Germline testing may benefit all patients with metastatic, recurrent cancer, data suggest
Multigene germline genetic testing should be considered for all patients with advanced cancer to better guide treatment selection, according to study results published in Journal of Clinical Oncology.
Researchers found that 8% of patients with metastatic or recurrent cancer had a germline alteration with therapeutic actionability.
“We know that tumor mutational profiling for identification of somatic alterations for targeted treatment is increasingly being performed in [patients with advanced cancer],” Zsofia K. Stadler, MD, oncologist at Memorial Sloan Kettering Cancer Center, told Healio. “We also know that the identification of germline alterations has important implications for our patients with cancer, including implementation of appropriate cancer surveillance measures, potential risk-reducing measures and, of course, predictive genetic testing for at-risk relatives. However, less is known about the clinical impact of germline findings on targeted cancer treatment.”
Investigators sought to assess how identification of a germline mutation in a cancer susceptibility gene may guide selection of treatment among a cohort of 11,947 patients (median age, 57 years; 53.2% women; 60% white) with advanced cancer. The most common of the more than 50 cancer types were breast (14%), prostate (14%), pancreatic (12%) and colorectal (11%).
Overall, 17% (n = 2,037) harbored a likely pathogenic or pathogenic germline variant and 9% (n = 1,042) had a likely pathogenic or pathogenic germline variant classified by the OncoKB precision oncology knowledge base as having possible therapeutic actionability (4% level 1, 4% level 3B and < 1% level 4).
BRCA1 and BRCA2 were the most common potentially actionable variants identified (42%), followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%) and PALB2 (5%).
Among the 9,079 patients with metastatic or recurrent cancer, researchers found that 8% harbored an OncoKB variant of level 1, defined as an FDA-recognized biomarker predictive of response to an FDA-approved drug in the indication, or level 3B, defined as a biomarker predictive of response to an investigational or FDA-approved drug in another indication. Of these, 61% with level 1 and 18% with level 3B findings received germline genotype-directed therapy.
Moreover, more than half (54%) of patients with BRCA1 or BRCA2 mutations, 75% of those with mismatch repair, 43% with PALB2, 35% with RAD51C or RAD51D, 24% with BRIP1 and 19% with ATM mutations underwent germline genotype-directed therapy.
Among the 188 patients with BRCA1 and BRCA2 mutations on treatment with a poly(ADP-ribose) polymerase inhibitor, 45% (n = 84) had tumors other than breast and ovarian cancer and received treatment in an investigational setting.
“In patients with advanced or recurrent cancer, 8% of patients harbored a germline mutation in a cancer gene with therapeutic actionability. Of these patients, 40% received the germline genotype-directed treatment,” Stadler said. “Our data suggest that all patients with advanced cancer may benefit from germline genetic analysis for identification of potential targeted treatments. As more germline genotype-directed therapies become available in early-stage cancers, we anticipate that the clinical utility of germline testing for identification of targeted treatment will continue to expand beyond only patients with advanced disease.”
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Zsofia K. Stadler, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: stadlerz@mskcc.org.
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