RAS野生型转移性结直肠癌EGFR抑制剂耐药机制的研究进展

抗表皮生长因子受体（epidermal growth factor receptor,EGFR）抗体的应用是转移性结直肠癌治疗进展中的里程碑。抗EGFR单抗和其他靶向药物的出现使转移性结直肠癌患者的中位总生存期从6个月提高至将近30个月,显著改善转移性结直肠癌患者的生存质量及预后。目前KRAS和NRAS被公认为是抗EGFR治疗原发耐药的结直肠癌患者疗效预测标志物,用于抗EGFR治疗的转移性结直结癌患者筛选。除了RAS,其他分子改变也可能影响抗EGFR的疗效。即使是抗EGFR治疗有效的患者也会在13~18个月间产生获得性耐药。本文将对目前已知的抗EGFR治疗耐药机制进行综述,并展望可能的逆转耐药策略,以期为转移性结直肠癌患者精准分子靶向治疗提供依据和指导。      

Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours

BackgroundMetastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs.MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT).ResultsEight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p = 0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p = 0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT.ConclusionThis meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.     

Controversies in antiepidermal growth factor receptor therapy in metastatic colorectal cancer

The randomized first‐line trials, including the CRYSTAL trial, the OPUS trial, and the PRIME trial, have demonstrated the significant efficacy of cetuximab or panitumumab in patients with v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild‐type tumors. The addition of an antiepidermal growth factor receptor (anti‐EGFR)‐directed monoclonal antibody to chemotherapy for these patients significantly improved progression‐free survival, response rates, and R0 resection rates to a greater extent than overall survival compared with patients who received chemotherapy alone. However, 2 recent randomized phase 3 trials, the MRC COIN trial and the Nordic VII trial, reported an unexpected lack of benefit from the addition of cetuximab to chemotherapy in the first‐line setting. In addition, recent retrospective analyses performed on a pooled data set from major clinical trials added more complexity, reporting an unexpected association of KRAS G13D mutation with a better clinical outcome compared with patients who had other KRAS mutations in the first‐line and salvage settings, whereas the other independent analysis failed to demonstrate a benefit from panitumumab in patients with the same KRAS G13D mutation. The anti‐EGFR monoclonal antibody‐associated skin toxicity and the controversial strategies of management also are discussed. In this review, the authors analyze the previous randomized clinical trials and more critically re‐evaluate recent trials and subgroup analyses to derive 3 factors that need to be taken into consideration regarding the addition of EGFR‐directed monoclonal antibodies to chemotherapy: the preclinical data on mechanisms of action between chemotherapy and anti‐EGFR antibodies along with mechanisms of resistance to anti‐EGFR antibodies, the role of cross‐over events in overall survival data, and the significant dose reductions of chemotherapeutic agents when combined with anti‐EGFR agents. Cancer 2013;119:1941–1950. © 2013 American Cancer Society.     

Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications.

BACKGROUND: Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of colorectal cancer (CRC). There are several potential strategies to target EGFR. However, monoclonal antibodies and low molecular weight tyrosine kinase inhibitors are the most advanced in clinical development. The majority of studies so far have merely required EGFRs to be expressed by CRC cells. The detection of EGFR expression is usually performed by immunohistochemistry (IHC) in the primary tumor. There are few data regarding the EGFR status in the corresponding distant metastases. PATIENTS AND METHODS: EGFR status was analyzed by IHC in 80 patients (31 male, 49 female) with CRC (70 colon, 10 rectum) and at least one distant metastatic lesion. Metastatic sites analyzed (n=80) were liver (79 patients) and lung (one patient). RESULTS: EGFR reactivity was similar in the primary tumor and the related metastases. Among the 80 paired primary/metastatic tumors, only five (6.3%) showed discordance in EGFR status: two cases with EGFR expression in the primary tumor but not in the metastasis, and three samples with EGFR expression in the metastasis but not in the primary tumor. CONCLUSIONS: Between the paired primary tumors and distant metastatic lesions, 94% of samples had concordant EGFR status when analyzed by IHC.     

Clinical efficacy and drug resistance of anti-epidermal growth factor receptor therapy in colorectal cancer

Colorectal cancer (CRC) ranked third in cancer related death and its incidence has been increasing worldwide. In recent decades important therapeutic advances have been developed in treatment of metastatic CRC (mCRC), such as monoclonal antibodies against epidermal growth factor receptor (anti-EGFR), which provided additional clinical benefits in mCRC. However, anti-EGFR therapies have limited usage due to approximately 95% of patients with KRAS mutated mCRC do not response to anti-EGFR treatment. Thus, KRAS mutation is predictive of nonresponse to anti-EGFR therapies but it alone is not a sufficient basis to decide who should not be received such therapies because; approximately fifty percent (40%-60%) of CRC patients with wild-type KRAS mutation also have poor response to anti-EGFR based treatment. This fact leads us to suspect that there must be other molecular determinants of response to anti-EGFR therapies which have not been identified yet. Current article summarizes the clinical efficacy of anti-EGFR therapies and also evaluates its resistance mechanisms.     

First‐line therapy for metastatic colorectal cancer: Current perspectives and future directions

The prognosis for patients with newly diagnosed inoperable metastatic colorectal cancer has steadily improved over the past two decades as new agents have been introduced into clinical practice and many new biomarkers have been discovered. In parallel with this progress, clinicians face increasingly complex treatment decisions. This review summarizes recent progress, with a historical perspective, which should help guide the clinician in decision making and optimal therapy selection. This review not only focuses on important and readily identifiable subsets, including primary tumor side and v‐RAF murine sarcoma viral oncogene homologue B (BRAF) mutations, but also discusses rarer molecular subgroups that may be important for determining treatment in the future.     

晚期结直肠癌内科治疗进展

晚期转移性结直肠癌的5年生存率低于10％。5-FU／LV方案治疗的中位生存期大约12个月。最近化疗方案的更新延长了患者的中位生存期。研究发现奥沙利铂、伊立替康联合5-FU／LV或者卡培他滨等化疗方案使中位生存期延长到20个月。奥沙利铂，伊立替康联合5-FU／LV比传统的单药5-FU／LV使生活质量改善时间延长。目前转移性结直肠癌标准的一线治疗方案为FOLFOX和FOLFIRI。正在进行的研究关注新的分子靶向药物（molecular targeted therapy）联合化疗治疗转移性结直肠癌，且部分试验取得了较好的疗效。本文将对5-FU、新一代化疗药物以及分子靶向药物在转移性结肠癌治疗的演进及新进展作一综述。     

Panitumumab: a new frontier of target therapy for the treatment of metastatic colorectal cancer

Panitumumab is a fully human monoclonal IgG₂ antibody targeting the EGF receptor (EGFR). This agent represents a new class of drug owing to its fully human nature, and no need for premedication and loading dose. Panitumumab selectively binds to EGFR, blocking the extracellular domain of the receptor, and has not been associated with the formation of any antibodies directed against it. The drug is indicated as monotherapy for the treatment of patients with EGFR-expressing metastatic colorectal carcinoma with non-mutated (wild-type) KRAS after failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy regimens. The safety profile is favorable and is generally well tolerated; the most common toxicities are skin rashes and diarrhea. Therefore, panitumumab’s hypersensitivity reaction rate is lower when compared with a chimeric monoclonal antibody such as cetuximab. Panitumumab increases the clinician’s repertoire of agents to treat metastatic colorectal carcinoma. The available clinical data are the most promising for a single-agent anti-EGFR monoclonal antibody in this disease at the present time. These new data open different clinical scenarios in metastatic colorectal carcinoma patients and encourage clinicians and basic researchers to investigate new therapeutic approaches for this patient subset.     

Cost-effectiveness of RAS screening before monoclonal antibodies therapy in metastatic colorectal cancer based on FIRE3 Study

The surprising results published by FIRE-3 revealed that the overall survival (OS) of RAS wild-type metastatic colorectal cancer (mCRC) patients treated with Cetuximab(Cmab) and FOLFIRI combination was prolonged to 33.1 months. The substantial increase in testing and treatment costs, however, impose a considerable health burden on patients and society. Hence the study was aimed to assess the cost-effectiveness of RAS screening before monoclonal antibodies (mAbs) therapy based on FIRE-3 study. Four groups were analyzed: group 1, patients with KRAS testing treated with Cmab and FOLFIRI; group 2, patients with RAS testing treated with Cmab and FOLFIRI; group 3, patients with KRAS testing treated with bevacizumab(Bmab) and FOLFIRI; group 4, patients with RAS testing treated with Bmab and FOLFIRI. A Markov model comprising 3 health states (progression-free survival, progressive disease and death) was built. The costs were calculated from a Chinese payer perspective, and survival was reported in quality-adjusted life-months (QALMs). Average total lifetime costs ranged from $104,682.44 (RAS-Bmab) to $136,867.44 (RAS-Cmab), while the survival gained varied from 16.88 QALMs in RAS-Bmab to 21.85 QALMs in RAS-Cmab. The cost per QALM was $6,263.86 for RAS-Cmab, $6,145.84 for KRAS-Bmab, $6,201.57 for RAS-Bmab and $6,960.70 for KRAS-Cmab respectively. The KRAS-Cmab strategy was dominated by the other 3 groups. The first-treatment cost of RAS-Cmab was the most influential one to the model. In all, the RAS screening prior to Cmab treatment in mCRC seems to be a cost-effective strategy in the time of monoclonal antibodies (mAbs) therapy with the most gained QALMs.     

Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer

Background:

Telomeres are TTAGGG tandem repeats capping chromosomal ends and partially controlled by the telomerase enzyme. The EGFR pathway putatively regulates telomerase function, prompting an investigation of telomere length (TL) and its association with anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC).

Methods:

Colorectal cancer cell lines were treated with multiple drugs and sensitivity determined. Clinical information was gathered from 75 patients who had received anti-EGFR drugs. Telomere length was measured using a validated qRT–PCR technique.

Results:

In CRC cell lines, TL independently predicted cetuximab sensitivity. Cells with shorter TL had growth inhibition of 18.6±3.41% as compared with 41.39±8.58% in longer TL (P=0.02). These in vitro findings were validated clinically, in a robust multivariate model. Among patients with KRas WT tumours, those with longer TL had a superior median progression-free survival (PFS) of 24.9 weeks than those with shorter TL; median 11.1 weeks, HR 0.31; P=0.048.

Conclusion:

Telomere length could be a potential unique biomarker predictive of clinical benefit (PFS) of mCRC patients treated with anti-EGFR therapy. This is the novel demonstration of a complex hitherto undescribed interaction, placing anti-EGFR therapy, EGFR pathway, and the telomerase complex within a clinical context.     

Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer

The discovery over 20 years ago by the Nobel Laureate Stanley Cohen of epidermal growth factor and its receptor, followed by the recognition that this receptor is overexpressed in multiple cancer types, has been of phenomenal significance. From these events the ‘Holy Grail’ of targeted therapy has looked increasingly realistic. Over the last 5 years this work has come of age with the licensing of multiple agents targeting this important mitogenic pathway in multiple tumor types. However, these agents and the technology behind them, while impressive, have resulted in lower clinical response rates than anticipated. In this review we will focus on the epidermal growth factor receptor-targeted therapies in colorectal cancer, why our expectations from these therapies have not yet been fulfilled and how we may predict those cancers that are likely to respond or be resistant to these therapies through a greater appreciation of the intricacy, diversity and dynamism of cellular signaling mechanisms.     

Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: Systematic review of different strategies

BackgroundDespite advances in precision oncology and immunotherapy of tumors, little progress has been made in metastatic colorectal cancer (mCRC) in recent years. Therefore, making the most of available therapies is a necessity. Several studies, based on the pulsatile behavior of RAS clones under EGFR blockade, investigated whether readministration of EGFR-targeted agents is effective beyond second line.MethodsA systematic review of studies of retreatment with anti-EGFR monoclonal antibodies has been performed from January 2005 to December 2018 according to PRISMA criteria from PubMed, ESMO and ASCO meetings libraries and Clinicaltrial.gov. Efficacy has been evaluated as objective response rate and survival in available publications. In addition, type and incidence of side effects occurring during on anti-EGFR retreatment have been considered.Results26 publications have been retrieved, of which 20 full-text articles and 6 abstracts and categorized as for the retreatment strategy into five groups: rechallenge (n = 10), reintroduction (n = 4), sequence (n = 5), dose escalation (n = 1) and mixed (n = 6). Data of efficacy displayed high heterogeneity across different strategies (objective response rate, ORR = 0.0–53.8%; disease control rate, DCR = 24.0–89.7%), with best results in the setting of rechallenge (ORR = 2.9–53.8%; DCR = 40.0–89.7%).ConclusionsRechallenge with anti-EGFR provides clinical benefit in molecularly selected mCRC patients beyond second line. Further ctDNA-guided studies comparing this option of treatment with current approved advanced line treatments are warranted.     

Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives.

Epidermal growth factor receptor (EGFR) belongs to a family of receptors known as the ErbB family (ErbB tyrosine kinase receptors) which comprises four proteins encoded by the c-erbB proto-oncogene. EGFR is known to activate a cascade of multiple signaling pathways that facilitate tumor growth process. EGFR has been shown to be overexpressed in colorectal cancer patient populations but its prognostic value in colorectal cancer progression remains unclear. The development of a panel of EGFR inhibitors could reduce the proliferation of tumor cells when used alone or in combination with cytotoxic drugs or radiation. This review focuses on the potential role of EGFR signaling in the survival of colorectal tumor cells and the possible modulation of such signaling pathways by EGFR inhibitors so as to increase tumor control or render tumor cells more sensitive to conventional therapy.     

Predicting the response to targeted therapy in metastatic colorectal cancer

Colorectal cancer is the second most common cause of cancer‐related deaths in Australia. The median survival of metastatic colorectal cancer remains poor, but novel targeted therapies offer promise in improving patient outcomes. However, it is vital to identify which patients with metastatic colorectal cancer will benefit from targeted therapy. Predictive biomarkers offer significant benefit by refining the treatment population to a subgroup that has a greater prospect of benefit from therapy. This provides efficacy benefits, but also minimizes the overall toxicity and cost of treatment. In this review we examine current knowledge regarding predictive biomarkers for targeted agents in metastatic colorectal cancer, with a particular focus on emerging biomarkers such as oncogenic mutations. We also highlight issues that require further exploration in the quest for personalized therapy in metastatic colorectal cancer.     

Liquid biopsy to detect resistance mutations against anti-epidermal growth factor receptor therapy in metastatic colorectal cancer

Colorectal cancer (CRC) is a major cause of mortality worldwide, associated with a steadily growing prevalence. Notably, the identification of KRAS, NRAS, and BRAF mutations has markedly improved targeted CRC therapy by affording treatments directed against the epidermal growth factor receptor (EGFR) and other anti-angiogenic therapies. However, the survival benefit conferred by these therapies remains variable and difficult to predict, owing to the high level of molecular heterogeneity among patients with CRC. Although classification into consensus molecular subtypes could optimize response prediction to targeted therapies, the acquisition of resistance mutations to targeted therapy is, in part, responsible for the lack of response in some patients. However, the acquisition of such mutations can induce challenges in clinical practice. The utility of liquid biopsy to detect resistance mutations against anti-EGFR therapy has recently been described. This approach may constitute a new standard in the decision algorithm for targeted CRC therapy.     

Molecular therapy of colorectal cancer: Progress and future directions

Colorectal cancer (CRC) remains one of the most common types of cancer and leading causes of cancer death worldwide. Although the introduction of cytotoxic drugs such as oxaliplatin, irinotecan and fluorouracil has improved the treatment of advanced CRC, the individual response to chemoradiotherapy varies tremendously from one patient to another. However, recent progress in CRC molecular therapies may provide new insight into the treatment of this disease. Currently, components of the EGFR, VEGF, Wnt and NF‐kB pathways are the most important targets for CRC therapy. This review chronicles the development of molecular CRC therapies over the past few decades. We also provide an update on the current progress of research concerning the molecular pathways leading to CRC and discuss the possible implications for CRC therapy.     

Impact of EGFR and EGFR ligand expression on treatment response in patients with metastatic colorectal cancer

Up to 50% of patients with colorectal cancer (CRC) have either synchronous or metachronous hepatic metastases in the course of their disease. Patients with metastatic CRC (mCRC) whose tumors express wild-type KRAS benefit from treatment with monoclonal antibodies (such as cetuximab or panitumumab) that target the epidermal growth factor receptor (EGFR). However, the therapeutic response to these antibodies is variable, and further predictive models are required. The present study examined whether expression of different EGFRs or their ligands in tumors was associated with the response to cetuximab treatment. Tumor tissues, collected during liver resection in 28 patients with mCRC, were analyzed. The protein expression levels of EGFR/ErbB1, ErbB2, ErbB3 and the EGFR ligands heregulin and amphiregulin were determined using Luminex 200^® and enzyme-linked immunosorbent assays. Computed tomography or magnetic resonance imaging was performed 4 weeks before and 6–8 weeks after treatment with cetuximab. Response to treatment was assessed using the response evaluation criteria for solid tumors (RECIST). The association between the protein expression levels of different EGFRs and their ligands with RECIST criteria was then analyzed to determine whether these protein levels could predict the treatment response to cetuximab. A total of 12 patients exhibited a partial response, 9 exhibited stable disease and 7 exhibited progressive disease after cetuximab therapy according to RECIST. The expression levels of EGFRs (EGFR/ErbB1, ErbB2 and ErbB3) and their ligands (heregulin and amphiregulin) were not significantly associated with the response to cetuximab therapy. Therefore, the present study indicated that EGFR or EGFR ligand expression did not predict treatment response in patients with CRC with liver metastases following cetuximab therapy.     

Panitumumab monotherapy in patients with previously treated metastatic colorectal cancer

BACKGROUND: The safety and efficacy of the fully human antibody panitumumab was evaluated in patients with metastatic colorectal cancer refractory to available therapies. METHODS: This phase 2 open-label, multicenter study of panitumumab enrolled patients with metastatic colorectal cancer who had progressed on chemotherapy that included a fluoropyrimidine and irinotecan or oxaliplatin, or both. All patients had tumors with > or =10% 1+ epidermal growth factor receptor (EGFr) staining by immunohistochemistry. Patients were stratified into 2 strata (high or low staining intensity) and received intravenous panitumumab 2.5 mg/kg weekly 8 of every 9 weeks until disease progression or unacceptable toxicity. RESULTS: In all, 148 patients received panitumumab, 105 in the high EGFr stratum, 43 in the low EGFr stratum. Overall response by central review was 9% (95% confidence interval [CI], 5%-15%) and was similar between strata. An additional 29% of patients had stable disease. Median progression-free survival was 14 weeks (95% CI, 8-16) and median overall survival was 9 months (95% CI, 6-10). Toxicities were manageable, with skin toxicity reported in 95% of patients (5% grade 3 or 4). Four patients discontinued therapy because of toxicity. No antipanitumumab antibodies were detected. One patient had an infusion reaction but was able to continue therapy. CONCLUSIONS: Panitumumab given weekly was well tolerated and had single-agent activity in previously treated patients with colorectal cancer. Dermatologic toxicity was common but rarely severe. Ongoing studies will determine panitumumab activity earlier in the course of treatment for colorectal cancer and in combination with other antineoplastic agents.     

EGFR在结直肠癌组织中的表达及其临床意义

目的：检测表皮生长因子受体（epidermal growth factor receptor,EGFR）在结直肠癌组织中的表达情况,分析其表达水平与各种主要临床病理学预后因子及长期生存的关系。方法：选取解放军307医院和301医院第二附属医院64例结直肠癌患者的石腊包埋肿瘤标本,以免疫组化方法检测结直肠癌肿瘤标本中EGFR的表达。通过单因素分析和多因素分析判断EGFR表达与临床病理学指标之间的关系;通过多因素分析（COX模型）判断EGFR表达水平与患者总生存期的关系。结果：所有患者肿瘤组织EGFR的阳性表达率为69%。T3期肿瘤EGFR阳性表达明显多于T1和T2期（P〈0.05）,淋巴结转移阳性者EGFR阳性表达明显多于无转移者（P〈0.05）,有远处转移者EGFR阳性表达明显多于无远处转移者（P〈0.05）;EGFR表达与患者性别、年龄、肿瘤原发部位、肿瘤大小、肿瘤分化程度等均无明显相关性。EGFR表达水平与患者总生存期无明显相关。结论：结直肠癌组织EGFR的表达与肿瘤TNM分期相关,与患者总生存期无明显相关。     

A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts

Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is overexpressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its beta-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present results indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor.