非小细胞肺癌化疗相关生物标志物的困惑与出路

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杨衿记. 非小细胞肺癌化疗相关生物标志物的困惑与出路.循证医学, 2013, 13(4): 195-198
YANG Jin-ji. Confusion and Way Out of Chemotherapy Related Biomarkers in Non-Small Cell Lung Cancer. Journal of Evidence-Based Medicine,2013, 13(4): 195-198 复制到剪切板

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非小细胞肺癌化疗相关生物标志物的困惑与出路

杨衿记

广东省人民医院肿瘤中心、广东省医学科学院、广东省肺癌研究所, 广州510080

作者简介:杨衿记（1967-）,男,广东阳江人,主任医师,肿瘤学博士,硕士研究生导师,主要研究方向为肺癌多学科综合治疗和基于基因、分子靶点的肺癌个体化治疗。

摘要

关键词: 非小细胞肺癌; 化疗; 生物标志物; 循证医学

中图分类号:R734.2 文献标识码:A

Confusion and Way Out of Chemotherapy Related Biomarkers in Non-Small Cell Lung Cancer

YANG Jin-ji

Author’s address： Cancer Center, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Lung Cancer Institute, Guangzhou 510080, China

Abstract

Key words: non-small cell lung cancer; chemotherapy; biomarkers ;evidence-based medicine

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1 背景

尽管表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变阳性或ALK融合基因阳性的局部晚期/转移性非小细胞肺癌（non-small cell lung cancer, NSCLC）走进了小分子酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）靶向治疗的个体化时代,但约70%的NSCLC至今尚未发现明确的驱动癌基因或仍没有成功开发的小分子靶向治疗药物可用,化疗依然是这些患者的标准治疗方法。而且,EGFR或ALK阳性NSCLC患者使用TKI治疗失败后,相当一部分患者需要接受化疗以克服耐药性,可以说,化疗仍然是晚期NSCLC治疗的基石。

2 困惑

普通NSCLC患者化疗能否像EGFR或ALK阳性患者靶向治疗一样存在生物标志物指导下的个体化治疗呢?近十多年来,人们对铂类药物相关生物标志物核苷酸切除修复交叉互补基因 1（excision repair cross-complementation group 1, ERCC1）、抗代谢类药物吉西他滨等的相关生物标志物核糖核苷酸还原酶1（ribonucleotide reductase M1, RRM1）能否作为预后和/或预测因子进行了深入的探索。很多临床研究认为,通过定量实时聚合酶链反应（quantitative real-time polymerase chain reaction, qRT-PCR）或免疫组化（immunohisto- chemistry, IHC）分析检测的ERCC1是一个预后或疗效预测的生物标志物^{[ 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19]},但也有不少研究显示ERCC1的表达与生存期（包括无进展生存期和总生存期）没有相关性^{[ 20, 21, 22, 23]}。上述这些研究的结论似乎是相互矛盾的,RRM1同样存在相似的尴尬^{[ 1, 23, 24, 25, 26, 27, 28]}。

问题的关键在哪里呢?

3 原因

我们首先归纳这些研究的特点：①大部分为回顾性研究,仅有的几个前瞻性试验大都是Ⅱ期研究,只有个别为Ⅲ期随机对照临床试验;②Meta分析来自摘要或文献,而不是基于个体患者数据;③广泛来源于NSCLC辅助化疗研究,因为存在大量石蜡包埋组织;④各项研究存在应用技术的异质性,不同实验室采用的检测ERCC1和RRM1的方法学和诊断截断值（cut-off value）不完全一致;⑤大部分应用单一的生物标志物;⑥阳性结果明显多于阴性结果,有可能存在发表偏倚问题。

表1 分子标志物各种检测方法的优缺点

IHC是检测生物标志物表达最便宜、最方便的方法,但存在诸多不足,如准确性有限,有时也存在特异性低的缺陷。生物标志物各种检测方法的优缺点见表1^{[ 29]}。总的来说,评价ERCC1、RRM1的最佳方法还未确立,所以只限于在临床试验使用。理想化地,除了通过生物标志物分析来选择患者从基于机制的治疗中获益外,应该开发功能性DNA修复测试。在DNA修复的背景中,相关生物标志物应能反映DNA修复通路的功能,而不仅仅提供局限于感兴趣蛋白质表达水平的信息^{[ 29]}。另外,也有研究者指出,IHC检测的ERCC1蛋白表达水平不能被确认为可以预测NSCLC辅助化疗的总生存期,可能有三种解释：第一,目前检测ERCC1表达水平的工具还不完善;第二,低估了其分子生物学的复杂性（如4种ERCC1蛋白质同分异构体各自的作用未被准确测评）;第三,也许ERCC1这个生物标志物本来就不是NSCLC患者获益于含铂化疗的一种有效预测因子^{[ 22]}。

因此,这些所谓的化疗相关生物标志物涉及的临床试验得出了自相矛盾的结论,根本原因有两个方面,从微观上说,是缺乏对这些生物标志物复杂的生物学功能特性的认识,无法确定它们在DNA修复通路和细胞分化周期中所发挥的关键作用;而且,除传统的ERCC1、RRM1等生物标志物外,尚未开发出新型的敏感性和特异性更佳的预测因子。从宏观上说,检测这些生物标志物的最佳方法学还有待完善。如目前商业途径可获得的16种ERCC1抗体,没有一种能识别4种ERCC1蛋白质同分异构体（ERCC1-201、ERCC1-202、ERCC1-203和ERCC1-204）;4种同分异构体中,仅ERCC1-202具有全面的核苷酸外切修复和顺铂耐药效能^{[ 22]}。此外,ERCC1和RRM1可能反映了DNA修复通路的共同活性^{[ 29]}。而且,我们对化疗相关生物标志物与已知的NSCLC驱动癌基因如EGFR基因突变和ALK融合基因等的相关性几乎一无所知,单一的生物标志物可能局限了我们对NSCLC生物学行为、肿瘤客观疗效和生存期的认知深度。

4 出路

我们处于循证医学、转化医学和个体化医学时代,只有充分利用转化医学的各种方法学,不断寻找和探索新的高级别证据,才能最终实现NSCLC患者的个体化治疗。针对化疗生物标志物相关的临床研究得出自相矛盾的结论,我们探索了其中的主要原因。未来NSCLC化疗相关生物标志物的出路在何方?

我们认为,至少应该做好如下四方面的工作：

第一,回归实验室,重新认识这些生物标志物复杂的生物学功能和特性,明确它们在DNA修复通路和细胞分化周期中所发挥的关键作用。这也符合“临床→实验室→临床→实验室”的转化医学模式。

第二,完善检测的方法学。注重DNA修复功能检验,强调充分检测生物标志物的多种同分异构体及其功能的重要性。如ERCC1蛋白质存在4种同分异构体,其中仅ERCC1-202具有全面的核苷酸外切修复和顺铂耐药效能,因此,必须特异性地检测ERCC1-202这个独特的功能性异构体^{[ 22]}。

第三,克服单一标志物的弊端。ERCC1和RRM1可能反映了DNA修复通路的共同活性,因此运用一整套的标志物（如ERCC1、RRM1、PARP和MSH2）可以强化统计学上的预测效能^{[ 29]}。此外,FASTACT-2研究显示,ERCC1蛋白表达与厄洛替尼治疗获益相关,并且这种获益不局限于EGFR突变患者,对于EGFR野生型患者同样可以从厄洛替尼治疗中获益^{[ 30]}, 该研究似乎提示,在已知的NSCLC驱动癌基因的信号转导通路上（如EGFR基因突变和ALK融合基因）观察ERCC1、RRM1等生物标志物的表达情况,这些生物标志物或许是NSCLC患者获益于TKI靶向治疗或化疗的可靠指标。所以,应尝试考虑把ERCC1、RRM1等生物标志物与NSCLC驱动癌基因有机结合来指导NSCLC的个体化治疗。

第四,利用大规模Ⅲ期随机对照临床试验（包括NSCLC新辅助化疗和辅助化疗）中足够量的肿瘤组织进行深入的基因组织学分析（如深度测序、差异性或聚类分析、肿瘤组织内铂类药物浓度分析等）,挖掘可能作为治疗靶点的基因改变和潜在的化疗相关生物标志物。

值得一提的是,上述措施离不开设计严谨和执行力良好的基于生物标志物的多中心随机对照临床试验。设立中心实验室、协调各实验室的质量控制是关键的步骤。

5 总结

综上所述,目前的证据还不足以常规推荐ERCC1、RRM1等生物标志物指导NSCLC化疗的临床实践。一方面,我们必须回到实验室仔细分析这些生物标志物的生物学结构和功能,重新认识与DNA修复活性相关的独特的功能性生物标志物,并探索潜在的生物标志物。另一方面,从宏观和微观上改良或改革分子生物学的检测方法,针对独特的功能性DNA修复通路生物标志物,设计严谨的随机对照临床试验,逐步走进生物标志物指导下的NSCLC个体化化疗时代。

The authors have declared that no competing interests exist.

参考文献

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2007

0.0

... 上述这些研究的结论似乎是相互矛盾的,RRM1同样存在相似的尴尬^{[1,23,24,25,26,27,28]} ...

2006

0.0

2002

7.837

0.0

2011

2.038

0.0

2007

18.038

0.0

2005

5.854

0.0

2012

7.384

0.0

2011

0.0

2008

3.392

0.0

2012

0.0

Tseden-Ish

, Choi

, Cho

, et al. Disease-free survival of patients after surgical resection of non-small-cell lung carcinoma and correlation with excision repair cross-complementation group 1 expression and genotype[J]. Respirology, 2012, 17(1): 127-133.

1Departments of Medicine 2 Pathology 3 Thoracic and Cardiovascular Surgery 4 Radiation Oncology 5 Radiology, Chonnam National University Hwasun Hospital 6 The Brain Korea 21 Project, Center for Biomedical Human Resources, Chonnam National University, Jeonnam, South Korea *Young-Chul Kim, Lung Cancer Clinic, Pulmonary Medicine, Chonnam National University Medical School, Hwasun Hospital 160, Ilsim-ri, Hwasun, Jeonnam, South Korea 519-809. Email: <a href="mailto:kyc0923@chonnam.ac.kr" title="Link to email address" shape="rect">kyc0923@chonnam.ac.kr</a>

Background and objective: Expression of excision repair cross-complementation group 1 (ERCC1) is recognized as a favourable prognostic marker in patients who have undergone surgical resection of non-small cell lung cancer (NSCLC). However, in patients treated with adjuvant chemotherapy after surgical resection, ERCC1 correlated with poor prognosis. Class III beta tubulin (TUBB3) is also known to be a predictive marker of the efficacy of treatment with taxanes or vinorelbine.

2008

3.392

0.0

Lee

, Min

, Han

, et al. ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small-cell lung cancer[J]. Lung Cancer, 2008, 60(3): 401-407.

Summary

Expression of excision repair cross-complementation group 1 (ERCC1) is important for resistance to platinum agents. Mutations of epidermal growth factor receptor (EGFR) are related to the responsiveness to tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). This study was performed to determine if ERCC1 expression and EGFR are related to the prognosis of resected NSCLC, and to determine if ERCC1 expression and EGFR mutations are related. We used immunohistochemistry (IHC) to evaluate ERCC1 expression in tumors from 130 patients with curatively resected NSCLC. The median H-score was used as a cut-off for ERCC1 IHC. EGFR mutations were analyzed in exons 18, 19 and 21. ERCC1 expression was detected in tumors from 80 patients (61.5%). ERCC1 was expressed more frequently in smokers and in squamous cell carcinomas. Patients with a positive ERCC1 expression survived longer than ERCC1-negative patients (median overall survival 7.6 years for ERCC1-positive vs. 4.0 years for ERCC1-negative, P = 0.046). Subsequent multivariate analysis suggested that ERCC1 expression is an independent prognostic marker of longer survival (hazard ratio: 0.598, 95% confidence interval: 0.357–1.001). EGFR mutations were found in 25 patients (19.2%) but did not affect overall survival. Interestingly, EGFR mutations were more frequent in ERCC1-negative tumors (12.5% in ERCC1-positive vs. 30% in ERCC1-negative tumors, P = 0.014). In conclusion, ERCC1 expression was identified as a positive prognostic marker in resected NSCLC. In addition, EGFR mutations were more frequently found in ERCC1-negative tumors.

2010

7.384

0.0

2010

2.147

0.0

Wang

, Zhao

, Yang

, et al. Positive expression of ERCC1 predicts a poorer platinum-based treatment outcome in Chinese patients with advanced non-small-cell lung cancer[J]. Med Oncol, 2010, 27(2): 484-490.

The goal of this study is to determine role of excision repair cross-complementing group 1 gene (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) expression in predicting response and survival in Chinese patients with advanced stage non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. Formalin-fixed, paraffin-embedded biopsy tissues were retrospectively obtained from 124 advanced NSCLC patients. Protein expression levels of ERCC1 and RRM1 were determined by immunohistochemistry (IHC). Associations between expression of ERCC1 and RRM1 and clinic-pathologic parameters were analyzed. The study shows that ERCC1 and RRM1 expression was detected in 43 (35%) and 50 (40%) of the 124 tumor samples, respectively. Expression of ERCC1 and RRM1 was negatively associated with tumor response. Fifty-four percent patients whose tumors did not express ERCC1 had partial response (PR) compared to 33% whose tumors expressed the protein (P = 0.022). Similarly, 54% patients whose tumor did not express RRM1 had PR compared to 36% whose tumors expression the protein (P = 0.042). Further, patients whose tumors lacked of ERCC1 but not RRM1 expression had a longer median survival time than those tumors expressed ERCC1 (13.4 months versus 9.1 months; P = 0.006), which is independent of other prognostic factors (P = 0.0066). In conclusion, tumor ERCC1 expression is associated with tumor response and patients’ survival in Chinese advanced NSCLC patients treated with platinum-based regimen and may serve as a biomarker in predicting tumor response and clinical outcome in the patient population.

1.Beijing Cancer Hospital and Institute Department of Thoracic Medical Oncology, Peking University School of Oncology Beijing 100036 China 2.The University of Texas M. D. Anderson Cancer Center The Department of Thoracic/Head and Neck Medical Oncology Houston TX USA 3.Beijing Cancer Hospital and Institute Department of Biostatistics, Peking University School of Oncology Beijing China

2009

18.038

0.0

2011

3.73

0.0

Hubner

, Riley

, Billingham

, et al. Excision repair cross-complementation group 1 (ERCC1) status and lung cancer outcomes: A meta-analysis of published studies and recommendations[J]. PLoS One, 2011, 6(10): e25164.

1 Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, United Kingdom 2 Department of Public Health, Epidemiology and Biostatistics, University of Birmingham, Birmingham, United Kingdom 3 Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom 4 MRC Midland Hub for Trials Methodology Research, University of Birmingham, Birmingham, United Kingdom 5 Department of Medicine, Royal Marsden NHS Foundation Trust, London, United Kingdom 6 Molecular Genetics Group, Imperial College, London, United Kingdom

Purpose

Despite discrepant results on clinical utility, several trials are already prospectively randomizing non-small cell lung cancer (NSCLC) patients by ERCC1 status. We aimed to characterize the prognostic and predictive effect of ERCC1 by systematic review and meta-analysis.

Methods

Eligible studies assessed survival and/or chemotherapy response in NSCLC or SCLC by ERCC1 status. Effect measures of interest were hazard ratio (HR) for survival or relative risk (RR) for chemotherapy response. Random-effects meta-analyses were used to account for between-study heterogeneity, with unadjusted/adjusted effect estimates considered separately.

Results

23 eligible studies provided survival results in 2,726 patients. Substantial heterogeneity was observed in all meta-analyses (I² always >30%), partly due to variability in thresholds defining ‘low’ and ‘high’ ERCC1. Meta-analysis of unadjusted estimates showed high ERCC1 was associated with significantly worse overall survival in platinum-treated NSCLC (average unadjusted HR = 1.61, 95%CI:1.23–2.1, p = 0.014), but not in NSCLC untreated with chemotherapy (average unadjusted HR = 0.82, 95%CI:0.51–1.31). Meta-analysis of adjusted estimates was limited by variable choice of adjustment factors and potential publication bias (Egger's p<0.0001). There was evidence that high ERCC1 was associated with reduced response to platinum (average RR = 0.80; 95%CI:0.64–0.99). SCLC data were inadequate to draw firm conclusions.

Conclusions

Current evidence suggests high ERCC1 may adversely influence survival and response in platinum-treated NSCLC patients, but not in non-platinum treated, although definitive evidence of a predictive influence is lacking. International consensus is urgently required to provide consistent, validated ERCC1 assessment methodology. ERCC1 assessment for treatment selection should currently be restricted to, and evaluated within, clinical trials.

2010

3.392

0.0

Chen

, Zhang

, Wang

, et al. The platinum-based treatments for advanced non-small cell lung cancer, is low/ negative ERCC1 expression better than high/positive ERCC1 expression? A meta-analysis[J]. Lung Cancer, 2010, 70(1): 63-70.

Abstract

Background

The predictive value of ERCC1 for prognosis and sensitivity to platinum-based chemotherapy in patients with non-small cell lung cancer (NSCLC) remains controversial. This meta-analysis was performed to provide an assessment of whether expression variations of ERCC1 are associated with objective response and median survival in patients with advanced NSCLC treated with platinum-based chemotherapy.

Methods

We searched MEDLINE, EMBASE and CNKI for all eligible studies and conducted a meta-analysis of 12 studies (n = 836 patients) that evaluated the correlation between ERCC1 levels (detected by immunohistochemistry or real-time reverse transcriptase PCR) and objective response or median survival in patients receiving platinum-based chemotherapy for advanced NSCLC. Pooled odds ratios (OR) for the objective response were calculated using the Mantel–Haenszel method. Pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios from each individual study.

Results

Among 836 tumors, ERCC1 expression was high/positive in 416 (49.8%) and low/negative in 420 (50.2%). Response to platinum-based chemotherapy was significantly higher in patients with ERCC1 low/negative expression (OR = 0.48; 95% CI, 0.35–0.64; P < 0.00001). Median survival time was significantly prolonged when ERCC1 low/negative expression was compared with ERCC1 high/positive expression (MR: 0.77; 95% CI, 0.47–1.07; P < 0.00001).

Conclusions

Low/negative expression of ERCC1 was associated with higher objective response and median survival in advanced NSCLC patients treated with platinum-based chemotherapy. ERCC1 may be a suitable marker of prognosis and sensitivity to platinum-based chemotherapy in patients with advanced NSCLC.

2009

18.038

0.0

2010

1.592

0.0

2011

4.522

0.0

2009

3.392

0.0

2007

4.473

0.0

2013

0.0

... 第三,也许ERCC1这个生物标志物本来就不是NSCLC患者获益于含铂化疗的一种有效预测因子^[22] ...

... 4种同分异构体中,仅ERCC1-202具有全面的核苷酸外切修复和顺铂耐药效能^[22] ...

... 如ERCC1蛋白质存在4种同分异构体,其中仅ERCC1-202具有全面的核苷酸外切修复和顺铂耐药效能,因此,必须特异性地检测ERCC1-202这个独特的功能性异构体^[22] ...

2013

18.038

0.0

2004

7.837

0.0

2006

18.038

0.0

2008

4.473

0.0

2012

3.392

0.0

2009

18.038

0.0

2013

18.038

0.0

... 生物标志物各种检测方法的优缺点见表1^[29] ...

... 在DNA修复的背景中,相关生物标志物应能反映DNA修复通路的功能,而不仅仅提供局限于感兴趣蛋白质表达水平的信息^[29] ...

... 此外,ERCC1和RRM1可能反映了DNA修复通路的共同活性^[29] ...

... ERCC1和RRM1可能反映了DNA修复通路的共同活性,因此运用一整套的标志物（如ERCC1、RRM1、PARP和MSH2）可以强化统计学上的预测效能^[29] ...

2013

25.117

0.0

... 此外,FASTACT-2研究显示,ERCC1蛋白表达与厄洛替尼治疗获益相关,并且这种获益不局限于EGFR突变患者,对于EGFR野生型患者同样可以从厄洛替尼治疗中获益^[30], 该研究似乎提示,在已知的NSCLC驱动癌基因的信号转导通路上（如EGFR基因突变和ALK融合基因）观察ERCC1、RRM1等生物标志物的表达情况,这些生物标志物或许是NSCLC患者获益于TKI靶向治疗或化疗的可靠指标 ...