NAD(P)H:Quinone oxidoreductase-1 C609T polymorphism analysis in human superficial bladder cancers: relationship of genotype status to NQO1 phenotype and clinical response to Mitomycin C

NAD(P)H:Quinone oxidoreductase-1 (NQO1) has been implicated in the bioreductive activation of the clinically active anticancer drug Mitomycin C (MMC) and a polymorphic variant of NQO1 which lacks functional enzyme activity (NQO1*2) has been linked with poor survival in patients treated with MMC. The relationship between NQO1 activity and cellular response to MMC is however controversial and the aim of this study was to determine whether the response of bladder cancer patients to MMC can be forecast on the basis of NQO1*2 genotype status. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue from 148 patients with low to intermediate grade (G1/G2) superficial (Ta/T1) bladder cancers and NQO1*2 genotype status determined by PCR-RFLP. NQO1*2 genotype status was retrospectively compared with clinical response to intravesical administered MMC with the primary end-point being time to first recurrence. NQO1 phenotype was determined by immunohistochemistry. Of the 148 patients genotyped, 85 (57.4%) were NQO1*1 (wild-type), 59 (39.8%) were NQO1*1/*2 (heterozygotes) and 4 (2.7%) were NQO1*2/*2. No NQO1 protein expression was detected in NQO1*2/*2 tumours. A broad spectrum of NQO1 protein expression existed in tumours genotyped as NQO1*1 and NQO1*1/*2 although tumours with NQO1*1 typically expressed higher NQO1 protein. A poor correlation existed between NQO1*2 genotype status and clinical response to MMC. The results of this retrospective study suggest that tailoring MMC therapy to individual patients with superficial bladder cancer on the basis of NQO1 genotype status is unlikely to be of clinical benefit.     

Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment

Glutathione S-transferase (GST) enzymes detoxify chemotherapeutic drugs, and several studies have reported differences in survival for cancer patients who have variant genotypes for GSTP1, GSTM1 or GSTT1 enzymes. A recently described polymorphism alters hepatic expression of GSTA1, a GST with high activity in glutathione conjugation of metabolites of cyclophosphamide (CP). To consider the possible influence of the reduced-expression GSTA1*B allele on cancer patient survival, we have conducted a pilot study of breast cancer patients treated with CP-containing combination chemotherapy. GSTA1 genotype was determined by polymerase chain reaction and restriction fragment length polymorphism. Kaplan-Meier methods and Cox proportional hazards models were used to evaluate survival in relation to genotype. Among 245 subjects, 35% were GSTA1*A/*A, 49% GSTA1*A/*B and 16% GSTA1*B/*B; the genotype distribution did not differ by ethnic group, age or stage at diagnosis. Among patients who had 0 or 1 GSTA1*B allele, the proportion surviving at 5 years was 0.66 (95% CI = 0.59-0.72), whereas for GSTA1*B/*B subjects the proportion was higher, 0.86 (95% CI = 0.67-0.95). Significantly reduced hazard of death was observed for GSTA1*B/*B subjects during the first 5 years after diagnosis, hazard ratio (HR) = 0.3, 95% CI = 0.1-0.8. The association varied with time, with no survival difference observed for subjects who survived beyond 5 years. These results, although based on a small study population, describe an apparent difference in survival after treatment for breast cancer according to GSTA1 genotype. Further studies should consider the possible association between the novel GSTA1*B variant and outcomes of cancer therapy.     

Single nucleotide polymorphism in the 5' tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients

Thymidylate synthase (TS) is the primary target of 5-fluorouracil (5-FU). A VNTR polymorphism in the TS promoter region is associated with the efficacy of 5-FU-based chemotherapy in colorectal cancer. A common G>C SNP at the 12th nucleotide of the second repeat in the TS*3 alleles has been recently described. The combination of SNP and VNTR allows the definition of 3 TS alleles: *2, *3G and *3C. The aim of our study was to evaluate the predictive value of clinical response and survival of these new defined TS alleles. TS genotypes of 89 patients diagnosed with metastatic colorectal cancer and undergoing 5-FU-based chemotherapy were carried out. The clinical outcome was evaluated according to the genotype (high expression genotype: *2R/*3G; *3C/*3G; *3G/*3G; and low expression genotype: *2R/*2R; *2R/*3C; *3C/*3C. A higher overall response was observed in the group of patients with a low expression genotype (p = 0.035). The probability of achieving a clinical response of patients with a low expression-related genotype was 2.9 higher than that of the other group (95% CI = 1.03-5.6, p = 0.04). The median time to progression was 12 months and 9 months in the low and high expression groups, respectively (p = 0.07, log rank test). Overall survival was significantly longer in the low expression group. In this group the median OS was not achieved at 50 months of follow-up in contrast to the 20 months observed in the high expression group (p = 0.03). TS genotype was an independent predictor of progression-free and overall survival in the Cox regression models after adjustment to the other clinical variables. The selection of patients who are likely to respond to 5-FU therapy may be considerably improved if the TS genotype were to include both the VNTR and the SNP located within the promoter region of the gene.     

Clinical Outcomes and Prognostic Factors Associated with the Response to Erlotinib in Non-Small-Cell Lung Cancer Patients with Unknown EGFR Mutational Status

Background: The efficacy of erlotinib is controversial in patients with unknown EGFR mutational status.The aim of this study was to identify the clinicopathological factors that are predictive of erlotinob treatmentoutcomes for NSCLC patients with unknown EGFR mutational status. Materials and Methods: A retrospectiveanalysis of 109 patients with advanced NSCLC who had previously failed at least one line of chemotherapy andreceived subsequent treatment with erlotinib (150 mg/day orally) was performed. A Cox proportional hazardmodel for univariate and multivariate analyses was used to identify the baseline clinical parameters correlatingwith treatment outcome, expressed in terms of hazard ratios (HRs) and 95% confidence intervals. Results: Themedian treatment duration was 15 weeks (range, 4-184). The disease control rate was 55%, including diseasestability for ≥3 months for 40% of the patients. Median progression-free survival and median overall survival(OS) were 4.2 and 8.5 months, respectively. The Cox model indicated that an Eastern Cooperative OncologyGroup performance status (ECOG PS) ≥2 (HR 3.82; p<0.001), presence of intra-abdominal metastasis (HR 3.42;p=0.002), 2 or more prior chemotherapy regimens (HR 2.29; p=0.021), and weight loss >5% (HR 2.05; p=0.034)were independent adverse prognostic factors for OS in NSCLC patients treated with erlotinib. Conclusions: Thisstudy suggests that NSCLC patients should be enrolled in erlotinib treatment after a first round of unsuccessfulchemotherapy to improve treatment success, during which they should be monitored for intra-abdominalmetastasis and weight loss.     

Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes.

PURPOSE: Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown. METHODS: We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling. RESULTS: Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes. CONCLUSION: In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.     

Impact of UGT1A1 genotype on the efficacy and safety of irinotecan-based chemotherapy in metastatic colorectal cancer

The phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second-line treatment for metastatic colorectal cancer. We evaluated the associations between the UGT1A1 genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. The UGT1A1 genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression-free survival, response rate, and safety were assessed. The UGT1A1 genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12-2.09; P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62-1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79-1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39-1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second-line chemotherapy in terms of efficacy and safety regardless of the UGT1A1 genotype.     

非小细胞肺癌组织PD-L1表达的预后意义及其与SUVmax的相关性

  目的  本研究前期探索了程序性死亡配体1（programmed death-ligand 1,PD-L1）在非小细胞肺癌（non-small cell lung carcinoma,NSCLC）组织表达及其与临床因素的关系,发现它与肿瘤分期存在正相关性,进一步分组研究其预后意义及与原发灶最大标准摄取值（maximum standardized uptake value,SUVmax）相关性。  方法  收集2008年4月至2014年8月122例就诊于天津医科大学肿瘤医院初治原发NSCLC患者的临床影像病理及随访资料,免疫组织化学法检测PD-L1表达情况,采用Kaplan-Meier法及Cox模型进行PD-L1表达的预后分析,Spearman检验分析PD-L1表达与SUVmax的相关性。  结果  早期NSCLC患者中,PD-L1（HR=4.518,95%CI:1.176-17.352,P=0.028）和肿瘤最大径（HR=1.404,95%CI:1.020-1.933,P=0.037）影响总生存时间（overall survival,OS）,是OS的独立预后因子,性别、年龄、病理类型、CEA水平和SUVmax分组对OS差异无统计学意义（P>0.05）;Ⅲ~Ⅳ期NSCLC患者中,性别、病理类型、肿瘤最大径和SUVmax分组是OS的影响因素,年龄、CEA水平、PD-L1表达水平不是OS的影响因素。本研究中,PD-L1表达与SUVmax水平无相关性。  结论  PD-L1表达是早期NSCLC患者独立预后因子,尚不能成为分期较晚患者的预后因素。PD-L1表达与原发灶SUVmax无相关性。      

Pre-treatment prognostic factors in stage III non-small cell lung cancer patients receiving combined modality treatment.

Approximately one-third of non-small cell lung cancer (NSCLC) patients present with locally advanced disease. Increasing numbers of clinical trials are being conducted in this group of patients and recently a new international staging system has been introduced, resulting in the sub-division of Stage III into IIIa (potentially operable disease) and IIIb (inoperable disease). Kaplan-Meier survival analyses and Cox regression analyses were used to analyze data from 129 Stage III NSCLC patients who had been treated on two consecutive Phase II trials testing combined modality treatment. The pretreatment characteristics of these patients were: median age--59 years, males/females--87/42, caucasian/non-caucasian--111/18, squamous cell or adenocarcinoma/large cell carcinoma--57/72, previous weight loss less than or equal to 5%/greater than 5%-76/46, previous history of cardiorespiratory disease--no/yes--91/36, performance status (PS) 0-1/2-3--102/27, Stage III, 2 groups--IIIa/IIIb--83/46, Stage III, 3 groups--IIIa T3 N0/IIIa N2/IIIb--41/41/47, surgical eligibility--eligible/ineligible--83/46. Kaplan-Meier statistics revealed significantly longer survival for PS 0-1 versus 2-3 (p = .001), for eligible versus ineligible for surgery (p = .003), for Stage-IIIa versus IIIb (p = .004), and for Stage-IIIa T3N0 versus IIIa N2 versus IIIb (p = .004). The best model developed from Cox regression analyses included stage (IIIa T3 N0 vs IIIa N2 vs IIIb), PS, and sex. These observations appear to have implications for clinical research in Stage III NSCLC.     

Efficacy of First-line Chemotherapy Affects the Second-Line Setting Response in Patients with Advanced Non-Small Cell Lung Cancer

Background: Chemotherapy is the mainstay of treatment for the majority of patients with advanced nonsmall cell lung cancer (NSCLC) without driver mutations and many receive therapies beyond first-line. Secondline chemotherapy has been disappointing both in terms of response rate and survival and we know relatively little about the prognostic factors. Materials and Methods: One thousand and eight patients with advanced NSCLC who received second-line chemotherapy after progression were reviewed in Shanghai PulmonaryHospital, China, from September 2005 to July 2010. We analyzed the effects of potential prognostic factors on the outcomes of second-line chemotherapy (overall response rate, ORR; progression free survival, PFS; overall survival, OS). Results: The response and progression free survival of first-line chemotherapy affects the ORR, PFS and OS of second-line chemotherapy (ORR: CR/PR 15.4%, SD 10.1%, PD2.3%, p<0.001; PFS: CR/PR 3.80 months, SD 2.77 months, PD 2.03 months, p<0.001; OS: CR/PR 11.60 months, SD 10.33 months, PD 6.57 months, p=0.578, p<0.001, p<0.001, respectively). On multivariate analysis, better response to first-line therapy (CR/PR: HR=0.751, p=0.002; SD: HR=0.781, p=0.021) and progression within 3-6 months (HR=0.626, p<0.001), together with adenocarcinoma (HR=0.815, p=0.017), without liver metastasis (HR=0.541, p=0.001), never-smoker(HR=0.772, p=0.001), and ECOG PS 0-1 (HR=0.745, p=0.021) were predictors for good OS following secondline chemotherapy. Conclusions: Patients who responded to first-line chemotherapy had a better outcome after second-line therapy for advanced NSCLC, and the efficacy of first-line chemotherapy, period of progression, histology, liver metastasis, smoking status and ECOG PS were independent prognostic factors for OS.     

A NAD(P)H:quinone oxidoreductase 1 polymorphism is a risk factor for human colon cancer.

Colon cancer is one of the most common cancers in North America and generally develops from colonic epithelial cells following initiation by carcinogens. We have shown that the phase II detoxifying enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1) contributes to the inhibition of carcinogen-induced colon cancer in rats at both the initiation and postinitiation stages. An inactivating polymorphism at base 609 of the NQO1 gene, (609)C (NQO1 *1) --> (609)T (NQO1 *2), occurs at high frequency in the human population. Thus, we carried out a case-control study to determine if this polymorphism is associated with an increased risk of developing colon cancer. A total of 298 patients with colon cancer and 349 healthy controls matched for age, gender, and ethnic origin were enrolled in the study. There was an increased incidence of the NQO1 *2/*2 genotype in patients with colon cancer, with a gender and age-adjusted odds ratio of 2.68 (95% confidence intervals, 1.14-6.28). However, the incidence of the NQO1 *1/*2 genotype was not increased in patients with colon cancer compared with controls. When the patient and control groups were stratified by tobacco and alcohol use, the incidences of the NQO1 *2/*2 genotype were increased in patients with colon cancer for tobacco and alcohol users and nonusers, suggesting that there is no interaction between the NQO1 base 609 polymorphism and tobacco or alcohol use. These results strongly suggest that NQO1 plays a significant role in preventing the development of colon cancer, and individuals with an NQO1 *2/*2 genotype are at an increased risk of developing this disease.     

Influence of tumor volume on survival in patients irradiated for non-small-cell lung cancer

PURPOSE: To investigate the importance of CT-defined total tumor volume (TTV) on overall survival (OS) in patients with unresectable or medically inoperable non-small-cell lung carcinoma (NSCLC). METHODS AND MATERIALS: Between 1991 and 1998, 150 evaluable patients with Stage I-IIIB NSCLC were treated with three-dimensionally planned conformal radiotherapy and curative intent at Duke University Medical Center. On the treatment-planning CT, the primary tumor and nodal volumes were identified and subsequently combined to form the TTV. The TTV was compared with the stage and outcome with respect to OS, local progression-free survival, and distant failure-free survival using the Kruskall-Wallis analysis of variance and Kaplan-Meier actuarial method. To account for the potentially confounding effects of therapeutic and patient-specific covariates on survival, the Cox proportional hazard regression model was used. RESULTS: The TTVs in patients with Stage I disease (median 19 cm3) were smaller than in patients with Stage II (median 80 cm3) or Stage III (median 97 cm3; p <0.001) disease. The Stage II TTVs were not significantly different from those of Stage III (post-hoc test according to Bonferroni). Prolonged OS was independently associated with a small TTV (<80 vs. >80 cm3 [median]; p = 0.01), young age (<60 vs. > or =60 years; p = 0.03), high Karnofsky performance status (< o r =70 vs. >70; p = 0.04), and female gender (p = 0.04). Both stage (p = 0.7) and T stage (p = 0.06) were of less importance for OS than was the TTV, according to multivariate modeling. Increased local progression-free survival (p = 0.001) and distant failure-free survival (p = 0.03) were independently associated with a small TTV (i.e., <80 cm3). The results were unchanged if the TTV was analyzed as a continuous variable. CONCLUSION: A strong independent association between a small CT-defined TTV and prolonged survival in patients with NSCLC selected for curative/definitive RT was found. Future therapeutic studies in NSCLC should consider stratifying/adjusting for differences in TTV to avoid confounding effects on survival from variations in the TTV at baseline.     

Association between polymorphisms in xenobiotic detoxification-related genes with prognosis of epithelial ovarian cancer

This study aimed to evaluate whether GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G and NQO2 c.-102A>C polymorphisms, involved in xenobiotic detoxification pathways, alter outcomes of epithelial ovarian cancer (EOC) patients. DNA from 84 EOC patients diagnosed at the University of Campinas Academic Hospital from January 1995 and July 2007 was analyzed by polymerase chain reaction and restriction fragment length polymorphism assays. The prognostic impact of genotypes of polymorphisms on progression-free survival and overall survival (OS) of EOC patients was examined using the Kaplan–Meier probability estimates and univariate and multivariate Cox proportional hazard ratio (HR) regression analyses. The significant results of Cox analyses were validated using a bootstrap resampling study (1000 replications). At 60 months of follow-up, lower OS was seen in patients with GSTT1 null genotype (50.0 vs. 76.7 %, P = 0.02) compared with the other genotype (Kaplan–Meier estimate). This outcome remained the same in univariate Cox analysis (HR 2.22, P = 0.02). After multivariate Cox analysis, patients with GSTT1 null (HR 2.11, P = 0.04, P _bootstrap = 0.04) and NQO2 AA (HR 2.13, P = 0.03, P _bootstrap = 0.04) genotypes were under greater risks of progressing to death when compared with those with others genotypes. Our data suggest, for the first time, that inherited abnormalities in xenobiotic detoxification pathway related to GSTT1 and NQO2 c.-102A>C polymorphisms act as independent prognostic factors for OS of EOC patients.     

Weekly and 3-weekly cisplatin concurrent with intensity-modulated radiotherapy in locally advanced head and neck squamous cell cancer

In loco-regionally advanced head and neck squamous cell cancer (HNSCC), concurrent 3-weekly cisplatin improves overall survival (OS) compared to radiotherapy alone, but is often associated with renal toxicity. The use of radiotherapy with accelerated fractionation schedules has been reported to improve survival but its optimal combination with chemotherapy is unclear. Retrospective analysis of treatment outcome and nephrotoxicity of radiotherapy given with an intensity-modulated approach (IMRT) concurrent with either 3-weekly or weekly cisplatin in 94 patients with stage III/IV HNSCC. Patients treated with weekly cisplatin were significantly older (p=0.0014) and received a significantly lower total cisplatin dose (p=0.0002). With a median follow-up of 2.8 years, at univariate analysis, 3-weekly cisplatin shows a longer OS (p=0.041) but progression-free survival (PFS) is similar for both schedules (p=0.47). Cisplatin doses >240 mg/m(2) were associated with better OS but not PFS. Chronic renal failure rate was significantly higher with 3-weekly cisplatin (p=0.04). Multivariate analysis (Cox regression controlling for age) confirmed the significant and independent impact of alcohol and smoking habits on both PFS (HR, 2.2) and OS (HR, 2.3), while the treatment schedule affected only OS (HR, 2.2). Weekly cisplatin is less nephrotoxic. Both schedules can be combined to curative IMRT. PFS was not significantly different even if patients treated with the weekly schedule were significantly older and received reduced cisplatin doses. The study suggests that the different cisplatin dose doesn't affect the PFS results if concomitant to IMRT. Controlled prospective studies are needed.     

The association between the ERCC1/2 polymorphisms and the clinical outcomes of the platinum-based chemotherapy in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis

The relationship between the ERCC1/2 single nucleotide polymorphisms (SNPs) and the clinical outcomes of the platinum-based chemotherapy in the non-small cell lung cancer (NSCLC) is still inconsistent and inconclusive despite extensive investigations have been conducted to address this question. In this meta-analysis, we aim to further explore the prognostic value of the ERCC1/2 SNPs in NSCLC by analyzing all currently available evidences. Relevant studies were searched in PubMed, Embase, and China National Knowledge Infrastructure. The inclusion criteria were platinum-based chemotherapy in NSCLC patients and evaluation of clinical outcomes in relation to the ERCC1 C118T, ERCC1 C8092A, ERCC2 Asp312Asn, and ERCC2 Lys751Gln. Clinical outcomes analyzed in this study included the overall response rate, overall survival (OS), and progression-free survival (PFS). Odds ratio (OR) or hazard ratio (HR) with 95 % confidence interval (CI) were calculated to examine the risk or hazard associated with each SNP. A total of 46 studies including 9,407 NSCLC patients were qualified for this meta-analysis. For ERCC1 C118T, the T allele was associated with a poor OS (HR?=?1.35, 95 % CI?=?1.04–1.75); for ERCC2 Asp312Asn, the Asn variant was linked to an unfavorable OS (HR?=?2.07, 95 % CI?=?1.11–3.88); and for ERCC2 Lys751Gln, patients with the Gln variant have a worse OS (HR?=?1.22, 95 % CI?=?1.05–1.41) and PFS (HR?=?1.35, 95 % CI?=?1.07–1.71). In addition, the main findings of the ERCC1/2 SNPs on chemotherapy toxicity were also summarized. This meta-analysis suggested that the ERCC1 C118T, ERCC2 Asp312Asn, and Lys751Gln may be useful biomarkers to predict the clinical outcomes of the platinum-based chemotherapy in NSCLC patients.     

Body Mass Index Influences the Salutary Effects of Metformin on Survival After Lobectomy for Stage I NSCLC

IntroductionMetformin, a common medication used in the treatment of diabetes mellitus is known to have anticancer effects. We hypothesized that the salutary effect of metformin on the survival of patients with stage I NSCLC is influenced by body mass index (BMI).MethodsPatients undergoing lobectomy for stage I NSCLC without neoadjuvant therapy were included. Univariate and multivariate survival analyses to examine the association between metformin use and overall survival (OS), disease-specific survival (DSS), and recurrence-free survival were performed, stratified by BMI (>25 kg/m² and ≤25 kg/m²). Expression of immune checkpoints in patients on metformin and not was performed in a separate cohort of 205 patients with advanced disease.ResultsFour hundred thirty-four stage I patients (including 74 metformin users) were deemed eligible for analysis. Univariate and multivariate analysis revealed an association between metformin use and OS (hazard ratio [HR] = 0.52; p = 0.04) as well as DSS (HR = 0.21; p = 0.04) but not recurrence-free survival (HR = 0.67; p = 0.33) in high-BMI patients only. In a separate cohort of 205 patients with tumors of all stages (including 35 metformin users), downregulation of immune checkpoint gene expression (programmed cell death 1, cytotoxic T-lymphocyte associated protein 4, B and T lymphocyte associated, CD27 molecule, lymphocyte activating 3, and inducible T cell costimulator) in metformin users was seen only in high-BMI patients, with upregulation of these genes seen in low-BMI patients with metformin use.ConclusionsMetformin use may be associated with better OS and DSS only in high-BMI patients. This hypothesis is supported by gene expression data of immune checkpoint genes in metformin users using a separate cohort of advanced-stage tumors. Further studies examining the interaction of BMI with metformin in NSCLC are worthwhile.     

KRAS突变晚期非小细胞肺癌分子分型、治疗及预后分析

目的:分析晚期Kirsten鼠类肉瘤(Kirsten rat sarcoma,KRAS)突变非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床病理特征、分子分型、治疗及预后。方法:回顾性分析2019年01-2022年01我院33例晚期KRAS+NSCLC患者的临床病理资料。分析KRAS亚型、TP53共突变及不同治疗方案和生存预后的相关性。结果:33例晚期KRAS+NSCLC患者,男性大约占90.9%（30/33);KRAS p.G12C突变为最常见分子分型,约42.4%（14/33）;另外,KRAS p.G12C突变人群对比其他KRAS突变患者,无进展生存期（progression-free survival,PFS)(6.5个月 vs 7.0个月;P=0.799)和总生存(overall survival,OS)(18.0个月 vs 24.0个月;P=0.266)均未见显著差异。亚组分析中,免疫联合化疗对比化疗+抗血管和单一化疗,可延长PFS(13.5个月 vs 7.5个月 vs 5.5个月;P=0.033),但OS却未见差异(25.0个月 vs 18.0个月 vs 25.0个月;P=0.854)。KRAS+/TP53+ NSCLC对比KRAS+/TP53-NSCLC,显著缩短PFS(5.5个月 vs 7.5个月;P=0.019)和OS(18.0个月vs 28.0个月;P=0.004)。多因素分析发现TP53共突变（HR=3.394;P=0.005）、治疗方案（HR=0.473;P=0.003）为PFS的预后因素;TP53共突变（HR=8.235;P=0.004）为OS的独立预后因素。结论:中国人群中,晚期KRAS+NSCLC患者男性较为多见,p.G12C为最常见分子分型。免疫治疗联合化疗可能延长晚期KRAS+NSCLC的PFS,但仍需进一步探索;TP53共突变可能为晚期KRAS+NSCLC不良预后因素。晚期NSCLC中KRAS和TP53共突变患者的治疗及预后需要进一步探索。     

Effect of body mass index on survival of patients with stage I non-small cell lung cancer

Background:Body mass index (BMI) has a U-shaped association with lung cancer risk.However,the effect of BMI on prognosis is controversial.This retrospective study aimed to investigate the effect of BMI on the survival of patients with stage I non-small cell lung cancer (NSCLC) after surgical resection.Methods:In total,624 consecutive stage I NSCLC patients who underwent radical resection were classified into four groups according to their BMI:underweight (BMI ＜ 18.5 kg/m2),normal weight (BMI =18.5-22.4 kg/m2),overweight (BMI =22.5-28.0 kg/m2),and obese (BMI ＞ 28.0 kg/m2).The effect of BMI on progression-free survival (PFS) and overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional hazards model.Postoperative complications in each group were analyzed using the Chi square test or Fisher's exact test.Results:A univariate analysis showed that PFS and OS were longer in the overweight group than in other groups (both P ＜ 0.05).A multivariate analysis showed that OS was longer in the overweight group than in other groups (compared with the other three groups in combination:hazard ratio [HR] =1.87,95％ confidence interval [CI] 1.30-2.68,P =0.003;compared with the underweight group:HR =2.24,95％ CI 1.18-4.25,P =0.013;compared with the normal weight group:HR =1.58,95％ CI 1.07-2.33,P =0.022;compared with the obese group:HR =2.87,95％ CI 1.48-5.59,P =0.002),but PFS was similar among the groups (HR =1.28,95％ CI 0.97-1.68,P =0.080).A subgroup analysis showed an association between being overweight and prolonged OS in patients at stage T1a (P =0.024),T1 b (P =0.051),and T2a (P =0.02),as well as in patients with a non-smoking history (P =0.001).Overweight patients had lower rates of postoperative complications,such as respiratory failure (compared with the underweight and obese groups:P =0.014),myocardial infarction (compared with the obese group:P=0.033),and perioperative death (compared with the other three groups:P=0.016).Conclusions:Preoperative BMI is an independent prognostic factor for stage I NSCLC patients after resection,with overweight patients having a favorable prognosis.