Résumé
Background: Breast cancer brain metastases (BCBM) represent a critical unmet clinical need in metastatic BC, as they are associated with significant morbidity and poor prognosis. The identification of novel therapeutic targets is therefore urgently needed in this context. In this study, we aimed to describe clinically actionable targets in breast cancer brain metastases (BMs) using comprehensive genomic profiling. Patients and methods: Genomic DNA was extracted from formalin-fixed paraffin-embedded archival BCBM samples from three institutions (all selected for tumor cellularity>30%). DNA samples with adequate quality were then analyzed using the commercially available Agilent SureSelect V6 whole exome sequencing (WES) kit and an Illumina NovaSeq 6000 platform. Pathogenic alterations were classified as actionable alterations (AA) if they met the updated metastatic BC or tumor-agnostic ESCAT I or II criteria of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) (Mosele et al, Ann Oncol 2024). Due to technical limitations, gene fusions and MSI-H status were not assessed. Hormone receptor (HR) and HER2 status were evaluated on the BCBM by ASCO-CAP criteria. Overall survival (OS) was defined as interval from first BM diagnosis to death or last follow-up, whichever occured first. Results: Tumor WES data from 56 BCBM samples was available. Thirty-three BCBMs (59%) were classified as HER2-. Among these, 8 (24%) presented AA of BRCA1 (N=2, 6%), BRCA2 (N=5, 15%), and PALB2 genes (N=1, 3%). These alterations were observed in 26% of HR-/HER2- BCBMs (5/19; N=2 BRCA1 and N=3 BRCA2, respectively) and in 21% of HR+/HER2- BCBMs (3/14; N=2 BRCA2, N=1 PALB2). ESCAT I/II PIK3CA/AKT1/PTEN-pathway alterations were also present in 50% (7/14) of HR+/HER2- BCBMs: 6 PTEN (2 mutations, 4 deletions) and 1 hotspot PIK3CA mutation. A rare non-hotspot PIK3CA mutation was also detected in an additional HR+/HER2- BCBM sample. Interestingly, we did not detect ESR1 mutations in HR+/HER2- BCBMs. Twenty-three BCBMs (41%) were classified as HER2+; among these, 3 (13%) presented a hotspot PIK3CA mutation and 7 (30%) presented a PTEN deletion. Among patients with HER2+ BCBMs, the identification of a hotspot PIK3CA mutation was significantly associated with worse prognosis (median OS from BM diagnosis 22.2 versus 53.0 months, log-rank p=0.034). Overall, an ESCAT I/II AA was detected in 66% (N=37) of all BCBMs, and in particular in 64% of HR+/HER2- BCBMs. Tumor mutational burden (TMB) data will be presented at the meeting. Conclusions: ESCAT I/II actionable genomic alterations are frequent in BCBMs, with a particularly high rate of tumor BRCA1/BRCA2/PALB2 alterations in the HER2- subgroup. These data highlight the potential for genomically targeted treatments in this setting. Furthermore, the negative prognostic impact of PIK3CA mutations in HER2+ BCBMs provides the rationale for the potential combination of PIK3CA inhibitors and HER2-targeted agents in this setting.
Citation Format: Gaia Griguolo, Antonio Collesei, Elisabetta Lazzarini, Maria Vittoria Dieci, Susan Fineberg, Michele Bottosso, Luc Bauchet, Federica Miglietta, Jack Jacob, Valerie Rigau, Valerio Pellegrini, Francesca Zanghi, Maria Cristina Guarascio, Matteo Fassan, William Jacot, Stefano Indraccolo, Amelie Darlix, Valentina Guarneri. Clinically actionable genomic alterations in breast cancer brain metastases [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS14-05.