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

Abstract

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.

Figure 1.

Flow Diagram. A total of 7,575 patients met inclusion criteria. Of these, 1,005 unique patients were identified with any variant in BRCA1, BRCA2, and/or PALB2, of which 272 unique patients had a P/LP variant. Of 272 unique patients, 12 had two P/LP variants and 4 had three P/LP variants. Among the 12 patients with two P/LP variants, 4 had one P/LP variant in BRCA1 and one P/LP variant in BRCA2, 5 had two P/LP variants in BRCA2, and 3 had 1 P/LP variant in BRCA2 and one P/LP variant in PALB2. Among the 4 patients with three P/LP variants, 1 patient had a P/LP variant in BRCA1 and two P/LP variants in BRCA2, 2 patients had three P/LP variants in BRCA2, and 1 patient had two P/LP variants in BRCA2 and one P/LP variant in PALB2. Rectangles denote patient-level data. Ovals denote variant-level data. *One patient with a P/LP variant in PALB2 had germline BRCA1/2 testing, but not germline PALB2 testing, and was classified as not having germline testing in this figure. P/LP, pathogenic/likely pathogenic; B/LB, benign/likely benign; VUS, variant of uncertain significance; CGT, clinical germline testing; m, months.