Genomic profiling of metaplastic breast carcinomas reveals genetic heterogeneity and relationship to ductal carcinoma

Abstract

Metaplastic breast carcinomas comprise a histologically heterogenous group of tumors. Although most are triple (estrogen/progesterone receptor, HER2) negative, these rare tumors are clinicopathologically distinct from other triple negative carcinomas and may be aggressive with worse chemotherapy responses. On the other hand, metaplastic carcinomas are histologically diverse, which is reflected in gene expression differences among subtypes. Whether metaplastic carcinomas are genetically distinct from other triple negative cancers and whether genetic differences underlie histologic subtypes remains poorly understood. We sequenced 408 cancer-related genes in 28 metaplastic carcinomas, including chondroid matrix-producing carcinomas (n = 10), spindle cell carcinomas (n = 5), and carcinomas with squamous (n = 5), mixed spindle/squamous (n = 5), and mixed metaplastic (n = 3) differentiation. Metaplastic carcinomas were highly enriched for PIK3CA/PIK3R1 (61%) and Ras-Map kinase (25%) pathway aberrations compared to other triple negative carcinomas (TCGA dataset 14%, p < 0.001 and 7%, p = 0.005, respectively) and harbored a high frequency of TP53 (64%) and TERT promoter (25%) mutations, but this varied among subtypes. Chondroid-matrix producing carcinomas lacked PI-3 kinase and Ras-Map kinase aberrations and TERT promoter mutations, compared to 100%, 39%, and 39% of non-matrix-producing tumors, respectively. TERT promoter mutations were enriched (47%) in spindle cell carcinomas and tumors with squamous or spindle/squamous differentiation. Spindle cell carcinomas lacked TP53 mutations, in contrast to other subtypes (78%, p = 0.003). Separate analysis of paired ductal carcinoma in situ and metaplastic carcinoma revealed shared clonality in all cases (n = 8). Activating PI-3 kinase and Ras pathway mutations were early events, and inactivating mutations in tumor suppressors including RB1, CDKN2A, and TP53 were associated with invasion in individual cases. Metaplastic components of two tumors showed genetic progression from separately sequenced paired invasive ductal carcinoma. The findings suggest that metaplastic carcinomas are genetically distinct from other triple negative breast cancers and highlight genetic heterogeneity that broadly correlates with histologic subtype. Heterologous elements progress from associated ductal carcinoma.

Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications

“…Broadly, our sequencing data recapitulate those of recent studies [7,10,36,37]. An inverse correlation between PI3KCA mutations and the chondroid phenotype has been documented [7,37], and while two out of ten PI3KCA-mutated cases showed chondroid differentiation, none of the cases were purely chondroid, nor were they specifically enriched. We also presented evidence for a significant enrichment of co-occurring mutations in TP53, PTEN, and PIK3CA in MBC, a novel finding that counters the long-held concepts that TP53 and PTEN [38], and PIK3CA and PTEN [39] mutations are mutually exclusive.…”

“…Our exome sequencing data highlight the relative paucity of mutations across these MBC cases and confirm the high frequency of TP53 mutation . Broadly, our sequencing data recapitulate those of recent studies . An inverse correlation between PI3KCA mutations and the chondroid phenotype has been documented , and while two out of ten PI3KCA‐ mutated cases showed chondroid differentiation, none of the cases were purely chondroid, nor were they specifically enriched.…”

Fibromatosis-like metaplastic carcinoma: a case report and review of the literature

“…They are, however, frequently mutated in several other types of cancers and represent one of the most frequently observed mutations after TP53 gene mutation. Interestingly, TP53 mutations seem to be less common in spindle cell MBCs or other low-grade MBCs compared to matrix-producing or high-grade MBC subtypes [19]. This is well in line with our case, as we found two PIK3R1 and a TERT-promotor mutation but no TP53 mutations.…”

“…From a molecular point of view, mutations in PIK3CA, PIK3R1 and PTEN genes are significantly more frequently found in MBC as compared to triple-negative breast carcinomas of no special type [17]. TERT-promotor mutations are relatively more frequently associated to MBC with spindle cell morphology as compared to other types of MBCs [18,19]. They are, however, frequently mutated in several other types of cancers and represent one of the most frequently observed mutations after TP53 gene mutation.…”

Metaplastic Breast Carcinoma: Update on Histopathology and Molecular Alterations

“…25 This was also evident in a recent sequencing study of 28 metaplastic carcinomas including different histologic variants. 30 Interestingly, this study showed that telomerase reverse transcriptase (TERT) promoter mutations vary among subtypes, as they are common in spindle cell carcinoma and SCC (47% of tumors) but are absent in metaplastic carcinomas with chondroid mesenchymal differentiation. Taken together, these studies suggest that metaplastic carcinomas are distinct from TNBCs, and that specific histologic variants of metaplastic carcinoma have both common and unique genetic defects, which needs to be further investigated.…”