In a study reported in the Journal of Clinical Oncology, Yadav et al found that germline pathogenic variants in the cancer predisposition genes ATM, BRCA2, CDH1, CHEK2, and PALB2 were associated with an increased risk of invasive lobular carcinoma of the breast, with no association with BRCA1 pathogenic variants being observed. Frequencies of pathogenic variants in patients with infiltrating ductal carcinoma were similar to those in patients with invasive lobular carcinoma, suggesting that histology should not affect the decision to obtain genetic testing.
Study Details
The study involved findings from clinical multigene panel testing in 2,999 women with invasive lobular carcinoma, 20,323 women with infiltrating ductal carcinoma, and 32,544 unaffected female controls in a population-based cohort from the CARRIERS consortium, as well as a clinical testing cohort consisting of 3,796 patients with invasive lobular carcinoma and 37,405 patients with infiltrating ductal carcinoma referred to Ambry Genetics for testing between March 2012 and December 2016. Frequencies of germline pathogenic variants in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with invasive lobular carcinoma and unaffected female controls, and between women with invasive lobular carcinoma and those with infiltrating ductal carcinoma.
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Key Findings
The frequency of pathogenic variants among women with invasive lobular carcinoma was 6.5% in the clinical testing cohort and 5.2% in the population-based cohort.
In case-control analysis in the population-based cohort, CDH1 (odds ratio [OR] = 15.74) and BRCA2 pathogenic variants (OR = 4.94) were associated with the highest risk of invasive lobular carcinoma; CHEK2, ATM, and PALB2 pathogenic variants were associated with moderate risk (ORs = 2–4), and BRCA1 pathogenic variants and CHEK2 p.Ile157Thr were not associated with clinically relevant risk (OR < 2).
The overall frequency of pathogenic variants in women with invasive lobular carcinoma was similar to that in those with infiltrating ductal carcinoma in both the clinical testing cohort (6.5% vs 9.2%) and population-based cohort (5.2% vs 5.9%). CDH1 pathogenic variants were more than 10-fold enriched in patients with invasive lobular carcinoma vs infiltrating ductal carcinoma in both cohorts. Pathogenic variants in BRCA1 were significantly reduced in invasive lobular carcinoma vs infiltrating ductal carcinoma in the clinical testing cohort (P = .002) but not in the population-based cohort. PALB2 pathogenic variants were significantly less frequent in invasive lobular carcinoma vs infiltrating ductal carcinoma in the clinical testing cohort (P = .005) but not in the population-based cohort. No other genes had a significant difference in the frequency of pathogenic variants among infiltrating ductal carcinoma vs invasive lobular carcinoma in either cohort.
The investigators concluded, “The study establishes that pathogenic variants in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of invasive lobular carcinoma, whereas BRCA1 pathogenic variants are not. The similar overall pathogenic variant frequencies for invasive lobular carcinoma and infiltrating ductal carcinoma suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to infiltrating ductal carcinoma, multigene panel testing may be appropriate for women with invasive lobular carcinoma, but CDH1 should be specifically discussed because of low prevalence (0.2% in the population-based cohort and 0.5% in the clinical testing cohort among invasive lobular carcinomas) and gastric cancer risk.”
Fergus J. Couch, PhD, of the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Institutes of Health and Breast Cancer Research Foundation. For full disclosures of the study authors, visit ascopubs.org.
