Binghe Xu

Polymorphisms of EGFR predict clinical outcome in advanced non-small-cell lung cancer patients treated with Gefitinib

PURPOSEnGenetic variations in EGFR may alter protein function and therefore the therapeutic efficacy of epidermal growth factor receptor inhibitors. This study investigated the association between polymorphisms in EGFR and clinical outcome in patients with advanced non-small-cell lung cancer (NSCLC) treated with Gefitinib.nnnMETHODSnA whole gene-based tag-SNP approach was used to determine the candidate SNPs in EGFR. Four tag SNPs, one CA simple sequence repeat (CA-SSR) in intron 1, one coding region SNP (R521K), and SNPs identified by resequencing in the tyrosine kinase domain of EGFR were selected to analyze their association with therapeutic outcome and survival in 84 advanced NSCLC patients treated with Gefitinib. Progression-free and overall survivals were computed by Cox model adjusted for clinical factors.nnnRESULTSnWe identified two EGFR polymorphisms, rs2293347 (D994D) and CA-SSR in intron 1, associated with clinical outcome of Gefitinib therapy. The response rate for the rs2293347GG or shorter CA repeat genotype was significantly higher than that for the rs2293347GA or AA or longer CA repeat genotype (71.2% versus 37.5%, P=0.0043 and 88.5% versus 48.3%, P=0.0005). The rs2293347GG genotype was also associated with longer progression-free survival compared with the rs2293347GA or AA genotype (11 months versus 3 months, P=0.0018). A combination of rs2293347GG and shorter CA repeat genotypes had more pronounced clinical benefit.nnnCONCLUSIONnThe D994D and CA-SSR polymorphisms in EGFR are potential predictors for clinical outcome in advanced NSCLC patients treated with Gefitinib.

XRCC1 polymorphisms and severe toxicity in lung cancer patients treated with cisplatin-based chemotherapy in Chinese population

Cisplatin kills tumor cells through DNA cross linking. Alterations in the function of DNA repair genes may affect DNA repair proficiency and influence cancer patients response to cisplatin. The predictability of DNA repair XRCC1 (X-ray repair cross-complementing group 1 protein) single nucleotide polymorphisms (SNPs) for cisplatin-based grades 3 and 4 chemotherapy-related toxicity in patients with newly diagnosed advanced lung cancer was evaluated. The genotypes of XRCC1 at the Arg194Trp, and Arg399Gln sites were determined by PCR-based restriction fragment length polymorphism (RFLP) methods. There was no statistically significant association between either the Arg194Trp or the Arg399Gln polymorphisms and hematologic grade 3 or 4 toxicity. However, carrying at least one variant XRCC1 Arg399Gln allele (399Arg/Gln or 399Gln/Gln) was associated with a significantly increased risk of overall grade 3 or 4 toxicity (odds ratio, 2.05; 95% confidence interval, 1.02-4.10; p=0.04); and grade 3 or 4 gastrointestinal toxicity (odds ratio, 2.53; 95% confidence interval, 1.06-6.03; p=0.03). Our results suggested that patients carrying at least one variant XRCC1 Arg399Gln allele have a 2.5-fold increased risk of grade 3 or 4 gastrointestinal toxicity when treated with first-line cisplatin-based chemotherapy.

The emerging role of hypoxia-inducible factor-2 involved in chemo/radioresistance in solid tumors.

The hypoxic condition is a common feature that negatively impacts the efficacy of radio- and chemotherapy in solid tumors. Hypoxia-inducible factors (HIF-1, 2, 3) predominantly regulate the adaptation to hypoxia at the cellular or organismal level. HIF-2 is one of the three known alpha subunits of HIF transcription factors. Previous studies have shown that HIF-1 is associated with chemotherapy failure. Accumulating evidence in recent years suggests that HIF-2 also contributes to chemo/radioresistance in solid tumors. Despite sharing similar structures, HIF-1α and HIF-2α had highly divergent and even opposing roles in solid tumors under hypoxic conditions. Recent studies have also implied that HIF-2α had a role in chemo/radioresistance through different mechanisms, at least partly, compared to HIF-1α. The present paper summarizes the function of HIF-2 in chemo/radioresistance in solid tumors as well as some of its novel mechanisms that contributed to this pathological process.

Cross-talk between EPAS-1/HIF-2α and PXR signaling pathway regulates multi-drug resistance of stomach cancer cell.

EPAS-1/HIF-2α (Endothelial PAS domain-containing protein 1/hypoxia-inducible transcription factors 2α) is a transcription factor expressed in a wide range of human cancers, including stomach cancer. Although EPAS-1 has been studied for years, its function in oncogenic transformation processes needs to be further investigated. In this study, we found that EPAS-1 would promote the growth of stomach cancer cell line BGC-823. Our results revealed that EPAS-1 interacts with Pregnane X Receptor (PXR), a nuclear receptor that regulates multiple genes transcription involved in multi-drugs resistance (MDR) process. Protein-protein interaction between EPAS-1 and PXR was identified by co-immunoprecipitation and GST-pull down assays. By this interaction, EPAS-1 recruited PXR to its response elements in promoter/enhancer regions of CYP3A4, a PXR target gene. Over-expression of EPAS-1 increased the expression of PXR responsive genes, enhanced the proliferation of BGC-823 cells and boosted the resistance of BGC-823 cells against the cytotoxicity of chemotherapeutic drugs, e.g. Mitomycin C and Paclitaxel. Reduction of EPAS-1 level via its siRNA disrupted the proliferation, and enhanced the susceptibility of BGC-823 cells to those chemotherapeutic drugs. Our findings suggested that EPAS-1 and PXR may cooperatively participate in development and especially MDR process of stomach cancer. These findings may contribute to more effective targeted drugs discovery for the stomach cancer therapy.

No association between XRCC1 polymorphisms and survival in non-small-cell lung cancer patients treated with platinum-based chemotherapy

Purpose: Genetic polymorphisms in DNA repair genes are thought to represent important determinants of platinum drug efficacy. The current study investigated whether single nucleotide polymorphisms (SNPs) in the X-ray repair cross complementing protein 1 (XRCC1) gene are associated with survival in non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. Experimental design: A total of 199 platinum-treated patients with stage III-IV NSCLC were recruited. Overall survival (OS) and progression-free survival (PFS) according to genotypes and haplotypes were analyzed using Kaplan-Meier method and assessed by log-rank test. Hazard ratios (HRs) were calculated using Cox proportional hazards models by adjusting for clinical factors. Results: During the median 26.5 months of follow-up, 159 deaths occurred. Regarding XRCC1 Arg194Trp, Arg280His, and Arg399Gln genotypes, no significant effects on survival were observed, although the 280Arg/His genotype was associated with a borderline-significant higher median survival time (20.0 months for Arg/His versus 16.0 months for Arg/Arg; P = 0.131). Moreover, no significant association of haplotypes with survival was found. Conclusions: This study showed no influence of the XRCC1 Arg194Trp, Arg280His, and Arg399Gln polymorphisms on survival in advanced NSCLC patients with platinum-based chemotherapy.

53BP1 depletion causes PARP inhibitor resistance in ATM-deficient breast cancer cells

BackgroundMutations in DNA damage response factors BRCA1 and BRCA2 confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors in breast and ovarian cancers. BRCA1/BRCA2-defective tumors can exhibit resistance to PARP inhibitors via multiple mechanisms, one of which involves loss of 53BP1. Deficiency in the DNA damage response factor ataxia-telangiectasia mutated (ATM) can also sensitize tumors to PARP inhibitors, raising the question of whether the presence or absence of 53BP1 can predict sensitivity of ATM-deficient breast cancer to these inhibitors.MethodsCytotoxicity of PARP inhibitor and ATM inhibitor in breast cancer cell lines was assessed by MTS, colony formation and apoptosis assays. ShRNA lentiviral vectors were used to knockdown 53BP1 expression in breast cancer cell lines. Phospho-ATM and 53BP1 protein expressions were determined in human breast cancer tissues by immunohistochemistry (IHC).ResultsWe show that inhibiting ATM increased cytotoxicity of PARP inhibitor in triple-negative and non-triple-negative breast cancer cell lines, and depleting the cells of 53BP1 reduced this cytotoxicity. Inhibiting ATM abrogated homologous recombination induced by PARP inhibitor, and down-regulating 53BP1 partially reversed this effect. Further, overall survival was significantly better in triple-negative breast cancer patients with lower levels of phospho-ATM and tended to be better in patients with negative 53BP1.ConclusionThese results suggest that 53BP1 may be a predictor of PARP inhibitor resistance in patients with ATM-deficient tumors.

Age-related disparity in immediate prognosis of Patients with Triple-negative breast cancer: A population-based study from SEER cancer registries

Background Triple-negative breast cancer (TNBC) has been demonstrated to carry poor prognosis, but whether or not there exists any age-related variation in TNBC outcomes has yet to be elucidated. The current population-based study investigated the early survival pattern of elderly women with TNBC and identified outcome-correlated factors. Patients and Methods We searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled female primary non-metastatic TNBC cases. The patients were subdivided into elderly (≥70 years) and young groups (<70 years). The survival status of elderly patients was compared to that of the younger women. The primary and secondary endpoints were cancer-specific survival (CSS) and overall survival (OS) respectively. Results 9908 female TNBC patients diagnosed from 2010 to 2011 were included in the current study (20.4% elderly). Elderly patients with relatively advanced diseases exhibited distinctly worse cancer-specific (log-rank, p<0.001) and overall survival (log-rank, p<0.001) than their young counterparts. Advanced age at diagnosis (≥70 years) was significantly predictive of poor outcome in terms of CSS (hazard ratio (HR), 2.125; 95% confidence interval (CI), 1.664 to 2.713; p<0.001) and OS (HR, 3.042; 95%CI, 2.474 to 3.740; p<0.001). Underuse of curative treatment especially radiotherapy was more prevalent in elderly women with stage II or III diseases than in younger patients. Conclusion Elderly patients with TNBC displayed elevated early mortality within the first two years of diagnosis compared to the younger individuals. The observed lower rate of loco-regional treatment might be associated with worse cancer-specific outcome for these patients.

Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first‐line treatment of patients with advanced breast cancer: Phase 3 randomized trial

In this prospective study, progression‐free survival (PFS) and the safety profiles of docetaxel/capecitabine (TX) and vinorelbine/capecitabine (NX) followed by capecitabine maintenance therapy were compared in patients with metastatic breast cancer.

Decreased serum HDL at initial diagnosis correlates with worse outcomes for triple-negative breast cancer but not non-TNBCs.

Purpose This study aimed to evaluate the associations between metabolic syndrome (MS) and its components at initial diagnosis and outcomes of breast cancer including triple-negative breast cancer (TNBC) and non-TNBC. Methods A cohort of 1,391 patients was reviewed between January 2004 and July 2008 (including 394 TNBC and 855 non-TNBC cases). MS and its components including body mass index (BMI), serum high-density lipoprotein (HDL) and triglycerides (TG) and their relationships with clinical outcomes were analyzed and then compared between groups. Results The incidences of MS and its components including BMI, the levels of HDL and TG were not differently distributed between the 2 groups (all ps >0.05). However, more TNBC than non-TNBC patients presented with hypertension and elevated serum glucose (20.3% vs. 14.9% and 16.0% vs. 10.8%, p = 0.018 and p = 0.012, respectively). TNBC patients had poorer 5-year relapse-free survival (RFS) than non-TNBC patients (72.8% vs. 84.2%, p<0.0001). Only in the TNBC group, patients with low high-density lipoprotein (HDL) demonstrated worse RFS and overall survival (OS; p<0.0001). Multivariate analysis identified that low HDL was an independent worse prognostic factor for both RFS (hazard ratio [HR] = 3.266, 95% confidence interval [95%CI], 2.087-5.112, p<0.0001) and OS (HR = 3.071, 95%CI, 1.732-5.445, p<0.0001) in TNBC patients. Conclusions Decreased level of HDL may predict worse outcomes both in terms of RFS and OS for TNBC patients but not for non-TNBC patients. Further investigations are warranted to detect the underlying mechanisms.

Association of GWAS-Identified Lung Cancer Susceptibility Loci with Survival Length in Patients with Small-Cell Lung Cancer Treated with Platinum-Based Chemotherapy

Genetic variants have been shown to affect length of survival in cancer patients. This study explored the association between lung cancer susceptibility loci tagged by single-nucleotide polymorphisms (SNPs) identified in the genome-wide association studies and length of survival in small-cell lung cancer (SCLC). Eighteen SNPs were genotyped among 874 SCLC patients and Cox proportional hazards regression was used to examine the effects of genotype on survival length under an additive model with age, sex, smoking status and clinical stage as covariates. We identified 3 loci, 20q13.2 (rs4809957G >A), 22q12.2 (rs36600C >T) and 5p15.33 (rs401681C >T), significantly associated with the survival time of SCLC patients. The adjusted hazard ratio (HR) for patients with the rs4809957 GA or AA genotype was 0.80 (95% CI, 0.66–0.96; Pu200a=u200a0.0187) and 0.73 (95% CI, 0.55–0.96; Pu200a=u200a0.0263) compared with the GG genotype. Using the dominant model, the adjusted HR for patients carrying at least one T allele at rs36600 or rs401681 was 0.78 (95% CI, 0.63–0.96; Pu200a=u200a0.0199) and 1.29 (95% CI, 1.08–1.55; Pu200a=u200a0.0047), respectively, compared with the CC genotype. Stratification analyses showed that the significant associations of these 3 loci were only seen in smokers and male patients. The rs4809957 SNP was only significantly associated with length of survival of patients with extensive-stage but not limited-stage tumor. These results suggest that some of the lung cancer susceptibility loci might also affect the prognosis of SCLC.