MOLECULAR BIOMARKERS AND HISTOLOGICAL PARAMETERS IMAPCT ON SURVIVAL AND RESPONSE TO FIRST- LINE SYSTEMIC THERAPY OF METASTATIC COLORECTAL CANCER PATIENTS
Background: Histological parameters of primary tumor (PT) and nodal metastases (N) are prognostic factors for survival of operable colorectal (CRC) patients (pts), but not predictive for response rate of systemic therapy. KRAS mutations (muts) in codons 12 and 13 are first recognized as a predictive factor for resistance to anti-EGFR monoclonal antibodies. Not all pts with wild-type KRAS (wt KRAS) respond to anti-EGFR antibody treatment. Additional mechanisms of resistance may activate muts of the other main EGFR effectors pathway, such as other mutatios in RAS gene, mutations in P13K and PTEN expression.
Methods: In the prospective study prognostic and predictive impact of histological parameters of PT, KRAS and BRAF muts on overall survival (OS) and objective response (OR) rate of mCRC pts treated with 1st line systemic th were analyzed. We additionally retrospectivelly eanalyzed other mutations in RAS genes and their impact on survival and time to progression.
Results: From November 2010 to December 2012 154 pts were enrolled, 95 men and 59 women. Muts in KRAS gene and V600E BRAF gene were found in 42 % of pts and in 3 % of pts respectively. Median OS of the pts with T1, T2 and T3 tumor was 65.4 months (95% CI, 55.7 -75.6), while in pts with T4 tumor, lymphangiosis, vascular and perineural invasion it has not been reached yet. Median OS of the pts with G1 and G2 of tumor differentiation (td) and of pts with G3 of td was 65.6 mo (95% CI, 53.7 - 77.5) and 25.3 mo (95% CI, 16.6 - 34.1) respectively. Median OS of the pts with stage N0 and N1 and of pts with stage N2 was 65.6 mo (95% CI, 56.4 - 74.8 ) and 58.0 mo (95% CI, 21.9 - 94.2) respectively. Median OS of wt KRAS pts and of mt KRAS pts was 56.5 mo (95% CI, 48.2 - 64.9) and 58 mo (95% CI, 52.6 - 63.4) respectively. Median OS of mut codon 12 pts and of mut codon 13 pts was 57 mo (95% CI, 50.9 - 64.4) and 44 mo (95% CI, 40.1 - 48.4) respectively. Median OS of wt BRAF pts and of mt BRAF pts was 59.2 mo (95% CI, 52.5 - 65.9) and 27.6 mo (95% CI, 12.6 - 42.5) respectively. Wt KRAS significantly affected the response to 1st systemic th (p = 0.028), while other parameters did not affected it, p= 0.07. In 14 pts (17%) additional mutations in NRAS gene, codon 61 and codon 146 were found. Median survival of wtNRAS , codon 61 and 146 pts was 67.1mo (50.3 – 67.6 mo), mtNRAS, codon 61 and 146 pts it has not been reached yet (p = 0.072). Median time to progression of wtNRAS , codon 61 and 146 pts was 11.7 mo (10.4 – 14.5 mo), mtNRAS, codon 61 and 146 pts was 7.9 mo (6.1- 11.0 mo), (p = 0.025).
Conclusions: Mt BRAF, N2 and G3 of td are poor prognostic factors for OS of mCRC pts. Wt KRAS significantly affected the response to 1st line systemic therapy. Histological parameters included in the analysis and mt BRAF did not affect significantly the efficacy of 1st line systemic therapy in mCRC pts.
Key words: Metastatic colorectal cancer, chemotherapy, targeted therapy, histologycal parameters, biomarkers