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J Clin Oncol. 2018 Oct 19:JCO1800328. doi: 10.1200/JCO.18.00328. [Epub ahead of print]

Identification of Incidental Germline Mutations in Patients With Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing.

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Thomas P. Slavin, Kar Wing Kevin Tsang, Susan L. Neuhausen, Stacy W. Gray, and Jeffrey N. Weitzel, City of Hope, Duarte; Kimberly C. Banks, Darya Chudova, Justin I. Odegaard, Rebecca J. Nagy, Christine E. Lee, and Richard B. Lanman, Guardant Health, Redwood City; Razelle Kurzrock, University of California, San Diego, Moores Cancer Center, San Diego, CA; Geoffrey R. Oxnard, Dana-Farber Cancer Institute; Aditya Bardia, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; Massimo Cristofanilli, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Angel A. Rodriguez, Houston Methodist Hospital; Funda Meric-Bernstam, The University of Texas MD Anderson Cancer Center, Houston, TX; Brian Leyland-Jones, Avera Cancer Institute, Sioux Falls, SD; Mike F. Janicek, Arizona Oncology Associates Gynecology Oncology, Scottsdale, AZ; Michael Lilly, Medical University of South Carolina, Charleston, SC; and Guru Sonpavde, The University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL.



To determine the potential for detection of incidental germline cancer predisposition mutations through cell-free DNA (cfDNA) analyses in patients who underwent solid tumor somatic mutation evaluation.


Data were evaluated from 10,888 unselected patients with advanced (stage III/IV) cancer who underwent Guardant360 testing between November 2015 and December 2016. The main outcome was prevalence of putative germline mutations identified among 16 actionable hereditary cancer predisposition genes.


More than 50 cancer types were studied, including lung (41%), breast (19%), colorectal (8%), prostate (6%), pancreatic (3%), and ovarian (2%). Average patient age was 63.5 years (range, 18 to 95 years); 43% were male. One hundred and fifty-six individuals (1.4%) had suspected hereditary cancer mutations in 11 genes. Putative germline mutations were more frequent in individuals younger than 50 years versus those 50 years and older (3.0% v 1.2%, respectively; P < .001). Highest yields of putative germline findings were in patients with ovarian (8.13%), prostate (3.46%), pancreatic (3.34%), and breast (2.2%) cancer. Putative germline mutation identification was consistent among 12 individuals with multiple samples. Patients with circulating tumor DNA copy number variation and/or reversion mutations suggestive of functional loss of the wild-type allele in the tumor DNA also are described.


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.

[Available on 2019-12-10]

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