我父亲肺鳞癌的治疗贴(2014年3月1日驾鹤西去）

老马 · 发表于 2012-8-12 00:51:50

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Clinical Cancer Researchclincancerres.aacrjournals.org
Published OnlineFirst February 8, 2012; doi: 10.1158/1078-0432.CCR-11-2511
Clin Cancer Res April 1, 2012 18; 1947
Frequency of Driver Mutations in Lung Adenocarcinoma from Female Never-Smokers Varies with Histologic Subtypes and Age at Diagnosis
Yang Zhang1,3, Yihua Sun1,3, Yunjian Pan1,3, Chenguang Li1,3, Lei Shen2,3, Yuan Li2,3, Xiaoyang Luo1,3, Ting Ye1,3, Rui Wang1,3, Haichuan Hu1,3, Hang Li1,3, Lei Wang1,3, William Pao4, and Haiquan Chen1,3
+ Author Affiliations

Authors' Affiliations: Departments of 1Thoracic Surgery and 2Pathology, Fudan University Shanghai Cancer Center; 3Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; and 4Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
Corresponding Author:
Haiquan Chen, Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai 200032, China. Phone: 86-21-6417-5590; Fax: 86-21-6268-6511; E-mail: hqchen1@yahoo.com; and William Pao, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232. Phone: 615-936-3524; Fax: 615-343-7602; E-mail: william.pao@vanderbilt.edu
Y. Zhang, Y. Sun, and Y. Pan contributed equally to this work and should be considered co-first authors.

Abstract
Purpose: Our previous study revealed that 90% [47 of 52; 95% confidence interval (CI), 0.79–0.96] of Chinese never-smokers with lung adenocarcinoma harbor known oncogenic driver mutations in just four genes EGFR, ALK, HER2, and KRAS. Here, we examined the status of known driver mutations specifically in female never-smokers with lung adenocarcinoma.

Experimental Design: Tumors were genotyped for mutations in EGFR, KRAS, ALK, HER2, and BRAF. Data on age, stage, tumor differentiation, histologic subtypes, and molecular alterations were recorded from 349 resected lung adenocarcinomas from female never-smokers. We further compared the clinicopathologic parameters according to mutational status of these genes.

Results: Two hundred and sixty-six (76.2%) tumors harbored EGFR mutations, 16 (4.6%) HER2 mutations, 15 (4.3%) EML4-ALK fusions, seven (2.0%) KRAS mutations, and two (0.6%) BRAF mutations. In univariate analysis, patients harboring EGFR mutations were significantly older (P < 0.001), whereas patients harboring HER2 mutations were significantly younger (P = 0.036). Higher prevalence of KRAS (P = 0.028) and HER2 (P = 0.021) mutations was found in invasive mucinous adenocarcinoma (IMA). The frequency of EGFR mutations was positively correlated with acinar predominant tumors (P = 0.002). Multivariate analysis revealed that older age at diagnosis (P = 0.013) and acinar predominant subtype (P = 0.005) were independent predictors of EGFR mutations. Independent predictors of HER2 mutations included younger age (P = 0.030) and IMA (P = 0.017). IMA (P = 0.006) and poor differentiation (P = 0.028) were independently associated with KRAS mutations.

Conclusions: The frequency of driver mutations in never-smoking female lung adenocarcinoma varies with histologic subtypes and age at diagnosis. These data have implications for both clinical trial design and therapeutic strategies. Clin Cancer Res; 18(7); 1947–53. ©2012 AACR.

老马 · 发表于 2012-8-12 01:02:21

Her2-Targeted Therapies in Non–Small Cell Lung Cancer
http://clincancerres.aacrjournals.org/content/12/14/4377s.full
Sensitivity to Her2-directed therapies is complex and involves the expression of not only Her2 but also other EGFR family members, their ligands, and molecules that influence pathway activity, such as insulin-like growth factor-1 receptor, PTEN, and p27. It is unclear whether agents targeting Her2 will prove successful in future clinical trials in a highly selected patient cohort, either with Her2 amplification or Her2 gene mutations. The frequency of Her2 mutations in NSCLC may be too low to justify a prospective clinical trial in this patient group. Nevertheless, the EGFR experience has taught us that responses can easily be diluted in an unselected cohort of patients.

Certainly, trials to date have been insufficiently powered to determine whether NSCLC patients with Her2 gene amplification (rather than overexpression by immunohistochemistry) benefit from Her2-targeted therapies. The frequency of Her2 amplification (2-23%) in NSCLC and the widespread availability of Her2 FISH analysis may justify a final study of trastuzumab monotherapy in this patient population.

The role played by Her2 as the obligate heterodimerization partner for the other EGFR family members renders Her2 an attractive target irrespective of receptor overexpression. Arguably, the most exciting Her2 approach will prove to be combinatorial approaches using an EGFR tyrosine kinase inhibitor together with Her2 dimerization inhibitors (e.g., pertuzumab).

Given the central part played by Her2 in receptor signaling, gene amplification witnessed in human malignancies, and the recent Her2 mutations documented in NSCLC, the failure of trastuzumab in clinical trials of NSCLC should not discourage further studies of these potentially important agents.

老马 · 发表于 2012-8-12 01:06:31

几种主要检测方法的比较— IHC、FISH、ELISA的区别？

a)IHC用特异的抗体检测HER2蛋白，其有以下特点：高敏、快速，在细胞或组织中精确定位过度表达蛋白，新鲜冰冻或石蜡包埋切片均能应用。优点：试剂应用较少，设备较简单。缺点是福尔马林固定或石蜡包埋切片可使HER2检出率降低。HER2抗原在福尔马林固定或石蜡包埋切片中抗降低，这和以下因素有关：组织固定的时间和自然状态、组织处理的方法、石蜡包埋的温度、保存时间（特别未染色切片）、检测的抗体。
b)FISH测定HER2基因的扩增已被用于乳腺癌的诊断，它有以下特征：高敏，通常采用福尔马林固定、石蜡包埋切片，固定、包埋切片中敏感性并不降低。但比IHC步骤复杂，需要一些较为特殊的设备，需要特异性和地高辛连接的HER2反义寡聚核苷酸，反义寡聚核苷酸和HER2结合存在于切片中，这可以通过针对于地高辛的免疫荧光素标记的抗体，用免疫荧光的方法测定。
c)ELISA能用于新鲜肿瘤组织或血清的HER2蛋白的测定，其结果可能和IHC及FISH测定有区别。ELISA法检测血清HER2蛋白的终点与IHC/FISH不同：ELISA检测脱落循环受体，而后两者检测扩增基因/细胞蛋白。血清中的HER2蛋白是细胞HER2蛋白100-110kD的细胞外区。

对于HER2状况作了IHC检测是否还要进行FISH检测？

a)IHC与FISH检测都可以比较准确的反映HER2状况，两者之间有较高的一致性。以百分比形式的IHC报告不能作为用药参考。罗氏提供的HER2检测手册中有检测标准流程和评分方法的详细介绍
b)IHC 3＋的患者与FISH＋的一致性达到89%，不同IHC 试剂检测的2＋的患者中有24%-53%的患者FISH＋，关键性临床试验数据显示赫赛汀对IHC 2+的患者仍然有效。
c)FISH检测从基因层面诊断HER2基因的扩增，可以更准确检测病人的HER2状况。目前国内也有1～2家中心可以进行此项检测复旦大学附属上海肿瘤医院病理科。

phpinfo · 发表于 2012-8-14 16:39:27

想问下，为啥要做胸部伽玛刀放疗呢？

老马 · 发表于 2012-8-14 17:20:50

本帖最后由老马于 2012-8-18 18:46 编辑

8月12日开始吃40mg原料量的2992.
8月14日住院，开始CIK+揽香烯治疗。

老马 · 发表于 2012-8-15 15:52:00

本帖最后由老马于 2012-8-15 23:28 编辑

星期一查了肿瘤指标和血生化（吃2992一粒后）：
cea 3.7,ca125 160，其它肿瘤指标正常。
白细胞3500（为什么这么低，有可能是用了一周的可乐必拓的关系），其它指标正常，肝，肾功能也正常。

老马 · 发表于 2012-8-15 23:28:10

一个新型pan-HER抑制剂HM781-36B在晚期实体肿瘤中应用的Ⅰ期临床试验

　　背景：HM781-36B是一个pan-HER酪氨酸酶抑制剂，对吉非替尼或厄洛替尼耐药性EGFR L858R/T790M双突变细胞有强烈的抑制作用。本Ⅰ期临床试验旨在确定HM781-36B的最大耐受剂量（MTD）、药代动力学和抗肿瘤活性。

　　方法：符合入组条件的患者为标准治疗无效的晚期恶性肿瘤患者。在剂量递增研究采用标准3+3模式，额外12例患者被纳入分子富集（molecular enrichment）的扩展队列。

　　结果：在剂量递增研究中，43例患者[中位年龄：55（25～82）岁，男性/女性：25/18例，ECOG PS 0/1/2/3：23/17/2/1例，中位既往化疗次数：4次]接受治疗。剂量限制性毒性（DLT）状况为5例3级腹泻，给药12 mg、16 mg、24 mg各出现1例，给药32 mg时有2例患者出现3级腹泻。MTD为24mg。最常见的药物相关不良事件为腹泻、口腔炎、皮疹、瘙痒和厌食。在41例可评估患者中，4例患者得到部分缓解（PR，1例未最后确认，缓解持续时间为11.9个月），19例患者疾病稳定（SD）。4例PR患者中，2例是Her2阳性乳腺癌患者。PR或SD患者中位治疗持续时间是3.87 （2.47～15.17）个月。在给药范围为0.5～24 mg，HM781-36B表现出与剂量递增成比例的线性药代动力学、半衰期较短和几乎无蓄积的特征。扩展队列中的额外12例患者接受24mg的治疗（6例EGFR 突变非小细胞肺癌，3例Her2阳性胃癌，2例Her2阳性乳腺癌，1例直肠癌）。

　　结论：HM781-36B在晚期实体瘤中应用安全且耐受性好。研究已经观察到HM781-36B抗肿瘤活性的初步证据。