Cortinovis D L, Andriani F, Livio A, Fabbri A, Perrone F, Marcomini B, Pilotti S, Mariani L, Bidoli P, Bajetta E, Roz L, Sozzi G
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Curr Cancer Drug Targets. 2008 Aug;8(5):342-8. doi: 10.2174/156800908785133204.
Inactivation of the FHIT and TP53 genes is frequently observed in primary non-small cell lung cancers (NSCLC) and cell lines and may contribute to resistance to apoptotic stimuli elicited by various anti-tumor drugs. To evaluate a possible relationship between FHIT and TP53 status and response to platinum-analogue regimens, we retrospectively selected 55 NSCLC patients treated with carboplatin/gemcitabine. Pre-treatment formalin fixed biopsies were analyzed for FHIT and p53 protein expression by immunohistochemistry and representative micro dissected tissue for TP53 mutations by DG-DGGE/sequencing. The FHIT-negative immunophenotype (FHIT-, pathologic) was found in 33 patients (60%) and p53 over expression/mutation (p53+, pathologic) in 25 patients (45%). The FHIT-/p53+ combination was present in 12 patients (22%). Overall, there was partial response in 21 patients (38%), with subgroup response rates of 33% in FHIT+/p53-, 46% in FHIT+/p53+, 38% in FHIT-/p53- and 33% in FHIT-/p53+ patients. Median progression-free survival (PFS) was 9.6, 7.9, 6.8 and 5.9 months and median overall survival (OS) was 12.8, 11.9, 10.5 and 8.7 months in the four groups, respectively. The Group comparison showed significantly worse PFS (p=0.04) in FHIT-/p53+ than the other groups. There was no significant difference in OS between the groups. A trend (p=0.07) for shorter OS was found in FHIT- cases suggesting that NSCLC tumors carrying this feature are less responsive to treatment. This retrospective study indicates that FHIT-/p53+ status might be a biological variable influencing the efficacy of carboplatin/gemcitabine treatment in NSCLC.
在原发性非小细胞肺癌（NSCLC）及细胞系中，经常观察到FHIT和TP53基因失活，这可能导致对各种抗肿瘤药物引发的凋亡刺激产生抗性。为了评估FHIT和TP53状态与铂类类似物方案疗效之间的可能关系，我们回顾性选择了55例接受卡铂/吉西他滨治疗的NSCLC患者。通过免疫组织化学分析预处理的福尔马林固定活检标本中FHIT和p53蛋白表达，并通过DG-DGGE/测序分析代表性显微切割组织中的TP53突变。33例患者（60%）出现FHIT阴性免疫表型（FHIT-，病理型），25例患者（45%）出现p53过表达/突变（p53+，病理型）。12例患者（22%）存在FHIT-/p53+组合。总体而言，21例患者（38%）出现部分缓解，FHIT+/p53-亚组缓解率为33%，FHIT+/p53+亚组为46%，FHIT-/p53-亚组为38%，FHIT-/p53+亚组为33%。四组患者的无进展生存期（PFS）中位数分别为9.6、7.9、6.8和5.9个月，总生存期（OS）中位数分别为12.8、11.9、10.5和8.7个月。组间比较显示，FHIT-/p53+组的PFS显著差于其他组（p=0.04）。各组间OS无显著差异。在FHIT-病例中发现OS有缩短趋势（p=0.07），提示具有该特征的NSCLC肿瘤对治疗反应较差。这项回顾性研究表明，FHIT-/p53+状态可能是影响卡铂/吉西他滨治疗NSCLC疗效的生物学变量。
