本帖最后由 等待一场奇迹 于 2014-5-23 09:13 编辑
Three patients underwent multiple repeat biopsies over the course of their disease (Fig. 5). The first patient (Fig. 5A) had adenocarcinoma that harbored the L858R EGFR mutation and a mutation in the tumor suppressor TP53. As expected, this patient experienced a substantial initial response to erlotinib lasting 8 months, at which time a lung core biopsy revealed adenocarcinoma with the same L858R and p53 mutations, as well as an acquired T790M EGFR mutation. After a 10-month interval without any EGFR TKI exposure, a second repeat biopsy performed on the same lung lesion as the first repeat biopsy revealed that the T790M mutation could no longer be detected. The patient subsequently responded to treatment in a clinical trial of erlotinib plus an investigational agent that does not target T790M. A second patient with an exon 19 deletion had a similar clinical course involving gain and loss of the T790M mutation in multiple biopsies from the same anatomical location during periods of erlotinib and chemotherapy treatment, respectively.
The lung core biopsy from the drug-resistant tumor of a third patient (Fig. 5B) demonstrated SCLC with the original EGFR L858R mutation plus an acquired PIK3CA mutation (Table 2). This patient was treated with chemotherapy and radiation for SCLC and her cancer went into a partial remission. After a 7-month interval without any erlotinib exposure, she developed a symptomatic pleural effusion and a thoracentesis revealed adenocarcinoma (negative for neuroendocrine markers) with the L858R EGFR mutation only; the PIK3CA mutation was not detectable. Erlotinib was readministered with a second clinical response. When this patient developed resistance once again, a soft tissue metastasis originating from bone revealed SCLC with the EGFR L858R and the PIK3CA mutation. In total, these findings provide a molecular link to the clinical observation that patients with EGFR-mutant NSCLC tumors will often respond to erlotinib after a TKI-free interval (10, 11). Without the continued selective pressure of the TKI, the genetic resistance mechanisms and potentially the phenotypic resistance mechanisms are lost.
这段话非常有趣， 他们研究了3个基因突变的病人，第一个在接受了8个月的特罗凯治疗后耐药（应该还是刚开始耐药），中断了EGFR抑制剂的治疗10个月之后（看图片显示应该是做了化疗），第二次活检发现T790已经检测不到了。这个病人随后吃特罗凯和另外一种在研发的不针对T790的药物有效。第二个病人有19突变，也出现了相似的情况。第三个病人转到了小细胞，并同时保持21点突变以及PIK3CA 突变，他接受7个月的放化疗之后病情得到缓解，之后只检测到了21突变，连PIK3CA也检测不到了。他继续吃特，当再次产生抗药性之后，活检发现他再次有小细胞，21突变以及PIK3CA突变。但是看表格，我看他们第二次有效时间也没有很长，我估摸大概4个月左右，想必再接下去效力会越来越弱。
这个跟论坛上说的只有19突变,T790才会通过不继续摄入EGFR抑制剂而消失的说法相悖。当然这只有2个21突变的例子，或许他们足够幸运。但是至少说明这种情况是存在的。有人可以通过E-化疗-E－化疗这种方式来保持对EGFR靶点的敏感。但就像你说的，他只阐明了结果，没说明理由。
这个试验让我感慨，癌症确实需要个性化治疗，如果哪天能够像这个实验一样可以随时检测到基因的变化，我们抗癌的路上就会少很多障碍。
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