Abstract PS5-01-20: Taxane induction before trastuzumab-endocrine therapy improves 10-year survival in ER-positive HER2-positive metastatic breast cancer: a propensity-matched real-world analysis of 646 patients

Abstract Background: CLEOPATRA trial, adding Pertuzumab to Docetaxel and Trastuzumab improved median overall survival (OS) from 40.8 to 57.1 months and remains guideline-defining for first-line HER2-positive metastatic breast cancer (MBC), albeit with risks of myelosuppression and long-term neurotoxicity. In HR+ HER2+ MBC, few studies presented good outcomes with addition of endocrine therapy (ET) and CDK4/6 inhibitors without chemotherapy (PERTAIN, SYSUCC-002, PERNETTA, BR 18-2 MINI). Robust real-world survival data comparing chemotherapy-free versus taxane-induction strategies in this subgroup are lacking. Methods: TriNetX Global Collaborative Network (152 sites, 2008-2024) was queried for adults (≥18 y) with incident HR+ HER2+ MBC treated with Trastuzumab (± Pertuzumab) plus ET. Patients receiving ≥1 dose of paclitaxel or docetaxel within 6 months of diagnosis before the first HER2-targeted dose constituted the induction cohort (IND, n = 365 pre-match); others served as controls (CTRL, n = 498). One-to-one propensity-score matching (caliper 0.10) on 13 demographics/comorbidities yielded 323 well-balanced pairs (N = 646); after matching all standardized differences were < 0.10 except male sex (3 % vs 0 %). Ten-year OS was the primary endpoint. Secondary outcomes were grade-coded neutropenia, sepsis, heart failure, emergency-department (ED) visits and intensive-care-unit (ICU) admission. Survival analysis done with univariate Kaplan Meier and Cox models. Results: Of 7184 HR+ HER2+ MBC cases, 2114 received first-line Trastuzumab (± Pertuzumab) + ET; 863 met prespecified criteria (365 IND, 498 CTRL); 646 remained after 1:1 matching. Matched cohorts were well balanced, with median age 52 years, 96 % female, 59 % White, 22 % Black. All baseline standardized differences < 0.10 (except male sex 3 % vs 0 %). Median follow-up was 1578 vs 1151 days (IND vs CTRL). Ten-year OS was 64.3 % in IND vs 53.1 % in CTRL (absolute gain 11.2 %; HR 0.64, 95 % CI 0.47-0.85, P = 0.002). Ten-year mortality fell from 31.9 % to 24.1 % (absolute risk reduction 7.8 %; NNT = 13). Survival curves diverged by 12 months and remained parallel. Induction increased neutropenia (25.7 % vs 13.9 %; HR 1.88, P < 0.001) and ED visits (63.5 % vs 51.7 %; HR 1.24, P = 0.009); with median time to first ED visit shortened from 1084 to 678 days in the IND group. Serious events were comparable: sepsis 17.6 % vs 14.9 % (P = 0.34), heart failure 18.0 % vs 16.4 % (P = 0.60), ICU admission 16.1 % vs 16.4 % (P = 0.92). Conclusions: In contrast to some signals from chemotherapy-free regimens in PERTAIN, SYSUCC-002 and PERNETTA, this real-world study shows that a short taxane induction in HR+ HER2+ MBC before trastuzumab-ET confers a 36 % relative and 11 % absolute 10-year OS advantage; one extra life saved per thirteen treated; at the cost of predictable, manageable myelosuppression and higher acute-care use without excess cardiotoxicity, sepsis or ICU need. This data strengthens guideline endorsements of chemotherapy-containing first-line regimens and asks for careful discussion if upfront de-escalation is considered, as well as provides a benchmark for ongoing chemo-sparing strategies utilized in other trials (DESTINY-Breast09, DEMETHER, etc.). Selection and lead-time bias are possible but were mitigated by robust propensity matching. Citation Format: M. Eysha, M. Elchouemi, W. Zhang, R. del Toro-Mijares, A. Asad, A. Elkhanany. Taxane induction before trastuzumab-endocrine therapy improves 10-year survival in ER-positive HER2-positive metastatic breast cancer: a propensity-matched real-world analysis of 646 patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-20.