Breast Cancer Hormone Receptor Status by Germline Cancer Predisposition Genes


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Grace Wei, Xia Wang

Abstract

Background

It is known that BRCA1 pathogenic variant (PV) carriers tend to develop ER-PR- breast cancers, while BRCA2 PV carriers tend to develop ER+PR+ breast cancers. Conversely, the genetic patterns of divergent breast cancer subtypes, namely ER+PR- and ER-PR+, are less well-understood. Poor survival outcomes associated with ER+PR- and ER-PR+ breast cancers highlight the need for improved understanding and early detection of these rarer variants. We sought to characterize genetic influences on divergent breast cancer hormone receptors by investigating the association between germline PVs and ERPR status.

Method

We conducted a retrospective chart review of breast cancer patients who underwent germline genetic testing for cancer predisposition genes at Moffitt Cancer Center’s (MCC) GeneHome clinic between January 2015 and February 2018. Differences in patient characteristics and genetic variants between ERPR status were assessed via chi-square analysis. All statistical analyses were performed via SPSS version 26.0. This study was approved by the MCC IRB.

Results

Our sample included 684 patients, including 61.7% ER+PR+, 24.4% ER-PR-, 12% ER+PR-, and 1.9% ER-PR+ breast cancers. Prevalence of ER+PR- breast cancers were greater in patients with additional cancer diagnoses (17.5%) compared to patients with only breast cancer diagnoses (10.6%) (p=0.02). As expected, ER-PR- and ER-PR+ breast cancers were significantly more prevalent among BRCA1 carriers compared to non-carriers. Interestingly, however, while ER+PR+ breast cancers were comparatively less prevalent among BRCA1 carriers compared to non-carriers (3.4%) (p<0.0001), this was not observed for ER+PR- breast cancers (p>0.05).

Conclusion

Advancements in understanding the molecular behavior of divergent ERPR breast cancer subtypes are needed to improve the robustness of genetic testing and early breast cancer detection. Within our cohort, ER+PR- breast cancers occurred more frequently in combination with other cancer histories, rather than in isolation. Further, whereas ER-PR- and ER-PR+ breast cancers shared similar BRCA1 expression patterns, ER+PR+ and ER+PR- did not, suggesting that differential behaviors may exist between these two subtypes. Further research on gene expression profiling is needed to elucidate the mechanisms underlying divergent breast cancers, particularly the ER+PR- subtype.

Impact statement

Unlike ER-PR- and ER-PR+ breast cancers, ER+PR+ and ER+PR- do not share similar BRCA1 profiles, suggesting there may be divergence in genetic behaviors.