Non-Lobular Invasive Breast Carcinomas with Bi-Allelic Pathogenic CDH1 Somatic Alterations: a Histologic, Immunophenotypic and Genomic Characterization.
Academic Article
Overview
abstract
CDH1 encodes for E-cadherin, and its loss of function is the hallmark of invasive lobular carcinoma (ILC). Albeit vanishingly rare, bi-allelic CDH1 alterations may be found in non-lobular breast carcinomas (NL-BCs). We sought to determine the clinicopathologic characteristics and repertoire of genetic alterations of NL-BCs harboring CDH1 bi-allelic genetic alterations. Analysis of 5,842 breast cancers (BCs) subjected to clinical tumor-normal sequencing with an FDA-cleared multi-gene panel was conducted to identify BCs with bi-allelic CDH1 pathogenic/likely pathogenic somatic mutations lacking lobular features. The genomic profiles of NL-BCs with CDH1 bi-allelic genetic alterations were compared to those of ILCs and invasive ductal carcinomas (IDCs), matched by clinicopathologic characteristics. Out of 896 CDH1-altered BCs, 889 samples were excluded based on diagnosis of invasive mixed ductal/lobular carcinoma or ILC or detection of monoallelic CDH1 alterations. Only 7 of 5,842 (0.11%) BCs harbored bi-allelic CDH1 alterations and lacked lobular features. Of these, 4/7 (57%) cases were ER-positive/HER2-negative, 1/7 (14%) was ER-positive/HER2-positive and 2/7 (29%) were ER-negative/HER2-negative. 5/7 (71%) were of Nottingham grade 2 and 2/7 (29%) were of grade 3. The NL-BCs with CDH1 bi-allelic genetic alterations included a mucinous carcinoma (n=1), IDCs with focal nested growth (n=2), IDC with solid papillary (n=1) or apocrine (n=2) features and an IDC of no special type (NST; n=1). E-cadherin expression as detected by immunohistochemistry was absent (3/5) or aberrant (discontinuous membranous/cytoplasmic/granular; 2/5). NL-BCs with CDH1 bi-allelic genetic alterations displayed recurrent genetic alterations including TP53, PIK3CA (57%, 4/7; each), FGFR1 and NCOR1 (28%, 2/7, each) alterations. As compared to CDH1-wildtype IDC-NSTs, NL-BCs less frequently harbored GATA3 mutations (0% vs 47%, p=0.03) but no significant differences were detected when compared to matched ILCs. NL-BCs with CDH1 bi-allelic genetic alterations are vanishingly rare, predominantly comprise IDCs with special histologic features, and have genomic features akin to luminal B ER-positive BCs.
