Pharmacogenetics of colorectal cancer

Colorectal cancer is one of the most common types of cancer in both men and women. Multiple chemotherapy combinations exist; however, there is currently no strategy for individualised therapy selection prior to treatment. Genetic polymorphisms in genes involved in the metabolism, transport or targets for the commonly used chemotherapy drugs (5-fluorouracil, irinotecan and oxaliplatin) have been described. Many require validation in large prospective trials before they can be used as markers for outcome and/or toxicity. This review describes the data available on polymorphisms in key genes that are associated with chemotherapy toxicity and response in colorectal cancer.     

Pharmacogenetics of colorectal cancer

Colorectal cancer is one of the most common types of cancer in both men and women. Multiple chemotherapy combinations exist; however, there is currently no strategy for individualised therapy selection prior to treatment. Genetic polymorphisms in genes involved in the metabolism, transport or targets for the commonly used chemotherapy drugs (5-fluorouracil, irinotecan and oxaliplatin) have been described. Many require validation in large prospective trials before they can be used as markers for outcome and/or toxicity. This review describes the data available on polymorphisms in key genes that are associated with chemotherapy toxicity and response in colorectal cancer.     

Oncologists' current opinion on the treatment of colon carcinoma

Colorectal cancer is a major global health problem with more than a million new cases diagnosed worldwide in 2005. In the United States, this malignancy is the third most common with 145,000 new cases and the second most lethal with 56,000 deaths in 2005. Unfortunately, preclinical diagnostic screening in the U.S. population is less than 30-40 percent. The last decade has ushered in exciting new advances for medical oncologists caring for patients with colorectal cancer. The older cytotoxic chemotherapy drug 5-fluorouracil underwent new formulation, and two new drugs, oxaliplatine and irinotecan, were investigated as adjunctive therapies. Finally, targeted therapies, including monoclonal antibodies against vascular endothelial growth factor (bevacizumab) and the epidermal growth factor receptor (cetuximab), are now standard treatment for metastatic colorectal carcinoma. Systemic adjuvant chemotherapy can be lifesaving in patients with locally advanced colorectal carcinomas, which represent 60-70 percent of cases. For patients with metastatic colorectal cancer, the survival rate has doubled. With more effective drugs in the therapeutic armamentarium, new controversies have arisen. Questions regarding the best schedules for classical cytotoxic chemotherapy were largely answered by contemporary clinical trials. The potential of molecular genetic markers for prognosis or prediction of drug-specific toxicity and efficacy have been explored, but their utility for clinical practice is still being investigated. We will review the rapidly changing, state-of-the-art combination chemotherapy for adjuvant and metastatic disease. We will discuss in detail the c-ERBB family of tyrosine kinases as therapeutic targets in colorectal cancer.     

Pharmacogenomics of Fluorouracil, Irinotecan, and Oxaliplatin in Hepatic Metastases of Colorectal Cancer

Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable interindividual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.     

Use of bevacizumab in metastatic colorectal cancer: report from the Mexican opinion and analysis forum on colorectal cancer treatment with bevacizumab (September 2009)

Colorectal cancer is one of the most common cancers worldwide, and although associated mortality rates in South American countries are generally among the lowest in the world, they are on the rise. The prognosis of patients diagnosed with metastatic colorectal cancer has improved markedly over the last 12 years, increasing from 5 months with best supportive care to almost 2 years with combination chemotherapy plus bevacizumab. New prognostic and predictive biomarkers have been identified to guide therapy. Prognostic markers indicate patient survival independent of therapy and include disease stage, mutational status, and carcinoembryonic antigen. More recently, predictive markers of treatment outcomes have been identified. The most studied are mutations of the KRAS and BRAF genes, which are associated with resistance to epidermal growth factor receptor-targeted therapy. Tumor blood vessels have a number of structural and functional abnormalities that result in increased tumor vascularity and growth driven by angiogenesis. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab, which binds to and neutralizes VEGF-A, has become a central part of the treatment of metastatic colorectal cancer. The addition of bevacizumab to fluorouracil (5-FU)/leucovorin, irinotecan plus bolus 5-FU/leucovorin, or irinotecan plus infusional 5-FU/leucovorin significantly improves the overall survival of patients with previously untreated metastatic colorectal cancer. In addition, a significant increase in overall survival is seen when bevacizumab is added to oxaliplatin plus infusional 5-FU/leucovorin (FOLFOX) in patients with metastatic colorectal cancer who progressed on a non-bevacizumab-containing regimen. Although the majority of studies were performed prior to the identification of KRAS and BRAF as predictive biomarkers, subsequent analysis has shown the benefits of bevacizumab occur independently of the mutational status of these genes. In patients who have progressed on a bevacizumab-containing regimen, continuation of bevacizumab is significantly associated with an improved survival based on observational cohort studies. Surgical resection is recommended in patients with metastatic colorectal cancer where complete removal of tumors can be achieved. Perioperative chemotherapy using FOLFOX for 3 months before and 3 months after surgery is associated with a 9% improvement in 3-year survival. The use of chemotherapy in patients initially deemed unresectable has produced resection rates approaching 40%, and the addition of bevacizumab to chemotherapy in this setting is feasible, safe, and effective. In a study of 219 patients, the addition of bevacizumab to FOLFOX was associated with a significant increase in major or complete pathologic response compared with FOLFOX alone. Improvements in patient survival have changed the treatment paradigm for metastatic colorectal cancer. Newer approaches view treatment not as distinct lines of therapy but as a continuum that includes personalized treatment plans offering maintenance therapy and even drug holidays between aggressive treatment periods. This approach achieves similar efficacy outcomes with reduced toxicity, and investigation of the role of bevacizumab as maintenance therapy is ongoing.     

Pharmacogenetics of irinotecan toxicity

Irinotecan is an anticancer drug approved in combination therapy for advanced colorectal cancer. Severe, life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the UDP glycuronosyltransferase 1 family, polypeptide A1 (UGT1A1) enzyme has been strongly associated with toxicity. A common dinucleotide repeat polymorphism in the UGT1A1 promoter region (UGT1A1*28) has been correlated with severe toxicity in cancer patients receiving irinotecan-containing therapy. Prospective screening of patients prior to chemotherapy selection may reduce the frequency of severe toxicities by allowing alternate therapy selections for patients carrying the UGT1A1*28 polymorphism.     

结直肠癌中伊立替康化疗疗效及毒性预测分子标志物

目的:分析结直肠癌中伊立替康化疗疗效及毒性预测分子标志物。方法:收集国内外发表的文献并对伊立替康作用机制、化疗的疗效和不良反应等进行分析。结果与结论:结直肠癌是最常见的恶性肿瘤之一,化疗在其综合治疗中发挥着重要的作用。由于肿瘤的异质性以及患者个体的差异性,不同的患者对于化疗的疗效和不良反应差异很大,因此寻找化疗药物的潜在分子标志物是很重要的,可以为患者制定个体化的治疗方案。     

Phase II study of combination chemotherapy with biweekly cetuximab and irinotecan for wild-type KRAS metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.     

奥沙利铂化疗致外周神经毒性的护理体会

奥沙利铂是一种新的铂类抗癌药,具有广谱的体外细胞毒性及体内抗肿瘤活性作用,对顺铂耐药的肿瘤模型仍然有效,常用于转移性结、直肠癌或辅助治疗原发性肿瘤完全切除后三期结肠癌,也适用于经5-氟尿嘧啶治疗失败的结、直肠癌转移患者。但其突出的不良反应是外周感觉神经毒性,主要表现为感觉迟钝和(或)感觉异常,遇冷加重,这种毒性作用与其剂量有关,可表现为急性神经毒性和迟发型感觉神经障碍,影响其疗效和患者的生活质量。研究表明,治疗前后给予肿瘤患者正确有效的护理措施对于提高化疗的疗效和改善患者的预后具有十分重要的临床意义。因此,本文对健康指导、预防、对症护理及心理护理四个方面的护理体会进行了归纳,以期为奥沙利铂毒副反应的有效护理提供更多的参考依据。     

Chemoresistance in non-small cell lung cancer

The treatment of advanced non-small-cell lung cancer (NSCLC is based on the combination of platin and one of the following agents: taxanes, gemcitabine, vinorelbine or irinotecan. There are no significant differences in efficacy among these combinations suggesting that the maximum efficacy has been reached. In this review, we will consider the mechanisms of chemoresistance of the five groups of cytotoxic drugs commonly used in the treatment of advanced NSCLC as well as the clinical studies which have assessed the value of chemoresistance markers. Breast Cancer Related Protein (BRCP) expression has been related to irinotecan and cisplatin (CDDP) resistance. DNA repair capacity influences response to CDDP and ERCC1 gene stands out as a predictive marker of CDDP sensitivity. Preliminary studies indicate that high tubulin III and stathmin mRNA levels correlate with response to paclitaxel and vinorelbine and that high expression of class III tubulin by tumor cells assessed immunohistochemically in patients receiving a taxane-based regimen is associated with a poor response to chemotherapy, and a shorter progression-free survival. High expression levels of ribonucleotide reductase has also been related to response to gemcitabine. Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1) genotype has been reported to be associated with time to progression and survival in patients treated with irinotecan. These data suggest that pharmacogenomic strategies may be used for developing customized chemotherapy in prospective studies. Adjuvant chemotherapy which had recently shown its usefulness in limited lung cancer represents another area of investigation for pharmacogenomic studies.     

Pharmacogenetic markers of toxicity for chemotherapy in colorectal cancer patients

Chemotherapeutic agents used in colorectal cancer are frequently associated with severe adverse reactions that compromise the efficacy of treatment. Predicting toxicity could enable therapy to be tailored. Genetic variations have been associated with toxicity in patients treated with fluoropyrimidines (5-fluorouracil, capecitabine and tegafur), oxaliplatin, irinotecan and cetuximab. Complexity of treatment and variability in toxicity classifications make it difficult to compare studies. This article analyzes the association between toxicity and polymorphisms in DPYD, TYMS, MTHFR, ABCB1, UGT1A1, ERCC1, ERCC2, XRCC1, GSTT1 and GSTM1. In addition, the state-of-the-art and future perspectives are discussed.     

ERCC-1在晚期结肠癌中的表达及与奥沙利铂化疗敏感性的关系

目的探讨核苷酸切除修复交错互补基因（ERCC1）在晚期人结肠癌中的表达水平,分析其与铂类药物化疗敏感性及生存时间的关系。方法以江西省肿瘤医院行结肠癌剖腹探查术患者44例的标本为材料,采用免疫组织化学SP法检测其ERCC1表达水平,所有入组患者随访2年。结果肿瘤组织中ERCC1的阳性率为50.00%,ERCC1阴性者铂类药物化疗有效率为59.1%（13/22）,而阳性者则为27.3%（6/22）,两者之间具有统计学差异（P=0.033）;Cox回归分析显示ERCC1表达为结肠癌患者独立预后因子（P=0.002）。结论ERCC1表达可作为预测结肠癌患者对铂类药物敏感性及预后判断的指标之一。     

伊立替康联合对症支持疗法在转移性结直肠癌治疗中的临床应用

目的 评价伊立替康联合对症支持疗法在不能耐受联合化疗的转移性结直肠癌患者治疗中的临床疗效及不良反应.方法 选取我院原发肿瘤、淋巴结及远处转移(TNM)分期均为Ⅳ期的结直肠癌患者共24例,卡氏行为状态评分为40～ 60分,完全随机将患者分为观察组(13例)和对照组(11例).观察组患者第1、8天给予伊立替康125 mg/m2静脉滴注,30 ～ 90 min内滴完,联合对症支持治疗;对照组患者单纯给予对症支持治疗.观察2组患者临床疗效和不良反应发生情况.结果 观察组治疗有效率为15.4％(2/13),疾病控制率53.8％(7/13);对照组治疗有效率为0,疾病控制率为8.2％(2/11).治疗1年后随访,观察组患者的生存率高于对照组[53.8％(7/13)比27.3％(3/11),P＜0.05].治疗后,观察组生存质量提高患者的比率高于对照组,差异有统计学意义[53.8％(7/13)比27.3％(3/11),P＜0.05].化疗的不良反应大多数患者可耐受,并未因此中断治疗.结论 与单纯给予对症支持治疗相比,伊立替康联合支持治疗可以改善不能耐受联合化疗的转移性结直肠癌患者的疾病控制率,提高患者生存率和生活质量,且患者耐受性和依从性好.     

Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele

Irinotecan is used widely in the treatment of several malignancies, but unpredictable severe toxicities such as myelosuppression and delayed-type diarrhea are sometimes experienced. Polymorphism of the UGT1A1 gene is one of the likely reasons for interindividual differences in irinotecan pharmacokinetics and severe toxicity. Also, polymorphic organic anion-transporting polypeptide 1B1 (OATP1B1, SLCO1B1) is reported to be involved in the hepatocellular uptake of SN-38. A 61-year-old man with lung cancer developed severe toxicities, including grade 3 diarrhea, grade 4 leukopenia, and grade 4 neutropenia, after the first cycle of irinotecan (60 mg/m) plus cisplatin chemotherapy. The irinotecan and SN-38 areas under the concentration-time curve from time zero to infinity in this patient were 43% and 87% higher than the corresponding mean values for 10 other patients with lung cancer treated with irinotecan (60-100 mg/m) normalized for the dose of irinotecan. Analysis of genetic variants in genes encoding the drug-metabolizing enzyme (UGT1A1) and transporter (SLCO1B1) involving irinotecan disposition revealed that this patient was homozygous for the SLCO1B1*15 allele, which may result in severe toxicities attributable to the extensive accumulation of SN-38. Screening of SLCO1B1*15 is suggested to be useful in irinotecan chemotherapy to avoid unpredicted severe toxicity, although the homozygous genotype is rare among the Japanese.     

Pharmacogenetics of irinotecan

Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.     

DNA copy number profiles correlate with outcome in colorectal cancer patients treated with fluoropyrimidine/antifolate-based regimens

For decades 5-fluorouracil (5-FU) has remained the treatment of choice in the adjuvant and palliative setting of colorectal cancer (CRC). The combinations of 5-FU or its oral prodrug capecitabine with irinotecan/oxaliplatin and the novel agents bevacizumab/cetuximab increased responses. However, the overall prognosis is poor, and predictive biomarkers of cytotoxic drugs activity are missing. Pharmacogenetic studies focused on candidate determinants of drug activity/metabolism, such as thymidylate synthase or dihydropyrimidine dehydrogenase, but reported controversial results. Given the heterogeneous and complex nature of CRC, it is likely that many aberrations underlying its progression can also affect therapeutic response. Therefore, high-throughput arrays for genome-wide-DNA aberrations play a pivotal role for new markers discovery by moving from hypothesis-driven, targeted-research to unbiased screening of the whole genetic spectrum. Chromosomal aberrations are critical events in tumorigenesis, and genomic regions harbouring DNA gains/losses have been identified in 85% of CRC patients. These aberrations change the expression of many genes, which might explain the differential effects of specific chemotherapeutic agents. In particular, recent studies reported correlations between DNA copy-number profiles and response to fluoropyrimidine-based regimens, such as leucovorin-modulated-5-FU+irinotecan (FOLFIRI), capecitabine+irinotecan (CAPIRI) and pemetrexed+irinotecan (ALIRI). Genome-wide profiling by oligonucleotide-based array-comparative-genomic-hybridization (aCGH) revealed genomic loci, of which the copy-number status may serve as marker for outcome after FOLFIRI and CAPIRI. Larger randomized and prospective trials of these aCGH platforms in CRC patients treated with fluoropyrimidine-based regimens are ongoing, and will ultimately demonstrate whether these findings can be of actual value to predict clinical outcome and direct the choice of therapy.     

非小细胞肺癌患者ERCC1表达与铂类药物化疗敏感性的相关性的系统分析

目的 分析非小细胞肺癌患者ERCC1表达与对铂类药物治疗敏感性的相关性。 方法 电子检索Medline（1991~2009.12）、Pubmed、CBMDisc等数据库,对回顾性病例研究和随机对照临床试验进行总结分析。 结果 共纳入10篇文献,包括9篇回顾性病例研究和1篇随机对照临床试验。9篇回顾性病例研究资料结果表明,ERCC1表达阴性患者对铂类药物的联合化疗方案的反应率明显高于阳性患者（P=0.02）;1篇文献报道化疗后肿瘤进展时间ERCC1阴性组患者显著长于ERCC1阳性组患者（P〈0.05）;化疗后中位生存期具有统计学差异的2篇报道均为ERCC1阴性组高于ERCC1阳性组 （P〈0.05）。RCT研究结果表明辅助化疗可以明显延长ERCC1阴性患者的生存期,但不能延长ERCC1阳性患者的生存期。 结论 非小细胞肺癌患者中ERCC1低表达者可以从铂类化疗方案中受益,高表达者对铂类药物的化疗敏感性差,需要更好的辅助治疗方案。ERCC1作为预测NSCLC对铂类药物化疗方案敏感性的指标并指导临床个体化治疗具有临床意义。     

Have we made progress in pharmacogenomics? The implementation of molecular markers in colon cancer

For the last 40 years, 5-fluorouracil (5-FU) has remained the treatment of choice in both the adjuvant and advanced treatment of colorectal cancer (CRC). However, 5-FU monotherapy produces response rates of only 10-20% in the advanced setting. 5-FU has been combined with newer agents, such as oxaliplatin and irinotecan, and this has significantly increased response rates to 40-50% in the advanced setting. More recently, novel biological agents, such as the monoclonal antibodies targeting either the epidermal growth factor receptor or vascular endothelial growth factor, have shown to provide additional clinical benefit for patients with metastatic CRC. A number of predictive markers have been identified for CRC to date. However, their usefulness as individual markers of response has led to somewhat inconclusive results. Therefore, there is a need to identify panels of predictive markers of response to therapy for advanced CRC, in order to improve these disappointing response rates. The advent of high-throughput methodologies, such as microarrays, enables tumor samples to be profiled on a global scale. This technology has been utilized to develop predictive markers for a wide range of tumor types to date, and hopefully this technology can be translated into the CRC setting with the hope of predicting the response of each individual tumor to chemotherapy.     

Recent advances in the pharmacological treatment of colorectal cancer

Recent advances in the treatment of colorectal cancer have lead to significant gains in response rates and survival. The combination of newer agents such as irinotecan and oxaliplatin with 5-fluorouracil/leucovorin using various dosing schedules in the metastatic setting has resulted in a steady improvement in the outcome of patients with colorectal cancer. Experimental therapies such as epidermal growth factor receptor inhibitors, vascular endothelial growth factor inhibitors and cyclooxygenase-2 inhibitors, have shown promise in early clinical trials and have acceptable toxicity profiles. Efforts towards improving risk-stratification of stage II colorectal cancer patients and optimising therapy in patients with advanced disease, have focused on molecular and genetic markers. It is hoped that the addition of new therapies to existing drug combinations, as well as further advances in the understanding of colorectal cancer biology, will lead to further improvement in survival and quality of life for patients.