PMID- 27184134 OWN - NLM STAT- MEDLINE DCOM- 20171016 LR - 20181113 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 14 IP - 1 DP - 2016 May 17 TI - MYC copy gain, chromosomal instability and PI3K activation as potential markers of unfavourable outcome in trastuzumab-treated patients with metastatic breast cancer. PG - 136 LID - 10.1186/s12967-016-0883-z [doi] LID - 136 AB - BACKGROUND: There is an unmet need for more efficient patient stratification for receiving trastuzumab in the metastatic breast cancer (mBC) setting, since only part of such patients benefit from the addition of this agent to chemotherapy. The aim of this study was to investigate the prognostic value of biomarkers including MYC and MET in mBC patients treated with trastuzumab-based regimens. METHODS: mBC patients, locally tested as HER2-positive, treated with trastuzumab and chemotherapy between 1998 and 2010 were evaluated. Paraffin tumors (n = 229) were retrospectively centrally assessed by immunohistochemistry (IHC) for HER2, ER, PgR and Ki67; fluorescence in situ hybridization (FISH) for HER2, TOP2A and centromere (CEN) 17, MYC and CEN8, MET and CEN7; qPCR for MYC, MET copy number (CN); and, for PI3K activation (PIK3CA mutations; PTEN and phospho-mTOR protein expression). Increased CEN CN was assessed based on normal cut-offs. Time to progression (TTP) and survival were evaluated from the initiation of trastuzumab as first line treatment. RESULTS: Among all tumors, 90 were HER2-negative upon central testing (ambiguous HER2) and the rest were true HER2-positive. Further, 156 patients presented with mBC upon relapse of pre-treated disease (R-mBC) and 65 were diagnosed at stage IV (de novo mBC). Concordance between FISH and qPCR on gene CN status was fair for MYC (Kappa = 0.458) and absent for MET. The presence of MYC CN gain with qPCR and the absence of PI3K activation were infrequent events (7 and 8 % of evaluable tumors, respectively), while 41 % of tumors had increased CEN CN in one or more chromosomes, indicative of chromosomal instability. The most consistent finding in the entire cohort and in the above patient subgroups with respect to outcome was the unfavourable effect of MYC CN gain, which was retained upon multivariable analysis (e.g., survival in the entire cohort, HR 6.02; 95 % CI 2.67-13.6; p < 0.001). Further unfavourable prognosticators were increased CEN CN in one chromosome in R-mBC but not in de novo mBC (multivariable interaction p = 0.048), PI3K activation in R-mBC (multivariable p = 0.004) and increased Ki67 for patient TTP. CONCLUSIONS: MYC gene copies, centromere status and PI3K activation may adversely impact trastuzumab treated mBC patient outcome and seem worthy validating in larger series. FAU - Gogas, Helen AU - Gogas H AD - First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece. hgogas@hol.gr. FAU - Kotoula, Vassiliki AU - Kotoula V AD - Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Alexopoulou, Zoi AU - Alexopoulou Z AD - Department of Biostatistics, Health Data Specialists Ltd, Athens, Greece. FAU - Christodoulou, Christos AU - Christodoulou C AD - Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece. FAU - Kostopoulos, Ioannis AU - Kostopoulos I AD - Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Bobos, Mattheos AU - Bobos M AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Raptou, Georgia AU - Raptou G AD - Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Charalambous, Elpida AU - Charalambous E AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Tsolaki, Eleftheria AU - Tsolaki E AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Xanthakis, Ioannis AU - Xanthakis I AD - Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. FAU - Pentheroudakis, George AU - Pentheroudakis G AD - Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. FAU - Koutras, Angelos AU - Koutras A AD - Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece. FAU - Bafaloukos, Dimitrios AU - Bafaloukos D AD - First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece. FAU - Papakostas, Pavlos AU - Papakostas P AD - Oncology Unit, Hippokration Hospital, Athens, Greece. FAU - Aravantinos, Gerasimos AU - Aravantinos G AD - Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece. FAU - Psyrri, Amanda AU - Psyrri A AD - Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece. FAU - Petraki, Kalliopi AU - Petraki K AD - Pathology Department, Metropolitan Hospital, Piraeus, Greece. FAU - Kalogeras, Konstantine T AU - Kalogeras KT AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. AD - Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece. FAU - Pectasides, Dimitrios AU - Pectasides D AD - Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece. FAU - Fountzilas, George AU - Fountzilas G AD - Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. AD - Aristotle University of Thessaloniki, Thessaloniki, Greece. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160517 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (Biomarkers, Tumor) RN - 0 (Proto-Oncogene Proteins c-myc) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - P188ANX8CK (Trastuzumab) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Biomarkers, Tumor/*metabolism MH - Breast Neoplasms/*drug therapy/*genetics/pathology MH - Centromere/metabolism MH - Chromosomal Instability/*genetics MH - Cohort Studies MH - Enzyme Activation/drug effects MH - Female MH - *Gene Dosage MH - Humans MH - Middle Aged MH - Multivariate Analysis MH - Neoplasm Metastasis MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Proportional Hazards Models MH - Proto-Oncogene Proteins c-myc/*genetics MH - Receptor, ErbB-2/metabolism MH - Survival Analysis MH - Trastuzumab/pharmacology/*therapeutic use MH - Treatment Outcome PMC - PMC4869295 OTO - NOTNLM OT - Amplification OT - Centromere copy number OT - FISH OT - HER2 OT - MET OT - MYC OT - Metastatic breast cancer OT - TOP2A OT - Trastuzumab OT - qPCR EDAT- 2016/05/18 06:00 MHDA- 2017/10/17 06:00 PMCR- 2016/05/17 CRDT- 2016/05/18 06:00 PHST- 2015/10/20 00:00 [received] PHST- 2016/04/28 00:00 [accepted] PHST- 2016/05/18 06:00 [entrez] PHST- 2016/05/18 06:00 [pubmed] PHST- 2017/10/17 06:00 [medline] PHST- 2016/05/17 00:00 [pmc-release] AID - 10.1186/s12967-016-0883-z [pii] AID - 883 [pii] AID - 10.1186/s12967-016-0883-z [doi] PST - epublish SO - J Transl Med. 2016 May 17;14(1):136. doi: 10.1186/s12967-016-0883-z.