The U.S. FDA granted Resolution Bioscience Inc. breakthrough device designation for its cell-free DNA (cfDNA) assay, currently under development as a qualitative, in vitro companion diagnostic (CDx) to detect homologous recombination deficiency (HRD) mutations and gene deletions.

The Resolution HRD liquid biopsy assay, which aims to help doctors identify and match cancer patients with a specific therapy based on their tumor’s genotype, is being evaluated in several clinical trials. If approved, it could be the first assay to detect gene deletions from cfDNA and differentiate between single copy and biallelic, or homozygous, gene deletions via a simple blood draw, Resolution CEO Mark Li told BioWorld. The assay would also detect biallelic loss of function through a combination of a deleterious mutation and a heterozygous deletion in the same gene.

Li said the Kirkland, Wash.-based company will share more details about the assay and its CDx strategy in the weeks ahead. Information regarding a specific timeline for FDA approval will be revealed later this year.

Liquid biopsy assays have the potential to increase access to personalized treatment for patients whose tissue biopsies are insufficient or not achievable, resulting in improved cancer monitoring and detection of any remnants of disease.

The Resolution HRD liquid biopsy assay works by capturing the small fragments of DNA that are shed from cancer tumors and preparing them for next-generation DNA sequencing. Li noted that the bulk of cfDNA floating in the peripheral bloodstream comes from normal cells being renewed and recycled by the body. The tumor-derived cfDNA, or ctDNA as it is known, may comprise less than 1% of a body’s total cfDNA, making detection of mutations especially challenging.

Mutations more common in some cancers

HRD mutations are seen in between 40% and 50% of ovarian cancer cases, 40% of triple-negative breast cancers and up to 25% of prostate cancers. They also have been detected in certain other cancers, such as pancreatic. “Shorter clinical turnaround times demonstrated by the Resolution HRD assay, compared to tissue NGS [next-generation sequencing], may lead to patients receiving effective therapies earlier and with potentially fewer side effects than alternative therapeutic options, such as chemotherapy,” Li said.

The HRD assay looks for homologous recombination deficiency and helps identify patients with either mutations or lost copies of those crucial DNA repair genes, Li explained, adding that mutations in any one of those genes have been shown to compromise the HRD DNA repair pathway. PARP inhibitors block another repair pathway, also causing cells to destabilize and die.

The assay operates on the company’s patented cfDNA NGS analysis platform, which includes proprietary targeted capture NGS chemistry and tightly coupled cloud-based bioinformatics.

“The Resolution cfDNA technology efficiently captures these rare tumor DNA molecules, prepares them for next-generation DNA sequencing, and analyzes the output data to detect three kinds of mutations: single nucleotide variants (SNVs), insertions and deletions (indels) and gene copy loss,” Li explained. “SNVs and indels can cause the damage to the transcribed protein, rendering it oncogenic or nonfunctioning. Gene loss can include the deletion of one (heterozygous) or both (homozygous) copies of a gene. Resolution was first to demonstrate the ability to detect gene deletions from cfDNA — a capability that requires exquisite sensitivity to minute drops in signal.”

Quick turnaround on results

The beauty of the Resolution HRD liquid biopsy assay is that it works with a single blood draw, making it a convenient, safer and noninvasive option for patients. “Tissue biopsies are not always possible, and many biopsies do not yield evaluable samples. For example, in prostate cancer, most patients develop metastasis in their bones, which makes biopsies painful and hard to evaluate,” Li said. The test also shaves time off the wait for results, delivering information on HRD mutations and gene deletions within a week vs. several weeks for a tissue biopsy, he added.

The HRD assay is not Resolution’s only CDx candidate. The company also has high hopes for its Ctdx-Lung assay, which it hopes to make available for patients with advanced non-small-cell lung cancer. Last month, the company reported results from a retrospective liquid biopsy comparison study between the Ctdx-Lung test and Redwood City, Calif.-based Guardant Health Inc.’s Guardant360 test. The study, conducted by researchers at the Dana Farber Cancer Institute, found that Resolution’s assay identified nearly twice as many gene fusion mutations with higher allele frequencies than the Guardant360 test – 13 of 16 vs. seven, respectively. The researchers presented the results at the American Association for Cancer Research annual meeting.

Resolution’s liquid biopsy technology also detected gene deletion in small-cell lung cancer in a study by researchers at Vanderbilt University, suggesting it could aid clinicians in monitoring of disease burden, the patient’s depth of response to a specific therapy and likelihood and timing of disease relapse.

Alameda, Calif.-based Oncocyte Corp. also is working on a liquid biopsy test for lung cancer. The company recently reported the launch of an analytical validation study to establish performance characteristics of the Determavu Lung assay system and then validate them in the company’s CLIA-certified laboratory. If the results are good, the company has predicted the lung cancer test could be commercially available in the second half of this year.