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Use of Germline Mutation Profiling in Patients With Advanced Cancers


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In a study reported in the Journal of Clinical Oncology, Zsofia K. Stadler, MD, and colleagues found that germline mutation testing revealed therapeutically actionable variants in 8% of patients with recurrent or metastatic cancers, with 40% of them receiving directed treatment.

As stated by the investigators: “Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer.”

Study Details


“Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer.”
— Zsofia K. Stadler, MD, and colleagues

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The study involved 11,947 patients with more than 50 different malignancies undergoing tumor genomic profiling at Memorial Sloan Kettering Cancer Center who prospectively consented to germline cancer predisposition gene analysis between 2015 and 2019. The most common malignancies were breast (14%), prostate (14%), pancreatic (12%), and colorectal cancers (11%).

In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Oncology knowledge base levels of evidence for gene classification include: level 1 = a U.S. Food and Drug Administration (FDA)-recognized biomarker predictive of response to an FDA-approved drug in a specific indication; level 3B = biomarker predictive of response to an FDA-approved or investigational drug in another indication; and level 4 = compelling biologic evidence of the biomarker as predictive of response to a drug.

Key Findings

Among the 11,947 patients, 2,037 (17%) were found to harbor a germline LP/P variant. On oncology knowledge base classification, 9% (n = 1,042) had an LP/P variant in a gene with therapeutic implications, including 4% with level 1, 4% with level 3B, and 1% with level 4 classification. Among the therapeutically actionable findings, BRCA1/2 accounted for 42%, CHEK2 for 13%, ATM for 12%, mismatch repair genes for 11%, and PALB2 for 5%.

Among the 9,079 patients with metastatic or recurrent cancer, 710 (8%) harbored a germline LP/P variant of level 1 (n = 371) or level 3B (n = 339) classification. Of these patients, 289 (3.2% of advanced cancer cohort and 41% of those with germline LP/P variant) received germline genotype-directed therapy, with such therapy received by 61% of those with level 1 findings and 18% of those with level 3B findings.

Directed therapy was received by 54% of BRCA1/2, 75% of mismatch repair gene, 43% of PALB2, 35% of RAD51C/D, 24% of BRIP1, and 19% of ATM variant carriers. Among 188 patients with BRCA1/2 LP/P variants who received a PARP inhibitor as directed therapy, 84 (45%) had tumors other than breast or ovarian cancer, with the therapy being given in an investigational setting for these patients.

The investigators concluded: “In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability, with 40% of these patients receiving germline genotype–directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.”

Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center, Precision, Interception and Prevention Program at Memorial Sloan Kettering Cancer Center, National Cancer Institute, and others. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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