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Identification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program

  • Bychkovsky, Brittany L.1, 2, 3
  • Li, Tianyu4
  • Sotelo, Jilliane2, 5
  • Tayob, Nabihah3, 4
  • Mercado, Joanna2, 6
  • Gomy, Israel2
  • Chittenden, Anu2
  • Kane, Sarah2, 7
  • Stokes, Samantha2
  • Hughes, Melissa E.1
  • Kim, Ji Seok1, 2, 8
  • Umeton, Renato4
  • Awad, Mark M.1, 3
  • Konstantinopoulos, Panagiotis A.1, 3
  • Yurgelun, Matthew B.1, 2, 3
  • Wolpin, Brian M.1, 3
  • Taplin, Mary-Ellen1, 3
  • Newmark, Randall E.9
  • Johnson, Bruce E.1, 3, 10
  • Lindeman, Neal I.3, 11
  • And 3 more
  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
  • 2 Division for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA
  • 3 Harvard Medical School, Boston, MA, USA
  • 4 Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
  • 5 Thermo Fisher Scientific, Waltham, MA, USA
  • 6 Genome Medical, South San Francisco, CA, USA
  • 7 Memorial Sloan Kettering Cancer Center, Clinical Genetics Service, New York, NY, USA
  • 8 Dewpoint Therapeutics, Boston, MA, USA
  • 9 Massachusetts General Hospital Research Institute, Partners Healthcare, Boston, MA, USA
  • 10 Center for Cancer Genomics, Dana-Farber Cancer Institute, Boston, MA, USA
  • 11 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
Published Article
Clinical Cancer Research
American Association for Cancer Research
Publication Date
Jun 01, 2022
DOI: 10.1158/1078-0432.CCR-21-2861
PMID: 35363308
PMCID: PMC9167798
PubMed Central
  • Article


Purpose: Tumor-only genomic testing can uncover somatic and germline pathogenic variants (P/LPs) in cancer predisposition genes. We describe the prevalence of P/LPs in BRCA1/2 and PALB2 (B1B2P2) across malignancies and the frequency of clinical germline testing (CGT) in patients with P/LPs in B1B2P2 identified on tumor-only testing. Experimental Design: Among 7,575 cancer patients tested between 2016–2018 with the OncoPanel tumor-only sequencing assay, we characterized P/LP frequencies by tumor type, receipt of CGT prior to or within 12 months (m) after OncoPanel, and factors associated with CGT. Results: 272 (3.6%) patients had OncoPanel-detected P/LPs in B1B2P2 : 37.5% of P/LPs were in BRCA-related cancers; the remainder were in non-BRCA tumors. P/LPs were detected in ≥5% of breast, pancreatic, prostate, ovarian, non-melanoma skin, endometrial, small-cell lung and colorectal cancers. 37.9% of patients with P/LPs received GCT prior to OncoPanel; an additional 10.7% underwent CGT within 12m of OncoPanel. Among 132 with CGT, 88.6% had ≥1 clinical factor for CGT compared to 47.1% who did not undergo CGT. Patients with BRCA -tumors were more likely to have CGT compared to those without (81.4% vs. 29.0%, p<0.0001). Among patients with CGT, 70.5% (93/132) of P/LPs were germline. Conclusions: Tumor-only genomic testing identified P/LPs in B1B2P2 in 3.6% of patients. 52.9% of patients with tumor-detected P/LPs and without CGT did not meet personal or family history criteria for CGT. Additionally, some patients with tumor-detected P/LPs were not referred for CGT, especially those with non-BRCA tumors. Given implications for treatment selection and familial cancer risk, processes to reliably trigger CGT from tumor-genomic findings are needed.

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