晚期NSCLC靶向和化疗方案选择的几个问题

Biomarkers Discovered That May Help Predict Response to Drugs Targeting KRAS-mutated NSCLC
April 7, 2013

http://www.aacr.org/home/public- ... he-news.aspx?d=3060

Effective targeted treatments for NSCLC with KRAS mutations are lacking.
MEK/PI3-kinase inhibitor combination is a promising treatment for this type of cancer.
Use of biomarkers could help guide treatment decisions.
WASHINGTON, D.C. — Scientists have identified biomarkers that may help predict whether patients with KRAS-mutated non-small cell lung cancer (NSCLC) will respond to concurrent treatment with an MEK inhibitor and a PI3 kinase inhibitor, a drug combination currently being investigated in ongoing clinical trials. The discovery was made as part of a study presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10, by Aaron N. Hata, M.D., Ph.D., a clinical fellow at the Massachusetts General Hospital in Boston.

Although several targeted therapies have been developed for patients with NSCLC, there are currently no proven targeted treatments for patients with NSCLC that harbors a KRAS mutation, which accounts for 20 percent to 25 percent of all NSCLC cases.

“Treatment with an MEK inhibitor and PI3 kinase inhibitor is a combination targeted therapy that may be effective for some patients with KRAS-mutant NSCLC, but it is not likely to be effective for all patients with this form of cancer,” said Hata. “We want to be able to know which patients are going to respond to this combination therapy so that we can identify them and tailor their treatment accordingly.”

To explore response to MEK and PI3 kinase inhibitors, Hata and colleagues studied a variety of NSCLC cell lines that all had mutated KRAS. They found that some of the cancer cell lines responded to the drug combination by undergoing a process of cell death called apoptosis, whereas others did not.

“Our results were not surprising from the standpoint that induction of cell death is known to be important for response of cancer cells to therapy,” Hata said. “What was surprising was the difference in apoptosis among the cell lines.”

Specifically, lack of a cell death response to the combination of MEK and PI3 kinase inhibitors correlated with the decreased expression of pro-cell death mediators and the upregulation of anti-cell death regulators.

“We found that three specific proteins predicted response,” Hata said. “Two of them, the BIM and PUMA proteins, induced cell death, and the third, the BCL-XL protein, inhibited cell death.”

In addition, prior research has shown that many KRAS-mutant lung cancers also have a mutation in the TP53 gene, and the protein that it generates, P53, is known to be involved in the cell death process. In this study, the researchers found that TP53 mutation status did not predict response to the MEK/PI3 kinase inhibitor combination, but it did affect how the cells underwent cell death.

“Our research so far has focused on human cancer cell lines,” Hata said. “We do not yet know if these correlations will hold true in patients.”

Ideally, Hata and his colleagues would like to determine whether the proteins they identified are predictive of patient response to MEK/PI3 kinase inhibitors in the clinic.

“The ultimate goal would be having the ability to measure levels of these proteins in patients before they go on treatment,” Hata said. “If they have favorable levels, that would tell us they are likely to respond to this treatment, and if they do not, it would be better to select a different treatment.”

第一代EGFR抑制剂的耐药情况
（1）EGFR Tyrosine Kinase Inhibitors in Lung Cancer: Clinical Implications of Mutations and Treatment Resistance
http://www.targetedhc.com/public ... reatment-Resistance
（2） Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132801/
NIHMS298935-supplement-Supplementary_Data.pdf (209.21 KB, 下载次数: 1279)

2013-5-27 00:22 上传

点击文件名下载附件

LOSS OF AMPLIFIED EGFR GENE WITH MUTATION AS A NOVEL MECHANISM OF ACQUIRED RESISTANCE TO EGFR-TKIS IN EGFR MUTATED NSCLC CELLS
http://oncologypro.esmo.org/meet ... th-mutati-1019.aspx
Background
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show notable effects for non-small cell lung cancers (NSCLC) harboring EGFR activating mutations. However, almost all patients eventually acquire resistance to EGFR-TKIs within several years. The major mechanisms of acquired resistance including 2nd mutation of T790M and amplification of MET have been identified. However, the mechanisms of other resistance remain unclear. In this study, we established novel erlotinib-resistant NSCLC cells and examined their resistant mechanisms.

Methods
NSCLC HCC827 cells have an EGFR Exon 19 deletion and gene amplification and are highly sensitive to erlotinib. The resistant cells were established by continuously exposing HCC827 cells to 0.1, 1 or 10 uM of erlotinib in 96 well plates for three months. The resistant mechanisms were determined by direct sequence analysis and EGFR FISH analysis.

Results
The fourteen and three resistant cells were established by 0.1 uM and 1uM of erlotinib exposure, respectively. No resistant cells appeared in the wells of 10 uM of erlotinib. The IC50 values of these resistant cells were more than 25-fold higher than that of parental cells. No 2nd mutation of T790M was detected in any of the resistant cells and MET gene amplification was detected in only one resistant cells. Instead, we found that 13/17 resistant cells were dominated by EGFR not amplified cells and one of resistant cells B10 consisted of more than 99.9% of EGFR not amplified cells, and that the parental cells consisted of only 2.5% of EGFR not amplified cells and 97.5% of EGFR amplified cells. EGFR not amplified clone 4D8 isolated from parental cells and showed resistance to erlotinib comparable to the resistant cells B10. Furthermore, we found that EGFR not amplified cells were constantly emerged from EGFR amplified clone isolated from parental cells under normal cell culture condition.

Conclusion
Loss of amplified EGFR gene with mutation causes acquired resistance in HCC827 cells when exposed to relatively low concentration of erlotinib while high concentration of erlotinib deprives HCC827 cells of the chance of emergence of resistant cells.

RET Fusions in NSCLC
Surgical series of 936 patients examined by PCR (with IHC and FISH validation)
13 cases found (1.4%)
     - 11 adenos, 2 adenosquamous
     - 7 women, 6 men
     - 9 KIF5B-RET, 3 CCDC6-RET, 1 NCOA4-RET
     - More often poorly differentiated（低分化）, young (<60 yrs), never smokers (82%), solid subtype


Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas.
http://www.ncbi.nlm.nih.gov/pubmed/23533264
Abstract
The discovery of RET fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes. In an unselected population of non-small cell lung carcinomas (NSCLCs), RET fusions are present in 1% to 2% of cases. This incidence increases substantially, however, in never-smokers with lung adenocarcinomas that lack other known driver oncogenes. Although preclinical data provide experimental support for the use of RET inhibitors in the treatment of RET fusion-positive tumors, clinical data on response are lacking. We report preliminary data for the first three patients treated with the RET inhibitor cabozantinib on a prospective phase II trial for patients with RET fusion-positive NSCLCs (NCT01639508). Confirmed partial responses were observed in 2 patients, including one harboring a novel TRIM33-RET fusion. A third patient with a KIF5B-RET fusion has had prolonged stable disease approaching 8 months (31 weeks). All three patients remain progression-free on treatment.

JCO：复旦大学陈海泉等研究表明RET融合基因对NSCLC患者具有临床意义

近来发现，RET融合基因存在于部分非小细胞肺癌亚群中(NSCLC)。由于对此类肿瘤认识较为有限，因此上海复旦大学癌症中心的王瑞博士与陈海泉博士等人对此进行了一项研究，他们对存在RET融合基因NSCLC患者的临床病理学特征进行了确定。该文发表于2012年11月13日在线出版的《临床肿瘤学杂志》(Journal ofClinical Oncology)上。

研究人员通过逆转录聚合酶链式反应(PCR)结合实时定量PCR策略，共对936例通过手术切除治疗的NSCLC患者的RET融合基因情况进行了检测，通过免疫组织化学以及原位荧光杂交分析，对结果进行了验证。同时对633例肺腺癌患者的EGFR、KRAS、HER2、 BRAF基因突变情况以及ALK基因重排情况进行了研究。此外研究人员还收集了患者特征，包括年龄、性别、吸烟史、肿瘤分期、级别、国际肺癌研究协会/美国胸科学会/欧洲呼吸学会对肺腺癌亚型的分类、以及无复发存活期等信息。

研究人员发现，在936例NSCLC患者中，有13例患者(633例腺癌患者中有11例，24腺鳞状细胞癌患者中有2例)完全检测到RET融合基因存在。在这13例患者中，有9例患者为KIF5B-RET，3例患者为CCDC6-RET，1例患者为新发现的NCOA4-RET融合基因。存在RET融合基因的肺腺癌患者，其肿瘤分化情况较差(63.6%，对于 RET v ALK，P = .029;对于RET v EGFR， P = .007)，患者年龄偏低(≤ 60岁; 72.7%)，非吸烟者(81.8%)多发，并且患者多见实体亚型(63.6%)、瘤体较小(≤ 3 cm)、以及N2病情(54.4%)。患者平均无复发存活期为20.9个月。

王瑞博士等人认为，RET融合基因存在于1.4%的 NSCLC患者以及1.7%的肺腺癌患者中，并且该基因具有可识别的临床病理特征，因此，可考虑进一步将RET融合基因用于临床应用，并对其进行靶向治疗研究。
丁香园：纳入这项研究的患者大部分来自中国，那么东亚人群与高加索人群的RET融合基因的分布是否存在差别？

陈海泉教授：中国人群和Pasi A. Janne等人在高加索人群研究相比，RET融合基因的发病率非常相近（2%左右），同样主要分布在不吸烟，小肿块肺腺癌患者中。但Pasi A. Janne等人未对西方人群携带RET融合基因患者其它临床病理特征进行分析，故需要进一步研究加以证实。

丁香园：论文中提到，存在RET融合基因的肺腺癌患者，其肿瘤分化程度较低，那么不同的RET融合类型对肿瘤分化程度是否有影响？

陈海泉教授：我们发现RET融合基因有三种融合类型，KIF5B-RET，CCDC6-RET和NCOA4-RET，前两种肿瘤分化程度都很低，之间无显著差别。最后一种因为只发现存在于一例患者，例数太少不能评价与前两种是否一致。

丁香园：目前有哪些靶向药物可用于携带RET融合基因的NSCLC患者？这项研究结果对临床应用以及肺癌的靶向治疗有何指导意义？

陈海泉教授：目前发现Vandetanib,Sorafenib和Sunitinib三种靶向药物能抑制RET在内的多种受体酪氨酸激酶的活性，杀伤携带RET融合基因的细胞。我们研究不仅发现携带RET融合基因患者主要特征为年纪较轻（≤60岁），不吸烟，病理类型为实体亚型及小肿块却出现纵隔淋巴结转移，而且提出了一种快速准确检测融合基因的方法，这为临床上筛选携带RET融合基因患者，推动以RET为靶点的酪氨酸激酶抑制剂进入治疗RET阳性的非小细胞肺癌临床试验提供了依据。

马哥辛苦了，是不是靶向、化疗也对kras突变有影响呀。妈妈易瑞沙耐药（十一个月）后，用血浆重新检测egfr、kras都由突变变成野生，不过您也说过血浆内癌细胞浓度不高，检测可能不准。但是妈妈易耐药后化疗效果确实都不好，重上靶向药的效果也不太理想。

老马 发表于 2013-4-24 19:37

                               
登录/注册后可看大图

５化疗对EGFR突变状态有没有影响？

一项临床实验，在有效缓解的病人当中，68.3%保持不变，25.6%从突变转 ...

这段没看懂。
说的是，化疗有效的病人中，68.3%突变保持不变，25.6%突变成野生？
突变到野生是不是等于EGFR的TKI没用了？

hsgoh 发表于 2013-4-24 21:51

                               
登录/注册后可看大图

请问，如果说特耐药，是T790M突变的话，那对其他有打egfr 的药会不会也交叉耐药？比如2992，凡德等等？我的 ...

我的理解是会无效啊。所以感觉只有EGFR突变的人很苦啊，一个靶点吃来吃去，想替换都不行。

老马 发表于 2013-4-24 19:37

                               
登录/注册后可看大图

５化疗对EGFR突变状态有没有影响？

一项临床实验，在有效缓解的病人当中，68.3%保持不变，25.6%从突变转 ...

       可不可以这么认为，化疗可以改变基因，从野生到突变或突变到野生，从无靶点到有靶点或靶点消失。哪我们原生的癌是什么样的？还是各种都有，因人而异。我得病最初没有做基因检查，培美加卡铂化疗两期无效后做的，EGFR和KRAS均未突变，我刚开始还以为未突变更好治呢，没想到倒是野生的更让人头疼。这医学用词好像和我们的常识有点拧。
       选靶向还是化疗，是不是第一时间应该有基因检测做参考？

老马，可不可以认为说易，特２９９２，均无效的话，上阿瓦阿帕阿西等着有效性比较大？老马，我不明白为什么我爸爸２１突变上正版易两个月无效，CEA上升，CT进展，后用健择四疗程稳定，健择四疗程时开始出现咳嗽气喘，3月31日开始上2992，服用一周左右咳嗽气喘缓解。但是13天左右出现在后背酸痛和左肋骨疼痛。服15天时去查CEA时上升(之前28.53，15天后36.45)这几天爸爸疼痛越来越频繁，考虑到爸爸有多发性胃溃疡不敢给他联合184。可是疼痛越来越不耐受，23号CT再次进展。医生逮建设继续化疗，用培美加恩度或者培美加阿瓦，考虑到爸爸经常窦性心动过速，恩度对心脏影响也大，所以选择了培美十阿瓦！知道可行不。或者如两期化疗后能有效控制的话还有什么靶向药可服用？麻烦老马或平安姐给予指教！谢谢。