Genomic Profiling of Advanced-Stage, Metaplastic Breast Carcinoma by Next-Generation Sequencing Reveals Frequent, Targetable Genomic Abnormalities and Potential New Treatment Options

Abstract

Context.-Metastatic metaplastic breast carcinoma (MPBC) is an uncommon, but aggressive, tumor resistant to conventional chemotherapy.Objective.-To learn whether next-generation sequencing could identify potential targets of therapy for patients with relapsed and metastatic MPBC.Design.-Hybridization capture of 3769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to a minimum of 50 ng of DNA extracted from 20 MPBC formalin-fixed, paraffinembedded specimens and sequenced to high uniform coverage.Results.-The 20 patients with MPBC had a median age of 62 years (range, 42-86 years). There were 9 squamous (45%), 9 chondroid (45%), and 2 spindle cell (10%) MPBCs, all of which were high grade. Ninety-three genomic alterations were identified, (range, 1-11) with 19 of the 20 cases (95%) harboring an alteration that could potentially lead to a targeted treatment option. The mostcommon alterations were in TP53 (n ¼ 69; 75%), PIK3CA (n ¼ 37; 40%), MYC (n ¼ 28; 30%), MLL2 (n ¼ 28; 30%), PTEN (n ¼ 23; 25%), CDKN2A/B (n ¼ 19; 20%), CCND3 (n ¼ 14; 15%), CCNE1 (n ¼ 9; 10%), EGFR (n ¼ 9; 10%), and KDM6A (n ¼ 9; 10%); AKT3, CCND1, CCND2, CDK4, FBXW7, FGFR1, HRAS, NF1, PIK3R1, and SRC were each altered in a single case. All 16 MPBCs (100%) that were negative for ERBB2 (HER2) overexpression by immunohistochemistry and/or ERBB2 (HER2) amplification by fluorescence in situ hybridization were also uniformly (100%) negative for ERBB2 amplification by next-generation sequencing-based copy-number assessment.Conclusions.-Our results indicate that genomic profiling using next-generation sequencing can identify clinically meaningful alterations that have the potential to guide targeted treatment decisions in most patients with metastatic MPBC.

Comprehensive profiling of metaplastic breast carcinomas reveals frequent overexpression of programmed death-ligand 1

“…5 Potentially targetable mutations identified in our study affected the PIK3CA/Akt/ mTOR signalling pathway (PIK3CA, AKT-1, PTEN) proposing benefits of using PIK3CA and mTOR inhibitors in MBCs. A study of five metastatic MBCs treated with the mTOR inhibitor, temsirolimus in combination with liposomal doxorubicin and bevacizumab showed promising preliminary results.…”

TiHo-0906: a new feline mammary cancer cell line with molecular, morphological, and immunocytological characteristics of epithelial to mesenchymal transition

“…CNVs affect the gene expression patterns by altering the gene dosage in human breast cancer 32–34 , hMBCs 7,32 , and breast cancer cell lines 35 . Additionally, specific CNGs are concordant with EMT-related genes up-regulation in multiple human cancer types 36 .…”

FBXW7 Pathway Functions as a Promising Therapeutic Target of Cholangiocarcinoma

“…Lessons learned from FBXW7-associated murine cancer models also convincingly demonstrated that it is a bona fide tumor suppressor gene with extensive functions [26]. Recent genetic profiles of human cancers based on high-throughput sequencing revealed that FBXW7 is among the most frequently mutated cancer genes [28][29][30][31][32][33]. Thus, FBXW7 has been illuminated to be a central mediator in tumorigenesis [34].…”