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Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies.
Cancer. 2016 09 01; 122(17):2654-62.C

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. © 2016 American Cancer Society. Cancer 2016;122:2654-2662. © 2016 American Cancer Society.

Authors+Show Affiliations

Foundation Medicine Inc, Cambridge, Massachusetts. Department of Pathology, Albany Medical College, Albany, New York.Foundation Medicine Inc, Cambridge, Massachusetts.Foundation Medicine Inc, Cambridge, Massachusetts. Department of Computational Biology, Zhejiang Cancer Hospital, Hangzhou, China.Foundation Medicine Inc, Cambridge, Massachusetts.Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida.Foundation Medicine Inc, Cambridge, Massachusetts.Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.Foundation Medicine Inc, Cambridge, Massachusetts.Foundation Medicine Inc, Cambridge, Massachusetts.Foundation Medicine Inc, Cambridge, Massachusetts.Foundation Medicine Inc, Cambridge, Massachusetts.Foundation Medicine Inc, Cambridge, Massachusetts.Department of Breast Oncology, Hackensack University Medical Center, Hackensack, New Jersey.Department of Hematology/Oncology, Avera Health, Sioux Falls, South Dakota.Foundation Medicine Inc, Cambridge, Massachusetts.Foundation Medicine Inc, Cambridge, Massachusetts.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27284958

Citation

Ross, Jeffrey S., et al. "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, 2016, pp. 2654-62.
Ross JS, Gay LM, Wang K, et al. Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies. Cancer. 2016;122(17):2654-62.
Ross, J. S., Gay, L. M., Wang, K., Ali, S. M., Chumsri, S., Elvin, J. A., Bose, R., Vergilio, J. A., Suh, J., Yelensky, R., Lipson, D., Chmielecki, J., Waintraub, S., Leyland-Jones, B., Miller, V. A., & Stephens, P. J. (2016). Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies. Cancer, 122(17), 2654-62. https://doi.org/10.1002/cncr.30102
Ross JS, et al. Nonamplification ERBB2 Genomic Alterations in 5605 Cases of Recurrent and Metastatic Breast Cancer: an Emerging Opportunity for anti-HER2 Targeted Therapies. Cancer. 2016 09 1;122(17):2654-62. PubMed PMID: 27284958.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: 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, Y1 - 2016/06/10/ PY - 2016/01/27/received PY - 2016/03/21/revised PY - 2016/04/01/accepted PY - 2016/6/11/entrez PY - 2016/6/11/pubmed PY - 2017/5/26/medline KW - ERBB2 KW - breast cancer KW - comprehensive genomic profiling KW - human epidermal growth factor receptor 2 [HER2]/neu KW - next-generation sequencing KW - short variants SP - 2654 EP - 62 JF - Cancer JO - Cancer VL - 122 IS - 17 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. © 2016 American Cancer Society. Cancer 2016;122:2654-2662. © 2016 American Cancer Society. SN - 1097-0142 UR - https://www.unboundmedicine.com/medline/citation/27284958/Nonamplification_ERBB2_genomic_alterations_in_5605_cases_of_recurrent_and_metastatic_breast_cancer:_An_emerging_opportunity_for_anti_HER2_targeted_therapies_ L2 - https://doi.org/10.1002/cncr.30102 DB - PRIME DP - Unbound Medicine ER -