1146 - Inter- and intra- tumor heterogeneity of somatic BRAF mutations in melanoma

Date 28 September 2012
Event ESMO Congress 2012
Session Publication Only
Topics Skin cancers
Pathology/Molecular Biology
Translational Research
Basic Scientific Principles
Basic Principles in the Management and Treatment (of cancer)
Presenter Samuel Murray
Authors S. Murray1, H. Linardou2, F. Siannis3, D. Bafaloukos4
  • 1Oncology, GeneKor SA, 15344 - Athens/GR
  • 2Medical Oncology, Metropolitan Hospital, 18547 - Athens/GR
  • 3Department Of Mathematics, University of Athens, 15000 - Athens/GR
  • 41st Department Of Medical Oncology, Metropolitan Hospital, 18547 - Athens/GR



Somatic mutations of BRAF are correlated with improved outcomes in patients with Melanoma treated with the anti-BRAF tyrosine kinase inhibitor Vemurafenib (PLX4032). Heterogeneity of patient responses to Vemurafenib in patients harboring BRAF mutations has questioned the stability of concordance between and within tumors. We conducted a systematic search of the literature to assess such status.


Using a broad search string including “BRAF”, “RAS”, “Melanoma”, “Cancer” and associated synonyms from inception through to 23/12/2011 in MEDLINE (PubMed) we identified articles providing information on Melanoma patients pertaining to concordance between synchronous (intra-) tumors; between primary and metastasis; and within (inter-) tumor heterogeneity. Data extraction was conducted by two investigators. Predictive values of testing for the presence of BRAF (True positive) and ‘no detectable mutation’ (True negative) were assessed and 95% confidence intervals calculated. Positive and Negative Predictive Values are presented (PPV, NPV).


Sixteen articles presented for synchronous, 13 for meta-synchronous, and 7 for retesting (intra-tumoral analysis). Data indicates that there is a significant level of dis-concordance: a) between synchronous tumors (PPV = 0.70 [0.59-0.79], NPV = 0.46 [0.35-0.56]); b) between meta-synchronous tumors (primary versus metastasis (PPV = 0.68 [0.54-0.80], NPV = 0.45 [0.32-0.58]); and within (intra-) tumors (PPV = 0.56 [0.49-0.69], NPV = 0.40 [0.29-0.52]).


Repetitive data sets indicated heterogeneity of BRAF genotype status between synchronous, meta-synchronous tumors, and also at the intra-tumoral level. PPV and NPV were worryingly high and outside of acceptable limits. Approximately 30% of patients may have dis-concordance in their BRAF reporting status. No obvious technical errors were identified to explain these differences. Several studies are now indicating that tumor heterogeneity may affect several cancer types, and this may impact on biomarker driven stratification. More data is eagerly awaited


All authors have declared no conflicts of interest.