Precision medicine aims to match the right treatment to the right patient based on the molecular characteristics of their cancer. PARP inhibitors are one type of targeted therapy that has shown promise in certain breast and ovarian cancers linked to defective DNA repair pathways. However, identifying predictive biomarkers remains an active area of research to optimize patient selection and response to these drugs.

Homologous Recombination Deficiency and BRCA Mutations

One of the best validated predictive biomarkers for PARP Inhibitor Biomarkers response is homologous recombination deficiency (HRD). Tumors with HRD rely on error-prone repair mechanisms like PARP-dependent backup pathways when homologous recombination is compromised. PARP inhibitors specifically exploit this vulnerability by trapping PARP at sites of single-strand DNA breaks, preventing repair and ultimately causing replication-dependent DNA double-strand breaks and tumor cell death.

A major cause of HRD is germline or somatic mutations in BRCA1 and BRCA2 genes which play crucial roles in DNA repair. Clinical trials have consistently shown PARP inhibitors produce durable responses in over 50% of patients with metastatic breast or ovarian cancers associated with BRCA1/2 mutations. Such mutations account for approximately 5-10% of breast cancers and up to 25% of high-grade serous ovarian cancers. Beyond BRCA, other genes involved in homologous recombination like ATM, CHEK2, PALB2, RAD51D have also been linked to PARP inhibitor sensitivity.

Genomic Scar Assay for BRCA

While BRCA mutation status is useful, it only identifies a subset of HRD tumors that may benefit. The genomic scar assay quantifies loss of heterozygosity (LOH), telomeric allelic imbalance, and large-scale state transitions as surrogate markers of defects in double-strand break repair throughout the genome. Cancers with a high “genomic scar score” are considered homologous recombination deficient or “BRCAness-like” independently of BRCA mutation status. The scar score has demonstrated utility in predicting response to platinum chemotherapy as well as PARP inhibitors such as olaparib and Talazoparib in clinical trials.

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