今天大姐陪同父母去乌镇玩了，好久没出门啦。:)
非小细胞肺癌中的PTEN突变及其与EGFR、ERBB2、KRAS和TP53突变的关系
PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers
作者：Jin G, Kim MJ, Jeon H-S, Choi JE, Kim DS, Lee EB,
期刊： 《LUNG CANCER》2010年9月3期69卷
Somatic mutations of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in non-small cell lung cancers (NSCLCs) have been investigated in but a small number of cases. In addition, the relationship between PTEN mutations and epidermal growth factor receptor (EGFR), KRAS, and TP53 mutations has not been investigated. Therefore, we investigated the frequency of PTEN mutations in 176 surgically resected NSCLCs and analyzed the relationship between PTEN mutations and EGFR, ERBB2, KRAS, and TP53 mutations. Mutations of PTEN (exons 1-9), EGFR (exons 18-21), ERBB2 (exons 19 and 20), KRAS (exon 1), and TP53 (exons 2-11) were determined by polymerase chain reaction and direct sequencing. PTEN mutations were present in 8 (4.5%) of the 176 tumors. PTEN mutations were only found in ever-smokers and were significantly more frequent in squamous cell carcinoma than in adenocarcinoma (10.2% vs 1.7%, P= 0.02). Mutations of EGFR, ERBB2, KRAS, and TP53 genes were found in 36 (20.5%), 2 (1.1%), 11 (6.3%), and 66 (37.5%) cases, respectively. Of the 8 tumors with PTEN mutations, 1 case concurrently had an EGFR mutation and 4 cases had TP53 mutations. However, PTEN mutations were not found in the tumors with KRAS mutation. Our findings indicate that PTEN mutations are relatively common in NSCLC, and thus analysis of PTEN mutations may facilitate a comprehensive understanding of the genetic alterations related to the EGFR signaling pathway.
PTEN 突变后其下游分子AKT 和mTOR 通路处于持续活化状态使乳腺癌内分泌治疗（针对ER）、赫赛汀（针对HER2）耐药，而使用依维莫司可以克服。
那么是否可以推论，PTEN突变概率高的肺鳞癌使用依维莫司会有疗效？
老马 发表于 2012-11-12 22:22 static/image/common/back.gif
今天大姐陪同父母去乌镇玩了，好久没出门啦。
能出去游玩是 最好的，祝福。
马帅哥你好！我哥哥今年47岁，2012年5月初发现非小细胞鳞癌，右肺4.4 公分伴有左肩骨转，5月12日用了一次健泽见顺铂化疗，骨髓抑制4级，5月底检查ct肿瘤长到5.5X3.7公分，医生说化疗效果不好，建议吃特罗凯，吃特3个月，每月查CT肿瘤略增大，9月底吃特第4个月复查肿瘤长到5.5X5.5公分，马上换成多西他赛加顺铂化疗2次，11月14日复查评估化疗效果，多西无效，进展迅速右肺肿瘤长到8.7X6.5公分，两肺见散在结节，胸腔积液，心包积液。本来以为我哥哥以前没用多西化疗过，化疗会有好的的效果，提前准备了2992，打算化疗控制后用各种靶向药轮换着吃，现在不知道怎么办了？为什么一个多月时间病情进展的这么快？拿到这结果我们全家人伤心的哭成一团。。。。请教马哥我哥哥现在下一步怎么治疗？谢谢您了！期待你的回复！
Tarceva's only been commercially available since late 2004, so there are just not many patients who have had the opportunity to be on it for more than 3 years. That said, I've treated or seen for second opinions a lot of patients who have responded for 6 or 12 or 18 months and then become resistant (either with slow or more convincing progression after that). I don't think we have any good data on the proportion still responding after 2 or 3 years, but I would estimate it to be a small proportion, perhaps 10% at 2 years and single digits by three years. There are certainly some patients out there who are still responding more than three years out from starting it, but it's not as many as we'd like.
One thing I wonder about, in the patients like your wife who respond so well for so long, is whether we should consider giving tarceva intermittently in order to potentially prolong the time that their cancer remains sensitive to tarceva. This is based on a presumption that cancer will develop a resistance within months or years in almost all cases, so perhaps we might have a patient come on and off of tarceva to reduce the "evolutionary pressure" for the cancer to develop that resistance. We do this with hormone therapies for prostate cancer in some cases, but it's not an approach that finds its way into lung cancer routinely. We don't have any evidence to support it, but it's something I and some members on the site have thought about.
http://onctalk.com/bbPress/topic.php?id=245
fiesta:
I am also interested in learning more about possible intermittent use of Tarceva. My father has been taking 150 mg Tarceva as a first-line treatment for two months now, and his recent CT scan showed some shrinkage of his primary tumor. Since he does not want to do chemotherapy, his treatment options are very limited. With this in mind, he may be willing to experiment with his Tarceva treatment.
How soon would it be appropriate to initiate intermittent use of Tarceva? If he did try intermittent use, how many weeks on/how many weeks off would he take it?
Could lowering the dose from 150 to 100 mg also delay the development of resistance (assuming the 100 mg dose was sufficient to keep the disease stable)? This doesn't seem like it would help as much since the cancer would still be continuously exposed to the drug, although the concentration would be lower.
Dr. West:
Full disclosure: This is an idea that has never been tested, and I don't know if it has even been done before casually with an individual patient. I just consider it to be a reasonable idea with a compelling rationale. Giving guidelines might suggest that I know how this situation should be managed, but nobody has ever officially recommended or studied this idea yet.
If I did pursue such a plan, it would need to be with a well-informed person who understands what we know and what we still don't know. I would be inclined to treat the patient to maximal response and then likely hold treatment but monitor the patient VERY closely (likely recommending to see the patient back in clinic within weeks, and repeating a scan after just a month), as I have heard of cases where there can be a rapid rebound of progression within just weeks after stopping EGFR inhibitors. I would not imagine that treating someone on a lower dose would have the same rationale of reducing the risk of developing resistance, as you indicated. And i would be inclined to restart tarceva as soon as a patient demonstrated clear, clinically meaningful progression, but I can't define exactly what that would be for a particular patient.
prem:
I have been on Iressa, then Tarceva and Zometa since 10/04 with good results. CEA has been been moving up from 2 to 10 over the last 8 months and the last bonescan (02/07) reported progression. I still feel healthy, am sticking with Tarceva and Zometa, but am looking at options to extend the effectiveness of Tarceva. Intermittent usage of Tarceva sounds like a creative option to consider.
Dr. West:
I am reluctant to stop a well-tolerated therapy for a patient based on very subtle findings suggestive but not extremely convincing for progression, such as rising tumor markers and/or more prominent asymptomatic bone lesions.There is increasing evidence to suggest that the alternatives for such patients may be very slow, ongoing asymptomatic progression on that treatment, or faster progression if the plan is changed and that therapy is withdrawn.I tend to be hesitant to discard treatments that may have value in prolonging survival, and I believe that very slow progression with a well-tolerated treatment can still prolong survival.
间歇疗法外国也有人尝试。
请问如果特无效（不是耐药）可以上2992吗？