Dual HER2 blockade with or without taxane induction in HR+/HER2+ metastatic breast cancer: A comparative analysis of clinical outcomes.

1059 Background: In the era of modern dual HER2 blockade, the necessity of taxane induction for ER+/HER2+ metastatic breast cancer (MBC) remains debated. While CLEOPATRA established pertuzumab/trastuzumab plus taxane as a standard backbone, emerging de-escalation strategies suggest that endocrine therapy (ET) combined with HER2 blockade may provide durable disease control in this favorable-prognosis subgroup (SYSUCC002, PERTAIN). Robust real-world comparative data addressing the survival–toxicity trade-off between chemotherapy-free versus taxane-induction approaches are limited. Methods: The TriNetX Global Collaborative Network (168 healthcare organizations; data updated Dec 2025) was queried for adults (≥18 years) with incident HR+/HER2+ MBC treated with dual HER2 blockade (trastuzumab + pertuzumab) plus ET. Patients receiving induction taxane (paclitaxel or docetaxel) comprised the induction cohort (IND); those treated with dual blockade + ET without induction comprised the chemotherapy-free cohort (Chemo-Free). 1:1 propensity-score matching (greedy nearest-neighbor; caliper 0.10) on demographics and comorbidities yielded 137 well-balanced pairs (N=274) with all post-match standardized mean differences <0.10. The primary endpoint was 3-year overall survival (OS; 1095-day window). Secondary outcomes included neutropenia, sepsis, heart failure, emergency department (ED) visits, and ICU admission. Results: Among 957 eligible patients, 153 received Chemo-Free and 804 received IND; 137 matched pairs were analyzed. Three-year OS was similar between cohorts with no statistically significant separation of survival curves (3-year OS 89.1% Chemo-Free vs 82.0% IND; HR 0.65 [0.32–1.31]; p=0.219). Deaths within 3 years were 13/137 (9.5%) in Chemo-Free versus 19/137 (13.9%) in IND, corresponding to an absolute death risk difference of −4.4% (95% CI −12.0% to +3.2%). Omitting induction was associated with reduced neutropenia (12.4% vs 21.9%; absolute risk reduction 9.5%; OR 0.51 [0.26–0.97] and a lower time-to-neutropenia hazard (HR 0.50 [0.28–0.91]; p=0.020). Serious adverse events and acute care utilization were not increased with Chemo-Free: heart failure 16.1% vs 16.1%; sepsis 10.9% vs 13.1%; ICU admission 11.7% vs 13.9%; ED visits 40.9% vs 45.3%. Conclusions: In a propensity-matched real-world cohort receiving contemporary dual HER2 blockade plus ET, a chemotherapy-free strategy demonstrated similar 3-year OS compared with taxane induction, with a clinically meaningful reduction in neutropenia (number needed to treat ≈11 to prevent one event) and no signal for higher sepsis, heart failure, or acute care utilization. These data support the feasibility of chemotherapy de-escalation in selected HR+/HER2+ MBC patients and motivate prospective validation to refine patient selection and minimize treatment-related toxicity.