Abstract PD7-05: Correlation of CDH1 alterations and aberrant E-cadherin expression in lobular carcinomas
Authors: Grabenstetter A , Mohanty AS , DeLair DF , Tan LK , Ross DS 
Published: May 2019

Background: E-cadherin (ECAD), encoded by the CDH1 gene, is expressed in the majority of invasive ductal carcinomas (IDC). In contrast, ECAD expression is lost in ˜90% of invasive lobular carcinomas (ILC) due to genomic alterations of CDH1. Immunohistochemical (IHC) staining for ECAD has thus increasingly been utilized to differentiate between ductal and lobular lesions. This study examines the correlation between CDH1 mutation profile, morphology and ECAD IHC status in invasive breast carcinomas (BC).

Methods: The Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) platform is a hybrid capture next-generation sequencing assay to detect somatic alterations in exons and selected introns of 468 cancer-related genes. Invasive BC tested from 1/2014 – 5/2018 which yielded a CDH1 alteration were identified and only cases with ECAD IHC results were included. Histologic features were extracted from pathology reports. All available H&E/ECAD slides were reviewed by two pathologists to confirm the histology and immunophenotype.

Results: CDH1 alterations were identified in 455 out of 4103 BC analyzed (11%) and ECAD IHC were available for 209 (46%) tumors. Most of the tumors were reported as ILC (70%, 147/209). The majority (77%, 161/209) were ECAD-negative but 23% (48/209) showed some ECAD staining. Table 1 summarizes the histologic subtypes and IHC results. Upon review of H&E/ECAD slides in cases with ECAD staining, the histologic subtype was re-classified in 52% (25/48) of cases (Table 2). For ECAD-negative BC, at least 61% (98/161) of CDH1 alterations were truncating mutations (frameshift deletion 47/161, nonsense 51/161) and 39% (63/161) were variants of unknown significance (VUS). In cases with ECAD staining, 48% (23/48) of CDH1 alterations were truncating mutations (frameshift deletion 12/48, nonsense 11/48) however 52% (25/48) were VUS.

Conclusion: In this study, 88% (141/161) of cases with negative ECAD staining and CDH1 alteration were classified as ILC, confirming the known observation that CDH1 alteration and loss of ECAD expression is relatively specific for a lobular phenotype. The correlation is, however, imperfect. A subset of BC (23%; 48/209) with CDH1 alteration still exhibits ECAD expression. Morphologically this subset consists of ILC in 60% (29/48), IMC in 25% (12/48) and IDC in 15% (7/48). Our preliminary findings suggest that aberrant ECAD expression can occur in BC with morphologic features of ILC due to certain CDH1 alterations that most likely result in non-functional ECAD complex. BC with histologic features of ILC should therefore not be re-classified as IDC/IMC based solely on the status of ECAD expression. Given that ILC is clinically distinct from IDC, correct classification based on morphological and molecular features is prudent.

Table 1:Histologic subtypes and ECAD IHC ILC (n = 147)IDC (n = 13)IMC (n = 49)ECAD staining   Negative141020Strong, diffuse4135Heterogenous0020Reduced/weak204IMC: invasive mammary with mixed ductal/lobular features

Table 2:Morphologic review of cases with ECAD stainingECAD stainingOriginal DX (n)Morphology Review DX  ILCIDCIMCStrong, diffuseILC (4)301 IDC (13)670 IMC (5)500HeterogenousIMC (20)10010Reduced/weakILC (2)200 IMC (4)301

Citation Format: Grabenstetter A, Mohanty AS, DeLair DF, Tan LK, Ross DS. Correlation of CDH1 alterations and aberrant E-cadherin expression in lobular carcinomas [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD7-05.