西妥昔单抗联合卡培他滨和顺铂一线治疗晚期胃癌相关预测因子的研究
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摘要
随着新型抗肿瘤药物的不断出现,晚期胃癌的治疗已经具有较多的选择。但是,无论是在近期疗效还是远期生存上,并无令人鼓舞的改善,还远不能满足临床需要。靶向EGFR抗肿瘤药物西妥昔单抗的问世,使多种实体肿瘤的疗效得到明显提高。最近的两个研究表明,西妥昔单抗联合化疗治疗晚期胃癌有良好的疗效,为了进一步明确西妥昔单抗治疗胃癌的疗效,我们在国内进行了西妥昔单抗联合卡培他滨和顺铂一线治疗晚期胃癌的EXTRA II期临床研究,对与研究方案疗效相关的生物标志进行了分析研究。拟通过本研究对西妥昔单抗联合XP方案一线治疗晚期胃癌的安全性及有效性进行评估,并找到具有预测意义的生物标志,指导临床用药,以提高治疗有效率,减少患者在经济及时间上的浪费,避免不必要的毒副作用。
本研究方案中包括三种作用机制不同的抗肿瘤药物,进行疗效相关生物标志分析时,综合考虑了可能与三种药物疗效相关的标志。西妥昔单抗是一种单抗类EGFR抑制剂,对其相关生物标志的确定,需要考虑EGFR信号通路的多个环节。本研究中检测的生物标志有EGFR上游的配体及相关细胞因子,包括EGF、TGF-α、AREG、EREG以及VEGF血清水平;EGFR自身的状态,包括表达水平以及是否存在基因扩增;对最重要的下游信号分子编码基因-KRAS基因是否存在突变也进行了检测。同时对与EGFR信号通路相关的多个基因的遗传多态性进行分析,包括EGF、EGFR、VEGF、HIF1A、FCGR2A、FCGR3A、HER 2、IL-8、CCND1等多个位点基因多态性。卡培他滨是一种氟尿嘧啶类抗代谢药物,经过体内多个环节代谢后,生成活性药物抑制DNA的合成。其代谢通路中的多个酶,包括TS、DPD、MTHFR、GSTP1等对其临床疗效和毒副作用有重要影响。本研究对影响这些酶活性及表达的相关基因多态性位点进行检测分析。顺铂作为一种直接作用于DNA的细胞毒性药物,临床疗效与多个DNA损伤修复酶关系密切。研究显示相关基因多态性对这些修复酶的表达水平以及顺铂临床疗效有重要影响。本研究对包括ERCC1、XPD、XRCC1、XRCC3等重要DNA修复酶基因多态性位点进行检测并与临床指标进行相关分析。这些生物标志的检测分别采用ELISA法和放射免疫法检测血清细胞因子水平,免疫组织化学法检测EGFR表达状态,显色原位杂交法检测EGFR基因拷贝数,直接测序法检测KRAS基因是否突变,基因多态性检测分别采用PCR-RFLP、直接测序法及SNPstream分型技术完成。
2007年4月至2008年4月间筛选未经治疗的晚期胃癌患者共54例,筛选失败2例,出组3例,49例患者接受至少一个周期治疗。47例可评价疗效患者中,完全缓解(CR) 1例,部分缓解(PR) 24例,疾病稳定(SD) 15例,疾病进展(PD) 7例。有效率(CR+PR) 53.2%,疾病控制率(CR+PR+SD) 85.1%,中位疾病进展时间(TTP)为5.23个月。尚不能评估总生存时间。本方案耐受性良好,不良反应发生的范围及严重程度均未明显超出单独使用三种抗肿瘤药物的情况。皮疹作为应用EGFR抑制剂所特有的不良反应,与本研究中患者临床获益密切相关。出现0/1度与2/3度皮疹患者有效率分别为40.0%和76.5%(P=0.016),TTP时间分别为3.6个月和6.5个月(P=0.006)。44例患者能提供肿瘤组织检测EGFR表达,EGFR阳性表达90.9%(40/44),EGFR高表达70.5%(31/44)。单因素分析未发现EGFR表达与疗效相关,但EGFR表达(++)和(+++)患者较EGFR表达(-)及(+)患者TTP时间有延长趋势(6.1个月vs. 5.0个月, P=0.114)。EGFR表达与皮疹显著相关(P=0.006),随着EGFR表达的增加,皮疹的发生率及严重程度都在增加。检测49例肿瘤组织标本,4例存在EGFR基因扩增(8.2%),存在EGFR基因扩增的标本同时均为EGFR高表达(+++)。4例EGFR基因扩增患者中,部分缓解3例,接近部分缓解1例(肿瘤缩小27.8%)。血清EGF水平与TTP时间相关(r=0.310, P=0.038)。根据ROC曲线设定截断值进一步分析发现,EGF高水平(>300ng/L)较低水平(≤300ng/L)患者TTP时间更长(5.9个月vs. 2.9个月, P=0.050)。血清EGF水平与疗效未见相关。血清TGF-α水平与TTP时间接近统计学意义的相关(r=0.271, P=0.063)。TGF-α高水平(>25ng/L)较低水平(≤25ng/L)患者TTP时间明显更长(6.1个月vs. 2.7个月,P=0.044)。血清TGF-α水平与疗效相关,有效患者血清TGF-α明显高于无效患者(36.6ng/L vs. 26.0ng/L, P=0.048)。检测49例患者肿瘤组织KRAS基因第2外显子12、13密码子均为野生型,未检出突变。本研究检测17个基因的21个多态性位点发现,TS基因5'-UTR串联重复序列多态性与TTP时间相关,携带3RG等位基因(2R/3RG, 3RC/3RG, 3RG/3RG)患者较不携带3RG等位基因(2R/2R, 2R/3RC, 3RC/3RC)患者TTP时间明显更长(6.1个月vs. 3.0个月, P=0.024);VEGF C936T多态性的T/T基因型患者TTP时间明显逊于C/T及C/C基因型患者(2.0个月vs. 5.2个月vs. 5.4个月, P=0.014),2例T/T基因型患者均在治疗期间疾病进展。
多因素生存分析(COX风险模型)发现,TS 5’-UTR串联重复序列多态性对入组患者TTP时间有明显影响(OR 0.156, 95% CI, 0.058-0.423, P=0.000),EGFR表达对TTP时间也有明显影响(OR 0.683, 95% CI, 0.473-0.987, P=0.042)。TGF-α血清水平(OR 0.440, 95% CI, 0.170-1.143, P=0.092)及EGF A61G多态性(OR 0.619, 95% CI, 0.374-1.025, P=0.062)对TTP时间影响也接近统计学意义。同时具有EGFR高表达(++和+++)和3RG基因型两种有利生物标志患者TTP时间明显优于携带任何一种不利生物标志患者(6.8个月vs. 3.6个月, P=0.024)。肿瘤EGFR高表达(++和+++)、同时血清EGF和TGF-α高水平患者TTP时间也明显优于其他患者(6.2个月vs. 3.0个月, P=0.033)。
以上结果表明,西妥昔单抗联合卡培他滨和顺铂一线治疗晚期胃癌疗效及耐受性良好。治疗初期皮疹的严重程度是应用西妥昔单抗是否临床获益的重要提示。EGFR高表达与西妥昔单抗治疗胃癌临床获益相关,且与皮疹发生关系密切,EGFR表达、皮疹发生以及临床获益三者间存在内在联系。EGFR基因扩增患者均临床有效,表明EGFR基因扩增可以准确反映EGFR信号通路的活跃程度,是西妥昔单抗治疗胃癌疗效预测的重要标志。血清EGF与TGF-α高水平与临床获益相关,提示西妥昔单抗可以有效阻断因自分泌环激活的EGFR信号通路,抑制肿瘤细胞的生长、增殖。胃癌KRAS基因不发生或甚少发生突变,KRAS状态不能够成为西妥昔单抗治疗胃癌的疗效预测标志。基因遗传多态性(药物基因组学)预测西妥昔单抗联合化疗治疗胃癌疗效是一种有效的途径。通过对相关生物标志进行检测,可以初步筛选出适合本研究方案治疗的患者。
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.
本研究方案中包括三种作用机制不同的抗肿瘤药物,进行疗效相关生物标志分析时,综合考虑了可能与三种药物疗效相关的标志。西妥昔单抗是一种单抗类EGFR抑制剂,对其相关生物标志的确定,需要考虑EGFR信号通路的多个环节。本研究中检测的生物标志有EGFR上游的配体及相关细胞因子,包括EGF、TGF-α、AREG、EREG以及VEGF血清水平;EGFR自身的状态,包括表达水平以及是否存在基因扩增;对最重要的下游信号分子编码基因-KRAS基因是否存在突变也进行了检测。同时对与EGFR信号通路相关的多个基因的遗传多态性进行分析,包括EGF、EGFR、VEGF、HIF1A、FCGR2A、FCGR3A、HER 2、IL-8、CCND1等多个位点基因多态性。卡培他滨是一种氟尿嘧啶类抗代谢药物,经过体内多个环节代谢后,生成活性药物抑制DNA的合成。其代谢通路中的多个酶,包括TS、DPD、MTHFR、GSTP1等对其临床疗效和毒副作用有重要影响。本研究对影响这些酶活性及表达的相关基因多态性位点进行检测分析。顺铂作为一种直接作用于DNA的细胞毒性药物,临床疗效与多个DNA损伤修复酶关系密切。研究显示相关基因多态性对这些修复酶的表达水平以及顺铂临床疗效有重要影响。本研究对包括ERCC1、XPD、XRCC1、XRCC3等重要DNA修复酶基因多态性位点进行检测并与临床指标进行相关分析。这些生物标志的检测分别采用ELISA法和放射免疫法检测血清细胞因子水平,免疫组织化学法检测EGFR表达状态,显色原位杂交法检测EGFR基因拷贝数,直接测序法检测KRAS基因是否突变,基因多态性检测分别采用PCR-RFLP、直接测序法及SNPstream分型技术完成。
2007年4月至2008年4月间筛选未经治疗的晚期胃癌患者共54例,筛选失败2例,出组3例,49例患者接受至少一个周期治疗。47例可评价疗效患者中,完全缓解(CR) 1例,部分缓解(PR) 24例,疾病稳定(SD) 15例,疾病进展(PD) 7例。有效率(CR+PR) 53.2%,疾病控制率(CR+PR+SD) 85.1%,中位疾病进展时间(TTP)为5.23个月。尚不能评估总生存时间。本方案耐受性良好,不良反应发生的范围及严重程度均未明显超出单独使用三种抗肿瘤药物的情况。皮疹作为应用EGFR抑制剂所特有的不良反应,与本研究中患者临床获益密切相关。出现0/1度与2/3度皮疹患者有效率分别为40.0%和76.5%(P=0.016),TTP时间分别为3.6个月和6.5个月(P=0.006)。44例患者能提供肿瘤组织检测EGFR表达,EGFR阳性表达90.9%(40/44),EGFR高表达70.5%(31/44)。单因素分析未发现EGFR表达与疗效相关,但EGFR表达(++)和(+++)患者较EGFR表达(-)及(+)患者TTP时间有延长趋势(6.1个月vs. 5.0个月, P=0.114)。EGFR表达与皮疹显著相关(P=0.006),随着EGFR表达的增加,皮疹的发生率及严重程度都在增加。检测49例肿瘤组织标本,4例存在EGFR基因扩增(8.2%),存在EGFR基因扩增的标本同时均为EGFR高表达(+++)。4例EGFR基因扩增患者中,部分缓解3例,接近部分缓解1例(肿瘤缩小27.8%)。血清EGF水平与TTP时间相关(r=0.310, P=0.038)。根据ROC曲线设定截断值进一步分析发现,EGF高水平(>300ng/L)较低水平(≤300ng/L)患者TTP时间更长(5.9个月vs. 2.9个月, P=0.050)。血清EGF水平与疗效未见相关。血清TGF-α水平与TTP时间接近统计学意义的相关(r=0.271, P=0.063)。TGF-α高水平(>25ng/L)较低水平(≤25ng/L)患者TTP时间明显更长(6.1个月vs. 2.7个月,P=0.044)。血清TGF-α水平与疗效相关,有效患者血清TGF-α明显高于无效患者(36.6ng/L vs. 26.0ng/L, P=0.048)。检测49例患者肿瘤组织KRAS基因第2外显子12、13密码子均为野生型,未检出突变。本研究检测17个基因的21个多态性位点发现,TS基因5'-UTR串联重复序列多态性与TTP时间相关,携带3RG等位基因(2R/3RG, 3RC/3RG, 3RG/3RG)患者较不携带3RG等位基因(2R/2R, 2R/3RC, 3RC/3RC)患者TTP时间明显更长(6.1个月vs. 3.0个月, P=0.024);VEGF C936T多态性的T/T基因型患者TTP时间明显逊于C/T及C/C基因型患者(2.0个月vs. 5.2个月vs. 5.4个月, P=0.014),2例T/T基因型患者均在治疗期间疾病进展。
多因素生存分析(COX风险模型)发现,TS 5’-UTR串联重复序列多态性对入组患者TTP时间有明显影响(OR 0.156, 95% CI, 0.058-0.423, P=0.000),EGFR表达对TTP时间也有明显影响(OR 0.683, 95% CI, 0.473-0.987, P=0.042)。TGF-α血清水平(OR 0.440, 95% CI, 0.170-1.143, P=0.092)及EGF A61G多态性(OR 0.619, 95% CI, 0.374-1.025, P=0.062)对TTP时间影响也接近统计学意义。同时具有EGFR高表达(++和+++)和3RG基因型两种有利生物标志患者TTP时间明显优于携带任何一种不利生物标志患者(6.8个月vs. 3.6个月, P=0.024)。肿瘤EGFR高表达(++和+++)、同时血清EGF和TGF-α高水平患者TTP时间也明显优于其他患者(6.2个月vs. 3.0个月, P=0.033)。
以上结果表明,西妥昔单抗联合卡培他滨和顺铂一线治疗晚期胃癌疗效及耐受性良好。治疗初期皮疹的严重程度是应用西妥昔单抗是否临床获益的重要提示。EGFR高表达与西妥昔单抗治疗胃癌临床获益相关,且与皮疹发生关系密切,EGFR表达、皮疹发生以及临床获益三者间存在内在联系。EGFR基因扩增患者均临床有效,表明EGFR基因扩增可以准确反映EGFR信号通路的活跃程度,是西妥昔单抗治疗胃癌疗效预测的重要标志。血清EGF与TGF-α高水平与临床获益相关,提示西妥昔单抗可以有效阻断因自分泌环激活的EGFR信号通路,抑制肿瘤细胞的生长、增殖。胃癌KRAS基因不发生或甚少发生突变,KRAS状态不能够成为西妥昔单抗治疗胃癌的疗效预测标志。基因遗传多态性(药物基因组学)预测西妥昔单抗联合化疗治疗胃癌疗效是一种有效的途径。通过对相关生物标志进行检测,可以初步筛选出适合本研究方案治疗的患者。
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.
引文
1. Wagner AD, Grothe W, Haerting J et al. Chemotherapy in advanced gastric cancer: A systematic review and meta-analysis based on aggregate data. J Clin Oncol 2006;24:2903–2909.
2. Pozzo C, Barone C. Is there an optimal chemotherapy regimen for the treatment of advanced gastric cancer that will provide a platform for the introduction of new biological agents? Oncologist. 2008;13:794-806.
3. Terashima M, Fujiwara H, Takagane A, et al. Role of thymidine phosphorylase and dihydropyrimidine dehydogenase in tumour progression and sensitivity to doxifluridine in gastric cancer patients. Eur J Cancer, 2002, 38(18): 2375-2381.
4. Lordick F, Lorenzen S, Hegewisch-Becker S, et al. Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1st line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI study group. J Clin Oncol 2007;25:4526a.
5. Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007;18:510–517.
6. Jin M, Shen L, Hu B, et al. Mature data on capecitabine (X) + fractionated cisplatin (P) as first-line therapy in patients (pts) with advanced gastric carcinoma (AGC). Proc Am Soc Clin Oncol, 2006, 24: abstract 4075.
7. Lee SS, Lee JL, Ryu MH, et al. Combination chemotherapy with capecitabine (x) and Cisplatin (p) as first line treatment in advanced gastric cancer: experience of 223 patients with prognostic factor analysis. Jpn J Clin Oncolol, 2007;37: 30-37.
8. Seol YM, Song MK, Choi YJ, et al. Oral Fluoropyrimidines (Capecitabine or S-1) and Cisplatin as First Line Treatment in Elderly Patients with Advanced Gastric Cancer: A Retrospective Study.Jpn J Clin Oncol. 2008 Nov 8. [Epub ahead of print]
9. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004,351:337-345.
10. Tejpar S, Peeters M, Humblet Y, et al. Phase I/II study of cetuximab dose-escalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), Pharmacodynamic (PD) and efficacy data. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings: 4037.
11. Pueztal L, Lewis CE, Lorenzen J, et al. Growth factors: regulation of normal and neoplastic growth. J Pathol 1993;169:191-201.
12. Sporn MB, Roberts AB. Autocrine growth factors and cancer. Nature 1985;313:745-7.
13. Wu W, O'Reilly MS, Langley RR, et al. Expression of epidermal growth factor (EGF)/transforming growth factor-alpha by human lung cancer cells determines theirresponse to EGF receptor tyrosine kinase inhibition in the lungs of mice.Mol Cancer Ther. 2007 ;6:2652-63.
14. Pino MS, Shrader M, Baker CH, et al. Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines. Cancer Res. 2006;66:3802-12.
15. Masago K, Fujita S, Hatachi Y, et al. Clinical significance of pretreatment serum amphiregulin and transforming growth factor-alpha, and an epidermal growth factor receptor somatic mutation in patients with advanced non-squamous, non-small cell lung cancer. Cancer Sci. 2008 Sep 22. [Epub ahead of print]
16. Shia J, Klimstra DS, Li AR, et al. Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study. Mod Pathol. 2005;18:1350-6.
17. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study.Lancet Oncol. 2005;6:279-86.
18. Helfrich BA, Raben D, Varella-Garcia M, et al. Antitumor activity of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in non-small cell lung cancer cell lines correlates with gene copy number and EGFR mutations but not EGFR protein levels. Clin Cancer Res. 2006;12:7117-25.
19. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer.J Natl Cancer Inst. 2005;97:643-55.
19. Kim MA, Lee HS, Lee HE,et al. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology. 2008;52:738-46.
20. Tsugawa K, Yonemura Y, Hirono Y, et al. Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers: correlation to clinical features. Oncology. 1998;55:475-81.
21. Bruns CJ, Harbison MT, Davis DW, Portera CA, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by anti-angiogenic mechanisms. Clinical Cancer Research. 2000;6:1936–1948.
22. Perrotte P, Matsumoto T, Inoue K, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clinical Cancer Research.1999;5:257–265.
23. Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. American Journal of Pathology.1997;151:1523–1530.
24. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.PLoS Med. 2005;2(1):e17.
25. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res. 2006;66(8):3992-5.
26. Horie N, Aiba H, Oguro K, et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct. Funct. 1995;20:191–197.
27. Kawakami K, Omura K, Kanehira E, et al. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 1999;19:3249–3252.
28. Kaneda S, Nalbantoglu J, Takeishi K et al.: Structural and functional analysis of the human thymidylate synthase gene.J. Biol. Chem. 1990;265:20277–20284.
29. Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J. Clin. Oncol. 2004;22:529–536.
30. Edler D, Glimelius B, Hallstr?m M et al. Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J. Clin.Oncol. 2002;20:1721–1728.
31. Takenoue T, Nagawa H, Matsuda K et al.:Relation between thymidylate expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method. Ann. Surg. Oncol. 2000;7:193–198.
32. Krippl P, Langsenlehner U, Renner W, et al. A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer 2003; 106:468–471.
33.马飞,徐兵河,林东昕,等. EGFR基因CA-SSR多态与晚期非小细胞肺癌吉非替尼临床疗效的关系中国肿瘤临床与康复2008;15:21-24.
34. Quintela-Fandino M, Hitt R, Medina PP, et al. DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy.J Clin Oncol. 2006;24:4333-9.
35. de las Pe?as R, Sanchez-Ronco M, Alberola V, et al. Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol. 2006;17:668-75.
36. Goekkurt E, Hoehn S, Wolschke C, et al. Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)--novel predictors for response and survival in gastric cancer patients.Br J Cancer. 2006;94:281-6.
37. van Kuilenburg AB, Maring JG, Schalhorn A, et al. Pharmacokinetics of 5-fluorouracil in patients heterozygous for the IVS14+1G > A mutation in the dihydropyrimidine dehydrogenase gene. Nucleosides Nucleotides Nucleic Acids. 2008;27:692-8.
38. Pander J, Gelderblom H, Guchelaar HJ. Pharmacogenetics of EGFR and VEGF inhibition.Drug Discov Today. 2007;12:1054-60.
39. F. Bibeau, E. Crapez, F. Di Fiore, et al. Association of FcγRIIa and FcγRIIa polymorphisms with clinical outcome in metastatic colorectal cancer patients (mCRC) treated with cetuximab and irinotecan. J Clin Oncol 26: 2008; abstr 11004.
40. Personeni N, Fieuws S, Piessevaux H, et al. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res. 2008;14:5869-76.
41. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol, 2008 ASCO Annual Meeting Proceedings:400.
42. Amado RG, Wolf M, Freeman D, et al. Panitumumab (pmab) efficacy and patient-reported outcomes (PRO) in metastatic colorectal cancer (mCRC) patients (pts) with wild-type (WT) KRAS tumor status. 2008 ASCO Gastrointestinal Cancers Symposium:278.
43. Van Cutsem E, Lang I, D'haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol, 2008 ASCO Annual Meeting Proceedings:2.
44. Bibeau F, Lopez-Crapez E, Di Fiore F, et al.Impact of Fc{gamma}RIIa Fc{gamma}RIIIa Polymorphisms and KRAS Mutations on the Clinical Outcome of Patients With Metastatic Colorectal Cancer Treated With Cetuximab Plus Irinotecan. J Clin Oncol. 2009 Jan 21. [Epub ahead of print]
45. Han SW, Oh DY, Im SA, et al. Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. Br J Cancer. 2009;100:298-304.
46. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer.N Engl J Med. 2008;359:1757-65.
47. Stella.G., Rojas Llimpe.F.L, Barone.C, et al. KRAS and BRAF mutational status and response to cetuximab combination therapy in advanced gastric cancer (GC) patients. 2009 ASCO Gastrointestinal Cancers Symposium:34.
2. Pozzo C, Barone C. Is there an optimal chemotherapy regimen for the treatment of advanced gastric cancer that will provide a platform for the introduction of new biological agents? Oncologist. 2008;13:794-806.
3. Terashima M, Fujiwara H, Takagane A, et al. Role of thymidine phosphorylase and dihydropyrimidine dehydogenase in tumour progression and sensitivity to doxifluridine in gastric cancer patients. Eur J Cancer, 2002, 38(18): 2375-2381.
4. Lordick F, Lorenzen S, Hegewisch-Becker S, et al. Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1st line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI study group. J Clin Oncol 2007;25:4526a.
5. Pinto C, Di Fabio F, Siena S, et al. Phase II study of cetuximab in combination with FOLFIRI in patients with untreated advanced gastric or gastroesophageal junction adenocarcinoma (FOLCETUX study). Ann Oncol 2007;18:510–517.
6. Jin M, Shen L, Hu B, et al. Mature data on capecitabine (X) + fractionated cisplatin (P) as first-line therapy in patients (pts) with advanced gastric carcinoma (AGC). Proc Am Soc Clin Oncol, 2006, 24: abstract 4075.
7. Lee SS, Lee JL, Ryu MH, et al. Combination chemotherapy with capecitabine (x) and Cisplatin (p) as first line treatment in advanced gastric cancer: experience of 223 patients with prognostic factor analysis. Jpn J Clin Oncolol, 2007;37: 30-37.
8. Seol YM, Song MK, Choi YJ, et al. Oral Fluoropyrimidines (Capecitabine or S-1) and Cisplatin as First Line Treatment in Elderly Patients with Advanced Gastric Cancer: A Retrospective Study.Jpn J Clin Oncol. 2008 Nov 8. [Epub ahead of print]
9. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004,351:337-345.
10. Tejpar S, Peeters M, Humblet Y, et al. Phase I/II study of cetuximab dose-escalation in patients with metastatic colorectal cancer (mCRC) with no or slight skin reactions on cetuximab standard dose treatment (EVEREST): Pharmacokinetic (PK), Pharmacodynamic (PD) and efficacy data. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings: 4037.
11. Pueztal L, Lewis CE, Lorenzen J, et al. Growth factors: regulation of normal and neoplastic growth. J Pathol 1993;169:191-201.
12. Sporn MB, Roberts AB. Autocrine growth factors and cancer. Nature 1985;313:745-7.
13. Wu W, O'Reilly MS, Langley RR, et al. Expression of epidermal growth factor (EGF)/transforming growth factor-alpha by human lung cancer cells determines theirresponse to EGF receptor tyrosine kinase inhibition in the lungs of mice.Mol Cancer Ther. 2007 ;6:2652-63.
14. Pino MS, Shrader M, Baker CH, et al. Transforming growth factor alpha expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines. Cancer Res. 2006;66:3802-12.
15. Masago K, Fujita S, Hatachi Y, et al. Clinical significance of pretreatment serum amphiregulin and transforming growth factor-alpha, and an epidermal growth factor receptor somatic mutation in patients with advanced non-squamous, non-small cell lung cancer. Cancer Sci. 2008 Sep 22. [Epub ahead of print]
16. Shia J, Klimstra DS, Li AR, et al. Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study. Mod Pathol. 2005;18:1350-6.
17. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study.Lancet Oncol. 2005;6:279-86.
18. Helfrich BA, Raben D, Varella-Garcia M, et al. Antitumor activity of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in non-small cell lung cancer cell lines correlates with gene copy number and EGFR mutations but not EGFR protein levels. Clin Cancer Res. 2006;12:7117-25.
19. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer.J Natl Cancer Inst. 2005;97:643-55.
19. Kim MA, Lee HS, Lee HE,et al. EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number. Histopathology. 2008;52:738-46.
20. Tsugawa K, Yonemura Y, Hirono Y, et al. Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers: correlation to clinical features. Oncology. 1998;55:475-81.
21. Bruns CJ, Harbison MT, Davis DW, Portera CA, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by anti-angiogenic mechanisms. Clinical Cancer Research. 2000;6:1936–1948.
22. Perrotte P, Matsumoto T, Inoue K, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clinical Cancer Research.1999;5:257–265.
23. Petit AM, Rak J, Hung MC, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases down-regulate vascular endothelial growth factor production by tumor cells in vitro and in vivo: angiogenic implications for signal transduction therapy of solid tumors. American Journal of Pathology.1997;151:1523–1530.
24. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.PLoS Med. 2005;2(1):e17.
25. Lievre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer.Cancer Res. 2006;66(8):3992-5.
26. Horie N, Aiba H, Oguro K, et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct. Funct. 1995;20:191–197.
27. Kawakami K, Omura K, Kanehira E, et al. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res. 1999;19:3249–3252.
28. Kaneda S, Nalbantoglu J, Takeishi K et al.: Structural and functional analysis of the human thymidylate synthase gene.J. Biol. Chem. 1990;265:20277–20284.
29. Popat S, Matakidou A, Houlston RS. Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis. J. Clin. Oncol. 2004;22:529–536.
30. Edler D, Glimelius B, Hallstr?m M et al. Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J. Clin.Oncol. 2002;20:1721–1728.
31. Takenoue T, Nagawa H, Matsuda K et al.:Relation between thymidylate expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method. Ann. Surg. Oncol. 2000;7:193–198.
32. Krippl P, Langsenlehner U, Renner W, et al. A common 936 C/T gene polymorphism of vascular endothelial growth factor is associated with decreased breast cancer risk. Int J Cancer 2003; 106:468–471.
33.马飞,徐兵河,林东昕,等. EGFR基因CA-SSR多态与晚期非小细胞肺癌吉非替尼临床疗效的关系中国肿瘤临床与康复2008;15:21-24.
34. Quintela-Fandino M, Hitt R, Medina PP, et al. DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy.J Clin Oncol. 2006;24:4333-9.
35. de las Pe?as R, Sanchez-Ronco M, Alberola V, et al. Polymorphisms in DNA repair genes modulate survival in cisplatin/gemcitabine-treated non-small-cell lung cancer patients. Ann Oncol. 2006;17:668-75.
36. Goekkurt E, Hoehn S, Wolschke C, et al. Polymorphisms of glutathione S-transferases (GST) and thymidylate synthase (TS)--novel predictors for response and survival in gastric cancer patients.Br J Cancer. 2006;94:281-6.
37. van Kuilenburg AB, Maring JG, Schalhorn A, et al. Pharmacokinetics of 5-fluorouracil in patients heterozygous for the IVS14+1G > A mutation in the dihydropyrimidine dehydrogenase gene. Nucleosides Nucleotides Nucleic Acids. 2008;27:692-8.
38. Pander J, Gelderblom H, Guchelaar HJ. Pharmacogenetics of EGFR and VEGF inhibition.Drug Discov Today. 2007;12:1054-60.
39. F. Bibeau, E. Crapez, F. Di Fiore, et al. Association of FcγRIIa and FcγRIIa polymorphisms with clinical outcome in metastatic colorectal cancer patients (mCRC) treated with cetuximab and irinotecan. J Clin Oncol 26: 2008; abstr 11004.
40. Personeni N, Fieuws S, Piessevaux H, et al. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res. 2008;14:5869-76.
41. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol, 2008 ASCO Annual Meeting Proceedings:400.
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