Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options.
BACKGROUND
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.


METHODS
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, paraffin-embedded 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 most-common alterations were in TP53 (n = 69; 75%), PIK3CA (n = 37; 40%), MYC (n = 28; 30%), MLL2 (n = 28; 30%), PTEN (n = 23; 25%), CDKN2A/B (n = 19; 20%), CCND3 (n = 14; 15%), CCNE1 (n = 9; 10%), EGFR (n = 9; 10%), and KDM6A (n = 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.
From the Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York (Drs Ross and Boguniewicz and Ms Sheehan); Research and Development, Foundation Medicine, Inc, Cambridge, Massachusetts (Drs Ross, Wang, Otto, Yelensky, Lipson, Ali, Morosini, Chliemlecki, Elvin, Miller, and Stephens); and the Department of Pathology, University of Indiana School of Medicine, Indianapolis (Dr Badve).
Jeffrey S
JS
Ross
Sunil
S
Badve
Kai
K
Wang
Christine E
CE
Sheehan
Ann B
AB
Boguniewicz
Geoff A
GA
Otto
Roman
R
Yelensky
Doron
D
Lipson
Siraj
S
Ali
Deborah
D
Morosini
Juliann
J
Chliemlecki
Julia A
JA
Elvin
Vincent A
VA
Miller
Philip J
PJ
Stephens
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D005091:Exons / Q000235:genetics; D005260:Female; D056914:Genomic Structural Variation; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns / Q000235:genetics; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D060787:Neoplasm Grading; D057285:Precision Medicine; D017422:Sequence Analysis, DNA / Q000379:methods