Prognosis and biological characteristics of ER-low metastatic breast cancer: results from a multicenter cohort and the TONIC trial.

Purpose: To assess prognosis of ER-low expression and its dynamics in HER2- metastatic breast cancer (BC) and to compare sensitivity to nivolumab between ER-low and triple-negative (TN) BC. Experimental design: Two cohorts were analyzed: a multicenter cohort of 982 patients with HER2- metastatic BC, and one prospective cohort of 110 patients with ER<10%/HER2- metastatic BC enrolled in the TONIC trial (testing nivolumab). Endpoints were: overall survival (OS) and post-relapse survival (PRS) in the retrospective cohort; progression-free survival (PFS), OS, and clinical benefit rate (CBR) in the TONIC trial. Results: ER-low BC were 7.3% of retrospective cases, 15/110 of the TONIC. In the retrospective cohort, patients with ER-low BC had significantly poorer OS (p<0.001) and numerically shorter PRS (p=0.230) compared to ER+/HER2- BC, and numerically longer OS (p=0.098) and significantly longer PRS (p=0.017) compared to TNBC. In the TONIC, patients with ER-low BC, compared to TN, showed similar response to nivolumab (CBR: 20.0% vs 22.1%, p=1), PFS (median 1.7 vs 2.0 months, p=0.5) and OS (median 5.3 vs 8.6 months, p=0.3). Among patients with primary ER+/HER2- BC (n=565), the conversion towards ER-low or TNBC at metastasis conferred independent negative prognostic impact both for OS (p=0.002 and 0.001, respectively) and PRS (p=0.018 and p=0.001, respectively). Discussion: We provided evidence of the prognostic role of ER-low expression and its dynamics in patients with HER2- metastatic BC. We offered insights into sensitivity to antiPD1 in metastatic BC, showing that patients with ER-low BC have comparable likelihood of responding to nivolumab as those with TNBC.