Characterization of HER2‐low breast cancer in young women with germline <i>BRCA1/2</i> pathogenetic variants: Results of a large international retrospective cohort study
Francesco Schettini, Eva Blondeaux, Chiara Molinelli, Raphaëlle Bas, Hee Jeong Kim, Antonio Di Meglio, Rinat Bernstein‐Molho, Sabine C. Linn, Katarzyna Pogoda, Estela Carrasco, Kevin Punie, Elisa Agostinetto, Nerea Lopetegui‐Lia, Kelly‐Anne Phillips, Angela Toss, Christine Rousset‐Jablonski, Marion Acheritogaray, Alberta Ferrari, Shani Paluch–Shimon, Robert Fruscio, Wanda Cui, Stephanie M. Wong, Claudio Vernieri, Maria Vittoria Dieci, Alexios Matikas, Mariya Rozenblit, Cynthia Villarreal‐Garza, Laura De Marchis, Fabio Puglisi, Leonor Vasconcelos de Matos, Monica Mariño, Luís Teixeira, Rossella Graffeo, Alessia Rognone, Alessandra Chirco, Nicoleta Zenovia Antone, Yara Abdou, Maximilian Marhold, Ivana Božović‐Spasojević, Alfonso Cortés, Luca Carmisciano, Marco Bruzzone, Giuseppe Curigliano, Aleix Prat, Matteo Lambertini
Abstract
BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.