage luminal breast cancer characteristics including also the impact on genomic risk. Overall, the impact of the evaluated endogenous exposures on breast cancer characteristics was relatively limited. Menopause was associated with stronger ER intensity, but with PR negativity. Women with early menarche were more likely to have PR positive disease. Oncotype RS, a well validated prognostic and predictive factor that is not a subject for inter-laboratory heterogeneity , was comparable in all of the evaluated subgroups. No other associations between parity, age of first delivery and age of menopause with tumor characteristics were identified.
Data suggest possible differential effect of reproductive risk factors and obesity according to breast cancer subtype, with parity, age at menarche, age at first birth, breastfeeding and obesity demonstrating stronger associations with luminal subtype compared to other subtypes [17, 20], however data on the effect of these factors of the intensity of ER and PR staining are scarce. In our analysis an association between early menarche and PR positivity was identified. This is in line with other studies showing a higher concordance of ER/PR positive breast cancer in women with early age of menarche [20–22].
In this study, we reported on the influence of endogenous estrogen exposures on outcome with a follow-up duration of more than 10 years. Interestingly, despite comparable tumor characteristics, early menopause and multiparity were each independently associated with worse outcomes, and these differences remained significant in multivariate analysis. Postmenopausal women also had worse OS compared to premenopausal women, but this difference did not remain significant in multivariate analysis and can probably be attributed to non-breast cancer mortality in older population.
Our finding of adverse outcomes of women who menopaused before the age of 45 is meaningful and might have important implication of treatment decisions. Menopause gives rise to cardiovascular morbidity and metabolic syndrome [23, 24]. Earlier age of menopause enhances the risk for cardiovascular morbidity and mortality [25–27]. Given the excellent prognosis of women with luminal early breast cancer, the most common cause of death in this population is cardiovascular disease [28, 29]. Adjuvant treatment for breast cancer might increase cardiovascular morbidity. Anthracycline based adjuvant chemotherapy that are often recommended to women with high genomic risk or to women with high clinical risk [18, 30], might cause cardiotoxicity. Adjuvant treatment with aromatase inhibitors, which are consider the standard of care in all postmenopausal women  and can often be considered for higher risk premenopausal in combination with ovarian function suppression , have increased odds for cardiovascular morbidity compared to both tamoxifen or placebo [33, 34]. Adjuvant radiation that is given to the vast majority of women after breast conserving surgery, is also associated with cardiovascular toxicity when treating left sided disease . Tailoring treatment decisions based on the individual risk of breast cancer recurrence and on other comorbidities including risk of cardiovascular disease are required. Modifications to reduce treatment related cardiovascular toxicity, such as anthracyclines sparing chemotherapy , shorter treatment with AIs  and omission of radiation or partial breast irradiation [37, 38] should be considered. Our findings demonstrated that age of menopause might also be an important factor when weighing the risk and benefit balance of treatment options.
Multiparity was also associated with worse DFS. This finding is significant and is in line with previous publications [39, 40], however due to the low number of multiparous women, the conclusions that can be drawn are limited. Multiparity might be associated with low socioeconomic status [41, 42], and hence lower adherence to treatment and higher risk of comorbidities . Multiparty is also an independent predictor for obesity [44, 45], which may also explain worse outcome after breast cancer diagnosis, both due inferior specific breast cancer survival  and non-breast cancer mortality . These hypotheses might partially explain our finding, however, our data on weight and socioeconomic status were insufficient. Larger scales studies are needed to elucidate the effect on multiparity on breast cancer outcome.
We acknowledge the limitations of a single-center retrospective cohort with inherent biases. The histopathological variables were not re-evaluated for the study by central pathology. On the other hand, considering the scarcity of data on the effect of endogenous estrogen on breast cancer characteristics our cohort represents a large number of patients with long duration of follow up. The effect on all known prognostic pathological characteristics were meticulously collected and the assessment of endogenous estrogen impact on Oncotype DX score is novel.
In conclusion, our results suggest little impact of endogenous estrogen exposure on breast cancer characteristics of early stage, luminal disease. Early menopause and multiparity were associated with worse outcome. These findings might be related to other comorbidities or direct influence on breast cancer pathogenesis. Given the impact of early menopause and multiparty on outcome, these variables should be taken into consideration in treatment decisions on early-stage luminal breast cancer.