The genomic landscape of HER2 negative metastatic breast cancer with loss of estrogen and progesterone receptors

Introduction: Loss of estrogen receptor (ER) and/or progesterone receptor (PR) might occur during the metastatic progression of ER positive and HER2 negative (ER+/HER2−) breast cancer (BC), but the underpinning molecular alterations remain elusive. We explored the genomic context of HER2− tumors with ER and/or PR loss to investigate potential drivers and actionable alterations that might help personalize treatment of ER+/HER2− BC. Methods: We accessed data from metastatic HER2− BC included in the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/−, n = 66) to those maintaining ER positivity (ER+/+, n = 364) or ER negativity (ER−/−, n = 50). We also compared metastatic ER+/+ BC with loss of PR (PR+/−, n = 111) to those maintaining PR positivity (PR+/+, n = 192) or PR negativity (PR−/−, n = 41). Results: In line with previous reports, ER+/− BC was associated with aggressive clinico-pathological characteristics and poor outcome. ER+/− BC showed significantly higher frequency of TP53 and RB1 mutations and lower frequency of PIK3CA and GATA3 mutations compared to ER+/+. ER+/− or PR+/− status was mutually exclusive with ESR1 mutations and was associated with a significantly higher tumor mutational burden. Moreover, ER+/− BC were enriched in driver alterations in the genes of the Notch and Retinoblastoma pathways and showed a significantly lower frequency of level 1 actionable alterations according to OncoKB. Conclusions: Loss of ER and/or PR may identify a distinct evolutionary trajectory of ER+/HER2− metastatic progression, largely non-overlapping with ESR1-mutant endocrine resistance. Further studies on matched primary and metastatic samples are warranted.