2341P - Novel therapeutic opportunities in metaplastic breast cancer

Background

Metaplastic breast cancer (MBC) is a rare and aggressive form of triple-negative breast cancer with limited therapeutic options. Despite being reported to display genomic features of homologous recombination (HR) deficiency (HRD) by whole-exome sequencing, MBCs rarely respond to neoadjuvant chemotherapy/immunotherapy. We sought to assess their HR and immune features using whole-genome sequencing (WGS) of MBCs and evaluated the efficacy of antibody-drug conjugates (ADCs) and DNA damage response (DDR)-targeting agents in preclinical MBC models.

Methods

MBCs were subjected to WGS (n=25) and RNAseq (n=31). HRD was assessed using HRDetect (‘gold standard’) and mutational signatures using Signal. ADC target expression was assessed transcriptomically. Efficacy of ADCs and DDR agents was assessed in vitro using MBC cell models (BT549, Hs578T and HCC1806). T-DXd efficacy was evaluated in vivo in HCC1806 xenografts in athymic mice.

Results

Despite most (13/25) MBCs displaying partial features of HRD (mutational signature 3), only 3/25 MBCs had a complete HRD pattern with tandem duplications, deletions with microhomology, dominant SBS/indel/rearrangement HRD mutational signatures and were classified by HRDetect as HRD. These 3 MBCs harbored somatic/germline pathogenic BRCA1 mutations (n=2) or a RAD51C intragenic inversion with LOH (n=1). Exposure to APOBEC mutational signature was detected in 15/25 (60%) MBCs, including the HRD cases. HLA homozygosity/LOH was more frequent in non-chondroid (7/15) than in chondroid (1/10) MBCs. TROP2 and ERBB2 expression was detected in MBCs by RNAseq, and MBC cell models were found to be sensitive to T-DXd, Sacituzumab govitecan, and ATR and Wee1 inhibitors in vitro, and to T-DXd in vivo. Combination of T-DXd and DDR agents in MBC models was found to be synergistic.

Conclusions

Most MBCs display an incomplete HRD phenotype and those with complete HRD harbor bi-allelic inactivation of HR-related genes. MBCs express targets for novel ADCs, and preclinical MBC models are sensitive to anti-HER2 and anti-TROP2 ADCs alone or in combination with novel DDR agents, targeting their incomplete HRD phenotype, other than PARP-inhibitors. These findings provide preclinical evidence for assessing the clinical efficacy of these therapeutic approaches.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

National Institutes of Health/National Cancer Institute (NIH/NCI), Breast Cancer Research Foundation.

Disclosure

S. Chandarlapaty: Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Boxer Capital, Nuvalent, Inivata, Neogenomics; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Personal and Institutional, Research Grant, Also consultant: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Also Officer: Odyssey Biosciences; Financial Interests, Personal, Stocks/Shares: Totus Medicines. M. Scaltriti: Financial Interests, Personal, Stocks or ownership, Also employee: AstraZeneca; Financial Interests, Personal, Other, Co-founder: Medendi. B. Weigelt: Financial Interests, Personal, Research Funding: Repare Therapeutics. J.S. Reis-Filho: Financial Interests, Personal, Speaker, Consultant, Advisor: Goldman Sachs, Bain Capital, Saga Diagnostics, MultiplexDX; Financial Interests, Personal, Speaker, Consultant, Advisor, Also membership of the scientific advisory boards: Repare Therapeutics, Paige.AI; Financial Interests, Personal, Advisory Board: VolitionRx, AstraZeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics, Personalis; Financial Interests, Personal, Other, Membership of the Board of Directors: Grupo Oncoclinicas. All other authors have declared no conflicts of interest.