Whole-Genome Sequencing Approach Identifies Cancer Patients Benefitting From PARP-Inhibitor Treatment

Targeted cancer therapies such as PARP inhibitors can be highly effective, but only for patients whose tumors carry specific DNA repair defects. Identifying these patients accurately remains challenging, as current commercial tests focus on a narrow set of genetic mutations and may miss others that also predict treatment response. As a result, some patients who could benefit from PARP inhibitors are not identified, while others receive treatments unlikely to help them. Now, a new genome-wide approach has shown promise in improving how these patients are selected.

In research led by Weill Cornell Medicine (New York, NY, USA), in collaboration with NewYork-Presbyterian (New York, NY, USA) and Illumina (San Diego, CA, USA), the team used whole-genome sequencing of tumor samples collected through a precision medicine initiative involving clinical partners and a sequencing technology provider. Using these data, the researchers trained an algorithm to detect homologous recombination deficiency, a DNA-repair defect that makes tumors vulnerable to PARP inhibitors and platinum-based chemotherapy.

Image: Whole-genome sequencing enables broader detection of DNA repair defects to guide PARP inhibitor cancer therapy (Photo courtesy of Illumina)

Unlike conventional tests that mainly search for BRCA1 and BRCA2 mutations, the algorithm evaluates genome-wide patterns of DNA damage associated with defective homologous recombination repair. This broader analysis captures alterations across many genes and structural changes that signal impaired DNA repair. Advances in sequencing technology have made whole-genome sequencing sufficiently affordable and scalable for this type of clinical application.

The researchers trained the algorithm using 305 tumor samples from patients with various cancers and validated it on an independent cohort of 556 tumors. Performance was then compared with commercial testing methods using an additional 212 samples. The algorithm identified homologous recombination deficiency in 21% of breast tumors, 20% of pancreatic and bile duct tumors, and 17% of gynecological tumors, with nearly one quarter of positive cases lacking BRCA1 or BRCA2 mutations.

The results, published in Communications Medicine, suggest that whole-genome sequencing can identify a broader group of patients who may benefit from PARP inhibitors than existing targeted tests. The approach also appeared to correct false-negative and false-positive predictions from commercial assays when compared with patient outcomes. With further validation, this strategy could improve treatment selection across multiple cancer types and help guide more precise use of DNA-damaging therapies. The researchers plan larger studies to assess the algorithm’s utility in routine clinical care.

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Weill Cornell Medicine
NewYork-Presbyterian
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