Hereditary vs Sporadic Invasive Lobular Carcinoma and Impact of Locoregional Therapy on Disease-Free Survival

INTRODUCTION: Pathogenic germline variants in the CDH1 gene result in hereditary diffuse gastric cancer syndrome, conferring a 50% lifetime risk of invasive lobular carcinoma (ILC) of the breast. Little is known about the distinction between hereditary and sporadic ILC, nor about the prevalence of other breast cancer susceptibility genes in ILC. METHODS: We evaluated an institutional cohort of patients with early stage ILC who underwent germline panel testing and determined the frequency and type of pathogenic variants. Patient, tumor, and treatment characteristics between hereditary and sporadic cases were compared. The log rank test was used to evaluate the relationship between local therapy and disease-free survival by variant status. RESULTS: In 246 patients with ILC, panel testing identified a pathogenic or likely pathogenic variant in 13% (n = 32). These variants occurred in 17 different genes, the most frequent being BRCA2 (31%) and CHEK2 (13%). Tumor stage, grade, receptor subtype, and operative therapy did not differ between hereditary and sporadic cases. Among patients with hereditary ILC, those who underwent breast conserving surgery or unilateral mastectomy had significantly shorter disease-free survival compared with those who underwent bilateral mastectomy (hazard ratio 4.1, 95% CI 1.2–13.6, p = 0.02). CONCLUSION: Surprisingly, we found the most common variant gene in patients with ILC was BRCA2 and not CDH1; this likely reflects higher population prevalence of BRCA2 mutation despite the much higher penetrance of CDH1 mutation for ILC specifically. For patients with hereditary ILC, bilateral mastectomy may improve disease-free survival, a finding not consistently demonstrated in hereditary invasive ductal carcinoma.