PMID- 25881079 OWN - NLM STAT- MEDLINE DCOM- 20160428 LR - 20220325 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 15 DP - 2015 Mar 23 TI - A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies. PG - 171 LID - 10.1186/s12885-015-1146-8 [doi] LID - 171 AB - BACKGROUND: To determine the prevalence of RET rearrangement genes, RET copy number gains and expression in tumor samples from four Phase III non-small-cell lung cancer (NSCLC) trials of vandetanib, a selective inhibitor of VEGFR, RET and EGFR signaling, and to determine any association with outcome to vandetanib treatment. METHODS: Archival tumor samples from the ZODIAC ( NCT00312377 , vandetanib +/- docetaxel), ZEAL ( NCT00418886 , vandetanib +/- pemetrexed), ZEPHYR ( NCT00404924 , vandetanib vs placebo) and ZEST ( NCT00364351 , vandetanib vs erlotinib) studies were evaluated by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in 944 and 1102 patients. RESULTS: The prevalence of RET rearrangements by FISH was 0.7% (95% CI 0.3-1.5%) among patients with a known result. Seven tumor samples were positive for RET rearrangements (vandetanib, n = 3; comparator, n = 4). 2.8% (n = 26) of samples had RET amplification (innumerable RET clusters, or >/=7 copies in > 10% of tumor cells), 8.1% (n = 76) had low RET gene copy number gain (4-6 copies in >/=40% of tumor cells) and 8.3% (n = 92) were RET expression positive (signal intensity ++ or +++ in >10% of tumor cells). Of RET-rearrangement-positive patients, none had an objective response in the vandetanib arm and one patient responded in the comparator arm. Radiologic evidence of tumor shrinkage was observed in two patients treated with vandetanib and one treated with comparator drug. The objective response rate was similar in the vandetanib and comparator arms for patients positive for RET copy number gains or RET protein expression. CONCLUSIONS: We have identified prevalence for three RET biomarkers in a population predominated by non-Asians and smokers. RET rearrangement prevalence was lower than previously reported. We found no evidence of a differential benefit for efficacy by IHC and RET gene copy number gains. The low prevalence of RET rearrangements (0.7%) prevents firm conclusions regarding association of vandetanib treatment with efficacy in the RET rearrangement NSCLC subpopulation. TRIAL REGISTRATION: Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR). FAU - Platt, Adam AU - Platt A AD - AstraZeneca, da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston, Hertfordshire, SG8 6HB, UK. adam.platt@astrazeneca.com. FAU - Morten, John AU - Morten J AD - AstraZeneca, Macclesfield, UK. john.morten@astrazeneca.com. FAU - Ji, Qunsheng AU - Ji Q AD - Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. qunsheng.ji@astrazeneca.com. FAU - Elvin, Paul AU - Elvin P AD - AstraZeneca, Macclesfield, UK. paul.elvin@astrazeneca.com. FAU - Womack, Chris AU - Womack C AD - AstraZeneca, Macclesfield, UK. chris.womack@astrazeneca.com. FAU - Su, Xinying AU - Su X AD - Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. xinying.su@astrazeneca.com. FAU - Donald, Emma AU - Donald E AD - AstraZeneca, Macclesfield, UK. emma.donald@astrazeneca.com. FAU - Gray, Neil AU - Gray N AD - AstraZeneca, Macclesfield, UK. adam.platt@astrazeneca.com. FAU - Read, Jessica AU - Read J AD - AstraZeneca, Macclesfield, UK. jessica.read@astrazeneca.com. FAU - Bigley, Graham AU - Bigley G AD - AstraZeneca, Macclesfield, UK. graham.bigley@astrazeneca.com. FAU - Blockley, Laura AU - Blockley L AD - AstraZeneca, Macclesfield, UK. laura.blockley@astrazeneca.com. FAU - Cresswell, Carl AU - Cresswell C AD - AstraZeneca, Macclesfield, UK. carl.cresswell@astrazeneca.com. FAU - Dale, Angela AU - Dale A AD - AstraZeneca, Macclesfield, UK. angela.dale@astrazeneca.com. FAU - Davies, Amanda AU - Davies A AD - AstraZeneca, Macclesfield, UK. amanda.davies@astrazeneca.com. FAU - Zhang, Tianwei AU - Zhang T AD - Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. tianwei.zhang@astrazeneca.com. FAU - Fan, Shuqiong AU - Fan S AD - Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. shuqiong.fan@astrazeneca.com. FAU - Fu, Haihua AU - Fu H AD - Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. haihua.fu@astrazeneca.com. FAU - Gladwin, Amanda AU - Gladwin A AD - AstraZeneca, Macclesfield, UK. amanda.gladwin@astrazeneca.com. FAU - Harrod, Grace AU - Harrod G AD - AstraZeneca, Macclesfield, UK. grace.harrod@astrazeneca.com. FAU - Stevens, James AU - Stevens J AD - AstraZeneca, Macclesfield, UK. james.stevens@astrazeneca.com. FAU - Williams, Victoria AU - Williams V AD - AstraZeneca, Macclesfield, UK. victoria.williams@astrazeneca.com. FAU - Ye, Qingqing AU - Ye Q AD - Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. qingqing.ye@astrazeneca.com. FAU - Zheng, Li AU - Zheng L AD - Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. li.zheng@astrazeneca.com. FAU - de Boer, Richard AU - de Boer R AD - Department of Hematology & Medical Oncology, Western Hospital, Melbourne, Victoria, Australia. Richard.DeBoer@wh.org.au. FAU - Herbst, Roy S AU - Herbst RS AD - Yale Comprehensive Cancer Center, New Haven, CT, USA. roy.herbst@yale.edu. FAU - Lee, Jin-Soo AU - Lee JS AD - National Cancer Center, Goyang, Republic of Korea. jslee@ncc.re.kr. FAU - Vasselli, James AU - Vasselli J AD - AstraZeneca, Wilmington, DE, USA. vassellija@MedImmune.com. AD - Current address - MedImmune, Gaithersburg, MD, USA. vassellija@MedImmune.com. LA - eng SI - ClinicalTrials.gov/NCT00312377 SI - ClinicalTrials.gov/NCT00364351 SI - ClinicalTrials.gov/NCT00404924 SI - ClinicalTrials.gov/NCT00418886 PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20150323 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Piperidines) RN - 0 (Quinazolines) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-ret) RN - EC 2.7.10.1 (RET protein, human) RN - YO460OQ37K (vandetanib) SB - IM MH - Aged MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/metabolism MH - Female MH - Gene Amplification MH - Humans MH - Lung Neoplasms/*drug therapy/genetics/metabolism MH - Male MH - Middle Aged MH - Piperidines/*therapeutic use MH - Prevalence MH - Proto-Oncogene Proteins c-ret/*genetics/*metabolism MH - Quinazolines/*therapeutic use MH - Retrospective Studies MH - Translocation, Genetic MH - Treatment Outcome PMC - PMC4412099 EDAT- 2015/04/17 06:00 MHDA- 2016/04/29 06:00 PMCR- 2015/03/23 CRDT- 2015/04/17 06:00 PHST- 2014/03/18 00:00 [received] PHST- 2015/02/27 00:00 [accepted] PHST- 2015/04/17 06:00 [entrez] PHST- 2015/04/17 06:00 [pubmed] PHST- 2016/04/29 06:00 [medline] PHST- 2015/03/23 00:00 [pmc-release] AID - 10.1186/s12885-015-1146-8 [pii] AID - 1146 [pii] AID - 10.1186/s12885-015-1146-8 [doi] PST - epublish SO - BMC Cancer. 2015 Mar 23;15:171. doi: 10.1186/s12885-015-1146-8.