乳腺癌耐药蛋白表达与晚期非小细胞肺癌铂类为主的化疗疗效及预后的关系

目的探讨乳腺癌耐药蛋白（BCRP）表达与晚期非小细胞肺癌（NSCLC）以铂类为主的化疗疗效及预后的关系。方法回顾性分析本院初治的B或期NSCLC患者86例,应用免疫组化方法检测每位患者肿瘤标本中的BCRP表达水平,应用SPSS 16.0进行统计分析,探讨BCRP表达水平与化疗疗效、无进展生存期（PFS）以及总生存期（OS）的关系。结果BCRP表达阴性患者的化疗有效率为44.0%,而表达阳性的患者为19.4%,两者之间差异有统计学意义（P=0.017）。BCRP表达阴性患者的PFS及OS较表达阳性的患者长,并且差异有统计学意义（P值分别为0.000和0.000）。多因素分析表明BCRP是独立影响PFS及OS的指标。结论BCRP表达水平与晚期NSCLC以铂类为主的化疗疗效及预后密切相关,对于进一步研究晚期NSCLC耐药机制,制定个体化治疗方案,延长患者生存期具有重要意义。     

P-gp、MRP1、BCRP在晚期NSCLC中的表达及意义

[目的]探讨P-gp、MRP1、BCRP在晚期非小细胞肺癌(NSCLC)中的表达,及其与NSCLC患者临床病理特征及化疗效果的关系。[方法]采用免疫组化SP法检测32例晚期NSCLC患者治疗前肿瘤标本中P-gp、MRP1、BCRP的表达。所有患者接受以铂类为主的化疗方案2个周期,分析P-gp、MRP1、BCRP表达情况与患者临床病理特征及化疗效果的关系。[结果]NSCLC肿瘤中P-gp、MRP1和BCRP阳性表达率分别为46.88%、75.00%和46.88%。腺癌中P-gp表达高于鳞癌;MRP1的表达与年龄有关,60岁以上的患者显示了更高的MRP1表达率。BCRP的表达与化疗效果相关,但P-gp和MRP1的表达与疗效无显著性相关。[结论]BCRP可以作为判断晚期NSCLC患者化疗效果的预测因子。     

Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML).

Expression of the multidrug resistance proteins P-glycoprotein, encoded by the MDR1 gene, multidrug resistance-associated protein (MRP1) and the lung resistance-related protein or major vault protein (LRP/MVP) is associated with clinical resistance to chemotherapy in acute myeloid leukemia (AML). Recently, the breast cancer-resistant protein (BCRP), the equivalent of mitoxantrone-resistant protein (MXR) or placental ABC transporter (ABCP), was described in AML. We investigated MDR1, MRP1, LRP/MVP and BCRP mRNA expression simultaneously in 20 paired clinical AML samples from diagnosis and relapse or refractory disease, using quantitative Taqman analysis. In addition, standard assays for P-glycoprotein expression and function were performed. BCRP was the only resistance protein that was expressed at a significantly higher RNA level (median 1.7-fold, P = 0.04) at relapsed/refractory state as compared to diagnosis. In contrast, LRP/MVP mRNA expression decreased as disease evolved (P = 0.02), whereas MDR1 and MRP1 mRNA levels were not different at relapse as compared to diagnosis. Also, at the protein level no difference of MDR1 between diagnosis and relapse was found. A significant co-expression of BCRP and MDR1 was found at diagnosis (r = 0.47, P = 0.04). The present results suggest that BCRP, but not MDR1, MRP1 or LRP/MVP is associated with clinical resistant disease in AML.     

Lung resistance-related protein as a predictor of clinical outcome in advanced testicular germ-cell tumours

This study was undertaken to investigate the expression and predictive value for outcome of multidrug resistance-associated (MDR) proteins P-glycoprotein (Pgp), MRP1, BCRP, and LRP, in advanced testicular germ-cell tumours (TGCT). Paraffin-embedded sections from 56 previously untreated patients with metastatic TGCT were immunostained for Pgp, MRP1, BCRP, and LRP. All patients received platinum-based chemotherapy after orchidectomy. Immunostaining was related to clinicopathological parameters, response to chemotherapy, and outcome. Strong and intermediate expressions of the different MDR-related proteins were: 27 and 41% (Pgp), 54 and 37% (MRP1), 86 and 7% (BCRP), and 14 and 29% (LRP). P-glycoprotein and MRP1 associated, respectively, to low AFP (P=0.026) and high LDH levels (P=0.014), whereas LRP expression associated with high beta-hCG levels (P=0.003) and stage IV tumours (P=0.029). No correlation was found between Pgp, MRP1, and BCRP expression and response to chemotherapy and survival. In contrast, patients with LRP-positive tumours (strong or intermediate expression) had shorter progression-free (P=0.0006) and overall survival (P=0.0116) than LRP-negative patients, even after individual log-rank adjustments by statistically associated variables. Our data suggest that a positive LRP immunostaining at the time of diagnosis in metastatic TGCT is associated with an adverse clinical outcome.     

MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid

ATP binding cassette (ABC) multidrug transporters such as P-glycoprotein (P-gp, ABCB1) and BCRP (ABCG2) confer resistance against anticancer drugs and can limit their oral availability, thus contributing to failure of chemotherapy. Like P-gp and BCRP, another ABC transporter, MRP2 (ABCC2), is found in apical membranes of pharmacologically important epithelial barriers and in a variety of tumors. MRP2 transports several anticancer drugs and might thus have a similar impact on chemotherapy as P-gp and BCRP. We here show that human MRP2 transduced into epithelial MDCKII cells efficiently transported the taxane anticancer drugs paclitaxel and docetaxel and that this transport could be substantially stimulated with the drug probenecid, a representative of a range of MRP2-stimulating drugs. Transport of 2 previously identified MRP2 substrates, etoposide and vinblastine, was likewise stimulated by probenecid. MRP2 further conferred substantial resistance against paclitaxel toxicity, and this resistance was 2.7-fold stimulated by probenecid. Our data indicate that MRP2 function might affect chemotherapy with taxanes, potentially influencing both tumor resistance and taxane pharmacokinetics. Moreover, coadministration of probenecid and other MRP2-stimulating drugs might lead to unforeseen drug-drug interactions by stimulating MRP2 function, potentially leading to suboptimal levels of taxanes and other anticancer drugs in plasma and tumor.     

Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma

Pancreatic ductal adenocarcinoma is among the top 10 causes of death from cancer in industrialized countries. In comparison with other gastrointestinal malignancies, pancreatic cancer is one of the tumors most resistant to chemotherapy. An important mechanism of tumor multidrug resistance is increased drug efflux mediated by several transporters of the ABC superfamily. Especially BCRP (ABCG2), MDR1 P-glycoprotein (ABCB1) and members of the MRP (ABCC) family are important in mediating drug resistance. The MRP family consists of 9 members (MRP1-MRP9) with MRP1-MRP6 being best characterized with respect to protein localization and substrate selectivity. Here, we quantified the mRNA expression of BCRP and of all MRP family members in normal human pancreas and pancreatic carcinoma and analyzed the mRNA level of the transporters most abundantly expressed in pancreatic tissue, BCRP, MRP1, MRP3, MRP4 and MRP5, in 37 tissue samples. In addition, we determined the localization of the 4 MRP proteins in normal human pancreas and in pancreatic carcinoma. The expression of BCRP, MRP1 and MRP4 mRNA did not correlate with tumor stage or grading. On the other hand, the expression of MRP3 mRNA was upregulated in pancreatic carcinoma samples and was correlated with tumor grading. The MRP5 mRNA level was significantly higher in pancreatic carcinoma tissue compared to normal pancreatic tissue. These data suggest that MRP3 and MRP5 are involved in drug resistance of pancreatic tumors and that quantitative analysis of their expression may contribute to predict the benefit of chemotherapy in patients with pancreatic cancer.     

乳腺癌耐药蛋白的研究进展

乳腺癌耐药蛋白(BVRP)是新近发现的一种肿瘤耐药相关蛋白．与P-gp和多药耐药相关蛋白(MRP)同属ABC转运蛋白超家族。本文对BCRP的发现、基因表达特征、与造血干细胞分化的关系、转运底物及其耐药逆转和临床意义等方面的研究进展进行综述。     

Correlation of Expression Levels of Copper Transporter 1 and Thymidylate Synthase with Treatment Outcomes in Patients with Advanced Non-small Cell Lung Cancer Treated with S-1/Carboplatin Doublet Chemotherapy

Background: Copper transporter 1 (CTR1) is a critical determinant of the uptake and cytotoxic effect of the platinumdrugs carboplatin and cisplatin. Thymidylate synthase (TS) is an enzyme involved in DNA synthesis and is associatedwith resistance of tumor cells to 5-fluorouracil. We investigated the correlation between CTR1 and TS expression levelsand treatment outcomes in patients with advanced non-small-cell lung cancer (NSCLC) treated with S-1/carboplatindoublet chemotherapy. Methods: Twenty-nine patients were enrolled in this study. Tumor expression of CTR1 andTS was measured immunohistochemically and analyzed for correlation with tumor response, progression-free survival(PFS), and overall survival (OS). Results: Tumor response was significantly better in patients with CTR1High tumorsthan in patients with CTR1Low tumors (64% vs. 18%, P = 0.02). Patients with TSLow tumors had a significantly longer OS(median 21.2 vs. 8.5 months, P = 0.02), but not PFS, than patients with TSHigh tumors. When CTR1 and TS co-expressionwas analyzed, patients with either CTR1High or TSLow tumors showed a significantly better tumor response (50% vs. 0%,P = 0.01), longer PFS (median 4.2 vs. 2.1 months, P = 0.03), and longer OS (median 21.2 vs. 8.5 months, P = 0.01) thanpatients with both CTR1Low and TSHigh tumors. Conclusions: Our study suggests that combined CTR1/TS expressionstatus has the potential to be an important predictor of good treatment outcomes in patients with advanced NSCLCtreated with S-1/carboplatin doublet chemotherapy.     

Novel mechanisms of drug resistance in leukemia.

A key issue in the treatment of acute leukemia is the development of resistance to chemotherapeutic drugs. Several mechanisms may account for this phenomenon, including failure of the cell to undergo apoptosis in response to chemotherapy, or failure of the drug to reach and/or affect its intracellular target. This review focuses on the latter mechanism, and on intracellular drug transport resistance mechanisms in particular. Expression of the ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) has generally been reported to correlate with prognosis in acute myeloid leukemia (AML). Additionally, but more controversial, expression of the ABC transporter multidrug resistance protein (MRP) and the vault-transporter lung resistance protein (LRP) have been correlated with outcome in AML. Despite these findings, functional efflux assays indicate the presence of non-Pgp, non-MRP transporters in AML. Recently, a novel ABC transporter, breast cancer resistance protein (BCRP) was cloned and sequenced in our laboratory. Transfection and overexpression of BCRP in drug-sensitive cells confers drug-resistance to the cells. BCRP is a half-transporter, and may homodimerize or form heterodimers (with a yet unknown half-transporter) to produce an active transport complex. Relatively high expression of BCRP mRNA is observed in approximately 30% of AML cases, suggesting a potential role for this new transporter in drug resistance in leukemia.     

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.     

Impact of BCRP/MXR, MRP1 and MDR1/P-Glycoprotein on thermoresistant variants of atypical and classical multidrug resistant cancer cells

The impact of the ABC transporters breast cancer resistance protein/mitoxantrone resistance associated transporter (BCRP/MXR), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance gene-1/P-glycoprotein (MDR1/PGP) on the multidrug resistance (MDR) phenotype in chemoresistance and thermoresistance was investigated in the parental human gastric carcinoma cell line EPG85-257P, the atypical MDR subline EPG85-257RNOV, the classical MDR subline EPG85-257RDB and their thermoresistant counterparts EPG85-257P-TR, EPG85-257RNOV-TR and EPG85-257RDB-TR. Within the atypical MDR subline EPG85-257RNOV expression of BCRP/MXR and of MRP1 were clearly enhanced (vs. parental and classical MDR lines). MDR1/PGP expression was distinctly elevated in the classical MDR subline EPG85-257RDB (vs. parental and atypical MDR sublines). In all thermoresistant counterparts basal expression of BCRP/MXR, MRP1 and MDR1/PGP was increased relative to thermosensitive sublines. Although it could be shown that the overexpressed ABC transporters were functionally active, however, no decreased drug accumulations of doxorubicin, mitoxantrone and rhodamine 123 were observed. Thus, expression of BCRP/MXR, MRP1 and MDR1/PGP was found to be dependent on the appropriate type of chemoresistance; correlating with a classical or atypical MDR phenotype. Within the thermoresistant variants, however, the increase in ABC transporter expression did obviously not influence the MDR phenotype.     

Caveolin-1 expression is significantly associated with drug resistance and poor prognosis in advanced non-small cell lung cancer patients treated with gemcitabine-based chemotherapy

Caveolin-1 was up-regulated in different drug-resistant cancer cell lines and was suggested to confer drug resistance by different mechanisms. However, the relation of caveolin-1 expression and the clinical response to chemotherapy and prognosis in non-small cell lung cancer (NSCLC) remains unknown. Total 73 NSCLC (stages IIIB and IV) patients who received gemcitabine-based chemotherapy and also had tumour specimens available before treatment were assessed for caveolin-1 expression using immunohistochemistry. Immunoreactivity of caveolin-1 was correlated with the response to chemotherapy, the clinicopathologic features, and the progression-free survival (PFS) and overall survival (OS) of all patients. Positive caveolin-1 immunostaining was found in 12 (16.4%) of the 73 patients. Eight of the twelve had disease progression and the other four patients remained stable after chemotherapy. Patients with caveolin-1 expression had a significantly lower response rate (complete or partial response, 0% versus 37.7%; P=0.01) and a poor PFS and OS (median survival time: PFS, 4.6 months versus 6.1 months, P=0.005; OS, 7.0 months versus 14 months, P<0.001) than those without caveolin-1 expression. Moreover, multivariate analyses indicated that caveolin-1 positivity was an independent prognostic factor for disease-free survival (DFS) (P=0.003) and OS (P=0.008), respectively. Caveolin-1 expression significantly correlated with drug resistance and a poor prognosis in advanced NSCLC patients treated with gemcitabine-based chemotherapy.     

Expressions of Topoisomerase IIα and BCRP in Metastatic Cells are Associated with Overall Survival in Small Cell Lung Cancer Patients

The aim of this study was to investigate the mRNA expression levels of multidrug resistance-associated proteins in chemo-na?ve metastatic lung cancer cells and to determine the correlation with response to chemotherapy and overall survival. Metastatic cells were obtained by transbronchial fine needle aspiration biopsy of enlarged mediastinal lymph nodes in 14 patients with small cell lung cancer (SCLC) and 7 patients with non-small cell lung cancer (NSCLC). After cytological confirmation of lung cancer type, total RNA was extracted from biopsy samples and reverse transcribed to cDNA, and real-time PCR for the genes of interest [P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), breast cancer resistance protein (BCRP), lung resistance protein (LRP) and topoisomerase IIα (TOPIIα)], was performed. We observed significantly decreased expression of BCRP and significantly increased expression of TOPIIα in metastatic SCLC cells compared to NSCLC. Furthermore, in SCLC high topoisomerase IIα and low BCRP expression levels positively correlated with longer overall survival. Our results showed higher expression levels of BCRP as well as lower levels of topoisomerase IIα in chemo-na?ve metastatic cells in NSCLC than in SCLC. These results correlate with previous observations that metastatic SCLC cells at the beginning of chemotherapy are potentially more sensitive to chemotherapeutic agents while in metastatic NSCLC cells resistance is usually inherent. We also showed that altered levels of topoisomerase IIα and BCRP in SCLC are important factors that contribute to resistance to chemotherapeutics that interfere with the enzyme and/or DNA and are highly associated with overall survival.     

Anticancer Effects of the Nitric Oxide-Modified Saquinavir Derivative Saquinavir-NO against Multidrug-Resistant Cancer Cells

The human immunodeficiency virus (HIV) protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO) was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein 1 (BCRP1) in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.     

TKI耐药后晚期EGFR突变型非小细胞肺癌对不同治疗的反应及预测性标志物的研究

  目的  评估TKI耐药后晚期EGFR突变型非小细胞肺癌（non-small cell lung cancer,NSCLC）在真实世界中化疗、化疗联合抗血管和免疫治疗的临床疗效以及最佳免疫治疗联合方案和探讨优势人群临床病理特征。  方法  回顾性分析2014年1月至2022年10月于广东省人民医院肿瘤医院收治229例TKI耐药后晚期EGFR突变型NSCLC患者的临床病理资料。本研究将纳入的患者分为非ICI治疗组（化疗和化疗联合抗血管）122例,ICI治疗组（含免疫治疗）107例,分析患者临床特征与治疗疗效之间的关系。  结果  纳入患者非ICI治疗组和ICI治疗组的中位无进展生存期（progression-free survival,PFS）分别为5.2个月和5.2个月（P=0.129）,中位生存期（overall survival,OS）分别为18.2个月和14.1个月（P=0.026）。进一步分析107例ICI治疗组,使用化疗联合免疫治疗、化疗联合抗血管联合免疫治疗和免疫单药或抗血管联合免疫治疗的中位PFS分别为5.6、6.7和2.3个月（P=0.074）,中位OS分别为15.5、18.6和8个月（P=0.165）。PD-L1表达≥50%患者的中位PFS和中位OS较PD-L1表达<50%患者明显延长（中位PFS:5.6个月vs. 5.0个月,P=0.040;中位OS:19.2个月vs. 12.6个月,P=0.046）。  结论  晚期EGFR突变型NSCLC患者TKI耐药后四药联合免疫治疗似乎呈现出更好的生存获益趋势,PD-L1表达是预测该人群免疫治疗获益的生物标志物。      

Expression of class III {beta}-tubulin is predictive of patient outcome in patients with non-small cell lung cancer receiving vinorelbine-based chemotherapy.

PURPOSE: To determine the prevalence and the prognostic value of microtubule component expression in tumors of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Expression of microtubular components was immunohistochemically examined in 93 tumor samples from untreated patients with stage III and IV NSCLC. All patients received vinorelbine-based chemotherapy. Response to chemotherapy, progression-free survival, and overall survival were correlated with the expression of microtubule proteins. RESULTS: The response rate was 27.3% (21 partial responses among 77 valuable patients). Although expression of microtubule components was not associated with the response rate, high class III beta-tubulin expression was correlated with resistance to vinorelbine, defined as disease progression under treatment. Patients whose tumors expressed high levels of class III beta-tubulin isotype had shorter progression-free survival and overall survival (P = 0.002 and 0.001, respectively). High Delta2 alpha-tubulin expression was associated with a shorter overall survival (P = 0.018). Tubulin II levels were not found to be correlated with patient outcome. A multivariate analysis, taking into account sex, age, histology, stage, weight loss, and class II beta-tubulin, class III beta-tubulin, and Delta2 alpha-tubulin levels, confirmed that class III beta-tubulin expression was independently correlated with progression-free survival (P = 0.04) and overall survival (P = 0.012). CONCLUSIONS: These findings suggest that a high level of expression of class III beta-tubulin in tumor cells is associated with resistance to vinorelbine and a poor prognosis in patients with NSCLC receiving vinorelbine-based chemotherapy.     

老年人晚期非小细胞肺癌化疗疗效及预后分析

目的探讨年龄≥65岁的晚期非小细胞肺癌（NSCLC）患者含铂方案化疗疗效及预后因素。方法回顾性分析70例年龄≥65岁的ⅢA～Ⅳ期NSCLC患者一线含铂方案化疗疗效及不良反应;Kaplan—Meier法分析生存情况,COX回归法进行多因素预后分析。结果全组中位化疗数为3个周期,共有53例患者可评价疗效,总有效率41．5％（22／53）,且疗效不受年龄影响（X^2=1．945,P=0．378）;中位无进展生存时间6．0个月,中位生存时间12．5个月;化疗相关血液毒性发生率高;多因素分析提示ECOG评分、远处器官转移数目、化疗周期数是影响预后的独立因素。结论老年晚期NSCLC患者一线含铂方案化疗具有较高疗效,但不良反应发生率高,化疗耐受性较差,合理选择患者是关键;ECOG评分差、多发远处器官转移患者难以从化疗中获益;而对于可耐受化疗患者,3—6周期化疗可明显改善预后。     

Thrombocytosis and immunohistochemical expression of connexin 43 at diagnosis predict survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy

Purpose

Patients with advanced non-small-cell lung cancer (NSCLC) have poor survival, and platinum-based chemotherapy agents are the standard first-line chemotherapy agents for advanced NSCLC. This study aimed to identify predictive factors associated with the response to chemotherapy and survival in 258 patients with advanced NSCLC treated with platinum-based chemotherapy.

Methods

Stage IIIA–IV NSCLC patients diagnosed in Kaifeng second people’s hospital (Henan, China) between March 2002 and September 2011 were retrospectively reviewed. All of the patients had received platinum-based chemotherapy, and patients were followed up to date of death or last follow-up to obtain data of response to chemotherapy and survival. Potential prognostic factors such as gender, age, tumor size, tumor type, histologic stage, anemia, calcium levels, ECOG performance status (PS), thrombocytosis, TTF-1, p63, and connexin 43 were analyzed. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan–Meier method and Cox regression model.

Results

A univariate analysis indicated that thrombocytosis and connexin 43 were found to be significant prognostic factors (p < 0.001) and ECOG PS, Hb levels, and p63 presented a tendency toward association with survival. Kaplan–Meier survival showed that the mean OS and PFS in chemotherapy responders with connexin 43 ≥+2 were significantly longer than in chemotherapy responders with connexin 43 ≤1+. In contrast, thrombocytosis was associated with increased mortality and resistance to chemotherapy in chemotherapy responders. In addition, all 21 patients of the 5-year OS were from chemotherapy responders with connexin 43 ≥+2 or non-thrombocytosis.

Conclusions

Thrombocytosis and connexin 43 absence may be reliable surrogate markers for the prediction of chemotherapy response and prognosis for patients with advanced NSCLC, and assessment of these factors may identify a population of patients with advanced NSCLC that is likely to have a prolonged life expectancy.