Evidence map›Paper›PMID 26608120›Full record

SynthesisEuropean journal of cancer (Oxford, England : 1990)2015

Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms.

Douglas B Johnson, Alexander M Menzies, Lisa Zimmer, Zeynep Eroglu, Fei Ye, Shilin Zhao, Helen Rizos, Antje Sucker, Richard A Scolyer, Ralf Gutzmer and 17 more

Open access · greenAbstract readMeta-AnalysisMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in European journal of cancer (Oxford, England : 1990), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 192 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
192citing papers in PubMed, 2 pooled it
14.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

192 citing papers in PubMed, 2 syntheses or guidelines pooled it, 328 citations in OpenAlex.

  1. Neoadjuvant treatment for stage III and IV cutaneous melanoma.The Cochrane database of systematic reviews · 2023
    Pooled it
  2. Pooled it
  3. Trial
  4. Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2018
    Trial
  5. Trial
  6. Article
  7. GTP biosynthesis is a therapeutic vulnerability in Rac1-mutant melanoma.bioRxiv : the preprint server for biology · 2026
    Article
  8. Review
  9. Review
  10. Observational
  11. Article
  12. Article
  13. Review
  14. Article
  15. Review
  16. Article
  17. Article
  18. Article
  19. Review
  20. Article

132 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

27 authors at 13 institutions in 5 countries.

Douglas B JohnsonDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: douglas.b.johnson@vanderbilt.edu.
Alexander M MenziesMelanoma Institute Australia, Sydney, NSW, Australia; Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
Lisa ZimmerDepartment of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
Zeynep ErogluDepartment of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA; Department of Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA.
Fei YeDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Shilin ZhaoDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Helen RizosCentre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Macquarie University, Sydney, NSW, Australia.
Antje SuckerDepartment of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
Richard A ScolyerMelanoma Institute Australia, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
Ralf GutzmerDepartment of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, Hannover, Germany.
Helen GogasFirst Department of Medicine, University of Athens Medical School, Athens, Greece.
Richard F KeffordMelanoma Institute Australia, Sydney, NSW, Australia; Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Macquarie University, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
John F ThompsonMelanoma Institute Australia, Sydney, NSW, Australia; Royal Prince Alfred Hospital, Sydney, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
Jürgen C BeckerTranslational Skin Cancer Research, German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
Carola BerkingDepartment of Dermatology, Ludwig-Maximilians-University, Munich, Germany.
Friederike EgbertsDepartment of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany.
Carmen LoquaiDepartment of Dermatology, University Medical Center, Mainz, Germany.
Simone M GoldingerDepartment of Dermatology, University Hospital Zürich, Switzerland.
Gulietta M PupoCentre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia.
Willy HugoDepartment of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Xiangju KongDepartment of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Levi A GarrawayDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Jeffrey A SosmanDepartment of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Antoni RibasDepartment of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Roger S LoDepartment of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA.
Georgina V LongMelanoma Institute Australia, Sydney, NSW, Australia; Centre for Cancer Research, The University of Sydney at The Westmead Millennium Institute, Westmead, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
Dirk SchadendorfDepartment of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany.
University of California, Los Angeles · USVanderbilt University Medical Center · USWestmead Institute · AUThe University of Sydney · AUUniversity of Duisburg-Essen · DEDana-Farber Cancer Institute · USEssen University Hospital · DELudwig-Maximilians-Universität München · DEMedizinische Hochschule Hannover · DENational and Kapodistrian University of Athens · GRUniversity Hospital of Zurich · CHUniversity Hospital Schleswig-Holstein · DEUniversity Medical Center of the Johannes Gutenberg University Mainz · DE

Funding

Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JOHN A GLASPY · 1985 to 2026
$134.5M
Transcriptional mechanisms and melanomaP01CA163222 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI DAVID E FISHER · 2013 to 2026
$25.3M
Vanderbilt Clinical Oncology Research Career Development ProgramK12CA090625 · NCI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Debra L. Friedman, Paula Jill Hurley · 2001 to 2026
$16.9M
TARGETED COMBINATORIAL TREATMENT OF BRAF MELANOMASP01CA168585 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI RIBAS, ANTONI · 2013 to 2017
$8.4M
NCI NIH HHS K12 CA090625NCI NIH HHS K12 CA0906525NCI NIH HHS P01 CA163222NCI NIH HHS P01 CA168585NCI NIH HHS P30 CA016042
6 · The paper itself

Abstract

backgroundAcquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance.

methodsWe compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing.

resultsAmong 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF(V600E/K) amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms.

conclusionsThis is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF-mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.

Indexed as

Drug Resistance, NeoplasmAntineoplastic AgentsAustraliaBiomarkers, TumorDisease-Free SurvivalDisease ProgressionDNA Mutational AnalysisEuropeFemaleGenetic Predisposition to DiseaseHumansKaplan-Meier EstimateMaleMelanomaMiddle AgedMutationAntineoplastic AgentsBiomarkers, TumorBRAF protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins B-rafAcquiredBRAFDabrafenibMAPKMEK1Meta-analysisNRASResistanceSpliceVemurafenib

Identifiers

PMID26608120
PMCPMC4666799
OpenAlexW2176310149

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.