Precision oncology has revolutionized cancer treatment in recent years with the introduction of targeted therapies that rely on identifying specific biomarkers. Poly ADP-ribose polymerase or PARP inhibitors are a class of targeted drugs that have shown great promise in certain cancers associated with DNA repair deficiencies. However, like other targeted therapies, identifying the right patients most likely to respond to PARP inhibitors remains a challenge. Ongoing research is focused on discovering reliable biomarkers that can help select optimal candidates for PARP inhibitor therapy.

The PARP family of proteins

Poly ADP-ribose polymerases or PARPs are a family of proteins involved in DNA damage repair. The most studied member, PARP1, plays a key role in single-strand break repair via the base excision repair pathway. Cancers with defects in homologous recombination repair (HRR) of DNA double-strand breaks, such as those caused by mutations in BRCA1 and BRCA2 genes, rely more on alternative repair pathways like PARP-mediated repair. PARP inhibitors are able to synthetically kill HRR-deficient cells by trapping PARP at sites of damaged DNA, preventing repair and ultimately causing replication-dependent cell death.

BRCA mutations as predictive biomarkers

Initial PARP inhibitor trials in ovarian and breast cancers demonstrated exceptionally high response rates in patients with germline BRCA1/2 mutations, validating the concept of exploiting DNA repair deficiencies. Mutations in BRCA1 and BRCA2 are considered the best validated biomarkers for response to PARP inhibitors to date. Several PARP inhibitors have now been approved for platinum-sensitive relapsed ovarian cancer and advanced breast cancer with a germline or somatic BRCA mutation. Ongoing studies are examining the utility of PARP inhibitors in earlier disease settings as well.

Beyond BRCA - Expanding the eligible population

While germline BRCA mutations predict high response rates, they remain relatively rare occurring in about 10-15% of ovarian cancers and 5-10% of breast cancers. Furthermore, not all BRCA mutation carriers respond equally to PARP inhibitors suggesting additional factors may influence outcomes. Significant effort is focused on identifying other predictive biomarkers that can expand the eligible population for PARP inhibitor therapy.

Emerging predictive biomarkers

Homologous recombination deficiency (HRD) score: Next-generation profiling assays like the Myriad myChoice HRD test quantify HRR deficiency based on large-scale genomic instability and loss of heterozygosity, serving as a proxy for wider defects in this pathway independent of any single gene. High HRD scores predict improved responses similar to BRCA mutation carriers.

Other HRR gene mutations: Beyond BRCA1/2, mutations or epigenetic silencing of additional HRR genes like ATM, ATR, FANCM, RAD51C/D have shown potential as predictive biomarkers. Studies demonstrate responses to PARP inhibition in carriers of rare mutations in these and other HRR genes.

Biomarkers of platinum sensitivity: Since PARP inhibitors mimic the effects of platinum drugs, biomarkers predictive of platinum responses like residual disease post-chemotherapy, disease-free interval or prior complete remission also predict benefit from PARP inhibitors.

Tumor molecular subtyping: Immunohistochemistry and gene expression profiling can define biologically distinct tumor subtypes with differential dependence on DNA repair pathways. The basal-like breast cancer subtype for example shows characteristics of homologous recombination deficiency.

PARP expression levels: Emerging evidence indicates higher PARP1/2 expression in tumor tissue may potentially increase sensitivity to catalytic PARP inhibitors by slowing repair kinetics. Quantitative measures of PARP levels are being explored as predictive biomarkers.

Liquid biopsy to monitor treatment response

With more PARP Inhibitors Biomarkers gaining approval, developing robust biomarkers is imperative to maximize therapeutic benefit from these promising agents. Monitoring tumor DNA in blood or other body fluids, known as liquid biopsies, provides a non-invasive tool to track treatment responses and resistance. Several studies now demonstrate changes in circulating tumor DNA levels strongly correlate with response to PARP inhibitors measured by radiographic imaging. Liquid biopsy promises to transform treatment monitoring and enable timely switching to alternative strategies upon development of resistance.

Precision oncology tailored to underlying molecular defects holds immense promise with PARP inhibitors. Ongoing research aims to discover robust predictive biomarkers beyond the currently validated BRCA mutations that can expand patient eligibility. Combining molecular profiling tools to define homologous recombination deficiency more broadly alongside assessment of emerging predictive markers shows potential to optimize selection of candidates most likely to benefit from PARP inhibition. Improved patient stratification will maximize clinical benefit from these targeted therapies. Similarly, liquid biopsy may enable dynamic, real-time monitoring of treatment responses and resistance, guiding clinical care and future trial designs. 

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