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Germline Genetic Testing After Tumor Sequencing Can Uncover Clinically Actionable Variants

NEW YORK – Germline genetic testing after tumor sequencing can uncover clinically actionable alterations among cancer patients, according to a new study from genetic testing company Invitae and its collaborators. 

Germline genetic testing is typically recommended for cancer patients who are thought to have hereditary disease, while tumor sequencing is generally performed on patients with advanced disease, but both can inform cancer treatment approaches.

The Invitae-led team conducted a retrospective cohort study of more than 2,000 cancer patients who underwent germline testing after previously having their tumor DNA sequenced to determine the yield and utility of such post-tumor sequencing germline testing. As they reported in a paper in JAMA Network Open on Wednesday, the researchers found that germline testing could identify clinically important variants, including ones not captured through tumor sequencing. 

"Tumor sequencing alone is not sufficient to provide the full genetic picture needed to inform cancer care," co-author Robert Nussbaum, chief medical officer of Invitae, said in a statement. "Our study uncovered a high rate of actionable findings from germline testing following tumor sequencing, including some which were missed by tumor profiling, offering a strong rationale for further integrating germline genetics into routine care for cancer patients."

He and his colleagues analyzed a cohort of 2,023 individuals who had undergone germline testing of hereditary cancer predisposition genes and who had either a current cancer diagnosis or a personal history of cancer. The participants all previously had their tumor sequenced, and the reasons they then underwent germline testing varied, including their tumor-based results, family history, and patient concern.

Slightly more than 30 percent of these patients had one or more pathogenic germline variants in known cancer predisposition genes.

Clinically important variants in certain key genes were more likely to be of germline origin, the researchers found. About 40 percent of pathogenic variants in BRCA1 and BRCA2 and 28 percent in MLH1, MSH2, MSH6, and PMS2 were of germline origin, while only about 4 percent of pathogenic TP53 variants were. According to current management guidelines, personalized therapy labels, and clinical trial eligibility, most of the pathogenic germline variants the researchers identified were potentially clinically actionable.

About 8 percent of these variants were not reported by tumor sequencing as either somatic or germline findings of clinical significance. They were largely missed due to the limits of tumor sequencing, differences in variant interpretation between the approaches, and differences in the genes tested. For the remaining patients, pathogenic germline variants were reported as clinically significant, though generally without an indication that they were germline rather than somatic in origin.

Additionally, 11.2 percent of patients didn't have their pathogenic germline variants detected until after they developed a second primary cancer that potentially could have been prevented, as 46 percent of those patients had pathogenic variants associated with screening or risk-reduction guidelines.

The high germline-positive rate the researchers found suggested to them that germline testing may not be utilized as often as it should. When they examined how the patients in their study who turned out to have a pathogenic germline variant would have been handled under current guidelines for follow-up germline genetic testing, they noted that under European Society for Medical Oncology recommendations, 82 percent of patients would have been recommended for follow-up testing, while 73 percent would have been recommended under MSK-IMPACT cohort criteria. This, they noted, suggests about 20 percent of patients with pathogenic germline variants did not meet the criteria for follow up, meaning those criteria may be too narrow in scope.

"Expanding germline testing guidelines will ensure all cancer patients who can benefit from comprehensive genetics in their care will receive this information," Nussbaum said. "By capturing genetic information on both tumor biology and a patient's inherited risk of disease, we can develop more effective, personalized treatment plans and help inform family members of additional inherited risk, helping improve outcomes for both patient and family."