Predictive And Prognostic Biomarkers For Patients Treated With Anti-EGFR Agents In Lung Cancer:A Systemic Review And Meta-Analysis

Background:Lung cancer has dreadful reputation in the world for its population and scare lethality. As the haze emerges, carcinogens in the air increase and the air quality deteriorates, the occurrence of lung cancer rockets speedily. It is gratified that more and more clinicians endeavor to figure out the mechanism of oncology and seek innovative therapeutic methods to rescue patients from cancers and the achievements seem to be positive. Although the clinicians propose and work out the standard chemotherapy, the survival benefit has reached an efficacy plateau. Now EGFR is came up with to be the target to attack tumors. And the agents which are developed based on the theory become the potential optional for advanced lung carcinoma. As most kinds of targeted therapy, the clinicians need to find effective biomarkers to identify appreciate patients.K-ras exerts considerable influence in the downstream signaling network of EGFR. Several articles has referred to that K-ras mutation status could reflect therapeutic responsiveness to anti-EGFR agents. Besides, PIK3CA has a complex function in the regulation of cell survival, for instance, it could be involved in the encoding of helical and kinase domains. When the part of PIK3CA gene mutates, which often are missense mutations, the cellular normal mechanism would be out of balance. Additionally, it has been reported that high expression of PTEN patients have longer survival, but the responsiveness to anti-EGFR agents is unclear.All above, several studies have investigated predictive and prognostic value of biomarkers for anti-EGFR agents among lung carcinoma patients. However, what they found are not on the same page.Objectives:This meta-analysis aimed to elucidate the relationships between biomarkers with outcomes of anti-EGFR agents on lung carcinoma, trying to investigate their predictive and prognostic value. Our goal was to seek an effective predictor to select more appropriate population for anti-EGFR agents.Materials and Methods:We performed a comprehensive systematic search of PubMed, Cochrane databases, EMBASE and Google to collect the articles referred to the associations of mutant K-ras, PIK3CA and PTEN deficiency with the efficacy of anti-EGFR agents in lung cancer. In analysis, we chose the ORR to reflect the responsiveness to anti-EGFR agents. In the same time, OS and PFS were used to evaluate the prognosis after anti-EGFR agent administration. The data about individual HRor RRwere pooled and reported. Stata 12.0 software dealt with statistical tests in study.Results:A total of 61 studies were brought into meta-analysis. The results showed that K-ras mutation owned significantly predictive value of anti-EGFR agents. The ORRs of two kinds of K-ras mutation status suggested K-ras mutation patients probably lack of sensitivity to anti-EGFR agents (RR=0.42,95%CI,0.33-0.55, P< 0.001).It implied that K-ras mutation possessed the prognostic value after treatment of anti-EGFR agents, for the mutant K-ras patients had a dramatically shorter OS and shorter PFS than wild-type K-ras patients. (OS:HR=1.37,95%CI,1.15-1.65,P=0.001; PFS:HR=1.33,95%CI,1.05-1.69,P=0.019).It indicated that K-ras mutant patients had poor survival benefits than wild-type patients. It may be a valid predictive and prognostic biomarker of anti-EGFR agents to select insensitive patients to anti-EGFR agents. The ORRs of two kinds of PIK3CA mutation status patients indicated that the predictive value was insignificant (RR=1.08,95%CI,0.17-6.66,P=0.938), and the results about OS did not show that significantly prognostic value (HR=0.79,95%CI: 0.23-2.68, P=0.706). The ORRs of different expression levels of PTEN indicated that the predictive value of PTEN deficiency was insignificant (RR=0.82,95%CI, 0.56-1.19, P=0286). Studies concentrated on OS of loss of PTEN showed that the insignificance prognostic value of loss of PTEN for anti-EGFR agents (HR=0.88, 95%CI,0.31-2.46,P=0.805).Conclusions:Our meta-analysis certified that, compared with K-ras mutation patients, K-ras wild type patients had better response to anti-EGFR agents. The results showed, for anti-EGFR, K-ras mutation may be an effective predictor in lung cancer. Whereas, the predictive and prognostic value of PTEN deficiency and PIK3CA mutation need to be further investigated.