Abstract P4-04-05: Molecular subtyping reveals the heterogeneity of metaplastic breast cancers

Abstract

Abstract Introduction: Metaplastic breast carcinoma (MBC) is a rare (1%) and aggressive histological special type of breast cancer, which often (>90%) displays a triple-negative (TN) phenotype. Microarray-based gene expression classifications of breast cancer have been described, including the ‘intrinsic subtypes’ (i.e. luminal A, luminal B, basal-like, HER2-enriched, normal breast-like and claudin-low) and the six TN molecular subtypes with therapeutic implications in preclinical models (i.e. basal-like I, basal-like II, mesenchymal-like, mesenchymal stem-like, immunomodulatory and luminal androgen receptor). In addition, single nucleotide polymorphism (SNP) array analyses have led to the development of classifiers to define whether TN breast cancers would have genomic aberrations consistent with those found in tumors arising in BRCA1 germline mutation carriers. Here we sought to define i) the heterogeneity of MBCs using distinct microarray-based classifiers and ii) whether MBCs display gene copy number profiles consistent with those of BRCA1 breast cancers. Material and Methods: Thirty consecutive MBCs were retrieved from the tumor banks of the authors’ institutions, reviewed by two pathologists and classified into three groups: carcinomas with spindle cell metaplasia (n = 12), with squamous metaplasia (n = 10), and with heterologous elements (n = 8). RNA and DNA were extracted from representative frozen sections containing >50% of cancer cells from each tumor and subjected to gene expression profiling using the HumanHT-12 v4 platform (Illumina) and gene copy number analysis using SNP 6.0 arrays (Affymetrix), respectively. ‘Intrinsic subtyping’ was performed according to the UNC guidelines, and subtyping into the six TN types using a dedicated website (https://cbc.mc.vanderbilt.edu/tnbc/). Classification of MBCs into BRCA1-like or non-BRCA1-like was performed using an algorithm to identify and quantify large-scale state transitions. Results: PAM50/claudin-low subtyping of MBCs revealed that all spindle cell carcinomas (n = 12) were consistently of claudin-low subtype, whereas MBCs with heterologous elements were classified as of basal-like (n = 6) and normal breast-like (n = 2), and squamous cell carcinomas as of basal-like (n = 5), claudin-low (n = 4) and normal-like (n = 1). Using the six TN subtypes, spindle cell MBCs were classified as mesenchymal stem-like (n = 4), immunomodulatory (n = 3), basal-like 2 (n = 3), or mesenchymal (n = 2) subtype. Carcinomas with heterologous elements were classified as basal-like 1 (n = 5) or mesenchymal (n = 3) subtype, whereas carcinomas with squamous metaplasia were of immunomodulatory (n = 5), basal-like 1 (n = 2), basal-like 2 (n = 2) or mesenchymal (n = 1) subtype. Out of the 26 samples where SNP 6.0 arrays were successfully performed, only 9 (35%) were classified as BRCA1-like, including two spindle cell carcinomas, two carcinomas with heterologous elements and five carcinomas with squamous metaplasia. Conclusion: MBCs constitute a heterogeneous group of tumors and the histological subclassification of these cancers is of importance, given that tumors with distinct metaplastic elements are classified differently according to current molecular subtyping methods. Only 35% of MBCs display BRCA1-like patterns of gene copy number aberrations. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-05.