Prognostic significance of K-Ras mutation rate in metastatic colorectal cancer patients
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Bruno Vincenzi1, Chiara Cremolini2, Andrea Sartore-Bianchi3, Antonio Russo4, Francesco Mannavola5, Giuseppe Perrone6, Francesco Pantano1, Fotios Loupakis2, Daniele Rossini2, Elena Ongaro7, Erica Bonazzina3, Emanuela Dell’Aquila1, Marco Imperatori1, Alice Zoccoli1, Giuseppe Bronte4, Giovanna De Maglio7, Gabriella Fontanini8, Clara Natoli9, Alfredo Falcone2, Daniele Santini1, Andrea Onetti-Muda6, Salvatore Siena3, Giuseppe Tonini1 and Giuseppe Aprile7
1 Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
2 Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy
3 Niguarda Cancer Center, Ospedale Niguarda Ca’ Granda, Milano, Italy
4 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy
5 Università Cattolica del Sacro Cuore, Rome, Italy
6 Department of Anatomical Pathology, Campus Bio-Medico University of Rome, Rome, Italy
7 Department of Medical Oncology, Azienda Ospedaliero-Universitaria, Udine, Italy
8 Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Università di Pisa, Pisa, Italy
9 Department of Medical, Oral and Biotechnological Sciences, University “G. D’Annunzio”, Chieti, Italy
Antonio Russo, email:
Bruno Vincenzi, email:
Keywords: K-Ras, mutation rate, colorectal cancer, bevacizumab, prognosis
Received: July 20, 2015 Accepted: August 09, 2015 Published: August 19, 2015
Introduction: Activating mutations of K-Ras gene have a well-established role as predictors of resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Their prognostic value is controversial, and no data regarding the prognostic value of mutation rate, defined as the percentage of mutated alleles/tumor sample, are available. We aimed to evaluate the prognostic value of K-Rasmutation rate in a homogenous cohort of mCRC patients receiving first-line doublet plus bevacizumab.
Patients and Methods: This retrospective study enrolled 397 K-Ras mutant mCRC patients from 6 Italian centers, and 263 patients were fully evaluable for our analysis. K-Ras mutation rate was assessed by pyrosequencing. Patients with less than 60% of cancer cells in tumor tissue were excluded. No patients received anti-EGFR containing anticancer therapy, at any time. Median mutation rate was 40% and was adopted as cut-off. The primary and secondary endpoints were PFS and OS respectively.
Results: At univariate analysis, K-Ras mutation rate higher than 40% was significantly associated with lower PFS (7.3 vs 9.1 months; P < 0.0001) and OS (21 vs 31 months; P = 0.004). A multivariate model adjusted for age at diagnosis, site of origin of tumor tissue (primary vs metastases), referral center, number of metastatic sites, and first-line chemotherapy backbone, showed that K-Ras mutation rate remained a significant predictor of PFS and OS in the whole population.
Discussion: Our data demonstrate an association between K-Ras mutation rate and prognosis in mCRC patients treated with bevacizumab-containing first-line therapy. These data deserve to be verified in an independent validation set.
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