| With the emerging of several new anti-tumor drugs, there is much more regimens to choice for advanced gastric cancer. But, for many years, there were very few improvements reported in the efficacy of treatments for advanced gastric cancer and the efficacy of those regimens are far away from clinician expectation. Several studies indicate that cetuximab combined with chemotherapy have a role in the first-line treatment of metastatic colorectal and lung cancer, with a 10 to 20% absolute increase in response rates reported. Cetuximab combined chemotherapy has shown promising activity in clinical studies of advanced gastric cancer as first or second setting. The aim of this phase II study is to observe the efficacy and safety of cetuximab combined with XP(cisplatin plus capecitabine) treating advanced gastric cancer as first line therapy and find the predictive biomarkers related to the regimen. If the predictive biomarker works, we will identify patients who can benefit from the regimen and relieve the economic and toxic burden of null patients and avoid wasting time and money.Considering there are three anti-tumor drugs in the regimen, the biomarkers, which were to analyze, would better related to those three drugs. Cetuximab is an EGFR-targeting antibody and the biomarkers that may relate to cetuximab must concern to the network of EGFR signaling pathway. The biomarkers determined included upstream ligand, such as serum EGF,TGF-α,AREG,EREG and VEGF; the status of EGFR, including EGFR expression and EGFR gene copy number; the status of KRAS (the most important downstream molecular). The polymorphisms of some involved genes, such as EGF, EGFR, VEGF, HIF1A, FCGR2A, FCGR3A, HER2, IL8, CCND1 and so on, may also have predictable value to cetuximab. The polymorphisms of other genes may relate to cisplatin and capecitabin were also determined, such as ERCC1, XPD, XRCC1, XRCC3, TS, MTHFR, DPD, GSTP1 and so on. Serum cytokines were measured using an antibody sandwich enzyme-linked immunosorbent assay and radioimmunoassay. EGFR expression was evaluated with an immunohistochemical technique. Chromogenic in situ hybridization (CISH) was used detecting EGFR gene copy number. KRAS mutation was detected by PCR-sequencing. Gene polymorphisms were determined by PCR-sequencing, PCR-RFLP and SNPstream genotyping system.Fifty-four patients were screened from Apr-2007 to Apr-2008, including 2 screen failures, 3 withdraw. Forty-nine patients received treatment more than 1 cycle and response was evaluated in 47 patients, with 1 CR, 24 PR, 15 SD and 7 PD. Response rate(RR) is 53.2% and disease control rate is 85.1%. The toxicity of the setting was moderate. Rash as a special adverse effect of EGFR inhibitors was related to efficacy of the regimen in this study. In patients with rash of grade 0/1 or grade 2/3, RR is 40.0% or 76.5% (P=0.016) and mTTP is 3.6m or 6.5m (P=0.006). The EGFR expression were detected in 44 tumors and 40 (91%) were found to have EGFR-positive tumors. EGFR expression was considered high (++ and +++) for 31 (71%) patients and low (negative and +) for 13 (29%) patients. Univariate analysis showed EGFR expression was unrelated to response, but high expression has a tendency of longer TTP (6.1m vs. 5.0m, P=0.114). EGFR expression related to the degree of rash. The EGFR high expression patients tend to have severe rash (P=0.001). EGFR gene amplification was detected in 4 (8.2%) of 49 tumors. Among the 4 patients with an increase in the EGFR gene copy number, all had high level of EGFR expression (+++) and 3 patients had partial response and 1 had minor response (tumor shrink 27.8%). Serum TGF-αwas much higher in CR+PR group than SD+PD group (36.6 vs. 26.0 pg/L, P=0.048) and tend to correlate with TTP (r=0.271, P=0.063). EGF correlated with TTP (r=0.310, P=0.038). The median time to progression of EGF-positive patients was significantly longer than that of EGF-negative patients (5.9m vs. 2.9m, P=0.050). The same was true of TGF-α-positive patients (6.1m vs. 2.7m, P=0.044). Among the 49 tumors, no KRAS mutation was detected in either codon 12 or codon 13, encoded by exon 2. Among the 21 gene polymorphisms in 17 genes, we found the polymorphism of TS 5'-UTR related to TTP. The TTP in patients with 2R/3RG, 3RC/3RG, 3RG/3RG genotypes gain an advantage over that of patients with 2R/2R, 2R/3RC, 3RC/3RC genotypes (6.1m vs. 3.0m,P=0.024). The polymorphism of VEGF C936T also related to TTP. The TTP in patients with T/T genotype was much shorter than the patients with C/T and C/C genotypes (2.0m vs. 5.2m vs. 5.4m, P=0.014) and two patients with T/T genotype all achieved PD.Multivariate analysis (COX model) showed an independent association between polymorphism of TS 5'-UTR and TTP (OR 0.156, 95% CI, 0.058-0.423, P=0.000). EGFR expression also assicatied with TTP (OR 0.683, 95% CI, 0.473-0.987, P=0.042) independently. TGF-αand polymorphism of EGF A61G showed a tendency of association with TTP. The TTP of patients with high expression of EGFR and 3RG genetype were much longer than other patients (6.8m vs. 3.6m, P=0.024). The TTP of patients with high expression of EGFR and serum EGF and TGF-αin high level were also much longer than others (6.2m vs. 3.0m, P=0.033).According to those data, we can conclude that this regimen is well-tolerated and effective to advanced gastric cancer. The rash, in the early days, is important hint to clinical benefit. High expression of EGFR relate to both clinical benefit and servere rash. EGFR expression, rash and clinical benefit have close internal relation. EGFR gene magnification relate to response, that hint it can reflect the activity of EGFR signal pathway exactly. Serum EGF and TGF-αwere related to clinical benefit, that hint cetuximab can inhibit EGFR signal pathway which actived by autocrine loop. KRAS mutations were seldom occoured in gastric cancer, that means KRAS mutation do not appear correlated with the response to cetuximab. Genetic polymorphism is maybe an effective way to predict efficacy of cetuximab combination therapy. We can use those predictive biomarkers to select right patients who can benefit from the regimen. |
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