Prospective Biomarker Study in Advanced RAS Wild-Type Colorectal Cancer: POSIBA Trial (GEMCAD 10-02)
Por:
García-Albéniz X, Alonso V, Escudero P, Méndez M, Gallego J, Rodríguez JR, Salud A, Fernández-Plana J, Manzano H, Zanui M, Falcó E, Feliu J, Gil M, Fernández-Martos C, Bohn U, Alonso C, Calderero V, Rojo F, Cuatrecasas M and Maurel J
Publicada:
1 nov 2019
Resumen:
Background RAS testing is used to select patients with anti-epidermal growth factor receptor (EGFR) therapies sensitivity in metastatic colorectal cancer (mCRC). However, other biomarkers such as BRAF, PIK3CA/PTEN, and p-IGF-1R+/MMP7+ (double positive [DP] phenotype) have not been prospectively assessed to predict anti-EGFR resistance. Materials and Methods We designed a multicenter prospective trial (NCT01276379) to evaluate whether the biomarkers BRAF mutation, PIK3CA mutation/PTEN loss, and DP phenotype can improve the prediction for 12-months progression-free survival (PFS) over the use of clinical variables exclusively in patients with RAS wild-type (WT) mCRC treated with standard chemotherapy plus biweekly cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFS based on the analysis of clinical and selected biomarkers (alpha = .05, beta = .2). The discriminatory capacity of the biomarkers was evaluated using receiver operating characteristic curves. Results We included 181 RAS WT patients. The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left-sided tumor, and resectable liver metastasis as the only metastatic site. The area under the curve (AUC) of the score containing the clinical variables was 0.67 (95% confidence interval [CI], 0.60-0.75). The AUC of the score with clinical variables and BRAF mutational status was 0.68 (0.61-0.75, p = .37). The AUC of the score with clinical variables and PI3KCA mutation/PTEN status was 0.69 (0.61-0.76, p = .32). The AUC of the score with clinical variables and DP phenotype was 0.66 (0.58-0.73, p = .09). Conclusion The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12-month PFS. Implications for Practice This prospective biomarker design study has important clinical implications because many prospective clinical trials are designed with the hypothesis that BRAF mutation per se and MEK and PIK3CA downstream pathways are critical for colorectal tumor survival. The results lead to the question of whether these pathways should be considered as passengers instead of drivers.
Filiaciones:
García-Albéniz X:
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
RTI Health Solutions, Barcelona, Spain
Alonso V:
Medical Oncology Service, Hospital Universitario Miguel Servet, Zaragoza, Spain
Escudero P:
Medical Oncology Service, Hospital Universitario Lozano Blesa, Zaragoza, Spain
Méndez M:
Medical Oncology Service, Hospital de Móstoles, Móstoles, Spain
:
Medical Oncology Service, Hospital General Universitario of Elche, Elche, Spain
Rodríguez JR:
Medical Oncology Service, Hospital Infanta Cristina, Badajoz, Spain
Salud A:
Medical Oncology Service, Hospital Universitari Arnau de Vilanova, Lleida, Spain
Fernández-Plana J:
Medical Oncology Service, Hospital Mútua de Terrassa, Spain
Manzano H:
Medical Oncology Service, Hospital Son Espases, Palma, Spain
Zanui M:
Medical Oncology Service, Hospital de Mataró, Mataró, Spain
Falcó E:
Medical Oncology Service, Hospital Son Llàtzer, Palma, Spain
Feliu J:
Medical Oncology Department, CIBERONC, Hospital Universitario La Paz, Madrid, Spain
:
Medical Oncology Service, Hospital de Sagunto, Sagunto, Spain
Fernández-Martos C:
Medical Oncology Department, Fundación Instituto Valenciano de Oncología, Valencia, Spain
Bohn U:
Medical Oncology Department, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
Alonso C:
Medical Oncology Department, Hospital de León, Spain
Calderero V:
Medical Oncology Department, Hospital General de Barbastro, Spain
Rojo F:
Pathology Service, Hospital Fundación Jiménez Díaz, Madrid, Spain
Cuatrecasas M:
Department of Pathology, Hospital Clínic, Banc de tumors Clínic-IDIBAPS
CIBEREHD and University of Barcelona, Spain
Maurel J:
Medical Oncology Department, Hospital Clínic of Barcelona, Translational Genomics and Targeted Therapeutics in Solid Tumors Group, IDIBAPS, University of Barcelona, Barcelona, Spain
hybrid, Green Published
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