1108P - BRAF mutation analysis in cell free tumoral DNA (cfDNA) of melanoma patients: preliminary results from the Spanish Melanoma Group prospective study...

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Melanoma and other Skin Tumours
Pathology/Molecular Biology
Translational Research
Presenter Maria Gonzalez-Cao
Citation Annals of Oncology (2014) 25 (suppl_4): iv374-iv393. 10.1093/annonc/mdu344
Authors M. Gonzalez-Cao1, V. Soriano2, D. Rodriguez3, T. Puertolas4, E. Muñoz5, A. Soria6, C. Mayo de Las Casas1, M.A. Molina1, E. Perez7, M. Magem8, A. Garcia9, J.L. Manzano10, J. Cortes5, R. Rosell1
  • 1Medical Oncology, 1Instituto Oncológico Dr Rosell, Hospital Universitario Quirón Dexeus, 08028 - Barcelona/ES
  • 2Medical Oncology, Fundación IVO, Valencia/ES
  • 3Medical Oncology, Hospital Insular de Gran Canaria, Las palmas/ES
  • 4Medical Oncology, Hospital Miguel Servet, Zaragoza/ES
  • 5Medical Oncology, Hospital Vall d’Hebron, Barcelona/ES
  • 6Medical Oncology, Hospital Universitario Ramon y Cajal, Madrid/ES
  • 7Medical Oncology, Hospital Costa del Sol, Malaga/ES
  • 8Medical Oncology, Hospital Sant Pau, Barcelona/ES
  • 9Medical Oncology, Hospital Marques de Valdecilla, Santander/ES
  • 10Medical Oncology, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916 - Badalona - Barcelona/ES

Abstract

Aim

Our data in BRAFV600 mutant melanoma patients treated with BRAF inhibitors showed a significant difference in median PFS by cfDNA status (3.5 months vs 13.57 months for BRAFV600 positive and negative, respectively p = 0.026)1. The Spanish Melanoma Group initiated a translational study to assess BRAFV600 mutation in cfDNA of stage IV BRAF mutant melanoma patients to determine the prognostic value of BRAFV600 mutation and its role in monitoring disease evolution (GEM1304) (ClinicalTrials.gov Identifier: NCT01960634).

Methods

A quantitative 5'-nuclease PCR based assay for determination of BRAFV600 mutation in cfDNA was developed and validated in 92 previously genotyped cancer patients. Planned accrual for GEM1304 study was 58 BRAFV600 mutated melanoma patients. Serum and plasma samples are collected before and during treatment until disease progression.

Results

The assay detected 2.5 pg mutated DNA/µL and a ratio of V600E versus wild type allele of 1:20000 with clinical sensitivity of 58% and specificity of 100%. Twenty-six patients, 47 samples, have been included to date. Pretreatment analysis was positive in serum in 16 (64%) and in plasma in 15 (60%) patients. Eleven patients have more than one sample; in four patients no mutation was detected in pretreatment and follow up samples (2 m+. 5 m+. 5 m+. 7 m+). BRAFV600 was detected in pretreatment samples in 6 patients.: in 4 responding patients BRAFV600 mutation was not detectable in subsequent analysis until disease progression (3m + , 6m, 8m + , 9m+). In two primary resistant patients, BRAFV600 persisted in follow up samples and time to death was less than 3 months. Discordant results between clinical response and cfDNA were found in one single patient: radiologic partial response was diagnosed but BRAFV600 mutation cfDNA load increased and patient died after 3 months on treatment. Re-evaluation of the previously performed scan showed new bone metastasis that had been inadvertent.

Conclusions

Noninvasive genotyping of ctDNA by PCR assay could allow effective translation to the clinical setting. BRAFV600 mutation in pretreatment samples and persistence of BRAFV600 mutation at first evaluation could be prognostic markers of survival. Updated results will be presented during the meeting.

Disclosure

M. Gonzalez-Cao: Work on this study was supported by a grant from Roche Pharmaceuticals. All other authors have declared no conflicts of interest.