Prognostic factors and the role of GnRHa in premenopausal HR+/HER2+ breast cancer achieving pathologic complete response after neoadjuvant chemotherapy.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who achieve a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) generally have favorable outcomes. However, in the hormone receptor-positive/HER2-positive (HR+/HER2+) subtype, prognostic heterogeneity may persist even after pCR. In particular, the role of gonadotropin-releasing hormone agonist (GnRHa) for ovarian function suppression in premenopausal patients remains unclear. We aimed to identify prognostic factors and evaluate the clinical impact of GnRHa in this population.

METHODS: We performed a retrospective analysis of prospectively collected cohorts from Samsung Medical Center and Asan Medical Center. A total of 332 premenopausal patients with HR+/HER2+ breast cancer who achieved pCR after anti-HER2 containing NAC (2008 - 2021) were included. Patients were categorized according to GnRHa use during adjuvant endocrine therapy. The primary endpoints were disease-free survival (DFS) and distant metastasis-free survival (DMFS), analyzed using Cox proportional hazards regression and the Kaplan-Meier method.

RESULTS: Among 332 patients, 218 (65.7%) did not receive GnRHa and 114 (34.3%) did. With a median follow-up of 65.8 months, clinical nodal stage (cN3) was identified as an independent adverse prognostic factor for both DFS (HR 5.92, p < 0.001) and DMFS (HR 13.60, p < 0.001). In contrast, GnRHa use was not significantly associated with survival outcomes. Patients with cN3 disease showed significantly worse outcomes than those with cN0-2 (5-year DFS: 80.0%% vs 96.2%; DMFS: 87.5% vs 97.9%). No clear survival differences were observed according to GnRHa use. Subgroup analyses showed no significant association between GnRHa and survival, although a trend toward improved outcomes was observed in the cN3 subgroup.

CONCLUSION: Prognostic heterogeneity persists among premenopausal HR+/HER2+ patients achieving pCR, with baseline nodal status as a key determinant of outcomes. GnRHa was not associated with improved survival overall, although a potential benefit in high-risk subgroups cannot be excluded. These findings support a risk-adapted approach to adjuvant endocrine therapy rather than uniform intensification.