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In this population-based study of 1,758 ER-positive breast cancer patients, we found that continuous and binary measures of lower ER quantity and lower intratumoral heterogeneity were

significantly associated with increased risk of breast cancer recurrence in minimally adjusted models, but did not carry significant prognostic value after adjusting for relevant clinical covariates. We found no evidence that ESR1 gene expression predicted recurrence risk. Our data showed modification of the association of ER expression with survival across strata of race, with ER status showing a significant association with outcomes among black but not white women.

ER expression has been shown to be an important prognostic and predictive biomarker in breast cancer; however, many aspects of its expression have remained underexplored, particularly in studies among racially diverse populations. In a cohort of black (n=523) and white (n=681) women, Ma et al. found quantitative percentage of ER positivity to be inversely associated with breast cancer-specific mortality risk, even after adjusting for age, race, study site, stage, and grade (p trend = 0.0003). Interestingly, the authors found when stratified by race, this association was significant among white women but not among black women.79 _{Our findings, in contrast, did not support independent predictive} value of ER quantity and suggested low ER status was associated with worse outcomes among black women only. Importantly, we measured recurrence outcomes and additionally adjusted for endocrine therapy receipt, which Ma et al. did not assess.

Studies examining ER positivity and recurrence, largely conducted in racially homogenous populations, have been inconsistent. Dowsett et al. reported that continuous ER H-score, which accounts for ER quantity and intensity, did not predict time to recurrence among women treated with endocrine therapy in multivariate adjusted models (HR: 0.9, 95% CI 079, 1.01 for anastrozole-treated patients; HR: 0.94, CI: 0.84, 1.04 for tamoxifen-treated patients).39 _{In contrast, Harigopal et al. found continuous ER to} be significantly associated with disease-free survival after adjusting for chemotherapy, endocrine therapy, menopausal status, tumor size, and node status (HR: 0.9, 95% CI: 0.84, 0.97).131 _{A recent meta-analysis} of ER load and survival outcomes in stage I – III breast cancer found that of 6 studies that considered continuous ER (either using percentage or histoscore), 3 did not find a significant association with increasing ER and better survival, 1 reported marginal significance, and 2 found significant association.132

These findings, alongside our results, illustrate the considerable clinical challenge of identifying patients at risk of recurrence. Our findings suggest that consideration of race may be important when interpreting ER status.

We found that higher heterogeneity (measured by Rao’s quadratic entropy) was associated with lower recurrence risk. This is in contrast to a prior study of intratumoral heterogeneity in 1,780

postmenopausal women in Sweden. High intratumoral heterogeneity, quantified using Rao’s quadratic entropy, was significantly associated with increased 25-year breast cancer-specific mortality in

multivariate adjusted analyses.43 _{Our study, which had a median follow-up of 6.6 years, found high} intratumoral heterogeneity to be a favorable tumor characteristic in minimally adjusted models, particularly among black women. In contrast to the Swedish study, low intratumoral heterogeneity in our study was found to be associated with high grade, and higher heterogeneity was associated with ER-positivity. Thus the effects of ER-heterogeneity are entangled with other ER clinical measures in ways that make

interpretation complex. It is also important to note that in contrast to Lindstrom et al., we evaluated early recurrence and they evaluated long-term survival. The long-term prognostic value of intratumoral

heterogeneity cannot be ruled out based on our findings.

Our study has several strengths, including a large population-based cohort that included a high proportion of black and young women, centrally-assessed tumor biospecimens, detailed demographic and clinical data, and extensive follow-up data. Our findings should be interpreted with consideration of some limitations. First, it is possible that benign breast tissue or ductal carcinoma in situ may have been included in automated assessment of ER positivity and intensity, resulting in nondifferential

misclassification bias. However, high level of agreement with clinical record has been reported in prior studies of IHC results in CBCS, which mitigates concern for this bias.40 _{Second, we did not account for} the full scope of treatment and access-related variables that may confound the association between ER status and recurrence, including chemotherapy receipt, delay of treatment, and early treatment cessation. Finally, our collection of follow-up data is ongoing and does not yet allow for analysis of breast cancer- specific and overall survival outcomes. Measuring these outcomes will be important to fully understanding ER as a long-term biomarker in heterogenous population-based cohorts.

4.6 Conclusions

Our study adds to the considerable body of evidence concerning ER by investigating sparsely reported outcomes, including ESR1 gene expression and intratumoral heterogeneity of expression, in a population of nearly 50% black and white women. Furthermore, we measure breast cancer recurrence, an outcome that is underexplored in cancer registries and yet increasingly important as the population of cancer survivors grows. We found that while no single measure of ER expression was independently associated with recurrence risk, the association between percent positivity and intratumoral heterogeneity may be modified by race. Future studies should continue to leverage patient, clinical, and biological data to better understand ER’s role as a biomarker and improve outcomes in ER-positive breast cancer.

CHAPTER 5: OUTCOMES OF HORMONE-RECEPTOR POSITIVE, HER2-NEGATIVE BREAST