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Germline Pathogenic Variants in CDH1, BRCA2, CHEK2, ATM, and PALB2 Associated with Increased Risk of Invasive Lobular Carcinoma

Multigene panel testing may be appropriate for women with invasive lobular carcinoma and to identify women at risk
27 Oct 2021
Breast cancer;  Pathology/Molecular biology

The largest study involving multigene panel testing of women with invasive lobular carcinoma describes the frequency of germline pathogenic variants (PVs) in invasive lobular carcinoma and the differences in gene-specific frequencies between invasive lobular carcinoma and infiltrating ductal carcinoma. The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of invasive lobular carcinoma, whereas BRCA1 PVs are not. The similar overall PV 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 and gastric cancer risk according to Fergus J. Couch of the Mayo Clinic in Rochester, MN, US and colleagues who published their findings on 21 October 2021 in the Journal of Clinical Oncology.

The authors wrote that women diagnosed with invasive lobular carcinoma of the breast rarely benefit from hereditary cancer testing because the involvement of PVs from cancer predisposition genes in invasive lobular carcinoma is not well-defined. Invasive lobular carcinoma is a distinct subtype of breast cancer with unique biologic characteristics and clinical outcomes.  

Germline PVs in CDH1 have been associated with hereditary diffuse gastric cancer and invasive lobular carcinoma. However, the magnitude of invasive lobular carcinoma risk related to PVs in CDH1 varies substantially between studies because of small numbers of carriers. The risk of invasive lobular carcinoma among carriers of PVs in other genes from multigene hereditary cancer testing panels has not been adequately defined. Some studies have reported that PVs in BRCA1 and TP53 do not predispose to invasive lobular carcinoma, whereas PVs in BRCA2 and the CHEK2 I157T missense variant have been associated with invasive lobular carcinoma. Previous studies have primarily evaluated the frequency of germline PVs in CDH1 and other genes among high-risk women with family history of breast cancer or young age at diagnosis.

The data set from the CAnceR RIsk Estimates Related to Susceptibility (CARRIERS) consortium included 3,437 women with invasive lobular carcinoma, 25,807 women with infiltrating ductal carcinoma, and 35,365 unaffected women. For the primary analysis, contributing studies enriched for young age or family history of breast cancer were excluded. Therefore, the primary analysis of this population-based cohort included 2,999 women with invasive lobular carcinoma, 20,323 women with infiltrating ductal carcinoma, and 32,544 unaffected female controls.

The clinical cohort data set included a nationwide sample of 3,796 adult women with invasive lobular carcinoma and 37,405 with infiltrating ductal carcinoma referred by genetic counsellors or clinical care providers across the US for clinically indicated germline genetic testing because of personal or family history of cancer.

Frequencies of germline PVs 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 infiltrating ductal carcinoma.

The frequency of PVs in breast cancer predisposition genes among women with invasive lobular carcinoma was 6.5% in the clinical cohort and 5.2% in the population-based cohort.

In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of invasive lobular carcinoma (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. 

BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of invasive lobular carcinoma.

Compared with infiltrating ductal carcinoma, CDH1 PVs were >10-fold enriched, whereas PVs in BRCA1 were substantially reduced in invasive lobular carcinoma.

In this article, the authors described the results from the largest study of germline PVs in cancer predisposition genes among women with invasive lobular carcinoma from a clinical testing cohort and a population-based cohort, both of which included large numbers of racially and ethnically diverse women from the US. They commented that multigene panel testing is appropriate for women with invasive lobular carcinoma and to identify women at risk of invasive lobular carcinoma because PVs in several genes predispose to this form of breast cancer. Predisposing PVs may also inform the selection of therapy for women with invasive lobular carcinoma.

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. JCO; Published online 21 October 2021. DOI: 10.1200/JCO.21.00640 

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