Synapse - Nonlobular invasive breast carcinomas with biallelic pathogenic CDH1 somatic alterations: A histologic, immunophenotypic, and genomic characterization

Nonlobular invasive breast carcinomas with biallelic pathogenic CDH1 somatic alterations: A histologic, immunophenotypic, and genomic characterization Journal Article

Authors:	Derakhshan, F.; Da Cruz Paula, A.; Selenica, P.; da Silva, E. M.; Grabenstetter, A.; Jalali, S.; Gazzo, A. M.; Dopeso, H.; Marra, A.; Brown, D. N.; Ross, D. S.; Mandelker, D.; Razavi, P.; Chandarlapaty, S.; Wen, H. Y.; Brogi, E.; Zhang, H.; Weigelt, B.; Pareja, F.; Reis-Filho, J. S.
Article Title:	Nonlobular invasive breast carcinomas with biallelic pathogenic CDH1 somatic alterations: A histologic, immunophenotypic, and genomic characterization
Abstract:	CDH1 encodes for E-cadherin, and its loss of function is the hallmark of invasive lobular carcinoma (ILC). Albeit vanishingly rare, biallelic CDH1 alterations may be found in nonlobular breast carci-nomas (NL-BCs). We sought to determine the clinicopathologic characteristics and repertoire of genetic alterations of NL-BCs harboring CDH1 biallelic genetic alterations. Analysis of 5842 breast cancers (BCs) subjected to clinical tumor-normal sequencing with an FDA-cleared multigene panel was conducted to identify BCs with biallelic CDH1 pathogenic/likely pathogenic somatic mutations lacking lobular features. The genomic profiles of NL-BCs with CDH1 biallelic genetic alterations were compared with those of ILCs and invasive ductal carcinomas (IDCs), matched by clinicopathologic characteristics. Of the 896 CDH1-altered BCs, 889 samples were excluded based on the diagnosis of invasive mixed ductal/lobular carcinoma or ILC or the detection of monoallelic CDH1 alterations. Only 7 of the 5842 (0.11%) BCs harbored biallelic 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. In total, 5/7 (71%) were of Nottingham grade 2, and 2/7 (29%) were of grade 3. The NL-BCs with CDH1 biallelic 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). However, NL-BCs with CDH1 biallelic genetic alterations displayed recurrent genetic alterations, including TP53, PIK3CA (57%, 4/7; each), FGFR1, and NCOR1 (28%, 2/7, each) alterations. Compared with CDH1 wild-type IDC-NSTs, NL-BCs less frequently harbored GATA3 mutations (0% vs 47%, P = .03), but no significant differences were detected when compared with matched ILCs. Therefore, NL-BCs with CDH1 biallelic genetic alterations are vanishingly rare, predominantly comprise IDCs with special histologic features, and have genomic features akin to luminal B ER-positive BCs.(c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.
Keywords:	gene; breast cancer; e-cadherin; expression; ductal; landscape; pattern; cdh1; lobular carcinoma; lobular; cancer; ductal carcinomas
Journal Title:	Modern Pathology
Volume:	37
Issue:	2
ISSN:	0893-3952
Publisher:	Nature Research
Date Published:	2024-02-01
Start Page:	100375
Language:	English
ACCESSION:	WOS:001133494300001
DOI:	10.1016/j.modpat.2023.100375
PROVIDER:	wos
PUBMED:	37925055
PMCID:	PMC11154908
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Fresia Pareja -- Source: Wos