| Background Two monoclonal antibodies (MoAb) targeted at epidermal growth factor receptor (EGFR), the chimeric IgG1 MoAb cetuximab and the fully humanized IgG2 panitumumab, have proven to be effective in combination with chemotherapy or as single agent for treatment of metastatic colorectal cancer (mCRC). However, among unselected patients with mCRC, only 10% to 20% of patients can truly benefit from the treatment. Therefore, there is a clear need for predictive biomarkers to maximize likelihood of response while minimizing toxicities and cost. Oncogenic activation of EGFR downstream effectors such as KRAS, BRAF and PIK3CA are found to be associated with poor prognosis in mCRC patients treated with anti-EGFR MoAbs. To data, KRAS mutations has been identified as a predictive marker of resistance to anti-EGFR MoAbs in patients with mCRC, and the use of anti-EGFR MoAbs is now restricted to mCRC patients with wild-type KRAS. However, the occurrence of KRAS mutations only account for approximately 30% to 40% of nonresponsive patients. In patients with KRAS wild-type tumors, it remains unclear why a large number of patients are still not responsive to the treatment. BRAF, PIK3CA mutations are found likely to be promising predictors for the resistance in these patients and in patients unselected by KRAS mutation status but required further evaluation before being incorporated in clinical practice. As some new studies emerging, data for KRAS and other biomarkers such as BRAF, PIK3CA mutations remain inconsistent, reflecting differences in datasets, methodologies and possibly tumor heterogeneity. Our initial literature search identified some 40 potentially relevant studies in these important aspects and no systematic review or meta-analysis has been conducted to summarize the evidence. In order to generate up-to-date evidence on the role of biomarkers in predicting responses to anti-EGFR MoAbs, we performed a meta-analysis to identify the predictive biomarkers for anti-EGFR MoAbs treatment, with a focus on KRAS, BRAF and PIK3CA mutations in patients with mCRC.Objectives The specific objectives of this study are:1) To systematically assess the value of KRAS, BRAF, PIK3CA mutations and their combinations in predicting objective response, progression-free survival (PFS) and overall survival (OS) in mCRC patients treated with anti-EGFR MoAbs; 2) To systematically assess the value of BRAF and PIK3CA mutations in predicting objective response, PFS and OS in wild-type KRAS mCRC patients treated with anti-EGFR MoAbs.Materials and methods Comprehensive computerized literature search of PUBMED, EMBASE, Chinese Biomedical Database and Wan Fang Digital Journals were performed. Studies meeting all the following 2 inclusion criteria were eligible and included:1) those exploring the relation between KRAS, BRAF and PIK3CA mutations and clinical outcomes of mCRC patients treated with anti-EGFR MoAbs; 2) those using one or more of the following as outcomes to assess tumor response and prognosis:objective response, PFS and OS. The primary endpoints were objective response, PFS and OS. The association between KRAS, BRAF or PIK3CA mutations and objective response rate (ORR) was expressed as a risk ratio (RR), namely the ORR in mutant patients divided by that in wild-type patients. The association between KRAS, BRAF or PIK3CA mutations and PFS or OS was expressed as a hazard ratio (HR). The pooled RR or HR was estimated by using the fixed-effect model unless heterogeneity was found and cannot be explained. Sensitivity analyses were carried out to check if modification of the inclusion criteria of the meta-analysis affected the final results. Begg's funnel plots and Egger's linear regression test were used to assess the possibility of publication bias. If deemed necessary, the Duval and Tweedie non-parametric "trim and fill" method would be used to estimate the "unbiased" effect.Results For KRAS mutations and clinical outcomes of anti-EGFR MoAbs treatment, a total of 25 studies were included in the final meta-analysis. KRAS mutations were detected in 38% (894/2354) of primary tumors. Compared to KRAS wild-type patients, we observed a significantly lower ORR (25 studies,2,321 patients; 14% vs.38%; RR 0.25,95% CI 0.17-0.38; P<0.001), significantly shorter PFS (8 studies,755 patients; Median PFS:3.0 vs.5.7 months; HR 1.94,95% CI 1.64-2.31; p<0.001) and significantly shorter OS (5 studies,502 patients; Median OS:6.9 vs. 12.4 months; HR 2.21,95% CI 1.77-2.75; p<0.001) in KRAS mutant patients.For BRAF mutations and clinical outcomes of anti-EGFR MoAbs treatment, a total of 11 studies were included in the final meta-analysis. BRAF mutations were detected in 9% (48/546) of primary tumors. Compared to BRAF wild-type patients, we observed a significantly lower ORR (4 studies,376 patients; 0% vs.36%; RR 0.14, 95% CI 0.04-0.53; p=0.004), significantly shorter OS (3 studies,297 patients; HR 3.11,95% CI 1.74-5.54; p<0.001), and trend towards shorter PFS (2 studies,182 patients; HR 1.79,95% CI 0.96-3.34; p=0.068) in KRAS wild-type mCRC patients with BRAF mutations. The effect of the BRAF mutations on the clinical outcomes of anti-EGFR MoAbs treatment was diluted in patients unselected by KRAS mutation status (ORR:7 studies,520 patients; 29% vs.33%; RR 0.86,95% CI 0.57-1.30; p=0.475; PFS:1 study,95 patients; HR 1.39,95% CI 0.52-3.69; p=0.513; OS:1 study, 95 patients; HR 2.31,95% CI,0.87-6.13; p=0.093).For PIK3CA mutations and clinical outcomes of anti-EGFR MoAbs treatment, a total of 10 studies were included in the final meta-analysis. PIK3CA mutations were detected in 12% (220/1764) of primary tumors. Compared to PIK3CA wild-type patients, we observed a lower ORR in KRAS wild-type mCRC patients with PIK3CA exon 9 mutations (4 studies,400 patients; 28% vs.38%; RR 0.79,95% CI 0.45-1.41; p=0.434) and a much lower ORR in those with exon 20 mutations (3 studies,377 patients; 0% vs.37%; RR 0.25,95% CI 0.05-1.19; p=0.082) although the result was not statistically significant for both mutations because of the small sample size. The RR for those with any PIK3CA mutations is 0.60 (6 studies,540 patients; 95% CI 0.37-0.99), marginally statistically significant (p=0.044) as a result of the increased sample size. As expected, the negative effect of the PIK3CA mutation on objective response was diluted in patients unselected by KRAS mutation status (Exon 20 mutations:RR 0.60,95% CI 0.14-2.63; Exon 9 mutations:RR 1.03,95% CI 0.56-1.89; All exons mutations:RR 0.75,95% CI 0.44-1.28). The above observation is also confirmed in one study that provided survival data in KRAS wild-type mCRC patients, in which PIK3CA exon 20 mutations were associated with shorter PFS (HR 2.52,95% CI 1.33-4.78; p=0.013) and OS (HR 3.29,95% CI 1.60-6.74; p=0.006). The predictive power of exon 20 mutation is greater than all exons mutations (PFS: HR 1.30,95% CI 0.91-1.86; p=0.170; OS:HR 1.41,95% CI 0.96-2.06; p=0.090) and exon 9 mutations (PFS:HR 1.11,95% CI 0.72-1.71; p=0.650; OS:HR 1.30,95% CI 0.82-2.05; p=0.280).Conclusions For unselected mCRC patients treated with anti-EGFR MoAbs, we found that KRAS mutations were significantly associated with lower ORR, shorter PFS and shorter OS. Several original studies also found that this negative effect of KRAS mutation on tumor response and survival is restricted to mCRC patients treated with anti-EGFR MoAb. Therefore, our findings suggest KRAS mutations can be used as predictive biomarker to screen patients who may resist to the anti-EGFR MoAbs treatment. It is estimated that 38% of mCRC patients have KRAS mutations. After excluding 14% of mCRC patients who may still respond to treatment even they carry KRAS mutations,33% of mCRC patients can truly benefit from examination of KRAS mutation status and then being exempted from the unnecessary treatment, a relatively big number. Further studies may need to identify patterns of multiple biomarkers to further increase the power of patient selection for anti-EGFR MoAbs treatment.For wild-type KRAS mCRC patients treated with anti-EGFR MoAbs, we found that BRAF mutations seem associated with lower ORR and shorter OS; PIK3CA exon 20 mutations seem associated with lower ORR. However, several original studies also found that BRAF or PIK3CA seems like to be general prognostic biomarker for mCRC patients. Therefore, our findings by no means suggest BRAF and PIK3CA can be used as additional biomarkers to screen patients who may resist to the treatment. Large studies, in particular in KRAS wild-type patients and in patients who are not treated with the MoAbs are needed in order to further confirm the relation and clarify its clinical implications. If BRAF or PIK3CA mutation is, indeed, a predictor of response to MoAb, how many mCRC patients could truly benefit from examination of BRAF or PIK3CA mutation status and then being exempted from the unnecessary treatment? It is estimated that 62% of mCRC patients are KRAS wild type, among whom 11% would have BRAF mutations and 3.2% PIK3CA exon 20 mutations. After excluding those who may still respond to the treatment even they carry a BRAF or PIK3CA mutation, only 7% of mCRC patients can truly benefit from examination of BRAF mutation status and only below 2% of mCRC patients can truly benefit from examination of PIK3CA mutation status, a relatively small number.
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