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 carcinomas (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.

Keywords: CDH1; E-cadherin; breast cancer; ductal; lobular.

Figure 1.. Landscape of somatic genetic alterations and clonal compositions in non-lobular breast cancers with CDH1 bi-allelic genetic alterations.

Heatmap showing non-synonymous mutations (top left), matching cancer cell fraction (top right) and copy number alterations (bottom left) in CDH1-altered non-lobular breast cancers. Cases are shown in columns and genes in rows. Histologic type, grade, sample type, estrogen receptor (ER) and HER2 status and dominant mutational signature as inferred by SigMA are shown in phenobars.

Figure 2.. Histologic features of non-lobular breast cancers with CDH1 bi-allelic genetic alterations.

Representative hematoxylin and eosin (H&E) micrographs and E-cadherin expression micrographs (insets) of CDH1-altered non-lobular breast cancers. (A-B) Invasive mucinous breast cancer type B (NL3), (C-F) Invasive ductal carcinomas (IDC) with focal nested growth, (G-J) IDC with solid papillary features (NL5-P and NL5-M), (K-L) Invasive ductal carcinoma of no special type (IDC-NST; NL1), (M-P) IDCs with apocrine features. NL5-M, NL5, metastatic tumor; NL5-P, NL5 primary tumor. Scale bar, 100 microns.

Figure 3.. Repertoire of genetic alterations in NL-BCs with CDH1 bi-allelic genetic alterations in comparison with matched CDH1-altered lobular carcinomas and matched invasive ductal carcinoma of no special type.

A. Comparison of the cancer genes most frequently affected by non-synonymous somatic mutations, amplifications, or homozygous deletions in NL-BCs with CDH1 bi-allelic genetic alterations (n=7) and age, menopausal status, sample type, grade, and ER/HER2 receptor status-matched ILCs (n=14) and matched IDC-NSTs (n=21). Cases are shown in columns and genes in rows. Genetic alterations are color-coded according to the legend. ER/HER2 status and sample type are shown on phenobars (down). *P < 0.05, Fisher’s exact test, two-tailed. (B)Tumor mutation burden (TMB) and (C) fraction of genome altered (FGA) in all groups. P values (Mann-Whitney U test) are shown.