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

Authors
  • 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
Type
Published Article
Journal
Clinical Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Jun 01, 2022
Volume
28
Issue
11
Pages
2349–2360
Identifiers
DOI: 10.1158/1078-0432.CCR-21-2861
PMID: 35363308
PMCID: PMC9167798
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

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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