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Prospective evaluation of BRAF, PI3K and PTEN as predictive and prognostic biomarkers in first-line advanced KRAS wild-type colorectal cancer treated with FOLFOX or FOLFIRI plus bi-weekly cetuximab. GEMCAD 10-02

Date

08 Oct 2016

Session

Poster Display

Presenters

Vicente Alonso

Citation

Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370

Authors

V. Alonso1, P. Escudero Emperador2, M. Mendez Urena3, J. Gallego4, J.R. Rodriguez5, J. Fernández6, A. Salud7, E. Falcó8, H. Manzano9, M. Zanui10, M. Gil11, U. Bohn Sarmiento12, C. Fernández Martos13, V. Calderero14, A.I. Ferrer15, M. Cuatrecasas16, F. Rojo17, J. Feliu18, J. Maurel19, X. García-Albéniz20

Author affiliations

  • 1 Medical Oncology, Hospital Miguel Servet, 50009 Zaragoza - Zaragoza/ES
  • 2 Medical Oncology, Hospital Clinico Universitario Lozano Blesa, Zaragoza/ES
  • 3 Medical Oncology, Hospital Universitario de Móstoles, Madrid/ES
  • 4 Medical Oncology, Hospital General Universitario de Elche, Elche/ES
  • 5 Medical Oncology, Hospital Infanta Cristina, Madrid/ES
  • 6 Medical Oncology, Hospital Mutua de Terrassa, Terrassa/ES
  • 7 Medical Oncology, Hospital Universitario Arnau Vilanova de Lleida, Lerida/ES
  • 8 Medical Oncology, Hospital Son Llatzer, Palma de Mallorca/ES
  • 9 Medical Oncology, Hospital Universitario Son Espases, Palma de Mallorca/ES
  • 10 Medical Oncology, Hospital de Mataro Consorcio Sanitario del Maresme, Mataro/ES
  • 11 Medical Oncology, Hospital de Sagunto, Valencia/ES
  • 12 Medical Oncology, Hospital de Gran Canaria Dr. Negrin, Las Palmas/ES
  • 13 Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia/ES
  • 14 Medical Oncology, Hospital de Barbastro, Barbastro/ES
  • 15 Medical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete/ES
  • 16 Pathological Anatomy, Hospital Clinic y Provincial de Barcelona, Barcelona/ES
  • 17 Pathological Anatomy, University Hospital "Fundacion Jimenez Diaz", Madrid/ES
  • 18 Medical Oncology, Hospital Universitario La Paz, Madrid/ES
  • 19 Medical Oncology, Hospital Clinic y Provincial de Barcelona, Barcelona/ES
  • 20 Department Of Epidemiology, T. H. Chan Harvard School of Public Health, Boston/US
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Resources

Background

In metastatic colorectal cancer (mCRC), mutation testing for KRAS exon 2 and recently exon 2, 3 and 4 KRAS and NRAS is widely implemented to select patients, sensitive to anti-EGFR therapies, i.e. cetuximab. The added predictive value of BRAF-ERK and PI3K- AKT signaling pathways remains controversial, mostly due to the retrospective nature and second-third lines studies.

Methods

We conducted a biomarker-evaluation phase II trial (ClinicalTrials.gov id: NCT01276379). We included 221 KRAS exon 2 WT patients and evaluated whole KRAS and NRAS mutations by pyrosequencing, BRAF and PI3K mutations by RT-qPCR and PTEN expression by immunohistochemistry. We followed patients every 3 months with abdominopelvic CT scan and clinical examination. We analyzed progression-free survival (PFS, time from inclusion to progression or death) and overall survival (OS, time from inclusion to death) in patients with BRAF wild-type (WT) vs. BRAF mutant and in patients with increased PI3K pathway activation (PI3K mutant or loss of PTEN expression) vs. low PI3K pathway activation (PI3K WT and preserved PTEN expression).

Results

BRAF mutational status was evaluable in 207 patients (20 mutated) and PI3K pathway activation status was evaluable in 193 (108 PI3K mutant or loss of PTEN expression). Patients were treated either with FOLFOX-Cetuximab (53%) or with FOLFIRI-Cetuximab (47%). Median follow-up was 24 (range 0.3-54) months. Patients had a median PFS of 11.4 (95% 9.8-13.2) months if BRAF WT and of 6.1 (3.5-8.3) months if BRAF mutant (adjusted HR = 2.00, 95% CI 1.16-3.46). Median OS for BRAF WT patients was 34.4 (95% 26.8-43.1) months and 9.7 (7.2-23.5) months for BRAF mutant patients (adjusted HR = 3.21, 95% CI 1.80-5.74). PI3K pathway activation status did not discriminate neither PFS (adjusted HR 0.83, 95% CI 0.61-1.13) nor OS (adjusted HR 1.24, 95% CI 0.80-1.91).

Conclusions

BRAF mutational status is both predictive and prognostic in patients with advanced KRAS WT colorectal cancer receiving Cetuximab-containing regimes as first line of therapy. PI3K pathway activation is not associated with Cetuximab resistance.

Clinical trial identification

EudraCT 2010-019236-12

Legal entity responsible for the study

Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)

Funding

Grupo Español Multidisciplinar en Cáncer Digestivo (GEMCAD)

Disclosure

All authors have declared no conflicts of interest.

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