PMID- 27284958 OWN - NLM STAT- MEDLINE DCOM- 20170525 LR - 20180301 IS - 1097-0142 (Electronic) IS - 0008-543X (Linking) VI - 122 IP - 17 DP - 2016 Sep 1 TI - Nonamplification ERBB2 genomic alterations in 5605 cases of recurrent and metastatic breast cancer: An emerging opportunity for anti-HER2 targeted therapies. PG - 2654-62 LID - 10.1002/cncr.30102 [doi] 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 microm of formalin-fixed paraffin-embedded (FFPE) sections. Comprehensive genomic profiling (CGP) was used to evaluate up to 315 genes (592x 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. (c) 2016 American Cancer Society. Cancer 2016;122:2654-2662. (c) 2016 American Cancer Society. CI - (c) 2016 American Cancer Society. FAU - Ross, Jeffrey S AU - Ross JS AD - Foundation Medicine Inc, Cambridge, Massachusetts. AD - Department of Pathology, Albany Medical College, Albany, New York. FAU - Gay, Laurie M AU - Gay LM AUID- ORCID: 0000-0003-2022-6130 AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Wang, Kai AU - Wang K AD - Foundation Medicine Inc, Cambridge, Massachusetts. AD - Department of Computational Biology, Zhejiang Cancer Hospital, Hangzhou, China. FAU - Ali, Siraj M AU - Ali SM AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Chumsri, Saranya AU - Chumsri S AD - Department of Hematology/Oncology, Mayo Clinic, Jacksonville, Florida. FAU - Elvin, Julia A AU - Elvin JA AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Bose, Ron AU - Bose R AD - Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. FAU - Vergilio, Jo-Anne AU - Vergilio JA AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Suh, James AU - Suh J AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Yelensky, Roman AU - Yelensky R AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Lipson, Doron AU - Lipson D AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Chmielecki, Juliann AU - Chmielecki J AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Waintraub, Stanley AU - Waintraub S AD - Department of Breast Oncology, Hackensack University Medical Center, Hackensack, New Jersey. FAU - Leyland-Jones, Brian AU - Leyland-Jones B AD - Department of Hematology/Oncology, Avera Health, Sioux Falls, South Dakota. FAU - Miller, Vincent A AU - Miller VA AD - Foundation Medicine Inc, Cambridge, Massachusetts. FAU - Stephens, Philip J AU - Stephens PJ AD - Foundation Medicine Inc, Cambridge, Massachusetts. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160610 PL - United States TA - Cancer JT - Cancer JID - 0374236 RN - 0 (Antineoplastic Agents) RN - 0 (Biomarkers, Tumor) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/therapeutic use MH - Biomarkers, Tumor/*genetics MH - Breast Neoplasms/drug therapy/*genetics/pathology MH - Carcinoma, Ductal, Breast/drug therapy/genetics/secondary MH - Carcinoma, Lobular/drug therapy/genetics/secondary MH - Female MH - Follow-Up Studies MH - Gene Expression Regulation, Neoplastic/drug effects MH - Genomics/*methods MH - High-Throughput Nucleotide Sequencing/methods MH - Humans MH - In Situ Hybridization, Fluorescence MH - Lymphatic Metastasis MH - Middle Aged MH - *Molecular Targeted Therapy MH - Mutation/*genetics MH - Neoplasm Invasiveness MH - Neoplasm Recurrence, Local/drug therapy/*genetics/pathology MH - Neoplasm Staging MH - Prognosis MH - Receptor, ErbB-2/antagonists & inhibitors/*genetics OTO - NOTNLM OT - ERBB2 OT - breast cancer OT - comprehensive genomic profiling OT - human epidermal growth factor receptor 2 [HER2]/neu OT - next-generation sequencing OT - short variants EDAT- 2016/06/11 06:00 MHDA- 2017/05/26 06:00 CRDT- 2016/06/11 06:00 PHST- 2016/01/27 00:00 [received] PHST- 2016/03/21 00:00 [revised] PHST- 2016/04/01 00:00 [accepted] PHST- 2016/06/11 06:00 [entrez] PHST- 2016/06/11 06:00 [pubmed] PHST- 2017/05/26 06:00 [medline] AID - 10.1002/cncr.30102 [doi] PST - ppublish SO - Cancer. 2016 Sep 1;122(17):2654-62. doi: 10.1002/cncr.30102. Epub 2016 Jun 10.