T790M突变和cMet扩增

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2014-1-6 12:21 上传

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19楼论文摘要翻译

Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib – implications for clinical trial design

在具有EGFR突变的肺癌患者对厄洛替尼和吉非替尼耐药之后中断使用TKI造成的爆发性进展对临床研究设计的影响

Jamie E. Chaft, Geoffrey R. Oxnard, Camelia S. Sima, Mark G. Kris, Vincent A. Miller, and Gregory J. Riely

Abstract

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Purpose: Treatment of patients with oncogene-addicted cancers with tyrosine kinase inhibitors (TKI) is biologically and clinically different than with cytotoxic chemotherapy. We have observed that some patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib (RECIST progression after initial benefit) have accelerated progression of disease after discontinuation of TKI. To examine this observation and define the course of patients following TKI discontinuation, we systematically evaluated patients enrolled on clinical trials of agents to treat acquired resistance to erlotinib or gefitinib.
目的：对于癌基因驱动的肿瘤患者，采用的TKI治疗与细胞毒性药物化疗具有生物学和临床上的区别。我们已经观察到在那些具有EGFR突变的肺癌患者中，在对厄洛替尼或者吉非替尼获得性耐药之后(初始获益后RECIST评价进展)，中断TKI治疗会加速疾病的进展。为了检验我们的观察和确定那些中断TKI治疗的患者，我们系统地评估了入组针对厄洛替尼或吉非替尼耐药的临床实验的患者。

Methods: We evaluated patients with EGFR-mutant lung cancer who participated in trials for patients with acquired resistance which mandated TKI discontinuation prior to administration of study therapy. Disease flare was defined as hospitalization or death attributable to disease progression during the “washout” period.
方法：我们评估了那些具有EGFR突变的肺癌且自愿入组针对耐药的临床实验的患者，他们被要求在开始接受治疗前要强制中断TKI的使用。爆发性进展被定义为在洗脱期(washout period)，由于疾病的进展导致的住院治疗或者死亡。

Results: Fourteen of 61 patients (23%; 95% CI 14-35%) experienced a disease flare. The median time to disease flare after TKI discontinuation was 8 days (range 3-21). Factors associated with disease flare included shorter time to progression on initial TKI (p=0.002) and the presence of pleural (p=0.03) or CNS disease (p=0.01). There was no association between disease flare and the presence of T790M at the time of acquired resistance.
结果：有23%(14/61)的患者出现了爆发性进展。在中断TKI治疗后到爆发性进展的中位时间为8天(3天-21天)。与爆发性进展相关的因子包括较短的从初始TKI治疗到进展的时间以及胸腔(p=0.03)或者中枢神经疾病(p=0.01)(这里应该是指胸膜转移和脑转移)的出现。在获得性耐药时T790M的出现与否与爆发性进展没有相关性。

Conclusion: In patients with EGFR-mutant lung cancer and acquired resistance to EGFR TKIs, discontinuation of erlotinib or gefitinib prior to initiation of study treatment is associated with a clinically significant risk of accelerated disease progression. Clinical trials in this patient population must minimize protocol mandated washout periods.
结论：在具有EGFR突变且对EGFR TKIs耐药的患者中，在开始接受临床试验的治疗之前中断厄洛替尼和吉非替尼的使用与临床上疾病加速进展的风险相关。在这部分患者群体中的临床实验必须最小化计划中的强制洗脱期。

nihms-509400.pdf (425.09 KB, 下载次数: 152)

2014-1-6 13:01 上传

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TBD

20楼评述翻译

Analyzing Disease Flares: Impact of Discontinuing Targeted Therapy Unclear
对爆发性进展的分析：不清楚中断靶向治疗的影响

Maurie Markman, MD
Published Online: Wednesday, March 21, 2012

The concept that patients with cancer may experience relatively rapid progression of their disease process following the withdrawal of a particular antineoplastic agent is certainly not a new concept.1 Although it is always difficult to distinguish what may legitimately be considered disease flare from the more likely scenario of the events simply representing the natural history of the malignancy, reports of such experiences after the discontinuation of hormonal therapeutic strategies have been well documented. More recently, disconcerting events have been described following the stopping of bevacizumab treatment in patients with malignant brain tumors.
癌症患者在停止一种特定的抗肿瘤药物之后可能出现疾病的快速进展已经不是一种新的概念了。虽然很难从那些更可能体现了恶性肿瘤自然病程的事件场景中合理地区分出什么是爆发性进展，但在停止激素治疗之后所表现出的类似状况的报告已经被充分地记录在册了。最近，（有文献）描述了在对恶性颅内肿瘤患者停止贝伐单抗的治疗后出现的令人不安的事件。

In the case of targeted antineoplastic drug therapy, a very solid theoretical rationale can be advanced to explain how discontinuation of therapy, either because of excessive toxicity or the documented failure of the regimen to favorably impact the course of the disease, might quite realistically result in far more rapid progression of the malignant process than predicted by observations of the cancer’s natural history in an individual patient.
在靶向抗肿瘤药物治疗的情况下，一个非常坚实的理论根据能够解释如何来停止治疗，由于过度的毒性或是已被证明失败的疗程，都会影响疾病的进程，实际上这可能极大地导致了很多肿瘤进程的快速进展，超过了由在患者个体中所观察到的癌症的自然病程所得到的预期。

It has long been appreciated that the secretion of greater local and circulating concentrations of growth factors that can overcome the inhibitory effects of a particular antineoplastic agent is one prominent mechanism of cancer resistance. Assuming that a targeted therapy has been effective in blocking access of an essential growth factor to a clinically relevant target, release of that blockade (following withdrawal of the therapy) may expose these active receptors to a local environment composed of far greater concentrations of the growth stimulatory substances.
（我们）已经充分认识到，生长因子在局部和循环浓度中更大量的分泌能够克服一种特定抗肿瘤药物的抑制效果，这是一种癌症耐药的显著的机制。假定靶向治疗有效的阻断了必要的生长因子到临床相关靶点的通路，撤出封锁(停止治疗)可能使这些活跃的受体暴露于由更高浓度的生长刺激物质所组成的局部环境中。

As a result, while disease progression may have unequivocally already occurred in a relatively small proportion of the malignant cells, it is theoretically reasonable to propose that the subsequent complete release from receptor blockage (due to discontinuation of the targeted antineoplastic) will result in acceleration of biological activity in a much larger percentage of the malignant cell population.
结果就是，一部分相对数量较少的肿瘤细胞可能已经明确产生了疾病的进展，（因此）从理论上能够合理地得出：随后完全释放对受体的阻断（因为中止了靶向抗肿瘤药物的治疗）将会导致在更大比例的肿瘤细胞群中产生加速的生理活性。

To address this clinically relevant question in the setting of treatment with tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR), investigators retrospectively examined the outcome of a group of patients who developed resistance to either gefitinib or erlotinib and were subsequently scheduled to participate in trials exploring novel strategies to overcome such resistance.3 As a component of the study designs, a prospectively defined “washout” period was included in which patients had the tyrosine kinase inhibitor discontinued before the new treatment was initiated. In this experience, disease flare, defined as death or required hospitalization prior to the initiation of the new therapy, was observed in 14 of 61 patients (23%). The median time to this event was only 8 days (range, 3-21 days), with the observed onset of significant symptoms, rapid increases in the extent of cancer, and short survival.
为了解决在采用EGFR TKI治疗情况下的这个临床相关的问题，研究者回顾性地检视了来自于一组对吉非替尼或厄洛替尼耐药的患者的研究结果，这些患者在耐药之后随即被安排加入新的克服耐药策略的临床试验中。作为研究设计的一个组成部分，一个预先定义的“洗脱期”被计为从患者停止使用TKI之后到开始接受新治疗之前的一段时间。在这个临床中，爆发性进展被定义为在接受新治疗之前患者的死亡或者需要住院接受治疗，这在61位患者中的14位中观察到了(23%)。至该事件出现的中位时间仅为8天(范围，3至21天)，以及观察到的带有显著症状的发病、肿瘤范围快速的增长、和缩短的生存时间。

While this single report cannot be considered definitive with regard either to defining the percentage of patients at risk or to the magnitude of symptomatic progression if disease flare occurs, the experience strongly suggests that lung cancer patients who are receiving EGFR tyrosine kinase inhibitors require careful monitoring if such therapy is discontinued secondary to disease progression, unacceptable toxicity, or patient choice.
该份单独的报告未能明确地定义处于危险中的患者的比例，也未能确定当爆发性进展时出现的症状的严重程度，其强烈建议接受EGFR TKI的肺癌患者当由于出现继发性疾病进展、不可耐受的毒性或者患者意愿而停止用药时，需要仔细地监控病情。

Finally, it will be important for the clinical oncology research community to continue to investigate the issue of disease flare in this setting as targeted antineoplastic therapy becomes an integral component of care in an increasing number of clinical settings.
最后，这对于临床肿瘤研究团体调查爆发性进展的问题来说是重要的，特别是在靶向抗肿瘤治疗已经成为增多的临床场景的一部分时。

这篇评述仍然在说明停止TKI后出现爆发性进展的一些相关信息，所谈到的内容之前都有涉及，这里就不用多说了

从心底感谢老马和Costa的专业介绍, 让我们有机会来了解抗癌的最新领域和最新成果. 我已特耐药,正担心停止用药时爆发性进展,以及如何后续. 现在可以好好学习了.

costa_na 发表于 2014-1-7 13:36
20楼评述翻译

Analyzing Disease Flares: Impact of Discontinuing Targeted Therapy Unclear

好多的英文，请问版主如果是cmet突变易特无效克有效但已经耐药再回来吃易，特可能有效吗？因为是忙试，只能通过克有效ap无效猜测是cmet。

期待更新，解开癌症面纱！

几点想法, 希望能得到老马,Cost, 憨老和众高手的光顾讨论.
•        暴发组中位数服药9个月，无暴发组中位数服药15个月。 一般讲服药期长的更易产生高浓度的生长刺激物质。是否是样本数较小的缘故?
•        “生长因子在局部和循环浓度中更大量的分泌能够克服一种特定抗肿瘤药物的抑制效果，这是一种癌症耐药的显著的机制。” 若是这样, 从EGFR药 换成VEGF药也难避免暴发。
•        因此, 像从特换成阿西, 可能特要逐渐减量。
•        23%不算少。30%的不明耐药机制中, 高浓度会是其中一主要机制?
•        憨老的换药大法着眼于基因引起的耐药机制。若1-3个月不会引起高浓度,  频繁换药会更安全?
•        易中断未出现暴发, 是否特中断也没事?

问题：病人21突变，如果易特耐药，T790药物无效，是否首先考虑存在MWT扩增，或可能是同时存在T790突点和MET扩增，使用列如184等MET靶点的药物后，可否再试T790靶点？肯请老马等高手指点！

老马哥好，met扩增吃易或特都会无效，met++是高表达扩增的几率是不是很大，以前做基因检测的组织还有，是不是吃药之前也应该先把T790检测一下，有没有可能第一次靶向药的时候同时存在EGFR+MET扩增+t790突变，导致第一次吃易或特就无效，麻烦马哥看看我的帖子给个建议是不是再做个别的检测http://www.yuaigongwu.com/forum. ... id=15923&extra=

受益匪浅，学习了，谢谢，马叔辛苦了。