Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer

In order to determine whether expression of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer (NSCLC) correlates with chemotherapeutic response, resected tumors from 22 patients with recurrent lung cancer who had undergone complete resection and received chemotherapy after the initial tumor recurrence were subjected to p27 immunostaining. Histological examination of the resected tumors revealed 14 adenocarcinomas, 7 squamous cell carcinomas and one adenosquamous cell carcinoma. Fifty percent or less and over 50% of the cells in the resected tumors of 11 patients each (groups 1 and 2, respectively) were p27-immunopositive. All but one patient received platinum-based chemotherapy after recurrence. Only one in group 1 achieved a partial response (PR) in chemotherapy whereas 2 and 4 in group 2 achieved complete and PRs, respectively. The chemotherapy response rate of group 2 (54%) was significantly higher than that of group 1 (9%, p=0.022). The times to recurrence after tumor resection of the 2 groups did not differ significantly (log-rank p=0.23, Wilcoxon p=0. 32), but survival after chemotherapy of group 2 was significantly better than that of group 1 (log-rank p=0.045, Wilcoxon p=0.028). It is suggested that high p27 expression levels in tumors may predict the good responses to platinum-based chemotherapy for NSCLC.     

NOB1 expression predicts early response to cisplatin-based chemotherapy in patients with advanced non-small cell lung cancer

Background: The aim of this study was to investigate the predictive value of Nin one binding (NOB1) expression for response to cisplatin-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).

Methods: A total of 105 consecutive patients with advanced NSCLC were retrospectively investigated between January 2012 and June 2014. We used transbronchial biopsy to collect cancer tissue samples. Immunohistochemistry were used in the detection of NOB1 protein expression. We assessed the chemotherapy early response by response evaluation criteria in solid tumours (RECIST) Version 1.1 at the end of the second cycle of chemotherapy.

Results: In the 105 transbronchial biopsy NSCLC specimens, 22 (21.0%) stained NOB1 ??, 35 (33.3%) stained +, 31 (29.5%) stained ++ and 17 (16.2%) stained +++. The early response rate to chemotherapy was 59.0% in overall NSCLC. Early response to chemotherapy has no relationship with patients' age, gender, smoke status, performance status and chemotherapy regimens (P>0.05), but related with TMN stage, histopathological grade, as well as NOB1 expression (P?P?=?0.008) for early response to chemotherapy.

Conclusion: Our results suggest that enhanced expression of NOB1 related with poor early response to cisplatin-based chemotherapy in patients with advanced non-small cell lung cancer.     

Relevance of p53, bcl-2 and Rb expression on resistance to cisplatin-based chemotherapy in advanced non-small cell lung cancer

PURPOSE: Tumors with p53 overexpression have been associated with enhanced resistance to cisplatin-based chemotherapy in a few and small studies involving non-small cell lung cancer. The relationships and interactions between p53, Rb and bcl-2 immunostaining, clinical parameters and response to cisplatin-based chemotherapy were evaluated in the present study. EXPERIMENTAL DESIGN: Histological specimens obtained by bronchial or fine-needle biopsy from patients who underwent cisplatin-based chemotherapy between 1992 and 1999 were evaluated by immunostaining. RESULTS: There were 102 patients, 88 men. Median age was 63 years; 47 had stage III and 55 stage IV disease. Forty-six tumor samples (45%) had positive immunostaining for p53, 61 (59%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for bcl-2. The response rate of the group with p53 positive immunostaining was 26% versus 57% of the p53 negative group (P=0.004). In multivariate analyses p53 positive immunostaining was identified as an independent predictive factor for resistance to cisplatin-based chemotherapy (P=0.006). CONCLUSIONS: Our study confirmed an association of p53 immunostaining and response rate of patients treated with cisplatin-based chemotherapy.     

clusterin、Bax及p53在非小细胞肺癌中的表达及相关性研究

背景与目的已有的研究表明簇集蛋白(clusterin)是近年新发现的凋亡相关因子,在多种肿瘤中上调表达,在肿瘤的发生发展中起重要作用。clusterin的抗凋亡作用与其他抗凋亡因子有相关性。本文旨在探讨clusterin、Bax和p53在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达情况及其与肺癌发生发展的关系。方法采用SP免疫组化方法和Western blot法,检测NSCLC组织中clusterin、Bax和p53的表达情况,并结合临床和病理资料进行分析。结果免疫组化显示clusterin在79.25%(42/53)的NSCLC组织中阳性表达。NSCLC组织中clusterin表达阳性率明显高于正常肺组织(χ2=23.68,P<0.05),与肿瘤的分化程度(rs=0.464,P<0.01)、临床分期(rs=0.320,P<0.01)及有无淋巴结转移(rs=0.255,P<0.05)呈正相关,但与年龄、性别及病理分型无关。clusterin与p53的表达呈正相关(rs=0.589,P<0.01),与Bax的表达呈负相关(rs=-0.346,P<0.01)。Western blot法显示clusterin在NSCLC组织中的表达水平明显高于正常肺组织(0.541±0.010比0.201±0.020,P<0.05)。结论clusterin可能通过抗凋亡机制在肺癌的生物学特性中发挥重要作用。     

The effect of HER2 expression on cisplatin-based chemotherapy in advanced non-small cell lung cancer patients

Introduction

The prognostic value of HER2 expression in patients with advanced non-small cell lung cancer remains controversial. The relationship between HER2 expression, and platinum resistance and patient survival, was investigated.

Methods

Seventy-three consecutive patients (median age, 61 years) with stage IIIB and IV non-small cell lung cancer, admitted between February 2004 and December 2006, were included in this study. Sixty-one patients received gemcitabine, given as two 1250 mg/m² doses on days 1 and 8 and, cisplatin, given as a 75 mg/m² dose on day 8. Twelve patients received vinorelbine, given as two 25 mg/m² doses on day 1 and 8, and cisplatin, given as a 75 mg/m² dose on day 1. Both treatment paradigms were repeated on a 21-day cycle. Tumor response was evaluated by comparing tumor size on computerized tomography scans before and after three cycles of chemotherapy. HER2 status was examined by immunohistochemical analysis of paraffin-embedded specimens.

Results

HER2 was positive in 21 of 73 patients (28.8%). Of the 21 patients with HER2 positivity, 13 (61.9%) responded to chemotherapy with either a complete response, partial remission, or evidence of stable disease. Of 52 HER2-negative patients, 48 (92.3%) exhibited a response to chemotherapy. The difference in response to therapy between HER2-positive and -negative patients was statistically significant (p = 0.003). The median overall survival duration for all patients was 13 months. Median overall survival time was 14 months for HER2-negative patients and 10 months for HER2-positive patients (log-rank p = 0.007).

Conclusion

Non-small cell lung cancer patients with high expression of HER2 exhibited resistance to cisplatin-based chemotherapies that are the standard treatment for this disease. Our results indicate that HER2 status may be a predictive and prognostic factor for cisplatin- based therapy response and disease survival.     

Correlation of p53 oncoprotein expression with chemotherapy response in small cell lung carcinomas

p53 oncoprotein expression was investigated in small cell lung carcinomas (SCLC) using immunohistochemical staining with antibodies against p53. A total of 50 pre-treatment biopsies were examined. We analyzed the relationship between p53 expression and these patients' relevant clinical characteristics, response to chemotherapy, time to progression, and overall survival. We found p53 overexpression in 46% of the samples but no association with clinical data or overall survival. Our results show a strong correlation of p53 staining with chemotherapy response. Multivariate analysis selected p53 as an independent predictive factor of chemotherapy response.     

Vascular endothelial growth factor, p53, Rb, Bcl-2 expression and response to chemotherapy in advanced non-small cell lung cancer

Vascular endothelial growth factor (VEGF) increases microvascular permeability and stimulates endothelial cell growth. p53 Overexpression has been associated with resistance to cisplatin-based chemotherapy in patients (pts) with NSCLC. The aim of this study was to evaluate the predictive role of VEGF for chemotherapy response, its relationship with p53, Rb, Bcl-2 and hemoglobin levels and its impact on overall survival in pts with advanced NSCLC. Bronchial or fine-needle biopsy specimens from 85 pts with NSCLC obtained before chemotherapy were analyzed using an immunohistochemical method for VEGF, p53, Rb and Bcl-2. There were 73 males and 12 females with a median age of 62.6 years. The majority of pts (48%) had squamous cell histology. Ten pts had stage IIIA, 25 stage IIIB and 50 stage IV. Thirty six (43%) pts had positive immunostaining for VEGF, 37 (44%) had positive p53, 53 (62%) had negative Rb and 4 (5%) had positive Bcl-2. VEGF was negatively correlated with Rb (r(s) = 0.26; P = 0.015), positively with Bcl-2 (r(s) = 0.22; P = 0.42), whereas no statistically significant correlation with p53, age, stage and histological type was found. In a logistic regression model, adjusting for treatment, VEGF expression was not associated with chemotherapy response (odds ratio (OR) = 1.01; P = 0.085 ), unlike p53 positivity and Rb negativity ( OR = 4.0, P = 0.005; OR = 2.6, P = 0.016, respectively). A statistically significant higher VEGF expression was detected in the subgroups defined, using as cut-off value Hb median level (13.3g/dl) (chi-square = 5.00; ; one d.f.; P = 0.025). At a median follow-up time of 8.4 years, 2-year survival was 21%. After adjustment for stage and chemotherapy treatment, VEGF expression was not associated with a better overall survival (OR = 1.06; P = 0.80), unlike Bcl-2 positivity showed a statistically significant effect (OR = 0.28; p = 0.02). Our results suggest that VEGF is weakly correlated with regulators of apoptosis and has not been shown to be an independent predictive factor for resistance to cisplatin-based chemotherapy and prognostic for survival.     

非小细胞肺癌组织LRP和p53表达及其与新辅助化疗关系的研究

目的：了解非小细胞肺癌（NSCLC）患者LRP和p53的表达与含铂方案新辅助化疗的疗效以及预后之间的关系。方法：通过免疫组化方法研究43例Ⅲ期NSCLC化疗前后肺癌标本LRP和p53的表达,并分析上述指标的表达与新辅助化疗疗效以及生存期的关系。结果：在化疗前后的戍对标本中,化疗后肺癌标本LRP和p53的表达[LRP为74．42％（32／43）,p53为72．09％（31／43）],明显高于化疗前[LRP为46．51％（20／43）,p53为48．84％（21／43）]。LRP阳性组化疗有效率为40％（8／20）,LRP阴性组73．91％（17／23）,LRP表达与化疗有效率呈负相关,P=0．033。p53阳性组化疗有效率76．19％（16／21）,p53阴性组40．91％（9／22）,p53表达与化疗有效率正相关,P=0．031。结论：Ⅲ期NSCLC化疗前LRP和p53表达有助预测含铂方案新辅助化疗的疗效。     

p53和PCNA与非小细胞肺癌

p53基因和增殖细胞核抗原(PCNA)均与非小细胞肺癌(NSCIE)的放疗有密切关系.两者同时高表达的NSCLC患者的生存期低于同时阴性者.研究p53基因和PCNA在NSCLC中的表达,及其与NSCLC放射敏感性和预后的关系,可以对临床制定个体化治疗方案和提高疗效起到积极作用.     

p53 mutations predict non-small cell lung carcinoma response to radiotherapy

In vitro and animal studies, the effect of loss of p53 function on radiosensitivity is controversial. p21Waf1/Cip1 is a potent inhibitor of cyclin-dependent kinases and p21 gene polymorphisms are associated with some human cancers. We sought to determine whether p53 mutations or p21 polymorphisms affect response to radiotherapy in patients with recurrent non-small cell lung carcinoma (NSCLC). Thirty-four patients with NSCLC who underwent radiotherapy for recurrent tumors after potentially curative resection were studied. Gene alterations or polymorphisms were analyzed in DNA from the primary tumor tissue, and the response to radiotherapy was based on the metastatic lesion. Mutations in exons 5-8 of the p53 gene were detected by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis. p21 gene polymorphisms were identified by restriction digestion (BsmAI or PstI) of PCR products. Mutations in p53 were found in 13 of 34 patients (38.2%). The response rates (complete plus partial) were 15.4% for patients with tumors having p53 mutations and 61.9% for patients with wild-type p53 (P = 0.013). There was no significant difference between p21 polymorphisms and response to radiation. p53 gene mutations predict response to radiotherapy in NSCLC. Our results provide clinical support for the in vitro model that loss of p53 function decreases radiosensitivity.     

晚期非小细胞肺癌对铂类药物的化疗敏感性与p53和p73基因多态的关系

目的探讨细胞凋亡相关基因p53和p73的遗传多态,与晚期非小细胞肺癌（NSCLC）对铂类药物化疗敏感性的关系。方法以聚合酶链反应（PCR）-限制性片段长度多态性（RFLP）和突变扩增阻抑系统（ARMS）分析方法,对165例以顺铂（DDP）或卡铂（CBP）为主进行化疗的晚期NSCLC患者,进行p53第72密码子Arg→Pro多态,和p73第2外显子G4C14-A4T14多态的检测,2～3个疗程后进行效果评价。以非条件Logistic回归模型比较不同基因型与化疗疗效的关系。结果携带p53 72Pro等位基因患者的化疗敏感性,是携带p53 72Arg／Arg基因型患者的2、46倍（95％CI,1．11～5．45,P=0．026）;而携带至少1个p73突变等位基因（A4T14）的患者,其化疗敏感性是携带p73 G4C14／G4C14基因型患者的2．22倍（95％讲,1．14～4、30,P=0．019）。2个多态位点合并分析结果显示,同时携带p53和p73野生基因型的患者,化疗有效率为7．7％;而携带1个、2个和≥3个p53和p73变异等位基因的患者,化疗有效率分别为34．8％、42．2％和40、7％。结论p53和p73基因遗传多态与晚期NSCLC患者对以铂类药物为主的化疗敏感性有关。     

Molecular predictors of response to chemotherapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer-related mortality in the United States with 222,520 new cases and 157,300 deaths anticipated in 2010. The primary objective of any cancer treatment is to improve patient outcomes including overall survival and quality of life while minimizing treatment toxicity. As our knowledge of the molecular mechanisms involved in the pathogenesis of lung cancer evolves, improved methods of therapeutic selection may help clinicians better realize these goals. Such selection may be accomplished by examining biomarkers within patients' tumors that may provide prognostic information such as risk of recurrence in early stage disease or predict benefit from specific therapies regardless of disease stage. Three such biomarkers have emerged--excision repair cross-complementation group 1, the regulatory subunit of the ribonucleotide reductase enzyme, and thymidylate synthase--and are actively being evaluated in patients with non-small cell lung cancer. This review will focus on the role of these biomarkers as predictive and/or prognostic markers in the selection of chemotherapy regimens in non-small cell lung cancer patients.     

Evaluation of response to chemotherapy with fiberoptic bronchoscopy in non-small cell lung cancer

Fiberoptic bronchoscopy was performed before and during administration of chemotherapy in 32 patients with unresectable non-small cell carconoma of the lung. Pretreatment findings varied with the histologic cell type. Direct visual and/or pathologic evidence of cancer was obtained in 11 of 11 patients with epidermoid, in 5 of 7 with large cell, and in 9 of 14 with adenocarcinoma. In 5 of the 32 patients, intrathoracic tumor was documented at bronchoscopy but not by chest x-ray. During chemotherapy, one of five episodes of response and eight of 21 episodes of chest tumor progression were detected solely by bronchoscopy, while in an additional two objective responses and six progressions, bronchoscopic and radiographic findings simultaneously improved or deteriorated. The likelihood of documenting disease progression by bronchoscopy also depended upon the histologic type of cancer. Enlarging chest tumor found solely by chest x-ray occurred exclusively in patients with large cell carcinoma and adenocarcinoma. During chemotherapeutic treatment of our pateints, addition of serial bronchoscopic examinations to standard means of assessing tumor response frequently allowed the earlier discontinuation of an ineffective drug regimen.     

The predictive value of neuroendocrine markers and p53 for response to chemotherapy and survival in patients with advanced non-small cell lung cancer

BACKGROUND: A minority of patients (30-40%) with advanced non-small cell lung cancer (NSCLC) have objective responses to chemotherapy. Therefore, defining molecular features that determine resistance or response to chemotherapy would have important implications in this disease. Several studies have suggested that patients whose tumors have neuroendocrine features may be more responsive to chemotherapy. In addition, increased expression of p53 may play a role in chemotherapy resistance in patients with NSCLC. METHODS: The objective of this study was to analyze retrospectively, the correlation between marker expression and response to chemotherapy and survival using immunohistochemistry for neuroendocrine markers and p53. Ninety patients with unresectable stage III or IV NSCLC, treated with platinum based combination chemotherapy were evaluated. The pathological specimens were obtained prior to chemotherapy. RESULTS: There was no statistically significant correlation between any individual marker and response to chemotherapy. However, patients with tumors with increased expression of p53 were more likely to have progressive disease following chemotherapy (P=0.02). Similarly, patients with tumors lacking neuroendocrine expression and with increased expression of p53 were more likely to have progressive disease when compared to patients with tumors with normal p53 expression and neuroendocrine differentiation (P=0.03). Normal expression of p53 along with the presence of neuroendocrine differentiation was a favorable factor for both survival (P=0.05) and time to disease progression (P=0.04) in the multivariate analysis. CONCLUSION: The presence of neuroendocrine markers alone was not predictive of response to chemotherapy and did not impact on the survival of this group of patients with advanced stage NSCLC. The normal expression of p53 together with neuroendocrine differentiation seems to impact favorably on overall survival time and time to disease progression without significant improvement in response to chemotherapy.     

非小细胞肺癌中p53、Glut-1表达与FDG摄取的关系

目的:探讨非小细胞肺癌(NSCLC)中p53、葡萄糖转运蛋白-1(Glut-1)表达与氟脱氧葡萄糖(FDG)摄取三者之间的关系。方法:84例NSCLC患者术前行PET/CT检查,应用免疫组化法对肿瘤组织进行p53及Glut-1染色,并作相关分析。结果:平均标准化摄取值(SUVave)3.6-13.2,平均7.8±3.0。SUVave与Dmax、TNM分期、病理类型、分化程度均无相关性。Glut-1表达平均(4.4±1.3)分。p53染色阳性者41例(48.8%)。Glut-1表达与SUVave值之间呈正相关(r=0.78,P<0.01)。Glut-1与p53表达之间无相关性(P=0.37),SUVave值与p53表达之间亦无相关性(P=0.79)。结论:NSCLC细胞摄取FDG与Glut-1有关,但后者并非唯一因素。Glut-1调节与p53基因无关。     

A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer

OBJECTIVE: Since the debate still exists whether cisplatin-based and carboplatin-based chemotherapy are equally effective for advanced non-small-cell lung cancer (NSCLC), a meta-analysis of trials was performed to compare the cisplatin-based with carboplatin-based regimens in first line chemotherapy of advanced NSCLC. METHODS: A literature search was performed in PubMed database, the Cochrane Central Register of Controlled Trials (CENTRAL) database, the Physician Data Query (PDQ) database and the American Society of Clinical Oncology (ASCO) annual meeting abstracts in January 2007. The following keywords were used: "non small cell lung cancer," or "Carcinoma, Non-Small-Cell Lung". Reference lists of original articles and review articles were also examined. The published languages and years were not limited. The trials searched were evaluated for eligibility and quality, and then the data were abstracted and analyzed. RESULTS: Eighteen randomized controlled trials (6906 patients) were identified from 4240 reports. The intention to treatment (ITT) analysis demonstrated that the cisplatin-based regimens had a higher overall response rate in comparison with carboplatin-based regimens (RR, 0.91; 95%CI, 0.84-0.99; P=0.02). However, the 1-year survival rate for the two platinum-based regimens were comparable (RR, 1.00, 95%CI, 0.94-1.07; P=0.93), Both subgroup analysis comparing the doublet or triplet regimens of cisplatin or carboplatin in combination with new agents and the same agents had achieved the same results. Cisplatin-based chemotherapy led to more frequent grade 3 or 4 of nausea and vomiting, and nephrotoxicity (OR, 0.39; 95%CI, 0.30-0.52; P<0.00001 and OR, 0.31; 95%CI, 0.17-0.56; P=0.0001), while carboplatin-based chemotherapy inclined to developing more grade 3 or 4 thrombocytopenia, however, there were no statistical significance (OR, 1.63; 95%CI, 0.94-2.82; P=0.08). The risk of grade 3 or 4 anemia, neutropenia and neurotoxicity was almost comparable between the two arms (OR, 0.78; 95%CI, 0.59-1.02; P=0.07; OR, 1.08; 95%CI, 0.80-1.45; P=0.61 and OR, 1.59; 95%CI, 0.81-3.14; P=0.18, respectively). The subgroup analyses of the comparison between the doublet or triplet regimens of cisplatin and carboplatin in combination with the same agents, respectively, also achieved similar results, with the exception of thrombocytopenia between the two groups (OR, 1.94; 95%CI, 1.47-2.68; P<0.00001), which showed statistically significant. Cisplatin arm inclined to causing more treatment-related deaths compared as carboplatin arm, but there was no statistical significance (OR, 0.70; 95%CI, 0.48-1.02; P=0.06). CONCLUSION: Given cisplatin-based regimens had a higher overall response rate as compared with carboplatin-based regimens, there was not a survival advantage in the cisplatin group. Therefore, the toxicity profile might play an important role in decision to choose cisplatin-based or carboplatin-based regimens.     

VEGF and TSP1 levels correlate with prognosis in advanced non-small cell lung cancer

Purpose

There is a need for biomarkers that may help in selecting the most effective anticancer treatments for each patient. We have investigated the prognostic value of a set of angiogenesis, inflammation and coagulation markers in patients treated for advanced non-small cell lung cancer.

Patients and methods

Peripheral blood samples were obtained from 60 patients before first line platinum-based chemotherapy ± bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Angiogenesis, inflammation and coagulation markers vascular endothelial growth factor (VEGF), their soluble receptors 1 (VEGFR1) and 2 (VEGFR2), thrombospondin-1 (TSP-1), interleukin-6 (IL6), sialic acid (SA) and tissue factor (TF) were quantified by ELISA.

Results

Except for TSP-1, pre- and post-treatment levels of all markers were higher in patients than in controls (p < 0.05). There was a positive and significant correlation between VEGF and VEGFR2 before treatment. VEGF also correlated with inflammatory markers IL-6 and SA. Moreover, there was a positive and significant correlation between levels of VEGFR1 and TF. Decreased levels of TSP-1 and increased levels of VEGF were associated with shorter survival. Bevacizumab significantly modified angiogenesis parameters and caused a decrease of VEGF and an increase of TSP-1.

Conclusion

Angiogenesis, inflammation and coagulation markers were increased in NSCLC patients. Increased levels of VEGF and low levels of TSP-1 correlated with a poor prognosis.     

泽菲联合盖诺治疗不能耐受顺铂的中晚期非小细胞肺癌临床观察

目的评价泽菲联合盖诺治疗不能耐受顺铂的中晚期非小细胞肺癌的疗效和毒性反应。方法74例中晚期非小细胞肺癌既往均未曾放疗或化疗。PS评分≤3分,生存期超过3个月,随机分为GN组25例（泽菲联合盖诺）,NP组24例（盖诺加顺铂）,GP组25例（泽菲加顺铂）。结果GN组、NP组和GP组有效率分别为44.0%、37.5%和44.0%,差异无显著性（P〉0.05）。GN组与另两组在Ⅲ、Ⅳ度血液学毒性方面比较差异无显著性（P〉0.05）,GN组非血液学毒性比较少（P〈0.05）。结论GN方案疗效较好且毒性较低,故尤其适合于不能耐受顺铂的晚期非小细胞肺癌患者。