Publication: ESMO 2026

Authors: Amir Sonnenblick (first and presenting), Mehran Habibi, Laura Lee, Eduardo Dias, Alfredo Santillan, Beth Sieling, Nicole Sookhan, Laila Samiian, Sasha Strain, Jaime Alberty, Massimo Cristofanelli, Priscilla McAuliffe, Samuel Benjamin, Sahra Uygun, Nicole Stivers, Raquel Weber, Andrea Menicucci, Willan Audeh, Joyce O’Shaughnessy

Title: Impact of Germline BRCA1 and BRCA2 Mutations on 70-Gene Signature Risk for patients enrolled in the FLEX Study

Abstract

Background: Germline BRCA1/2 mutations are associated with distinct breast cancer phenotypes. This analysis evaluated the relationship between BRCA mutations and genomic risk among patients enrolled in the FLEX Study.

Methods: Patients with known non-VUS BRCA1 and BRCA2 mutations and a reference group with no known pathogenic mutations enrolled in the prospective observational FLEX registry (NCT03053193) with MammaPrint® (MP) and BluePrint® (BP) genomic testing were included. Chi-square and t-tests were conducted across MP/BP categories for all clinical subtypes and among HR+HER2− with p<0.05 reported as significant.

Results: Among the entire population (N=3338), 85 patients had BRCA1, 105 BRCA2, and 3148 had no BRCA1/BRCA2 germline mutations. Clinical subtype distribution showed HR+HER2− as the most common across groups (BRCA1: 58/85 [68.2%]; BRCA2: 72/105 [68.6%]; no mutation: 2354/3148 [74.8%]), with higher TNBC representation in the BRCA1 group (14/85 [16.5%]; p<0.001). MP High Risk 2 (H2) was most frequent in BRCA1 (50.6%), followed by BRCA2 (30.5%) and no mutation (15.5%) groups, with BP Basal observed in 47.1%, 13.3%, and 9.7% of patients, respectively (all p<0.001). Over half of patients with BRCA1 were under the age of 50, pre/peri‑menopausal, had Grade 3 tumors, and Ki‑67 >20% (all p<0.001).

Within the HR+HER2− subgroup, these differences were maintained with over half of patients with BRCA1 under the age of 50, pre/peri‑menopausal, Grade 3, and Ki‑67 >20%. 39.7% of patients with BRCA1 had H2, while 26.4% of patients with BRCA2 and 8.0% of patients with no mutation had H2. BP Basal remained enriched in BRCA1 (34.5%) compared with BRCA2 (8.3%) and no mutation (3.9%) (all p<0.001).

Conclusion: In this analysis, mutation status was associated with significant differences in clinical and MP/BP subtypes, including higher rates of MP H2 and higher BP Basal classification among patients with BRCA1 mutations. These findings further suggest a natural enrichment of BRCA1 mutations within H2 and Basal subgroups, a pattern that remained consistent within HR+HER2− disease. Ongoing research is investigating whole transcriptome and clinical differences within this subset of patients enrolled in FLEX.