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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Review Series

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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Figure 1

BRCA function in maintenance of genomic stability — lethality with PARP inhibition.

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BRCA function in maintenance of genomic stability — lethality with PARP ...
Schematic illustrating the key functions of BRCA1/2 in maintaining genomic stability and the mechanisms underlying synthetic lethality with PARP inhibition. BRCA1/2 play critical roles in maintaining genomic integrity through three major mechanisms. (A) Homologous recombination–mediated (HR-mediated) repair of DNA double-strand breaks. PARP is recruited to sites of single-strand DNA breaks and facilitates their repair. In HR-deficient cells lacking functional BRCA1/2, double-strand break repair is compromised, resulting in genomic instability and ultimately cell death. (B) Protection of stalled replication forks from nucleolytic degradation. BRCA1 and BRCA2 also play essential roles in protecting stalled replication forks from degradation. During replication stress induced by PARPi treatment, PARP-DNA complexes become trapped on DNA, causing replication fork stalling. BRCA1 and BRCA2 facilitate loading of RAD51 onto stalled replication forks, preventing nucleases, such as MRE11, from degrading newly synthesized DNA. In the absence of BRCA1 or BRCA2, RAD51 loading fails to occur, leaving replication forks vulnerable to nucleolytic degradation and resulting in replication fork collapse and cytotoxicity. (C) Suppression of single-stranded DNA gap formation during DNA replication. Both PARP and BRCA1/2 suppress single-stranded DNA gap formation during DNA replication. PARP inhibition in BRCA1/2-mutant cells results in loss of both gap suppression mechanisms, leading to the accumulation of single-stranded DNA gaps and ultimately cell death. BER, base excision repair; ssDNA, single-stranded DNA; SSB, single-strand break.