Clinicopathologic characterization of breast carcinomas in patients with non-BRCA germline mutations: results from a single institution's high-risk population

Abstract

As multigene panel testing for hereditary cancer syndromes becomes commonplace, germline mutations in genes other than BRCA1/2 are increasingly identified in breast cancer patients. While histopathologic features of BRCA-mutated breast cancers have been well-characterized, less is known about non-BRCA-related hereditary cancers. We herein investigate the clinicopathologic characteristics of breast cancers in women with non-BRCA germline mutations. Out of 612 women who underwent germline testing, 16 (2.6%) women with 18 cancers had mutations in non-BRCA genes: ATM, CHEK2, PALB2, TP53, BMPR1A, BRIP1, MUTYH, and RAD50. An additional 2 cancers were identified in a woman with a diagnosis of Bloom syndrome (BLM mutation) who was not germline tested. Average age at diagnosis was 50 (range: 27-77), and 65% had no personal cancer history. The majority (79%) of tumors were grade 1 to 2; 35% were either lobular or ductal with lobular features. Stromal responses varied from absent to desmoplastic to sclerotic; 69% of cases had an in situ component. With the exception of a brisk lymphocytic response in BLM- and TP53-mutated cancers, lymphocytic infiltration was mild or absent. In summary, the majority of non-BRCA-related hereditary breast cancers represent the patient's sentinel malignancy. Lobular features were seen in a subset, and high-grade, immunogenic carcinomas were uncommon except in the setting of BLM and TP53 mutations. Overall, these findings demonstrate a range of involved genes in non-BRCA mutation carriers with breast cancer and histopathologic heterogeneity in the associated cancers, arguing against use of histomorphology to inform panel testing algorithms.

Keywords: Breast cancer; Breast carcinoma; Familial cancer; Germline mutations; Non-BRCA mutations.