Impact of germline <i>BRCA</i> status on clinical outcomes of patients with HR+/HER2- early breast cancer.

559 Background: Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 (g BRCA1/2 ) genes increase the risk for breast cancer (BC) development.The prognostic significance of gBRCA1/2 in patients with hormone receptor-positive/HER2-negative (HR+/HER2) early BC is still controversial. Methods: This cohort study derived from a prospectively-maintained institutional database of all consecutive patients with BC who underwent germline testing, including BRCA1 , BRCA2 and PALB2 , at the European Institute of Oncology (May 2002-Jan 2024). The study population comprised patients with stage I-III HR+/HER2- (estrogen receptor expression &gt;1%) invasive BC who underwent surgery and (neo)adjuvant treatment, as endocrine therapy (ET) +/- chemotherapy (CT) (Jan 2000-Dec 2022). Primary endpoints were distant relapse-free interval (DRFI) and invasive disease-free survival (iDFS) by STEEP 2.0. Univariate and multivariate Cox proportional-hazard models were employed for survival analyses, with left-truncated models to account for the time from BC diagnosis to germline testing. Results: A total of 1,730 patients were included in the analyses, with 52 (3%) BRCA1 , 180 (10%) BRCA2 , and 9 (0.5%) PALB2 PV carriers. Compared to non-carriers, patients with gBRCA 1/2 and gPALB2 PVs were younger (median age: 39 vs 42 yrs, p&lt;.001), had advanced disease stage (stage II-III: 71% vs 58%, p&lt;.001), higher tumor grade (G3: 54% vs 26%, p&lt;.001) and Ki-67 expression (median: 26% vs 20%, p&lt;.001). Patients with gBRCA 1/2 and gPALB2 PVs were also more likely to receive neoadjuvant (13% vs 6%, p&lt;.001) and/or adjuvant CT (56% vs 36%, p&lt;.001) and mastectomy (56% vs 45%, p=.002). All patients received adjuvant ET, as tamoxifen or aromatase inhibitor +/- GnRH analogue. No patient received adjuvant olaparib or CDK4/6 inhibitor. At a median follow-up of 9.7 (IQR 6-13.9) years, 335 (19%) patients experienced local relapse, 316 (18%) distant metastasis, and 124 (7.2%) died due to BC. At multivariate analyses, gBRCA2 P/LPVs were independently associated with shorter DRFI (HR 1.46, 95%CI 1.04–2.06, p=.028) and iDFS (HR 1.34, 95 CI 1.01–1.78, p=.045), regardless of stage, nodal status, (neo)adjuvant CT, type of surgery and adjuvant ET, whereas gBRCA1 were not. Exploratory analyses showed that among 232 gBRCA1/2 carriers, 47 (20%) and 96 (41%) were eligible for adjuvant olaparib or abemaciclib therapy per OlympiA and monarchE criteria, respectively, with 37 (16%) eligible for both therapies. Additional analyses to unravel interaction of gBRCA status with adjuvant treatment are underway. Conclusions: Patients with HR+/HER2- early BC harboring gBRCA2 PVs had a significantly increased risk of recurrence, with a potentially distinct impact of BRCA2 vs BRCA1 . Only a small proportion of this population currently qualify to adjuvant treatment escalation with targeted therapies, underscoring the need of expanding the therapeutic options in this setting.