| Contributors: |
Arecco, L.; Bruzzone, M.; Bas, R.; Kim, H. J.; Di Meglio, A.; Bernstein-Molho, R.; Hilbers, F. S.; Pogoda, K.; Carrasco, E.; Punie, K.; Bajpai, J.; Agostinetto, E.; Lopetegui-Lia, N.; Partridge, A. H.; Phillips, K. A.; Toss, A.; Rousset-Jablonski, C.; Curigliano, G.; Renaud, T.; Ferrari, A.; Paluch-Shimon, S.; Fruscio, R.; Cui, W.; Wong, S. M.; Vernieri, C.; Couch, F. J.; Dieci, M. V.; Matikas, A.; Rozenblit, M.; Méndez, D. Aguilar-y.; De Marchis, L.; Puglisi, F.; Fabi, A.; Graff, S. L.; Witzel, I.; Rodriguez Hernandez, A.; Fontana, A.; Pesce, R.; Duchnowska, R.; Pais, H. L.; Sini, V.; Sokolovi, E.; de Azambuja, E.; Ceppi, M.; Blondeaux, E.; Lambertini, M. |
| Description: |
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. |