Association of germline homologous recombination deficiency mutations with HER2 status conversion from negative to positive following neoadjuvant chemotherapy in breast cancer.

Abstract

1034 Background: Neoadjuvant therapy (NT) is well established in breast cancer management, with subsequent adjuvant therapy guided by biomarker status and tumor response. While rare, biomarker status can change post-NT. The mechanisms driving conversion and optimal treatment strategies remain unclear. This study aimed to investigate clinicopathological characteristics, including germline mutations, in patients who underwent HER2 status conversion from negative to positive (N-P) after NT. Methods: Patients treated with NT for breast cancer between 2012 and 2023 were retrospectively identified from the Stanford STRIDE database. Clinicopathological features, including demographics, genetic data, treatment history, pathological characteristics, and recurrence, were collected through chart review. ER, PR, and HER2 status were assessed using immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH), with HER2 interpretation following ASCO/CAP guidelines relevant at the time of testing. Per institutional policy, both IHC and FISH were routinely performed for HER2 assessment. Results: A total of 28 patients with HER2 status change were identified; 26 (93%) were female and 2 (7%) male, with a median diagnosis age of 47 years (IQR 39–58). Most patients were ER-positive (N=24, 86%) at diagnosis. Among 25 patients who underwent germline testing, 56% harbored mutations in homologous recombination deficiency genes, including BRCA2 (5, 20%), BRIP1 (4, 16%), PALB2 (2, 8%), ATM (2, 8%), and BRCA1 (1, 4%). Post-NT, patients were classified into HER2 groups: 36% (10/28) in Group 1, 46% (13/28) in Group 1b (HER2 low amplified with HER2/cell <6 and ratio >2), 14% (4/28) in Group 3, and 4% (1/28) in Group 4. Adjuvant HER2-directed therapy was administered to 24 patients (89%): trastuzumab in 8 (29%), trastuzumab and pertuzumab in 12 (43%), and trastuzumab emtansine in 4 (14%); 4 patients (14%) did not receive adjuvant HER2 therapy. Recurrence occurred in 8 patients (29%), including 3 with germline mutations. One non-mutated case involved discordant HER2-positive recurrence with ipsilateral in-breast recurrence and liver metastases, testing HER2-positive by FISH despite IHC 0. Conclusions: This study highlights that a majority of patients who underwent HER2 status conversion after NT harbored homologous recombination deficiency mutations, suggesting a potential mechanistic basis. Furthermore, while 85.8% of patients received adjuvant HER2-directed therapy, the rarity of HER2-positive recurrences underscores the potential for overtreatment. Further studies are needed to elucidate the mechanisms of HER2 status conversion from negative to positive after NAT which will improve the efficacy of treatment strategies and patient outcomes.