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Incidental Germline Mutations in Patients With Advanced Solid Tumors Identified by Cell-Free Circulating Tumor DNA Testing

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Key Points

  • Germline mutations were identified in 1.4% of patients, with mutations in BRCA1 and BRCA2 being the most common.
  • Mutations were most common in patients with ovarian, prostate, pancreatic, and breast cancers. 

In a study reported in the Journal of Clinical Oncology, Slavin et al determined the prevalence of a set of germline cancer predisposition gene mutations incidentally identified by cell-free circulating tumor DNA (cfDNA) testing in patients with advanced solid tumors.

Study Details

The study involved 10,888 consecutive patients with stage III or IV solid tumors who underwent Guardant360 cfDNA testing as part of clinical care between November 2015 and December 2016. The main outcome of the study was to determine the prevalence of putative germline mutations among 16 actionable hereditary cancer predisposition genes, consisting of APC, ATM, BRCA1, BRCA2, CDKN2A, KIT, MLH1, NF1, PTEN, RB1, RET, SMAD4, STK11, TP53, TSC1, and VHL. Patients had more than 50 cancer types, including lung (41%), breast (19%), colorectal (8%), prostate (6%), pancreatic (3%), and ovarian (2%). The average patient age was 63.5 years and 43% were male.

Prevalence of Germline Mutations

Overall, 156 patients (1.4%) had putative hereditary cancer mutations in 11 genes. BRCA1 and BRCA2 mutations were the most common, being found in 41 and 81 patients (78% of patients combined), followed by CDKN2A (n = 10), ATM (n = 5), and TP53 (n = 5). Germline mutations were more common in patients aged < 50 years vs ≥ 50 years (3.0% vs 1.2%, P < .001). The prevalence among those aged < 50 vs ≥ 50 years was 2.1% vs 1.2% (P = .017) when patients with breast cancer were excluded from analysis and 4.7% vs 1.4% among only patients with breast cancer. Germline mutations were most common among patients with ovarian (8.13%), prostate (3.46%), pancreatic (3.34%), and breast (2.2%) cancer. Identification of germline mutations was consistent among 12 individual patients who had multiple samples tested.

The investigators concluded, “Detection of putative germline mutations from cfDNA is feasible across multiple genes and cancer types without prior mutation knowledge. Many mutations were found in cancers without clear guidelines for hereditary cancer genetic counseling/testing. Given the clinical significance of identifying hereditary cancer predisposition for patients and their families as well as targetable germline alterations such as in BRCA1 or BRCA2, research on the best way to validate and return potential germline results from cfDNA analysis to clinicians and patients is needed.”

The study was supported by a grant from the National Cancer Institute and by STOP CANCER, the American Cancer Society, and the Avon Foundation.

Thomas P. Slavin, MD, of City of Hope National Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

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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