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Hua Bai,
Zhijie Wang,
Yuyan Wang,
Minglei Zhuo,
Qinghua Zhou,
Jianchun Duan,
Lu Yang,
Meina Wu,
Tongtong An,
Jun Zhao, Jie Wang
[show abstract]
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ABSTRACT: This study evaluated occurrence and potential clinical significance of intratumoral EGFR mutational heterogeneity in Chinese patients with non-small cell lung cancer (NSCLC).
Eighty-five stage IIIa-IV NSCLC patients who had undergone palliative surgical resection were included in this study. Of these, 45 patients carried EGFR mutations (group-M) and 40 patients were wild-type (group-W). Each tumor sample was microdissected to yield 28-34 tumor foci and Intratumoral EGFR mutation were determined using Denaturing High Performance Liquid Chromatography (DHPLC) and Amplification Refractory Mutation System (ARMS). EGFR copy numbers were measured using fluorescence in situ hybridization (FISH).
Microdissection yielded 1,431 tumor foci from EGFR mutant patients (group-M) and 1,238 foci from wild-type patients (group-W). The EGFR mutant frequencies in group-M were 80.6% (1,154/1,431) and 87.1% (1,247/1,431) using DHPLC and ARMS, respectively. A combination of EGFR-mutated and wild-type cells was detected in 32.9% (28/85) of samples by DHPLC and 28.2% (24/85) by ARMS, supporting the occurrence of intratumoral heterogeneity. Thirty-one patients (36.5%) were identified as EGFR FISH-positive. Patients harboring intratumoral mutational heterogeneity possessed lower EGFR copy numbers than those tumors contained mutant cells alone (16.7% vs. 71.0%, P<0.05). Among 26 patients who had received EGFR-TKIs, the mean EGFR mutation content was higher in patients showing partial response (86.1%) or stable disease (48.7%) compared with patients experiencing progressive disease (6.0%) (P = 0.001). There also showed relationship between progression-free survival (PFS) and different content of EGFR mutation groups (pure wild type EGFR, EGFR mutation with heterogeneity and pure mutated EGFR) (P = 0.001).
Approximately 30% of patients presented intratumoral EGFR mutational heterogeneity, accompanying with relatively low EGFR copy number. EGFR mutant content was correlated with the response and prognosis of EGFR-TKIs.
PLoS ONE 01/2013; 8(2):e54170. · 4.09 Impact Factor
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Shuhang Wang,
Tongtong An,
Jianchun Duan,
Lijian Zhang,
Meina Wu,
Qinghua Zhou,
Jinfeng Chen,
Minglei Zhuo,
Lu Yang,
Yuyan Wang,
Hua Bai, Jie Wang
[show abstract]
[hide abstract]
ABSTRACT: Genetic aberrancies within epidermal growth factor receptor (EGFR) pathway are associated with therapeutic outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, the impact of chemotherapy on EGFR-related genes alterations has not been defined in NSCLC. Our study aims to investigate the impact of neoadjuvant chemotherapy (Neoadj-Chemo) on EGFR activating mutations and associated EGFR-TKIs resistance-related genes.
Matched tumor samples were obtained retrospectively from 66 NSCLC patients (stages IIb-IIIb) corresponding to pre- and post- Neoadj-Chemo. EGFR mutations were detected by denaturing high performance liquid chromatography (DHPLC) and confirmed by Amplification Refractory Mutation System technology (ARMS), KRAS mutations, T790M mutation and c-MET amplification were identified using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), ARMS, and real-time PCR, respectively.
Before Neoadj-Chemo, EGFR mutations were identified in 33.3% (22/66) of NSCLC patients. Only 18.2% (12/66) of patients carried EGFR mutations after Neoadj-Chemo (p = 0.013). The median peak value of EGFR 19 exon mutations decreased non-significantly after Neoadj-Chemo. KRAS mutation rate decreased from 4.6% (3/66) to 3.0% (2/66) with Neoadj-Chemo. Although the overall percentage of patients exhibiting c-MET amplifications (6.1% [4/66]) did not change with Neoadj-Chemo, two patients transitioned from negative to positive c-MET amplification, and two patients reversed these changes post-Neoadj-Chemo. T790M mutations were absent from all samples.
Neoadjuvant chemotherapy tends to decrease the mutation frequency of EGFR mutation and downstream genes, which suggests that real-time samples analysis for genetic aberrancies within EGFR pathways have important value to delineate specific patient populations and facilitate individualized treatment.
PLoS ONE 01/2013; 8(3):e51021. · 4.09 Impact Factor
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Jian Zhu,
Jianchun Duan,
Hua Bai,
Zhijie Wang,
Lai Wei,
Jun Zhao,
Minglei Zhuo,
Shuhang Wang,
Lu Yang,
Tongtong An,
Meina Wu,
Yuyan Wang, Jie Wang
[show abstract]
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ABSTRACT: BACKGROUND: It is well known that genetic alternation of epidermal growth factor receptor (EGFR) plays critical roles in tumorgenesis of lung cancer and can predict outcome of non-small-cell lung cancer treatment, especially the EGFR tyrosine-kinase inhibitors (EGFR-TKIs) therapy. However, it is unclear whether epigenetic changes such as DNA methylation involve in the response to the EGFR-TKI therapy. METHODS: Tumor samples from 155 patients with stages IIIB to IV NSCLC who received EGFR-TKI therapy were analyzed for DNA methylation status of Wnt antagonist genes, including SFRP1, SFRP2, SFRP5, DKK3, WIF1, and APC, using methylation specific PCR (MSP) method. EGFR mutations detections were performed in the same tissues samples using Denaturing High Performance Liquid Chromatography (DHPLC). RESULTS: We found that Wnt antagonists tend to methylate simultaneously. Methylation of sFRP1 and sFRP5 are reversely correlated with EGFR mutation(P = 0.005, P = 0.011). However, no correlations of methylations of other Wnt antagonist genes with EGFR mutation were found. The patients with methylated SFRP5 have a significant shorter progression free survival than those with unmethylated SFRP5 in response to EGFR-TKI treatment (P = 0.002), which is independent of EGFR genotype. CONCLUSIONS: Patients with unmethylated SFRP5 are more likely to benefit from EGFR-TKI therapy.
Journal of Experimental & Clinical Cancer Research 09/2012; 31(1):80. · 2.15 Impact Factor
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Zhijie Wang,
Xuchao Zhang,
Hua Bai,
Jun Zhao,
Minglei Zhuo,
Tongtong An,
Jianchun Duan,
Lu Yang,
Meina Wu,
Shuhang Wang,
Yuyan Wang,
Yilong Wu, Jie Wang
[show abstract]
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ABSTRACT: Objective: To identify the clinicopathological characteristics and clinical outcomes of Chinese patients with non-small cell lung cancer (NSCLC) and to investigate possible associations of NSCLC with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at the Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization and confirmed by immunohistochemistry. EGFR mutations were determined using denaturing high-performance liquid chromatography. Results: The incidence of EML4-ALK was 9.7% (11/113). Patients with EML4-ALK were more likely to present the EGFR wild type (WT; p = 0.033). Response to EGFR-tyrosine kinase inhibitor (TKI) was similar between patients with EML4-ALK rearrangement and EGFR mutation (33.3 vs. 46.9%, p = 0.451), but progression-free survival (PFS) was inferior compared to those with EGFR mutation (2.1 vs. 8.8 months, p = 0.032), and similar to patients with WT/nonrearrangement (2.1 vs. 2.2 months, p = 0.696; and general p = 0.023 between the three cohorts). Moreover, 2 patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared to patients with single EML4-ALK rearrangement. Conclusions: Patients with EML4-ALK conferred similar objective response rates after EGFR-TKI although inferior PFS compared to those with EGFR mutation. Coexistence of EML4-ALK and EGFR mutation might represent a separate NSCLC genotype.
Oncology 09/2012; 83(5):248-256. · 2.27 Impact Factor
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ABSTRACT: BACKGROUND: EGFR mutation is a strong predictive factor of EGFR-TKIs therapy. However, at least 10% of patients with EGFR wild-type are responsive to TKIs, suggesting that other determinants of outcome besides EGFR mutation might exist. We hypothesized that activation of phosphorylated EGFR could be a potential predictive biomarker to EGFR-TKIs treatment among patients in wild-type EGFR. METHOD: Total of 205 stage IIIb and IV NSCLC patients, tissue samples of whom were available for molecular analysis, were enrolled in this study. The phosphorylation of EGFR at tyrosine 1068 (pTyr1068) and 1173 (pTyr1173) were assessed by immunohistochemistry, and EGFR mutations were detected by denaturing high performance liquid chromatograph (DHPLC). RESULTS: Among 205 patients assessable for EGFR mutation and phosphorylation analysis, 92 (44.9%) were EGFR mutant and 165 patients (57.6%) had pTyr1173 expression. Superior progression-free survival (PFS) was seen after EGFR-TKIs therapy in patients with pTyr1068 expression compared to pTyr1068 negative ones (median PFS 7.0 months vs. 1.2 months, P<0.001). Inversely, patients with pTyr1173 had a shorter PFS (4.8 months VS. 7.7 months, P=0.016). In subgroup of patients with wild-type EGFR, pTyr1068 expression positive ones had a significantly prolonged PFS (4.2 months vs.1.2 months P<0.001) compared with those without pTyr1068 expression.Sixteen patients with both wild-type EGFR and pTyr1068 who responded to EGFR-TKIs had median PFS of 15.6 months (95%CI: 7.28-23.9). CONCLUSION: pTyr1068 may be a predictive biomarker for screening the population for clinical response to EGFR-TKIs treatment; especially for patients with wild-type EGFR.
Journal of Experimental & Clinical Cancer Research 08/2012; 31(1):65. · 2.15 Impact Factor
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Hua Bai,
Zhijie Wang,
Keneng Chen,
Jun Zhao,
J Jack Lee,
Shuhang Wang,
Qinghua Zhou,
Minglei Zhuo,
Li Mao,
Tongtong An,
Jianchun Duan,
Lu Yang,
Meina Wu,
Zhen Liang,
Yuyan Wang,
Xiaozheng Kang, Jie Wang
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ABSTRACT: EGFR mutation is a predictor of epidermal growth factor receptor-tyrosine kinase inhibitor treatment response in patients with non-small-cell lung cancer (NSCLC). However, it remains unclear whether chemotherapy affects EGFR mutation status in NSCLC. We investigated the influence of chemotherapy on EGFR mutations in plasma and tumor tissues from patients with NSCLC.
Samples were derived from three cohorts: one, 264 patients with advanced NSCLC who received first-line chemotherapy with matched pre- and postchemotherapy blood samples; two, 63 patients with stages IIb to IIIb disease with pre- and post-neoadjuvant chemotherapy tumor tissues; and three, 79 patients with advanced NSCLC who underwent palliative surgery. EGFR mutation status was determined and analyzed to reveal potential impact of chemotherapy.
In the first cohort, EGFR mutations were detected in 34.5% of the prechemotherapy plasma samples (91 of 264) but in only 23.1% of the postchemotherapy plasma samples (61 of 264). The decrease in EGFR mutation rate was statistically significant (P < .001). Patients whose EGFR mutations switched from positive to negative after chemotherapy had a better partial response (PR) than patients with a reverse change (P = .037). A similar decrease in EGFR mutation rate was observed in tissues after neoadjuvant chemotherapy in the second cohort (34.9% [22 of 63] v 19.0% [12 of 63]; P = .013). In the third cohort, 38.0% of the tumors (30 of 79) showed an intratumor heterogeneity of EGFR mutation, whereas 62.0% (49 of 79) were homogeneous, either with EGFR mutation or no mutation.
Our results suggest that chemotherapy may reduce EGFR mutation frequency in patients with NSCLC, likely the result of a preferential response of subclones with EGFR mutations in tumors with heterogeneous tumor cell populations.
Journal of Clinical Oncology 07/2012; 30(25):3077-83. · 18.37 Impact Factor
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ABSTRACT: ObjectiveTo observe the efficacy and safety of cetuximab combined with chemotherapy in advanced non-small-cell lung cancer (NSCLC),
and to investigate the association of status of K-RAS gene mutation and epidermal growth factor receptor (EGFR) genotype with
clinical outcome.
MethodsBetween Jan. 2006 and Sep. 2009, nineteen patients with advanced NSCLC received cetuximab (≥4 weeks) combined with chemotherapy
in Department of Thoracic Oncology at Beijing Cancer Hospital. Response, survival and toxicity were retrospectively assessed,
epidermal growth factor receptor (EGFR) protein expression was evaluated by ELISA Kit. The status of K-RAS gene mutation was
tested by PCR-RFLP and EGFR gene amplification was measured by EGFR fluorescence in situ hybridization (FISH).
ResultsPartial response(PR) was observed in 26.3%(5/19) of the patients and stable disease(SD) in 52.6%(10/19). Median progression
free survival(PFS) was 6 months (95% CI: 3.6–8.4). Median overall survival (MST) and 1-year survival rate(SR) were 10.6 months
(95% CI: 6.6–14.6) and 47.6%, respectively. Mild or moderate skin rash was the most common toxicity related with cetuximab.
K-RAS gene mutation, EGFR protein level and amplification have little correlation with prognosis.
ConclusionCetuximab combined with chemotherapy was tolerable and the skin rash related with cetuximab was mild to moderate. Cetuximab
may prolong survival of the patients who failed to previous chemotherapy.
Chinese Journal of Cancer Research 04/2012; 21(4):265-271. · 0.18 Impact Factor
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ABSTRACT: The presence of epidermal growth factor receptor (EGFR) mutations is predictive of a better response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and initial chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC). The aim of this study is to analyze the association between the EGFR mutations and the outcome of combined chemoradiotherapy in stage III non-squamous NSCLC.
Patients with stage III non-squamous NSCLC whose EGFR mutation status had been identified were retrospectively analyzed. The response of 87 patients to combined chemoradiotherapy, the two-year survival rate, and the response of 128 patients to initial chemotherapy were evaluated.
The response rate to combined chemoradiotherapy was 84.6% (33/39) in EGFR mutation-positive patients, significantly higher than the 56.3% (27/48) response rate in EGFR mutation-negative patients (P=0.004). Two-year survival rates were 53.8% and 50% in EGFR mutation-positive and mutation-negative patients, respectively. There was no significant difference in the overall survival for both patient groups. The overall response rate to initial chemotherapy was 34.5% (19/55) in EGFR mutation-positive patients, compared with the 21.9% (16/73) response rate in EGFR mutation-negative patients.
EGFR mutation-positive status can predict better response to combined chemoradiotherapy, but is not associated with overall survival in patients with stage III non-squamous NSCLC.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 09/2011; 14(9):715-8.
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Meina Wu,
Yuyan Wang,
Tongtong An,
Jun Zhao,
Lu Yang,
Jianchun Duan,
Zhijie Wang,
Minglei Zhuo,
Hua Bai,
Xuyi Liu, Jie Wang
[show abstract]
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ABSTRACT: As there is a sharp increase in the incidence of lung cancer in women in recent years, it has brought broad concerns with its unique clinical and epidemiological characteristics and better prognosis. The aim of this study is to analyze the clinical data of women with advanced non-small cell lung cancer (NSCLC) retrospectively to explore the prognostic factors.
Clinical data of 541 female patients with advanced NSCLC were collected and followed up till death. The primary endpoint is overall survival (OS). SPSS 11.0 statistical analysis software was used for univariate and multivariate analysis.
The mean age is 59 years (20 years-86 years), adenocarcinoma account for 80.2% (434/541). The median OS was 15 months (95%CI: 13.87-16.13), and 1, 2, 5-year survival rates were 58.8%, 23.7% and 3.20% respectively. Univariate analysis showed that clinical stage, ECOG score, weight loss, clinical symptoms, liver/bone/brain metastasis and received more than one chemotherapy regimen, good response to the first-line chemotherapy, EGFR-TKI targeted therapy and radiotherapy treatment were significantly correlated with the OS and survival rate (P < 0.05). Combined with multivariate analysis, weight loss before treatment, ECOG score, received EGFR-TKI targeted therapy and response to first-line chemotherapy were independent prognostic factor for survival (P < 0.05).
There is a higher percentage of adenocarcinoma in female NSCLC. Weight loss before treatment, ECOG score, EGFR-TKI targeted therapy and response to first-line chemotherapy may become independent prognostic factors for survival of female patients with advanced NSCLC.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 03/2011; 14(3):245-50.
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ABSTRACT: The epidermal growth factor receptor tyrosine kinase inhibitor (EGFRTKI) shows favorable antitumor activity against chemorefractory non-small cell lung cancer (NSCLC). However, patients with advanced NSCLC have limited treatment options available if they are refractory to EGFR-TKI. To study the influence of the retreatment EGFR-TKI after failure of first-line TKI, we carried out this retrospective study.
Total 71 patients were analyzed who experienced treatment failure from their initial use of EGFR-TKI. After a period of time, they were retreated with TKI as tumor progression was observed.
Of the 71 patients who received retreatment TKI, it was observed in 7% in partial response (PR), 36.6% in stable disease (SD), 56.3% in progressive disease (PD). Disease control rate (DCR) was 43.7%. Twenty-six (36.6%) patients were well controlled by retreatment with TKI monotherapy for not less than 3 months. Five (7.0%) patients had partial response. Exon 21 mutation, PFS not less than 6 months during initial treatment TKI, and the interval not less than 3 months between initial treatment, and retreatment with TKI was associated with a good progression free survival based on univariate COX analysis (P=0.034; P=0.013; P=0.046).
It has been shown the possibility that retreatment with TKI might be useful when (1) Exon 21 has active mutation, (2) initial treatment shows a favorable PFS (≥ 6 months), and (3) there has been a period of time (≥3 months) following the termination of the initial TKI treatment.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 03/2011; 14(3):261-5.
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ABSTRACT: Gastrointestinal metastasis unusually occurs in primary lung cancer instead of lung, liver, brain, bone and adrenal. Recently, we has treated two patients with primary lung cancer metastasized to gastrointestinal system consequently. This paper will conduct the diagnosis, treatment and follow-up report and review related literature in order to deepen the understanding of rarely metastases of lung cancer to avoid misdiagnosis and missed diagnosis.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 03/2011; 14(3):278-80.
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Shuhang Wang,
Tongtong An, Jie Wang,
Jun Zhao,
Zhijie Wang,
Minglei Zhuo,
Hua Bai,
Lu Yang,
Yan Zhang,
Xin Wang,
Jianchun Duan,
Yuyan Wang,
Qingzhi Guo,
Meina Wu
[show abstract]
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ABSTRACT: Non-small cell lung cancer (NSCLC) with KRAS mutation may be resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). This study aims to evaluate a plasma-based KRAS mutation analysis and the clinical significance of plasma KRAS mutation as a predictive marker for tumor resistance to EGFR-TKIs in patients with NSCLC.
DNA extracted from plasma and matched tumor tissues were obtained from 273 patients with advanced stage NSCLC. Patients were followed up prospectively for treatment outcomes. KRAS mutations in codon 12 and 13 were detected using PCR-restriction fragment length polymorphism. Mutations in plasma and matched tumors were compared. Associations between KRAS mutation status and patients' clinical outcomes were analyzed.
KRAS mutation was found in 35 (12.8%) plasma samples and 30 (11.0%) matched tumor tissues. The consistency of KRAS mutations between plasma and tumors is 76.7% (23 of 30; kappa = 0.668; P < 0.001). Among 120 patients who received EGFR-TKI treatment, the response rate was only 5.3% (1 of 19) for patients with plasma KRAS mutation compared with 29.7% for patients with no KRAS mutation in plasma DNA (P = 0.024). The median progression-free survival time of patients with plasma KRAS mutation was 2.5 months compared with 8.8 months for patients with wild-type KRAS (P < 0.001).
KRAS mutation in plasma DNA correlates with the mutation status in the matched tumor tissues of patients with NSCLC. Plasma KRAS mutation status is associated with a poor tumor response to EGFR-TKIs in NSCLC patients and may be used as a predictive marker in selecting patients for such treatment.
Clinical Cancer Research 02/2010; 16(4):1324-30. · 7.74 Impact Factor
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ABSTRACT: Many studies concluded that epidermal growth factor receptor (EGFR) gene amplification might be related with the prognosis in non-small cell lung cancer. However, the results were not consistent. To identify whether EGFR gene amplification could affect the prognosis, a meta-analysis was conducted based on the published works.
According to inclusion and exclusion criteria, articles were selected from medical electronic databases searching, including PubMed, Cochrane library and CNKI. The qualities of included articles were scored based on the European Lung Cancer Working Party scale, and the hazard ratio (HR) and the 95% confidence interval (CI) were also collected. Meta-analysis was completed using software Review Manager 4.2.
Forest plot from 12 studies in which 1 221 included patients were all treated with EGFR-TKI showed that the prognosis of patients harboring EGFR gene amplification were superior to negative ones (HR=0.82, 95%CI: 0.68-0.99, P=0.04), and for Caucasian patients who received EGFR-TKI, the survivals were longer in EGFR gene amplification positive cases than those without amplification (HR=0.42, 95%CI: 0.31-0.57, P<0.001). Meta results from 8 studies in which 658 included patients did not receive EGFR-TKI indicated that the casualty hazard of amplification positive patients was comparable with negative ones. However, for Asia patients who failed to receive EGFR-TKI, the prognosis of patients with EGFR gene amplification were inferior to negative ones (HR=1.88, 95%CI: 1.21-2.93, P=0.005).
EGFR gene amplification may be a positive predictive factor in terms of survival for Caucasian patients receiving EGFR-TKI rather than Asia patients. However, the prognosis was inferior in Asia patients with EGFR amplification to those without the amplification, if they failed to receive EGFR-TKI.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 12/2009; 12(12):1247-54.
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ABSTRACT: To investigate whether the clinical characteristics, treatment modalities and prognosis of elderly (>/= 70 years) patients with advanced non-small cell lung cancer (NSCLC) differed from those of young (</= 45 years) patients.
This retrospective study included 256 elderly patients and 143 young patients with chemotherapy-naive advanced NSCLC treated at Department of Thoracic Medical Oncology in Beijing Cancer Hospital from March 1995 to May 2007. All patients received first-line chemotherapy. Clinical data were analyzed using chi-square test, Log-lank test, Cox regression and Kaplan-Meier survival analysis.
(1) Women, adenocarcinoma and stage IV disease were more common in young patients (46.2% vs 22.3%, P = 0.000, 71.3% vs 54.7%, P = 0.001 and 72.7% vs 61.7%, P = 0.026), when compared with elderly patients. The smoker rate in young women was also higher (95.5%). (2) The disease control rate (DCR) of first-line chemotherapy was similar between young and elderly patients (P = 0.257). Platinum-based combination chemotherapy was a benefit factor for the disease control rate of first-line chemotherapy, whatever in young patients (P = 0.047) or in elderly patients (P = 0.028). Hematologic toxicities were similar between these 2 groups. (3) There was no significant difference in terms of median progression free survival (PFS) or median overall survival (OS) between young and elderly patients (P = 0.399 and P = 0.869, respectively). (4) Easten Cooperative Oncology Group (ECOG) score, DCR for first-line chemotherapy and the regimen of second-line chemotherapy were all independent prognostic factors (P = 0.000, 0.021 and 0.000 in young patients, P = 0.007, 0.000 and 0.000 in elderly patients, respectively).
Women, adenocarcinoma and stage IV disease were more common in young patients when compared with elderly patients. The increased incidence of NSCLC in young women may be associated with the high smoker rate. The OS and PFS were not significantly different between young and elderly patients.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 11/2009; 32(11):830-4.
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ABSTRACT: The goal of this study is to determine role of excision repair cross-complementing group 1 gene (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) expression in predicting response and survival in Chinese patients with advanced stage non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy. Formalin-fixed, paraffin-embedded biopsy tissues were retrospectively obtained from 124 advanced NSCLC patients. Protein expression levels of ERCC1 and RRM1 were determined by immunohistochemistry (IHC). Associations between expression of ERCC1 and RRM1 and clinic-pathologic parameters were analyzed. The study shows that ERCC1 and RRM1 expression was detected in 43 (35%) and 50 (40%) of the 124 tumor samples, respectively. Expression of ERCC1 and RRM1 was negatively associated with tumor response. Fifty-four percent patients whose tumors did not express ERCC1 had partial response (PR) compared to 33% whose tumors expressed the protein (P = 0.022). Similarly, 54% patients whose tumor did not express RRM1 had PR compared to 36% whose tumors expression the protein (P = 0.042). Further, patients whose tumors lacked of ERCC1 but not RRM1 expression had a longer median survival time than those tumors expressed ERCC1 (13.4 months versus 9.1 months; P = 0.006), which is independent of other prognostic factors (P = 0.0066). In conclusion, tumor ERCC1 expression is associated with tumor response and patients' survival in Chinese advanced NSCLC patients treated with platinum-based regimen and may serve as a biomarker in predicting tumor response and clinical outcome in the patient population.
Medical Oncology 07/2009; 27(2):484-90. · 2.14 Impact Factor
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Hua Bai,
Li Mao,
Hang Shu Wang,
Jun Zhao,
Lu Yang,
Tong Tong An,
Xin Wang,
Chun Jian Duan,
Na Mei Wu,
Zhi Qing Guo,
Yi Xu Liu,
Hong Ning Liu,
Ye Yu Wang, Jie Wang
[show abstract]
[hide abstract]
ABSTRACT: Mutations in the epidermal growth factor receptor (EGFR) kinase domain can predict tumor response to tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). However, obtaining tumor tissues for mutation analysis is challenging. We hypothesized that plasma-based EGFR mutation analysis is feasible and has value in predicting tumor response in patients with NSCLC.
Plasma DNA samples and matched tumors from 230 patients with stages IIIB to IV NSCLC were analyzed for EGFR mutations in exons 19 and 21 by using denaturing high-performance liquid chromatography. We compared the mutations in the plasma samples and the matched tumors and determined an association between EGFR mutation status and the patients' clinical outcomes prospectively.
In 230 patients, we detected 81 EGFR mutations in 79 (34.3%) of the patients' plasma samples. We detected the same mutations in 63 (79.7%) of the matched tumors. Sixteen plasma (7.0%) and fourteen tumor (6.1%) samples showed unique mutations. The mutation frequencies were significantly higher in never-smokers and in patients with adenocarcinomas (P = .012 and P = .009, respectively). In the 102 patients who failed platinum-based treatment and who were treated with gefitinib, 22 (59.5%) of the 37 with EGFR mutations in the plasma samples, whereas only 15 (23.1%) of the 65 without EGFR mutations, achieved an objective response (P = .002). Patients with EGFR mutations had a significantly longer progression-free survival time than those without mutations (P = .044) in plasma.
EGFR mutations can be reliably detected in plasma DNA of patients with stages IIIB to IV NSCLC and can be used as a biomarker to predict tumor response to TKIs.
Journal of Clinical Oncology 06/2009; 27(16):2653-9. · 18.37 Impact Factor
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Meina Wu,
Jun Zhao,
Sonya Wei Song,
Minglei Zhuo,
Xin Wang,
Hua Bai,
Shuhang Wang,
Lu Yang,
Tongtong An,
Yan Zhang,
Jianchun Duan,
Yuyan Wang,
Qingzhi Guo,
Xuyi Liu,
Ninghong Liu, Jie Wang
[show abstract]
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ABSTRACT: The study aimed to investigate associations of tumor tissue EGFR mutations with response to the front-line chemotherapy and prognosis in advanced non-small cell lung cancer (NSCLC) patients. EGFR genotypes of 145 chemotherapy-naive patients with Stage IIIB and IV NSCLC were examined by using denaturing high-performance liquid chromatography (DHPLC). All patients received the front-line chemotherapy. There were 69 patients who received gefitinib therapy (32 as second-line and 37 as third-line therapy). About 37.9% (55/145) of the patients was detected to have EGFR mutations in their tumor tissue DNA. The response rate (RR, complete response plus partial response) to the chemotherapy for mutated EGFR carriers was 34.5% (19/55), similar to 33.3% (30/90) for wild-type EGFR carriers (P=0.881). The patients with EGFR mutations had increased median survival time and 1- and 2-year survival rate than those with wild-type EGFR (23 vs 16 months, 86.38% vs 62.64%, 38.78% vs 27.16%, P=0.0273). Among Stage IV NSCLC patients, mutated EGFR carriers had a longer progression-free survival (PFS) than wild-type EGFR carriers (5 vs 3 months, P=0.040). Cox multivariate regression analysis showed that response to the front-line chemotherapy (RR vs PD) and EGFR mutation were independent prognostic factors (HR=0.461, 95% CI: 0.271-0.783, P=0.0042; HR=0.598, 95% CI: 0.372-0.961, P=0.0335, respectively) for patients with advanced NSCLC. We conclude that EGFR mutations in the Chinese patients with advanced NSCLC were not associated with response to the front-line chemotherapy, but Stage IV NSCLC patients with mutated EGFR had a longer PFS after the front-line chemotherapy. EGFR mutation is an independent prognostic factor for Chinese advanced NSCLC.
Lung cancer (Amsterdam, Netherlands) 06/2009; 67(3):343-7. · 3.14 Impact Factor
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Hua Bai,
Jun Zhao,
Shu-Hang Wang,
Tong-Tong An,
Xin Wang,
Mei-Na Wu,
Jian-Chun Duan,
Lu Yang,
Qing-Zhi Guo,
Ning-Hong Liu, Jie Wang
[show abstract]
[hide abstract]
ABSTRACT: To study the application of denaturing high performance liquid chromatography (DHPLC) as a screening tool in detecting plasma and matched tissue epidermal growth factor receptor (EGFR) mutations for advanced non-small-cell lung cancer (NSCLC).
Plasma DNA samples and matched tumors from 230 cases of NSCLC were analyzed for EGFR mutations in exons 19 and 21 using DHPLC. The mutations in the plasma samples and the matched tumors were compared, and the association between EGFR mutations and the clinicopathological features were evaluated.
Mutation of EGFR was found by DHPLC to be 33.5% (77/230) in tissues and 34.3% (79/230) in matched peripheral blood samples. Consistency of EGFR mutation status between tissues and matched plasma DNA was confirmed (kappa is 0.74, P < 0.01). The sensitivity and specificity of DHPLC for detecting EGFR mutation were 96.9% and 91.9%, respectively (kappa is 0.88). EGFR mutations in both tissue and blood was correlated with histology type (OR = 3.38, 95% CI 1.81 - 6.36, P < 0.05) and smoking status (OR = 1.61, 95% CI 1.13 - 2.28, P < 0.05), but no association with age, sex and stage was found (P > 0.05).
The detection of EGFR mutation is highly consistent in tissues and in plasma DNA samples. DHPLC may serve as a preliminary screening tool for detecting EGFR mutations.
Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 01/2009; 31(12):891-6.
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ABSTRACT: DeltaDNMT3B (a new DNMT3B subfamily) expression is initiated through a novel promoter. We identified at least 7 transcription variants of deltaDNMT3B as a result of alternative pre-mRNA processing. The aim of this study was to detect the expression pattern of deltaDNMT3B variants in non-small cell lung cancer (NSCLC) and to explore the role of deltaDNMT3B variants in regulating the promoter-specific DNA methylation.
Specific polymerase chain reaction (PCR) primer sets were designed to distinguish individual deltaDNMT3B variants according to their splicing patterns. The expressions of seven deltaDNMT3B variants were measured in 13 cell lines, 109 NSCLC patients, and the corresponding normal lung tissues using reverse transcription-PCR (RT-PCR). The status of the p16 and RASSF1A promoter methylations in the tumors was detected using a methylation specific PCR (MSP). The relationships of the expression patterns of the deltaDNMT3B variants were analyzed by observing the status of p16 and RASSF1A promoter methylations in the tumors. The siRNA and the anti-sense oligo-dioxynucleotide specifically targeting the junction of exon 5 and 7 of deltaDNMT3B were designed and transfected by lipofectmane 2000 into H1299 and H358 cell lines. RASSF1A promoter methylation from cells treated by siRNA-deltaDNMT3B4/2 was detected using MSP and Bisulfite sequencing, and Western blotting was used to detect the protein expression of DNMT3B and ADNMT3B. Cell growth and cell cycle distribution were measured by applying real-time cell growth analysis and flowcytometry, respectively.
ADNMT3B variants, not DNMT3B, were the predominant transcripts in both NSCLC cell lines and primary tumors. The expression of deltaDNMT3B4 strongly correlated to the promoter methylation status of RASSF1A in a primary NSCLC. The knockdown of deltaDNMT3B4/2 by RNA-interference or anti-sense approaches resulted in a complete demethylation of RASSF1A promoter with the reactivation of a RASSF1A gene expression in less than 12 hours, but no effect resulted from the p16(INK4a) promoter in the NSCLC cell lines.
These results demonstrate an important role of deltaDNMT3B4/2 in the maintenance of promoter-specific DNA methylation in a cell type specific manner and provide a novel cell model for the study of the regulation of replication-independent DNA methylation.
Chinese medical journal 10/2008; 121(17):1712-21. · 0.86 Impact Factor
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Zhijie Wang,
Jianchun Duan,
Qingzhi Guo,
Zhigang Wei,
Weicheng Xue,
Meina Wu,
Jun Zhao,
Lu Yang,
Tongtong An,
Xuyi Liu, Jie Wang
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ABSTRACT: Currently, platinum-based regimes are standard first-line chemotherapy for non-small cell lung cancer. The aim of this study is to evaluate the efficacy, influencing factors and adverse events of celecoxib plus platinum-based chemotherapy in advanced non-small cell lung cancer as first-line treatment.
Previously untreated patients of advanced non-small cell lung cancer with COX-2 positive, confirmed by immunohistochemical staining, were randomized to receive GP, NP or TP regimens. Celecoxib of 400 mg Bid was given, po 5-7 days before chemotherapy,and not stopped until evidence of disease progression or toxicity. Adverse events were cirtified according to NCI-CTC criteria. Kaplan-Meier method was used to analyze the survival rate. COX regression was used to define the predictive factors. Primary endpoint: median survival time, 1-year survival rate and median progression free survival time. Secondary endpoint: response rate and toxicity.
Forty-four evaluable patients were enrolled in the study from February 2005 to March 2007. Response rate was 45%, disease control rate 59%. Median progression free survival time and median survival time were 6months (95%CI: 4-8 months) and 18 months (95%CI: 9-27months), respectively. One-year survival rate was 68%. Numbers of chemotherapy cycles and overall evaluation were the predictive factors for PFS in COX model (P =0.023 and 0.000). No factor was defined to affect survival time. Neutropenia and nausea/vomit were the most common toxicity.
Celecoxib combined with platinum-based chemotherapy appears to be well tolerated and demonstrates encouraging activity in patients of previously untreated advanced NSCLC.
Zhongguo fei ai za zhi = Chinese journal of lung cancer 06/2008; 11(3):425-30.
