Abstract C35: Different prognostic relevance of KRAS genotype in metastatic colorectal cancer (MCRC) patients fitting for triplet chemotherapy plus VEGF-inhibitor, unfit for intensive medical treatment and post-progression.
Authors: Bruera Gemma , Cannita Katia , Alesse Edoardo , Ficorella Corrado , Ricevuto Enrico 
Published: August 2014

Background: Prognosis of MCRC patients treated with bevacizumab and chemotherapy is not significantly different according to KRAS genotype. Specific mutations confer different aggressiveness. In vitro, codon 12 mutations increase aggressiveness by differential KRAS pathways regulation. Different codon 12 mutations modify biological activity of mutated KRAS proteins. Biological aggressiveness of codon 12 mutant tumors confers worse clinical behavior. RAS/RAF/MEK/ERK pathway increases VEGF expression and represses negative angiogenesis regulators; its aberrations stimulate angiogenesis and influence response to anti-VEGF. Prognostic role of prevalent c.35 G&gt;A KRAS mutation in first line FIr-B/FOx, post-progression, and in patients unfit for FIr-B/FOx was evaluated.

Methods: KRAS codon 12/13 were screened by SNaPshot and/or sequencing. Efficacy was evaluated and compared according to KRAS genotype, using log-rank.

Results: At 21.5 months follow-up, 59 fit MCRC patients were treated with first line FIr-B/FOx: wild-type, 31 (53%); mutant, 28 (47%). KRAS mutations: c.35 G&gt;A (G12D), 15 (25.4%); c.35 G&gt;T, 7 (11.8%); c.38 G&gt;A, 3 (5%); other, 3 (5%). KRAS genotype wild-type compared to mutant did not significantly affect PFS (14 and 11 months) and OS, even if OS seems favorable in wild-type (38 and 20 months). PFS of c.35 G&gt;A mutant compared to wild-type was not significantly different. OS was significantly worse in c.35 G&gt;A patients (14 months) compared to: wild-type (p = 0.002); other mutant (39 months) (p = 0.05). Wild-type compared with mutant did not show significantly different PFS (10 and 10 months) nor OS (17 and 12 months), after progression. PFS and OS after progression were significantly worse in c.35 G&gt;A compared to wild-type and/or other mutant patients. Among patients unfit for FIr-B/FOx, and treated with conventional medical treatments, KRAS genotype wild-type compared to mutant significantly affected PFS (8 and 6 months), while not OS (13 and 8 months). c.35 G&gt;A mutation significantly affected worse PFS and OS compared to wild-type and/or other mutations.

Conclusions: KRAS genotype, wild-type compared to mutant, did not significantly affect prognosis in MCRC patients treated with first line FIr-B/FOx, while it significantly affected worse efficacy (PFS) in patients unfit for intensive medical treatments. KRAS c.35 G&gt;A mutant status compared to wild type and other mutant, may significantly affect worse prognosis of patients, treated with first line intensive regimen (FIr-B/FOx), after progression, or unfit for FIr-B/FOx, probably due to increased biological aggressiveness. It did not affect worse PFS only in patients treated with first line FIr-B/FOx, probably due to effectiveness of intensive medical treatment consisting of triplet chemotherapy and VEGF inhibitor.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C35.

Citation Format: Gemma Bruera, Katia Cannita, Edoardo Alesse, Corrado Ficorella, Enrico Ricevuto. Different prognostic relevance of KRAS genotype in metastatic colorectal cancer (MCRC) patients fitting for triplet chemotherapy plus VEGF-inhibitor, unfit for intensive medical treatment and post-progression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C35.