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

TitleIdentification and Management of Pathogenic Variants in BRCA1, BRCA2, and PALB2 in a Tumor-Only Genomic Testing Program.
Publication TypeJournal Article
Year of Publication2022
AuthorsBychkovsky BL, Li T, Sotelo J, Tayob N, Mercado J, Gomy I, Chittenden A, Kane S, Stokes S, Hughes ME, Kim JSeok, Umeton R, Awad MM, Konstantinopoulos PA, Yurgelun MB, Wolpin BM, Taplin M-E, Newmark RE, Johnson BE, Lindeman NI, Macconaill LE, Garber JE, Lin NU
JournalClin Cancer Res
Date Published2022 Jun 01
KeywordsBRCA1 Protein, BRCA2 Protein, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Humans, Lipopolysaccharides, Male, Neoplasms

PURPOSE: Tumor-only genomic testing can uncover somatic and germline pathogenic variants [pathogenic/likely pathogenic (P/LP)] 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 patients with cancer tested between 2016 and 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 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, nonmelanoma skin, endometrial, small cell lung, and colorectal cancers. 37.9% of patients with P/LPs received CGT prior to OncoPanel; an additional 10.7% underwent CGT within 12 months of OncoPanel. Among 132 with CGT, 88.6% had ≥1 clinical factor for CGT compared with 47.1% who did not undergo CGT. Patients with BRCA tumors were more likely to have CGT compared with 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. In addition, 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.

Alternate JournalClin Cancer Res
PubMed ID35363308
PubMed Central IDPMC9167798
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
P50 CA168504 / CA / NCI NIH HHS / United States
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