Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies

Jeffrey S. Ross, Laurie M. Gay, Kai Wang, Siraj M. Ali, Saranya Chumsri, Julia A. Elvin, Ron Bose, Jo Anne Vergilio, James Suh, Roman Yelensky, Doron Lipson, Juliann Chmielecki, Stanley Waintraub, Brian Leyland-Jones, Vincent A. Miller, Philip J. Stephens

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

BACKGROUND: Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified. METHODS: DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements. RESULTS: Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein. CONCLUSIONS: Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016.

Original languageEnglish (US)
Pages (from-to)2654-2662
Number of pages9
JournalCancer
Volume122
Issue number17
DOIs
StatePublished - Sep 1 2016

Fingerprint

Breast Neoplasms
Mutation
Therapeutics
Cadherins
Fluorescence In Situ Hybridization
Immunohistochemistry
Phosphatidylinositol 3-Kinase
Lobular Carcinoma
Ductal Carcinoma
Cyclin D1
Mutation Rate
Standard of Care
DNA Sequence Analysis
Epidermal Growth Factor Receptor
Paraffin
Formaldehyde
Genes
Catalytic Domain
Neoplasms
Proteins

Keywords

  • breast cancer
  • comprehensive genomic profiling
  • ERBB2
  • human epidermal growth factor receptor 2 [HER2]/neu
  • next-generation sequencing
  • short variants

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer : An emerging opportunity for anti-HER2 targeted therapies. / Ross, Jeffrey S.; Gay, Laurie M.; Wang, Kai; Ali, Siraj M.; Chumsri, Saranya; Elvin, Julia A.; Bose, Ron; Vergilio, Jo Anne; Suh, James; Yelensky, Roman; Lipson, Doron; Chmielecki, Juliann; Waintraub, Stanley; Leyland-Jones, Brian; Miller, Vincent A.; Stephens, Philip J.

In: Cancer, Vol. 122, No. 17, 01.09.2016, p. 2654-2662.

Research output: Contribution to journalArticle

Ross, JS, Gay, LM, Wang, K, Ali, SM, Chumsri, S, Elvin, JA, Bose, R, Vergilio, JA, Suh, J, Yelensky, R, Lipson, D, Chmielecki, J, Waintraub, S, Leyland-Jones, B, Miller, VA & Stephens, PJ 2016, 'Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies', Cancer, vol. 122, no. 17, pp. 2654-2662. https://doi.org/10.1002/cncr.30102
Ross, Jeffrey S. ; Gay, Laurie M. ; Wang, Kai ; Ali, Siraj M. ; Chumsri, Saranya ; Elvin, Julia A. ; Bose, Ron ; Vergilio, Jo Anne ; Suh, James ; Yelensky, Roman ; Lipson, Doron ; Chmielecki, Juliann ; Waintraub, Stanley ; Leyland-Jones, Brian ; Miller, Vincent A. ; Stephens, Philip J. / Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer : An emerging opportunity for anti-HER2 targeted therapies. In: Cancer. 2016 ; Vol. 122, No. 17. pp. 2654-2662.
@article{6d41fe304d8a44c1a04f8c3f3a6f46ac,
title = "Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies",
abstract = "BACKGROUND: Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified. METHODS: DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements. RESULTS: Of 5605 cases, 698 (12.5{\%}) featured ERBB2 alterations, including 596 (10.6{\%}) ERBB2 amplifications (ERBB2amp) and 138 (2.4{\%}) ERBB2mut; 38 cases (0.7{\%}) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90{\%}) or extracellular (15 cases; 11{\%}) domains. Both primary BC (52 cases; 38{\%}) and metastatic site biopsies (86 cases; 62{\%}) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50{\%}), invasive ductal carcinoma (IDC) (40 cases; 29{\%}), invasive lobular carcinoma (ILC) (27 cases; 20{\%}), and mucinous mBC (2 cases; 1{\%}). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49{\%}); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42{\%}); cadherin 1, type 1 (CDH1) (37{\%}); MYC (17{\%}); and cyclin D1 protein (CCND1) (16{\%}). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein. CONCLUSIONS: Within this large series, 1.8{\%} of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016.",
keywords = "breast cancer, comprehensive genomic profiling, ERBB2, human epidermal growth factor receptor 2 [HER2]/neu, next-generation sequencing, short variants",
author = "Ross, {Jeffrey S.} and Gay, {Laurie M.} and Kai Wang and Ali, {Siraj M.} and Saranya Chumsri and Elvin, {Julia A.} and Ron Bose and Vergilio, {Jo Anne} and James Suh and Roman Yelensky and Doron Lipson and Juliann Chmielecki and Stanley Waintraub and Brian Leyland-Jones and Miller, {Vincent A.} and Stephens, {Philip J.}",
year = "2016",
month = "9",
day = "1",
doi = "10.1002/cncr.30102",
language = "English (US)",
volume = "122",
pages = "2654--2662",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "17",

}

TY - JOUR

T1 - Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer

T2 - An emerging opportunity for anti-HER2 targeted therapies

AU - Ross, Jeffrey S.

AU - Gay, Laurie M.

AU - Wang, Kai

AU - Ali, Siraj M.

AU - Chumsri, Saranya

AU - Elvin, Julia A.

AU - Bose, Ron

AU - Vergilio, Jo Anne

AU - Suh, James

AU - Yelensky, Roman

AU - Lipson, Doron

AU - Chmielecki, Juliann

AU - Waintraub, Stanley

AU - Leyland-Jones, Brian

AU - Miller, Vincent A.

AU - Stephens, Philip J.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - BACKGROUND: Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified. METHODS: DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements. RESULTS: Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein. CONCLUSIONS: Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016.

AB - BACKGROUND: Activating, nonamplification ERBB2 mutations (ERBB2mut) are not detected by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), but are detected by DNA sequencing and may predict clinical responses to human epidermal growth factor receptor (HER2)-targeted therapy. The authors queried 5605 advanced/metastatic breast cancers (mBC) to uncover the frequency of ERBB2mut genomic alterations. Clinical responses to anti-HER2 therapeutics were identified. METHODS: DNA was extracted from 40 µm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592× mean coverage depth). Results were analyzed for base substitutions, short indels, copy number changes, and selected rearrangements. RESULTS: Of 5605 cases, 698 (12.5%) featured ERBB2 alterations, including 596 (10.6%) ERBB2 amplifications (ERBB2amp) and 138 (2.4%) ERBB2mut; 38 cases (0.7%) had co-occurring ERBB2amp and ERBB2mut. ERBB2mut predominantly affected the kinase (124 cases; 90%) or extracellular (15 cases; 11%) domains. Both primary BC (52 cases; 38%) and metastatic site biopsies (86 cases; 62%) were found to harbor ERBB2mut, which were distributed across carcinoma not otherwise specified (NOS) (69 cases; 50%), invasive ductal carcinoma (IDC) (40 cases; 29%), invasive lobular carcinoma (ILC) (27 cases; 20%), and mucinous mBC (2 cases; 1%). Genes commonly coaltered with ERBB2 were tumor protein 53 (TP53) (49%); phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (42%); cadherin 1, type 1 (CDH1) (37%); MYC (17%); and cyclin D1 protein (CCND1) (16%). CDH1 mutations were enriched in ERBB2mut mBC (P<0.0006) and associated with recurrent mBC. Selected patients with ERBB2mut, without ERBB2amp, who responded to anti-HER2 targeted therapies are presented herein. CONCLUSIONS: Within this large series, 1.8% of cases harbored ERBB2mut, which are undetectable by standard-of-care IHC or FISH tests. Metastatic BC driven by ERBB2mut respond to anti-HER2 targeted therapies, and expanding clinical trials designed to detect ERBB2mut by CGP and optimize targeted treatments are warranted. Cancer 2016.

KW - breast cancer

KW - comprehensive genomic profiling

KW - ERBB2

KW - human epidermal growth factor receptor 2 [HER2]/neu

KW - next-generation sequencing

KW - short variants

UR - http://www.scopus.com/inward/record.url?scp=84983081945&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84983081945&partnerID=8YFLogxK

U2 - 10.1002/cncr.30102

DO - 10.1002/cncr.30102

M3 - Article

C2 - 27284958

AN - SCOPUS:84983081945

VL - 122

SP - 2654

EP - 2662

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 17

ER -