The Efficacy Analysis Of FOLFOX Combined With Targeted Therapy In The First Line Treatment Of Advanced Colorectal Cancer With K-ras Wild Type And The Research About K-ras Secondary Mutation

Objective Comparison of the clinical efficacy of anti-EGFR monoclonal antibody (cetuximab) and anti-VEGF monoclonal antibody (bevacizumab) in advanced colorectal cancer with K-ras wild type.At the same time,we researched whether wild type K-ras gene can occur secondary mutation in using anti-EGFR monoclonal antibody,which conversely led to acquired drug resistance of anti-EGFR targeted therapy.Methods 1.From January 2008 to February 2014,seventy-two patients diagnosed as advanced colorectal cancer with K-ras wild type in the People’s Liberation Army General Hospital were collected.The efficacy of FOLFOX regimen combined with the bevacizumab or cetuximab as the first-line treatment in advanced colorectal cancer with K-ras wild type were analyzed retrospectively;2.In recent years,fifty patients diagnosed as advanced colorectal cancer with K-ras gene wild type in the Hospital were collected. After adjuvant chemotherapy or palliative chemotherapy,we detected again the K-ras gene,Braf gene and NRAS Exon2、Exon3、Exon4 in tumor tissue and calculated the secondary mutation rate of K-ras.Results 1.Seventy-two patients were evaluated.In FOLFOX group,the ORR was 14.3%,the DCR was 75.0%,the mPFS was 8.0 months;in FOLFOX+BEV group,the ORR was 64.7%,the DCR was 94.1%,the mPFS was 10.0 months;in FOLFOX+C225 group,the ORR was 59.3%,the DCR was 92.6%,the mPFS was 9.2 months.Between FOLFOX group and FOLFOX+BEV group,the ORR(x2=12.10,P=0.0005) difference was statistically significant;between FOLFOX group and FOLFOX+C225 group,the ORR(x2=12.01,P=0.0005) difference was statistically significant;between FOLFOX+BEV group and FOLFOX+C225 group,the ORR(x2=0.13,P=0.72) difference was no significant;however, the difference of the three groups of DCR and mPFS were no significant(P>0.05).2.In fifty cases,there were three cases of K-ras secondary mutation.mutation rate was 6%(3/50).The K-ras secondary mutation of the adjuvant chemotherapy with recurrence group,the palliative chemotherapy without progression group,the palliative chemotherapy with progression group were respectively 0%(0/13),0%(0/16) and 14.3%(3/21).The difference of the three group was no statistically significant(x2-4.4,P=0.11).The rate of the palliative chemotherapy with progression group was 14.3%(3/21),including chemotherapy group:0%(0/5) and chemotherapy combined with cetuximab group:18.8%(3/16).In the palliative chemotherapy with or without progression group,the rate of the use of cetuximab in less than 10 months was 5.9%(1/17),however,the rate of the use of cetuximab in more than 10 months was 25.0%(2/8).when including one case of secondary BRAF mutations,the rate was 37.5%(3/8).but,the difference had no statistically significant(P>0.05).After chemotherapy or targeted therapy we detected thirty six cases of Braf in fifty cases,including thirty four cases of wild type and two cases of the mutation type(one of case was wild type before treatment).The mutation rate was 5.6%(2/36).After chemotherapy or targeted therapy we detected 34 cases of NRAS Exon2、Exon3、Exon4 in fifty cases,including thirty four cases of wild type and no cases of the mutation type. Conclusion In this study,compared with FOLFOX regimen,the short term and long term clinical efficacy of FOLFOX regimen combined with anti-EGFR monoclonal antibody targeted therapy improved significantly, so the FOLFOX regimen could be used as one of chemotherapy regimen combined with anti-EGFR targeted therapy.The clinical efficacy of two kinds of different mechanisms of targeted therapy drugs---the anti-EGFR monoclonal antibody and anti-VEGF monoclonal antibody were equivalent,so they could all be chosen as first line targeted drug in the treatment of advanced colorectal cancer with k-ras wild type. Cetuximab acquired drug resistance may be related with secondary K-ras mutations,and with the increase of use of cetuximab, the probability of secondary K-ras mutation was likely to increase.When the progress of the illness with using cetuximab in the clinical work, we could puncture tumor again and detect combined gene,in order to confirm the significance of continuing using anti-EGFR targeted therapy.