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

Jeffrey S. Ross, Sunil Badve, Kai Wang, Christine E. Sheehan, Ann B. Boguniewicz, Geoff A. Otto, Roman Yelensky, Doron Lipson, Siraj Ali, Deborah Morosini, Juliann Chliemlecki, Julia A. Elvin, Vincent A. Miller, Philip J. Stephens

Research output: Contribution to journalArticle

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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, 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.

Original languageEnglish (US)
Pages (from-to)642-649
Number of pages8
JournalArchives of Pathology and Laboratory Medicine
Volume139
Issue number5
DOIs
StatePublished - May 1 2015

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Breast Neoplasms
Therapeutics
Neoplasm Genes
Fluorescence In Situ Hybridization
Paraffin
Introns
Formaldehyde
Exons
Neoplasms
Immunohistochemistry
Drug Therapy
DNA
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medical Laboratory Technology
  • Medicine(all)

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Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. / Ross, Jeffrey S.; Badve, Sunil; Wang, Kai; Sheehan, Christine E.; Boguniewicz, Ann B.; Otto, Geoff A.; Yelensky, Roman; Lipson, Doron; Ali, Siraj; Morosini, Deborah; Chliemlecki, Juliann; Elvin, Julia A.; Miller, Vincent A.; Stephens, Philip J.

In: Archives of Pathology and Laboratory Medicine, Vol. 139, No. 5, 01.05.2015, p. 642-649.

Research output: Contribution to journalArticle

Ross, JS, Badve, S, Wang, K, Sheehan, CE, Boguniewicz, AB, Otto, GA, Yelensky, R, Lipson, D, Ali, S, Morosini, D, Chliemlecki, J, Elvin, JA, Miller, VA & Stephens, PJ 2015, 'Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options', Archives of Pathology and Laboratory Medicine, vol. 139, no. 5, pp. 642-649. https://doi.org/10.5858/arpa.2014-0200-OA
Ross, Jeffrey S. ; Badve, Sunil ; Wang, Kai ; Sheehan, Christine E. ; Boguniewicz, Ann B. ; Otto, Geoff A. ; Yelensky, Roman ; Lipson, Doron ; Ali, Siraj ; Morosini, Deborah ; Chliemlecki, Juliann ; Elvin, Julia A. ; Miller, Vincent A. ; Stephens, Philip J. / Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options. In: Archives of Pathology and Laboratory Medicine. 2015 ; Vol. 139, No. 5. pp. 642-649.
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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, 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.",
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T1 - Genomic profiling of advanced-stage, metaplastic breast carcinoma by next-generation sequencing reveals frequent, targetable genomic abnormalities and potential new treatment options

AU - Ross, Jeffrey S.

AU - Badve, Sunil

AU - Wang, Kai

AU - Sheehan, Christine E.

AU - Boguniewicz, Ann B.

AU - Otto, Geoff A.

AU - Yelensky, Roman

AU - Lipson, Doron

AU - Ali, Siraj

AU - Morosini, Deborah

AU - Chliemlecki, Juliann

AU - Elvin, Julia A.

AU - Miller, Vincent A.

AU - Stephens, Philip J.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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, 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.

AB - 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, 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.

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