Multigene Panel Testing Deemed Appropriate for Invasive Lobular Carcinoma

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Researchers say they have identified germline pathogenic variants (PVs) that are associated with an increased risk of invasive lobular carcinoma (ILC) of the breast.

PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 were associated with an increased risk of ILC, but PVs in BRCA1 were not, according to the researchers. They reported these findings in the Journal of Clinical Oncology.

The researchers noted that the involvement of PVs from cancer predisposition genes is not well-defined in ILC. To gain some insight, they used population-based and clinical high-risk cohorts to assess the risks of ILC conferred by inherited PVs.


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The population-based cohort included 2999 patients with ILC, 20,323 patients with infiltrating ductal carcinoma (IDC), and 32,544 control individuals. The clinical cohort included 3796 patients with ILC and 37,405 patients with IDC.

The mean age at ILC diagnosis was about 54 years in the clinical cohort and 64 years in the population-based cohort. In both cohorts, more than 95% of ILCs were estrogen receptor-positive, and more than 92% were HER2-negative.

The researchers compared the frequencies of germline PVs in 12 known breast cancer predisposition genes — ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53 — among patients with ILC, those with IDC, and control individuals.

The team also looked at 9 other cancer predisposition genes — CDKN2A, MLH1, MRE11A, MSH2, MSH6, NBN, NF1, PMS2, and RAD50.

Results

Among patients with ILC, the cumulative frequency of PVs in the 12 breast cancer predisposition genes was 6.5% in the clinical cohort and 5.2% in the population-based cohort.

In a case-control analysis of the population-based cohort, the risk of ILC was highest in CDH1 PV carriers (odds ratio [OR], 15.74; 95% CI, 5.08-50.22), followed by BRCA2 (OR, 4.94; 95% CI, 3.22-7.41) and CHEK2 (OR, 2.56; 95% CI, 1.71-3.73) PV carriers.

The CHEK2 p.Ile157Thr variant was associated with a moderate risk of ILC in the population-based cohort (OR, 1.76; 95% CI, 1.18-2.54; P =.004) but was not associated with an increased risk in the clinical cohort (OR, 1.29; 95% CI, 0.79-1.97; P =.27).

PVs in ATM and NBN were associated with a moderate risk of ILC (ORs greater than 2) in the clinical cohort only. PVs in PALB2 were associated with an increased risk of ILC in the population-based cohort (OR, 3.47; 95% CI, 1.72-6.55; P <.001). PVs in BRCA1 were not associated with an increased risk of ILC in either cohort.

The researchers noted that the overall frequency of PVs was similar between ILC and IDC patients in both cohorts. However, CDH1 PVs were significantly enriched in ILCs (P <.001 for both cohorts), and PVs in BRCA1 were reduced in ILCs (P =.002 in the clinical cohort; P =.08 in the population-based cohort).

“Multigene panel testing is appropriate for women with ILC and to identify women at risk of ILC because PVs in several genes predispose to this form of breast cancer,” the researchers concluded. “Predisposing PVs may also inform the selection of therapy for women with ILC.”

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Yadav S, Hu C, Nathanson KL, et al. Germline pathogenic variants in cancer predisposition genes among women with invasive lobular carcinoma of the breast. J Clin Oncol. Published online October 21, 2021. doi:10.1200/JCO.21.00640



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