Expanding the therapeutic scope of PARP inhibitors in breast cancer: current indications and future directions
Charlotte S. Walmsley, Adela Rodriguez, Panagiotis A. Konstantinopoulos, Geoffrey I. Shapiro, Sara M. Tolaney, Judy E. Garber, Filipa Lynce
Charlotte S. Walmsley, Adela Rodriguez, Panagiotis A. Konstantinopoulos, Geoffrey I. Shapiro, Sara M. Tolaney, Judy E. Garber, Filipa Lynce
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Expanding the therapeutic scope of PARP inhibitors in breast cancer: current indications and future directions

Abstract

Homologous recombination repair deficiency (HRD) occurs in approximately 10% of breast tumors and represents a major targetable vulnerability across multiple cancer types. Impairment of the homologous recombination DNA repair pathway — arising through somatic and germline mutations in homologous recombination repair genes, epigenetic mechanisms, and transcriptomic changes — leads to genomic instability and a reliance on error-prone repair mechanisms. Poly (ADP-ribose) polymerase (PARP) inhibitors harness the synthetic lethality of HRD and PARP inhibition, with current approvals encompassing both early-stage and advanced breast cancer in patients with germline BRCA1/2 (gBRCA1/2) mutations. However, emerging evidence suggests efficacy of PARP inhibitors beyond gBRCA1/2-mutated breast cancer to tumors with other homologous recombination repair defects that confer a “BRCAness” phenotype. This Review examines opportunities to broaden the use of PARP inhibitors in breast cancer and underscores the importance of innovative biomarkers, combination strategies, and next-generation agents to maximize therapeutic impact.

Authors

Charlotte S. Walmsley, Adela Rodriguez, Panagiotis A. Konstantinopoulos, Geoffrey I. Shapiro, Sara M. Tolaney, Judy E. Garber, Filipa Lynce

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