title: A retrospective analysis of RET translocation, gene copy number gain and expression in NSCLC patients treated with vandetanib in four randomized Phase III studies.
abstract: 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.
  
  
  BACKGROUND
  Randomized Phase III clinical trials ( NCT00312377 , ZODIAC; NCT00418886 , ZEAL; NCT00364351 , ZEST; NCT00404924 , ZEPHYR).
authors.affiliation: AstraZeneca, da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston, Hertfordshire, SG8 6HB, UK. adam.platt@astrazeneca.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Platt
authors.affiliation: AstraZeneca, Macclesfield, UK. john.morten@astrazeneca.com.
authors.forename: John
authors.initials: J
authors.lastname: Morten
authors.affiliation: Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. qunsheng.ji@astrazeneca.com.
authors.forename: Qunsheng
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authors.lastname: Ji
authors.affiliation: AstraZeneca, Macclesfield, UK. paul.elvin@astrazeneca.com.
authors.forename: Paul
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authors.lastname: Elvin
authors.affiliation: AstraZeneca, Macclesfield, UK. chris.womack@astrazeneca.com.
authors.forename: Chris
authors.initials: C
authors.lastname: Womack
authors.affiliation: Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. xinying.su@astrazeneca.com.
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.affiliation: AstraZeneca, Macclesfield, UK. emma.donald@astrazeneca.com.
authors.forename: Emma
authors.initials: E
authors.lastname: Donald
authors.affiliation: AstraZeneca, Macclesfield, UK. adam.platt@astrazeneca.com.
authors.forename: Neil
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authors.affiliation: AstraZeneca, Macclesfield, UK. jessica.read@astrazeneca.com.
authors.forename: Jessica
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authors.lastname: Read
authors.affiliation: AstraZeneca, Macclesfield, UK. graham.bigley@astrazeneca.com.
authors.forename: Graham
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authors.lastname: Bigley
authors.affiliation: AstraZeneca, Macclesfield, UK. laura.blockley@astrazeneca.com.
authors.forename: Laura
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authors.lastname: Blockley
authors.affiliation: AstraZeneca, Macclesfield, UK. carl.cresswell@astrazeneca.com.
authors.forename: Carl
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authors.affiliation: AstraZeneca, Macclesfield, UK. angela.dale@astrazeneca.com.
authors.forename: Angela
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authors.affiliation: AstraZeneca, Macclesfield, UK. amanda.davies@astrazeneca.com.
authors.forename: Amanda
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authors.affiliation: Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. tianwei.zhang@astrazeneca.com.
authors.forename: Tianwei
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authors.affiliation: Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. shuqiong.fan@astrazeneca.com.
authors.forename: Shuqiong
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authors.affiliation: Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. haihua.fu@astrazeneca.com.
authors.forename: Haihua
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authors.lastname: Fu
authors.affiliation: AstraZeneca, Macclesfield, UK. amanda.gladwin@astrazeneca.com.
authors.forename: Amanda
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authors.lastname: Gladwin
authors.affiliation: AstraZeneca, Macclesfield, UK. grace.harrod@astrazeneca.com.
authors.forename: Grace
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authors.lastname: Harrod
authors.affiliation: AstraZeneca, Macclesfield, UK. james.stevens@astrazeneca.com.
authors.forename: James
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authors.lastname: Stevens
authors.affiliation: AstraZeneca, Macclesfield, UK. victoria.williams@astrazeneca.com.
authors.forename: Victoria
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authors.lastname: Williams
authors.affiliation: Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. qingqing.ye@astrazeneca.com.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Innovation Cancer Center, AstraZeneca R&D, Shanghai, China. li.zheng@astrazeneca.com.
authors.forename: Li
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authors.lastname: Zheng
authors.affiliation: Department of Hematology & Medical Oncology, Western Hospital, Melbourne, Victoria, Australia. Richard.DeBoer@wh.org.au.
authors.forename: Richard
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authors.lastname: de Boer
authors.affiliation: Yale Comprehensive Cancer Center, New Haven, CT, USA. roy.herbst@yale.edu.
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.affiliation: National Cancer Center, Goyang, Republic of Korea. jslee@ncc.re.kr.
authors.forename: Jin-Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: AstraZeneca, Wilmington, DE, USA. vassellija@MedImmune.com.|Current address - MedImmune, Gaithersburg, MD, USA. vassellija@MedImmune.com.
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mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000627:therapeutic use*; D015995:Prevalence; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism*; D011799:Quinazolines / Q000627:therapeutic use*; D012189:Retrospective Studies; D014178:Translocation, Genetic; D016896:Treatment Outcome
chemical_list: D010880:Piperidines; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C452423:vandetanib