PMID- 25480824 OWN - NLM STAT- MEDLINE DCOM- 20150917 LR - 20220413 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 20 IP - 1 DP - 2015 Jan TI - Oncogenic alterations in ERBB2/HER2 represent potential therapeutic targets across tumors from diverse anatomic sites of origin. PG - 7-12 LID - 10.1634/theoncologist.2014-0234 [doi] AB - BACKGROUND: Targeted ERBB2/HER2 inhibitors are approved by the U.S. Food and Drug Administration for the treatment of breast, gastric, and esophageal cancers that overexpress or amplify HER2/ERBB2, as measured by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. Activating mutations in ERBB2 have also been reported and are predicted to confer sensitivity to these targeted agents. Testing for these mutations is not performed routinely, and FISH and IHC are not applied outside of these approved indications. MATERIALS AND METHODS: We explored the spectrum of activating ERBB2 alterations across a collection of approximately 7,300 solid tumor specimens that underwent comprehensive genomic profiling using next-generation sequencing. Results were analyzed for base substitutions, insertions and deletions, select rearrangements, and copy number changes. RESULTS: Known oncogenic ERBB2 alterations were identified in tumors derived from 27 tissues, and ERBB2 amplification in breast, gastric, and gastroesophageal cancers accounted for only 30% of these alterations. Activating mutations in ERBB2 were identified in 131 samples (32.5%); amplification was observed in 246 samples (61%). Two samples (0.5%) harbored an ERBB2 rearrangement. Ten samples (2.5%) harbored multiple ERBB2 mutations, yet mutations and amplifications were mutually exclusive in 91% of mutated cases. CONCLUSION: Standard slide-based tests for overexpression or amplification of ERBB2 would fail to detect the majority of activating mutations that occur overwhelmingly in the absence of copy number changes. Compared with current clinical standards, comprehensive genomic profiling of a more diverse set of tumor types may identify approximately 3.5 times the number of patients who may benefit from ERBB2-targeted therapy. CI - (c)AlphaMed Press. FAU - Chmielecki, Juliann AU - Chmielecki J AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA jchmielecki@foundationmedicine.com pstephens@foundationmedicine.com. FAU - Ross, Jeffrey S AU - Ross JS AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Wang, Kai AU - Wang K AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Frampton, Garrett M AU - Frampton GM AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Palmer, Gary A AU - Palmer GA AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Ali, Siraj M AU - Ali SM AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Palma, Norma AU - Palma N AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Morosini, Deborah AU - Morosini D AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Miller, Vincent A AU - Miller VA AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Yelensky, Roman AU - Yelensky R AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Lipson, Doron AU - Lipson D AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA. FAU - Stephens, Philip J AU - Stephens PJ AD - Foundation Medicine, Cambridge, Massachusetts, USA; Department of Pathology, Albany Medical College, Albany, New York, USA jchmielecki@foundationmedicine.com pstephens@foundationmedicine.com. LA - eng PT - Journal Article DEP - 20141205 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Quinazolines) RN - 0VUA21238F (Lapatinib) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - K16AIQ8CTM (pertuzumab) RN - P188ANX8CK (Trastuzumab) SB - IM MH - Antibodies, Monoclonal/therapeutic use MH - Antibodies, Monoclonal, Humanized/therapeutic use MH - Breast Neoplasms/drug therapy/*genetics/immunology MH - DNA Copy Number Variations MH - Female MH - Gene Amplification MH - Gene Expression Regulation, Neoplastic MH - *High-Throughput Nucleotide Sequencing MH - Humans MH - In Situ Hybridization, Fluorescence MH - Lapatinib MH - Mutation MH - Quinazolines/therapeutic use MH - Receptor, ErbB-2/antagonists & inhibitors/*genetics/immunology MH - Stomach Neoplasms/drug therapy/*genetics/immunology MH - Trastuzumab PMC - PMC4294606 OTO - NOTNLM OT - Antibodies OT - High-throughput nucleotide sequencing OT - Humanized OT - Lapatinib OT - Monoclonal OT - Mutation OT - Pertuzumab OT - Trastuzumab COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2014/12/07 06:00 MHDA- 2015/09/18 06:00 PMCR- 2016/01/01 CRDT- 2014/12/07 06:00 PHST- 2014/12/07 06:00 [entrez] PHST- 2014/12/07 06:00 [pubmed] PHST- 2015/09/18 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - theoncologist.2014-0234 [pii] AID - T14234 [pii] AID - 10.1634/theoncologist.2014-0234 [doi] PST - ppublish SO - Oncologist. 2015 Jan;20(1):7-12. doi: 10.1634/theoncologist.2014-0234. Epub 2014 Dec 5.