Background: The place of endocrine therapy (ET) in the treatment of hormone receptor-positive (HR+), HER2+ metastatic breast cancer (MBC) is still not clearly defined. Data suggest that blocking both HR and HER2 signaling pathways could be an efficacious strategy to overcome secondary resistance. Methods: We aimed to retrospectively evaluate the impact of first line (L1) therapy for HR+/HER2+ MBC patients (pts) included between 2008- 2017 in the French real-world ESME MBC database (NCT03275311). Our primary endpoints were median overall survival (mOS) and median first progression-free survival (mPFS1). We used descriptive statistics and the Kaplan-Meier method to report patient characteristics and outcomes. Cox proportional hazards models and a propensity score were constructed to report and adjust for prognostic factors. Results: From the 23,501 female pts in the ESME MBC cohort, 1,790 pts had HR+/HER2+ MBC treated with Trastuzumab (T, n=1,089) or Trastuzumab-Pertuzumab (TP, n=701) during L1. Among them, 1,584 pts received antiHER2 therapy+CT+/-ET and 206 pts, antiHER2+ET only. Pts with antiHER2+CT+/-ET had more often ECOG performance status 0 (29.5% vs 15.8%, p<0.001), grade III tumors (36.6% vs 25.6%, p=0.007), time to MBC < 6 mo (51.6% vs 29.1%, p<0.001), TP as antiHER2 therapy (43.2% vs 9.4%, p<0.001), ≥3 metastatic sites (23.2% vs 14.8%, p=0.007), visceral metastasis (56.5% vs 42.4%, p<0.001), and less often bone-only disease (18.4% vs 35%, p<0.001) than pts with antiHER2+ET. In multivariable analysis, antiHER2+CT+/-ET was not superior to antiHER2+ET (Table), while TP was superior to Trastuzumab, and this result was confirmed by matching pts using a propensity score (p=0.76 for mOS and p=0.85 for mPFS1). Using the time-dependent ET variable among pts with antiHER2+CT, pts with maintenance ET had significantly better PFS1 and OS than those without (adjusted HR for PFS1=0.70 [95%CI 0.60-0.82], adjusted HR for OS=0.47 [95%CI 0.39-0.57], p<0.001). Conclusions: These data suggest that endocrine therapy could be an interesting less toxic alternative to chemotherapy in combination with antiHER2 therapy as first line treatment for HR+/HER2+ MBC pts.

*The multivariable analysis also included: tumor grade, age at MBC, time to MBC, no of metastatic sites, type of metastases, ECOG performance status.