EGFR突变状态可以通过化疗进化吗?
社论

EGFR突变状态可以通过化疗进化吗?

Eric S. Kim1那David J. Stewart2那Alok A. Khorana1

1James P. Wilmot Cancer Center, and the Department of Medicine, University of Rochester, Rochester, NY, USA; 2医疗肿瘤科,渥太华医院,渥太华,加拿大

对应:Alok A. Khorana, M.D. 601 Elmwood Ave, Box 704, Rochester, NY 14642, USA. Email: alok_khorana@urmc.rochester.edu

2012年10月15日提交。公布2012年11月20日。

doi: 10.3978/j.issn.2304-3865.2012.11.09


表皮生长因子受体(EGFR)通过口服酪氨酸激酶抑制剂(TKIS)和基于铂的化疗是先进的非小细胞肺癌(NSCLC)的重要治疗策略。然而,大量患者患有肿瘤,肿瘤是有本质上抵抗化学疗法和/或TKI的肿瘤,甚至甚至那些最初最终产生获得性阻力的人。试图鉴定最有可能从特定代理商的患者识别患者的子集,所谓的“个性化药物”方法迄今为止患者的子集。当研究NSCLC中的近期III期临床试验时,发生了一个主要成功的临床试验表明EGFR中的细胞突变是对肿瘤反应的重要预测生物标志物(12)。然而,对铂基化疗后对二线TKI的肿瘤反应小于EGFR突变患者对第一线TKI的响应,表明化疗治疗后的抗性机制(3.4.)。This discrepancy in the predictive value of EGFR mutations between first- and second-line treatments with TKIs could be due to various mechanisms that are yet to be answered.

在最近发表的文章中Journal of Clinical Oncology5.),白和同事对理解这种差异在EGFR突变的预测值中对理解这种差异进行了重要贡献。调查人员研究了三种不同的队列:第一,264名高级NSCLC患者,他们接受了匹配的前后等离子体样品的一线化疗;其次,63名患者接受新辅助化疗的预治疗组织标本;第三,79例高级NSCLC患者接受了姑息手术。在所有三个队列的患者中确定了EGFR突变状态。BAI和同事应祝贺他们特别努力收集挑战性肿瘤标本,特别是79种来自姑息切除的样本。他们报告了新颖的信息,即血浆和肿瘤组织样品中的化疗后,EGFR突变率显着降低。此外,少数患者,其肿瘤最初是EGFR野生型,后来确定化疗后患有EGFR突变。这些发现可以为第一和第二线TKI之间的EGFR突变的预测值不一致提供部分解释。治疗医生在进展时获得额外的活组织检查是相对罕见的。 Hence, based on their findings, patients who lose sensitizing EGFR mutations following chemotherapy may end up receiving TKIs in 2nd或3.RD.与次优益处的系列。在第三队队列中,BAI及其同事报告说,38%的肿瘤表明EGFR突变的肠内异质性。这是一种挑衅性的发现,具有几种潜在的影响。作为作者状态,EGFR突变变换可能与EGFR-突变和野生型肿瘤细胞的肠型EGFR突变和可变敏感性的异质性有关,如其发现达到对化疗的部分反应的患者更有可能与达到稳定疾病或渐进性疾病的人有EGFR突变转变。

A limitation of this report is in interpreting the findings from the first and second cohorts in that predictive value of post-chemotherapy EGFR mutation status in tumor response to 2nd或3.RD.线路TKI是未知的。白和同事(5.)州在引言中,EGFR突变与BR.21试验中TKI治疗的结果无关(3.)或在Isel(Iressa肺癌中的Iressa Survival评估)研究(4.),将Erlotinib或Gefitinib与安慰剂与铂类化疗失败的患者进行比较。这可能会夸大实际的发现。例如,在BR.21试验中,EGFR突变患者的反应率显着增加(27%)vs.7%)TKI后,虽然无统计学意义的虽然无统计学意义,但与EGFR野生型患者相比,危险比为0.12的P值为0.55(6.)。For the ISEL study of gefitinib, EGFR mutation status correlated with response (37.5%vs.2.6%),患者存活分析不足(7.)。同样,兴趣(iRessa NSCLC试验评估响应和生存与纳克劳雷)的研究,EGFR突变状态预测响应和GEFITINIB上的PFS优势在Docetaxel(8.)。简而言之,初始活检标本的EGFR突变状态似乎为对二线TKIS的响应提供潜在的预测值。展示在化疗前化疗后化疗预测值的优越性将是必要的,以验证白和同事的研究结果。

在进行先进的化学疗法时,肿瘤细胞可以获得可能使肿瘤耐药于后续治疗患者的分子变化(9.)。交替具有不同作用机制的多种试剂并未改善临床结果(10.)。Another potential mechanism for reduced tumor response to second-line TKIs following platinum-based chemotherapy may be due to broad reduction in membrane transporters for both chemotherapy and targeted therapy (11.)。最近的发现表明,NSCLC中的组织铂浓度明显与降低的肿瘤收缩和减少的存活率有显着相关(12.)。此外,在高铂基化疗剂量下的NSCLC剂量 - 反应曲线的平坦化(13.)表明化疗抗性最重要的因素之一是药物吸收所需因素的缺乏,例如铜转运蛋白Ctr1(在铂的情况下)。在过去3个月内接受化疗或靶向疗法的患者的肿瘤表达显着低于患有较长间隔疗法的患者(14.)。The correlation with time from last chemotherapy or targeted therapy was stronger than the correlation with time from last cytotoxic therapy alone. This suggests that chemotherapy or targeted therapy may result in a broad reduction in membrane transporters and that this, in turn, may generate broad cross resistance. This could also explain why gefitinib maintenance after concurrent chemoradiation (cisplatin plus etoposide) was associated with significant decrease in overall survival but not in progression-free survival compared with placebo in stage III NSCLC (15.)。两只武器死亡的原因被认为是由于疾病的进展。在进行进展时,在进展时,接受化疗和吉替尼的患者的肿瘤更可能对吸收后续剂所需的膜转运蛋白的肿瘤更容易抑制膜转运蛋白,导致整体存活率下降但不会无进展的存活率。

The finding that 38% of tumors in the study from Bai等等。证明EGFR-wild类型和mutan的混合物t foci implies that the results from routine EGFR mutation analysis clinicians use to make treatment decision may not be as precise as they are perceived to be. As a result, we raise the possibility that tumors with EGFR mutation shift following chemotherapy are more likely to harbor heterogeneous EGFR mutation status, and therefore are more susceptible to imprecise determination of EGFR mutational status. Their findings would have been strengthened if they were able to implement the analysis from the third cohort into the second cohort. Percent change in frequency of EGFR mutant foci in response to chemotherapy may have been a better endpoint to corroborate their conclusions. We, however, realize that it would be extremely difficult to examine multiple foci for EGFR mutation in pre-chemotherapy specimens prior to resection.

In this targeted-therapy era, we heavily rely on molecular test results from a single biopsy which likely represents a small focus of molecularly heterogeneous tumor. Their provocative finding from the third cohort provides at least a partial justification to pursue additional biopsy either at the same site or at a different site of metastasis when initial biopsy reveals EGFR-wild type but patients otherwise fit the characteristics that are frequently associated with EGFR-mutant tumors. Further investigation at a larger scale involving patients from the institutions of different countries is warranted.

In conclusion, there could be multiple reasons for reduced tumor response to second-line TKIs following platinum-based chemotherapy and discrepancy in the predictive value of EGFR mutations between first- and second-line treatments. Bai and colleagues reported influence of chemotherapy on EGFR mutation as a potential explanation through extensive tissue-based analysis. Further investigation in this area is necessary to develop an enhanced strategy for second-line treatment and to determine optimal sequence of targeted agents and chemotherapy. Finally, rapid determination of EGFR mutation status at time of diagnosis prior to initiating first-line therapy may allow a majority of patients with EGFR mutations to receive TKIs in first-line setting. By this approach, we could avoid the potential problem with chemotherapy-induced EGFR mutation shift in second or third-line setting.


致谢

Khorana博士得到了国家癌症研究所(K23 CA120587),全国心脏,肺和血液研究所(R01HL095109)和V基金会的支持。

披露:作者宣称没有利益冲突。


References

  1. Maemondo M,Inoue A,Kobayashi K,等。Gefitinib或突变EGFR的非小细胞肺癌的化学疗法。n Engl J Med 2010; 362:2380-8。
  2. Mok Ts,Wu Yl,Thongprasert S等人。吉维替尼或卡铂 - 肺腺癌中的紫杉醇。n Engl J Med 2009; 361:947-57。
  3. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123-32.
  4. 撒切尔n,chang a,parikh p等人。Gefitinib加上先前治疗难治性先进的非小细胞肺癌患者的最佳支持护理:由随机,安慰剂控制,多期式研究(Iressa肺癌患者)的结果。2005; 366:1527-37。
  5. Bai H, Wang Z, Chen K, et al. Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer. J Clin Oncol 2012;30:3077-83.
  6. Zhu CQ, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2008;26:4268-75.
  7. Hirsch FR,Varella-Garcia M,Bunn Pa,JR等。吉非替尼的分子预测因子在先进的非小细胞肺癌中III阶段安慰剂对照研究中。J Clin incol 2006; 24:5034-42。
  8. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010;28:744-52.
  9. Stewart DJ。Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. Crit Rev Oncol Hematol 2010;75:173-234.
  10. Stewart DJ,Tomiak E,Shamji FM,等。再生化疗方案的II期研究,用于晚期非小细胞肺癌。肺癌2004; 44:241-9。
  11. Stewart DJ。吉替尼维持在第三阶段非小细胞肺癌。J Clin incol 2008; 26:4849-50;作者回复4850-1。
  12. Kim Es,Lee JJ,He G,等。非小细胞肺癌组织铂浓度与肿瘤反应。J Clin incol 2012; 30:3345-52。
  13. Stewart DJ,Chiritescu G,Dahrouge S等人。化疗剂量 - 非小细胞肺癌和隐含电阻机制的反应关系。癌症治疗Rev 2007; 33:101-37。
  14. Stewart Dj,Issa JP,Kurzrock R等人。Defitabine对肿瘤全球DNA甲基化和难治性固体肿瘤和淋巴瘤的I阶段试验中的其他参数。临床癌症res 2009; 15:3881-8。
  15. Kelly K,Chansky K,Gaspar Le等。III期维护吉非替尼试验或安慰剂在同时进行化学疗法和DocoTaxel合并后III阶段III阶段非小细胞肺癌:SWOG S0023。J Clin incol 2008; 26:2450-6。
Cite this article as:Kim ES, Stewart DJ, Khorana AA. Can EGFR mutation status evolve with chemotherapy? Chin Clin Oncol 2013;2(1):1. doi: 10.3978/j.issn.2304-3865.2012.11.09