Finally, the poor predictive value of LOH itself for treatment outcomes suggests a limitation of the HRD biomarker in this respect, the researchers concluded.
Potential advantages of using LOH method
However, the potential advantages of the LOH method include the minimal sequence reads and the ability to integrate the LOH into current targeted gene capture workflows, the researchers wrote, and the LOH score appears to be a reliable predictor of HRD positivity.
“Although we have found that the regions targeted by our assay are insufficient to identify HRD-associated mutational signatures, future refinements to this approach could integrate minimal additional sequencing targets designed to robustly identify such signatures in concert with LOH events,” they concluded.
Study shares the details of detection methodology
“Tumors with HRD are sensitive to certain cancer chemotherapeutic agents [PARP inhibitors],” said Dr. Krumm, in an interview. “Until recently, HR-deficient tumors were primarily identified via inactivating BRCA1 or BRCA2 mutations, but now it is understood that an entire repair pathway can be affected and can result in HRD. Therefore, we sought to implement an NGS-based approach that could detect the ‘HRD phenotype’ in the DNA of tumors,” he said.
The approach developed by Dr. Krumm and colleagues and presented in the current study “is not the first in the field, as some commercial tests have similar approaches,” he said. However, the current study is important, “because it openly publishes the methodology and detailed results of our validation work in bringing HRD detection online in our clinical lab,” he said.
“One of the advantages of a genome-wide approach is that we can identify HR-deficient tumors, even when BRCA1 and BRCA2 do not have any detectable loss-of-function mutations,” said Dr. Krumm. “HRD detection is a relatively young test in the field of next-generation sequencing (NGS)–based cancer diagnostics. One of the challenges currently is the lack of large, standardized reference data sets or reference materials that can be used to compare tests and methodology in a clinical setting. We hope that by publishing our methods, more data sets can be generated and published,” he said.
Some specific challenges to using the test clinically today include the need for a paired tumor plus blood sample, and the need for a relatively high fraction of tumor content in the sample, Dr. Krumm noted.
“This test is currently being used in a clinical setting at the University of Washington, as it is a laboratory-developed test (LDT) and part of our clinically validated NGS platform,” said Dr. Krumm. “This test highlights how LDTs can advance clinical testing capabilities and improve the care of our patients and illustrates the UW Medicine position that LDTs are a necessary and important part of the clinical care. That said, we anticipate that additional validation studies, including long-term clinical effectiveness and outcome studies, will be required to bring HRD testing into a commercial platform that undergoes FDA review,” he explained.
The study was supported by the Brotman Baty Institute for Precision Medicine, the National Institutes of Health, and the Department of Defense, Ovarian Cancer Research Program Clinical Development Award. Dr. Krumm disclosed stock and ownership interests in Reference Genomics.
