[Show abstract][Hide abstract] ABSTRACT: Background:
A rapid surge of female breast cancer has been observed in young women in several East Asian countries. The BIM deletion polymorphism, which confers cell resistance to apoptosis, was recently found exclusively in East Asian people with prevalence rate of 12%. We aimed to evaluate the possible role of this genetic alteration in carcinogenesis of breast cancer in East Asians.
Female healthy volunteers (n = 307), patients in one consecutive stage I-III breast cancer cohort (n = 692) and one metastatic breast cancer cohort (n = 189) were evaluated. BIM wild-type and deletion alleles were separately genotyped in genomic DNAs.
Both cancer cohorts consistently showed inverse associations between the BIM deletion polymorphism and patient age (≤35 y vs. 36-50 y vs. >50 y: 29% vs. 22% vs. 15%, P = 0.006 in the consecutive cohort, and 40% vs. 23% vs. 13%, P = 0.023 in the metastatic cohort). In healthy volunteers, the frequencies of the BIM deletion polymorphism were similar (13%-14%) in all age groups. Further analyses indicated that the BIM deletion polymorphism was not associated with specific clinicopathologic features, but it was associated with poor overall survival (adjusted hazard ratio 1.71) in the consecutive cohort.
BIM deletion polymorphism may be involved in the tumorigenesis of the early-onset breast cancer among East Asians.
[Show abstract][Hide abstract] ABSTRACT: Although global and Asian studies on second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer have confirmed its efficacy and safety, a pivotal postcommitment study to consolidate the evidence regarding the Taiwanese population was warranted. This open-label single-arm study assessed the objective response rate to a tailored dose of single-agent pemetrexed in Taiwanese patients with advanced nonsmall cell lung cancer who had received prior chemotherapy.
Patients with stage IIIB/IV disease were treated with pemetrexed on day 1 of each 21-day cycle. A 500 mg/m² dose was administered in cycle 1. For cycle 2, the dose was increased to 1000 mg/m² (if there was no toxicity above predefined levels) or decreased to 375 mg/m². All patients received standard supplemental therapy. Patient follow-up continued until 18 months after the last patient was enrolled in this study or death. All patients were included in all analyses.
Of the 33 patients who were enrolled, 25 (75.8%) received the 1000 mg/m(2) dose during cycle 2; 18 patients were dropped from the study, including 17 (51.5%) who had died by the time of analysis. The objective response and disease control rates were 18.2% (95% confidence limits [CI]: 7.0-35.5) and 54.5% (95% CI: 36.4-71.9), respectively. No patients exhibited a complete response. There were two serious drug-related adverse events (neutropenia and leukopenia) and two drug-related adverse events that resulted in removal from the study. Decreased neutrophil/granulocyte counts were the most frequently observed drug-related grade 3/4 events (9 patients, 24 treatment cycles).
The objective response rate, disease control rate, and safety and tolerability profile in this population of Taiwanese patients were consistent with the published findings that were conducted using Asian and Western populations. These findings support the use of single-agent, second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer in Taiwanese patients.
No preview · Article · Sep 2013 · Journal of the Formosan Medical Association
[Show abstract][Hide abstract] ABSTRACT: Introduction: Patients with stage III non-small-cell lung cancer (NSCLC) usually require a combined modality therapeutic approach. Induction chemotherapy prior to curative surgery is frequently used in routine practice for patients with resectable stage III NSCLC. However, the survival advantage of the induction chemotherapy remains to be validated.
Methods: This study recruited patients aged 18 years or older with stage III NSCLC registered in the Taiwan Cancer Registry Database between January 2004 and December 2007. Based on the presence or absence of induction/adjuvant chemotherapy, those eligible patients were divided into four groups. Cisplatin-containing regimens should be used in the induction and/or adjuvant chemotherapy. Kaplan-Meier survival curves, log-rank tests, and the Cox proportional hazards regression model were used to assess the influence of various risk factors on survival time.
Results: The study group included 177 stage III NSCLC patients receiving curative operation. Ninety-three (53%) patient received induction cisplatin-based chemotherapy The median follow-up time was 28.3 months. The percentage of all cause of death for patients receiving induction chemotherapy without or with adjuvant chemotherapy were 46.0% and 44.6%, respectively. The percentage of all cause of death for patients receiving surgery alone or followed by adjuvant chemotherapy were 70.0% and 55.9%, respectively. Multivariate analysis identified cisplatin-based induction chemotherapy as an independent prognostic factor for all causes of death (Hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.37-0.92, P = 0.0198) and lung cancer specific death (HR 0.53, 95% CI 0.33-0.86, P = 0.0096).
Conclusion: Cisplatin-based induction chemotherapy should be considered in the treatment plan for stage III NSCLC patients.
[Show abstract][Hide abstract] ABSTRACT: In the era of targeted therapy, the association between lung adenocarcinoma patient survival and malignant pleural effusion (MPE) remains unclear. This study investigated the clinical characteristics, survival, and epidermal growth factor receptor (EGFR) mutation status of lung adenocarcinoma patients with MPE.During June 2005 to December 2010, consecutive pleural effusions were collected prospectively. Patient clinical characteristics, EGFR mutation status, and overall survival (OS) were analysed.We collected MPEs from 448 patients in stage IV lung adenocarcinoma at initial diagnosis. Median OS for patients with MPEs at initial diagnosis and following disease progression were 14.3 months and 21.4 months, respectively (p=0.001). There were 296 (66.1%) patient harbouring EGFR mutations; mutation rate among patients with MPEs at initial diagnosis and following disease progression were 68.2% and 56.6%, respectively (p=0.044); L858R mutation rate was also higher among the former (32.6% vs. 18.1%; p=0.009). Multivariate analysis revealed that patients who developed MPEs following disease progression, harboured EGFR mutations, and received EGFR-TKI therapy had longer OS. Patients in stage IV lung adenocarcinoma with MPEs at initial diagnosis have shorter overall survival and higher EGFR mutation rate, especially for L858R, than patients who develop MPEs following disease progression.
Full-text · Article · Sep 2012 · European Respiratory Journal
[Show abstract][Hide abstract] ABSTRACT: Lung cancer in young patients (less or equal to 45 years) is uncommon and has clinical characteristics different from that in older patients. We investigated the outcomes and prognostic factors of young patients with advanced non-small cell lung cancer (NSCLC).
From January 2000 to December 2009, we enrolled patients aged ≤45 years and diagnosed with stage IIIB or IV NSCLC. Their clinical data, including age, gender, performance status, histologic types, disease stages, laboratory data at diagnosis, treatment modalities, and survival were reviewed and analyzed. A Cox proportional hazard model was used to calculate the hazard ratio (HR) and its 95% confidence interval (CI).
A total of 144 patients with advanced NSCLC were included. Female patients were more prevalent (n = 74, 51.4%). Adenocarcinoma was the most common histologic type (n = 119, 82.6%) in both genders (male, n = 54, 77.1%; female, n = 65, 87.8%). Epidermal growth factor receptor (EGFR) sequences were determined using tumor specimens from 58 patients, and 29 showed an EGFR mutation. No significant difference in median survival was found between patient groups with and without the EGFR mutation (798 vs. 708 days, p = 0.65). In multivariate analysis, male gender (HR, 1.70; 95% CI: 1.08-2.68), body mass index (BMI) less than 25 kg/m(2) (HR, 2.72; 95% CI: 1.39-5.30), stage IV disease (HR, 2.62; 95% CI: 1.50-4.57), and anemia (HR, 2.08; 95% CI: 1.15-3.77) were associated with a short survival time.
Low BMI, stage IV disease, anemia at diagnosis, and male gender were the negative prognostic factors for young patients with advanced NSCLC.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to determine the prognostic significance of clinical factors and staging systems for survival of hepatocellular carcinoma (HCC) patients who are candidates for therapeutic clinical trials.
From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into six published phase II trials assessing various therapeutic regimens. Of these, 156 chemotherapy-naive patients with Child-Pugh class A and Barcelona Clinic Liver Cancer stage C disease were included in this analysis. Twenty-seven relevant clinical characteristics were analyzed to identify prognostic factors of survival. Beyond these prognosticators, the predictive ability of eight staging systems (the tumor-node-metastasis, Okuda, Cancer of the Liver Italian Program [CLIP], Chinese University Prognostic Index, Japanese Integrated Staging, Tokyo, National Taiwan University Risk Estimation, and Advanced Liver Cancer Prognostic System [ALCPS] score) were compared using the Akaike information criteria.
The median overall survival time was 129 days (95% confidence interval, 111-147 days). Significant predictors of a shorter overall survival time were an Eastern Cooperative Oncology Group performance status score ≥2, the presence of symptoms, ascites, an aspartate transaminase level more than two times the upper limit of normal, and regional lymph node involvement. The ALCPS and CLIP scores were superior to the other systems for predicting survival.
The prognosis of patients with advanced HCC who are candidates for therapeutic clinical trials is affected by several factors related to the patient, liver function, and the tumor. The ALCPS and CLIP scores appear to be superior to the other systems for predicting survival.
[Show abstract][Hide abstract] ABSTRACT: Tumor tissue is often not obtainable or suitable for molecular-based epidermal growth factor receptor (EGFR) mutational analysis in advanced non-small-cell lung cancer (NSCLC). This retrospective and single-institution study was conducted to evaluate the role of effusion immunocytochemistry using two EGFR mutant-specific antibodies for the detection of relevant EGFR mutations in NSCLC, along with the selection of candidates for first-line therapy with EGFR tyrosine kinase inhibitors (TKIs).
Immunocytochemistry using two antibodies binding specifically to the major forms of mutant EGFR, L858R, and E746-A750 deletion (delE746-A750), was performed on cell blocks of malignant pleural effusion (MPE) from 78 patients with lung adenocarcinoma, who received first-line EGFR TKIs. The yield of EGFR-mutation detection and prediction of response rate and progression-free survival to TKI treatment by immunocytochemistry were compared with those by clinical characteristics and EGFR sequencing using cell-derived RNA from MPEs.
Of the 78 MPE samples, direct sequencing using cell-derived RNA identified L858R mutation in 42 cases, deletions in exon 19 in 12 cases (delE746-A750 in eight cases), other types of mutations in three cases, and wild-type EGFR in 21 cases. Effusion immunocytochemistry with these two mutant-specific antibodies exhibited a sensitivity of 71% and 88% and a specificity of 86% and 96% for identifying predefined L858R and delE746-A750 mutations, respectively. Effusion immunocytochemistry provided a superior prediction of tumor response and progression-free survival to first-line EGFR TKIs than did clinical characteristics like sex and smoking status. Patients whose effusion immunocytochemistry showed a reaction to either of the two antibodies had a comparable TKI response rate (67% versus 72%) to those with EGFR mutations assessed by direct sequencing from cell-derived RNA.
Effusion immunocytochemistry could be introduced into clinical practice to identify more NSCLC patients likely to have benefit from first-line TKI treatment, especially for those without adequate tissue for molecular-based EGFR analysis.
Full-text · Article · Apr 2012 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: The echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion represents a novel target in a subset of non-small cell lung cancer, especially adenocarcinoma. EML4-ALK fusion is mutually exclusive with epidermal growth factor receptor (EGFR) mutations. To understand the impact of EML4-ALK on the prognosis of non-small cell lung cancer, we examined EML4-ALK fusion in lung adenocarcinoma from patients with wild-type EGFR and analyzed their clinical treatment outcomes.
Lung adenocarcinoma patients with malignant pleural effusions having wild-type EGFR and measurable target lesions were enrolled for EML4-ALK analysis by reverse transcription-polymerase chain reaction and direct sequencing. Demographic data, EML4-ALK status, and survival data were analyzed. We also performed fluorescence in situ hybridization on some available tumor samples to validate the PCR result. In addition, K-ras mutation was analyzed for patients without EML4-ALK fusion genes.
A total of 116 patients with wild-type EGFR sequencing results had complete clinical data for analysis. No patients received ALK inhibitor therapy. There were 39 patients (34%) with the EML4-ALK fusion gene. The concordance rate between reverse transcription-polymerase chain reaction and fluorescence in situ hybridization was 85%. The K-ras mutation rate for patients without EML4-ALK fusion gene was 6.5%. By multivariate analysis, patients who had better performance status (p < 0.001) and EML4-ALK translocation (p = 0.017) had longer overall survival. Comparing patients with tumors harboring variant 1 with those harboring nonvariant 1 EML4-ALK fusion genes, there were no significant differences in clinical factors and survival outcome.
For lung adenocarcinoma patients with wild-type EGFR, EML4-ALK translocation is associated with longer overall survival.
Full-text · Article · Nov 2011 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: Thyroid transcription factor 1 (TTF-1) positivity correlates with a higher prevalence of epidermal growth factor receptor (EGFR) mutation in lung adenocarcinoma. It is unknown whether TTF-1 expression affects the clinical outcome of patients with advanced lung adenocarcinoma, who have received EGFR tyrosine kinase inhibitors (TKIs) during the treatment course.
This study enrolled patients with advanced lung adenocarcinoma who had results of EGFR mutation analysis and TTF-1 immunostaining. The impact of TTF-1 expression on overall survival (OS) and progression-free survival (PFS) under EGFR TKI treatment was evaluated. Multivariate analyses were done to examine the independent predictors of OS and PFS.
Of 496 patients with advanced lung adenocarcinoma, 443 had TTF-1-positive adenocarcinoma. Patients with TTF-1-positive lung adenocarcinoma had longer OS than did those with TTF-1-negative lung adenocarcinoma (median survival, 27.4 vs 11.8 months, P = .001). In patients with EGFR TKI treatment, those with TTF-1-positive lung adenocarcinoma and mutant EGFR had longer OS. In patients with EGFR mutation, those with TTF-1-positive lung adenocarcinoma had longer PFS than did those with TTF-1-negative lung adenocarcinoma (median survival, 8.7 vs 5.7 months, P = .043). Multivariate analysis showed that negative TTF-1 expression is a predictor for shorter OS, and a predictor for shorter PFS under EGFR TKI treatment.
TTF-1 shows independent prognostic significance in advanced lung adenocarcinoma. Patients with TTF-1-negative lung adenocarcinoma have not only shorter OS, but also shorter PFS under EGFR TKI treatment, despite the existence of mutant EGFR. Further studies are needed to investigate the optimal treatment of patients with TTF-1-negative lung adenocarcinoma.
[Show abstract][Hide abstract] ABSTRACT: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. Patients and Methods: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations.
Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months).
Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed.
Full-text · Article · Jun 2011 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: Erlotinib and gefitinib are tyrosine kinase (TK) inhibitors of epidermal growth factor receptor (EGFR) that are effective in treating non-small cell lung cancer (NSCLC). This study aimed to compare their clinical uses and the influence of EGFR mutation.
The usages of erlotinib and gefitinib in advanced NSCLC were analyzed. Clinical data and EGFR mutational status of tumors were collected.
Seven hundred and sixteen (716) patients received gefitinib (n=440) or erlotinib (n=276) for stage IIIb or IV NSCLC. Erlotinib was prescribed more frequently than gefitinib in males (58.2% vs. 41.8%, p<0.001), smokers (60.5% vs. 39.5%, p<0.001), and non-adenocarcinoma (70.6% vs. 29.4%, p<0.001). Of the 716 study patients, 327 underwent testing for EGFR mutations (170 with mutant EGFR and 157 with wild-type EGFR). Adenocarcinoma in patients with mutant EGFR and non-smoker status in patients with wild-type EGFR were associated with better overall survival after TK inhibitor treatment. In both patient groups with mutant EGFR or wild-type EGFR, the effectiveness of gefitinib and erlotinib, including drug response or overall survival, were not different.
Our study revealed the obvious disparity in drug selection between erlotinib and gefitinib in clinical practice. Type of TK inhibitors did not influence treatment outcomes in patients with EGFR mutation or wild-type EGFR.
Full-text · Article · May 2011 · Lung cancer (Amsterdam, Netherlands)
[Show abstract][Hide abstract] ABSTRACT: Gefitinib is effective in treating advanced non-small cell lung cancer (NSCLC), especially in Asian patients in whom the prevalence of epidermal growth factor receptor (EGFR) mutation was high. We analyzed our gefitinib treatment use in patients for advanced NSCLC to study the influence of clinical factors on the treatment outcomes in a tertiary referral medical center in Taiwan. Clinical data and EGFR mutational status of the tumors were collected. A total of 907 patients received gefitinib for advanced NSCLC: 466 patients (51.4%) underwent testing for EGFR mutations, and the other 441 patients did not. In the 466 patients who were tested for EGFR mutations, 272 (58.4%) had EGFR mutations, and an EGFR mutation was a prominent factor for objective response to gefitinib (67.3% vs. 18.3% in wildtype EGFR, p < 0.001). In the 441 patients who did not receive EGFR mutation sequencing, nonsmoker status, female sex, and adenocarcinoma cell type were predictors for better gefitinib response (p < 0.005). We found that testing for EGFR mutations was helpful in NSCLC patients in Taiwan to guide the use of gefitinib. In patients with positive activating EGFR mutations, gefitinib efficacy was prominent and significant. Therefore, analysis for EGFR mutation should be advocated. In those patients who have unknown EGFR mutation status, demographic and histopathology characteristics can be relied on to judge the potential efficacy of gefitinib use.
[Show abstract][Hide abstract] ABSTRACT: Background
Epidermal growth factor receptor antagonists, such as gefitinib, erlotinib, and cetuximab, have been used in treating carcinomas. The efficacies have been proposed to correlate with skin reactions, but the most important predictive indicator is still unknown. Our aim was to investigate the types of skin toxicities and to analyze the major therapeutic predictive indicators in Taiwan.MethodsA retrospective analysis was used to study 68 patients with advanced non-small-cell lung cancer receiving gefitinib.ResultsAcneiform eruption (41.2%), xerosis (38.2%), pruritus (26.5%), and paronychia (16.2%) composed most of the skin reactions. The univariate analysis revealed paronychia as the most substantial survival predictive indicator (p = 0.0427). In the multivariate analysis, older patients with paronychia had better prognosis (p = 0.0050). Women tended to develop paronychia (p = 0.1098). Xerosis positively correlated with paronychia (p = 0.0082).Conclusion
Paronychia is the most indicative survival predictive factor among the skin manifestations, and it correlates with age, gender, and xerosis. Elucidation of the relationship between cutaneous reactions can provide information on the epidermal growth factor receptor signaling mechanism of skin.
Full-text · Article · Mar 2011 · Dermatologica Sinica
[Show abstract][Hide abstract] ABSTRACT: Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are target enzymes of inhibition by pemetrexed, an antifolate for treatment of advanced non-small-cell lung cancer (NSCLC). This study is to evaluate the association of TS and DHFR expressions and the treatment efficacy of pemetrexed in NSCLC patients. From January 2006 to October 2008, patients with advanced NSCLC treated with pemetrexed after prior chemotherapy were included. The TS and DHFR expressions in tumor tissues were examined by immunohistochemistry and evaluated by a semiquantitative histologic score (H-score). The H-score was derived from the degrees of intensity of tumor cells multiplied by the percentage of positive neoplastic cells. The medical records were reviewed and analyzed with respect to patients' characteristics, histology types, treatment responses and survivals. Among 268 NSCLC patients treated with pemetrexed, 49 had tumor specimens available for TS and DHFR evaluation. The TS expression was positively correlated with DHFR expression (r(2)=0.11, p=0.02). Patients with low TS (≤150) expression had a longer median progression-free survival (PFS) than those with high TS (>150) expression (4.8 vs. 3.4 months; p=0.01). Patients with low DHFR expression (≤120) also had a longer median PFS than patients with high DHFR expression (>120), which was not statistically significant (5.8 vs. 3.6 months; p=0.33). In patients with adenocarcinoma, the low TS patient group also had a longer median PFS and a longer median overall survival (OS) as compared with patients with high TS expression (PFS, 4.8 vs. 3.8 months, p=0.03; OS, 21.4 vs. 10.0 months, p=0.03). Nevertheless, the association of DHFR expression level and median PFS as well as OS were not statistically significant. TS expression, rather than DHFR, may be an important predictive factor for treatment efficacy of pemetrexed in NSCLC patients.
No preview · Article · Feb 2011 · Lung cancer (Amsterdam, Netherlands)
[Show abstract][Hide abstract] ABSTRACT: There are no reports about epidermal growth factor receptor (EGFR) mutations and the responsiveness to pemetrexed treatment. In order to understand the influence of EGFR mutations on pemetrexed response, we performed EGFR sequencing of lung adenocarcinoma from patients undergoing pemetrexed treatment and analyzed their response to pemetrexed. The pemetrexed-treated lung adenocarcinoma patients with adequate specimens for EGFR sequencing and measurable target lesions were enrolled for response analysis. Demographic data, EGFR mutation status, response to pemetrexed, and survival data were collected. From January 2004 to December 2008, 156 patients with measurable target lesions and EGFR sequencing results had complete clinical data for analysis. The patients with EGFR mutations (N=93) had a better response rate (p=0.016) and longer progression-free survival (PFS) (p=0.030) than those with wild type EGFR (N=63). By multivariate analysis, those who had better performance status (p=0.013) and EGFR mutations (p=0.021) had a longer PFS. In conclusion, lung adenocarcinoma patients receiving pemetrexed with EGFR mutations have a better response rate and longer PFS than those with wild type EGFR.
Full-text · Article · Nov 2010 · Lung cancer (Amsterdam, Netherlands)
[Show abstract][Hide abstract] ABSTRACT: Clinical application of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib has revolutionized systemic treatment for advanced non-small-cell lung cancer (NSCLC) patients. The therapeutic efficacy of EGFR-TKI monother-apy as a first-line, second-line, or salvage treatment in subsequent lines of treatment has been demonstrated in several phase III trials. Current evidence does not support the regular use of gefitinib or erlotinib in combination with chemotherapy or with other targeted agents. Female gender, nonsmoking status, adenocarcinoma histology, and East Asian ethnicity are the main favorable clinical predictive factors for successful EGFR-TKI treatment. The most important predictive factor for tumor response or long progression-free survival using EGFR-TKI treatment is the presence of sensitive activating EGFR mutations in tumor tissue. The detection of resistant EGFR mutations or K-ras mutation in tumor samples are the two major negative predictors for tumor response or progression-free survival. Second mutation such as T790M in EGFR exon 20 or MET gene amplification often can be found in the tumor tissues of patients who develop resistance to EGFR-TKI treatment. Clinical tri-als using second-generation EGFR-TKIs, especially those that are irreversible, are ongoing. The treatment strategy for advanced stage NSCLC patients has shifted from being chemotherapy-dominant to a sequential chemotherapy or EGFR-TKI approach.
Full-text · Article · Oct 2010 · European journal of clinical & medical oncology
[Show abstract][Hide abstract] ABSTRACT: Non-small cell lung cancers carrying epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), but patients ultimately develop drug resistance and relapse. Although epithelial-mesenchymal transition (EMT) can predict resistance to EGFR TKIs, the molecular mechanisms are still unknown.
To examine the role of EMT regulators in resistance to gefitinib. Methods: The expression level of EMT regulators in gefitinib-sensitive cells (PC9) and gefitinib-resistant cells (PC9/gef) was determined using quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of EMT regulators on gefitinib resistance in vitro, and a xenograft mouse model was used for in vivo confirmation. In addition, cancer cells from 44 patients with malignant pleural effusions of lung adenocarcinoma were collected for analysis of EMT regulator mRNA by quantitative real-time reverse transcription-polymerase chain reaction.
Slug expression, but not that of snail, twist, or zeb-1, was significantly increased in PC9/gef compared with PC9 cells. Slug knockdown in PC9/gef cells reversed resistance to gefitinib, and overexpression of Slug in PC9 cells protected cells from gefitinib-induced apoptosis. Silencing of Slug in gefitinib-resistant cells restored gefitinib-induced apoptosis primarily through Bim up-regulation and activation of caspase-9. Slug enhanced tumor growth in a xenograft mouse model, even with gefitinib treatment. In clinical samples, Slug expression was significantly higher in cancer cells with resistance to EGFR TKIs than in treatment-naive cancer cells.
Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.
Full-text · Article · Oct 2010 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Previous exploratory analysis of epidermal growth factor receptor (EGFR) mutational status in tumor samples from randomized clinical studies suggested that patients with activating mutation of the EGFR had better survival than those harboring wild-type EGFR.
We analyzed the EGFR sequence of tumor samples from advanced stage non-small cell lung cancer patients previously participated in treatment clinical trials. Responses to chemotherapy and survival of EGFR mutation-positive or -negative patients were compared.
Tumor samples from 122 patients were available for analysis. EGFR mutation was present in 58 patients (47.5%). In 105 stage IIIB/IV patients, there was a nonstatistically significant trend toward a higher chemotherapy response rate of patients with mutated EGFR than those with wild-type EGFR (44.6% versus 30.6%, p = 0.162). Female, never-smoking, and adenocarcinoma patients lived longer than male (p = 0.0139), smoking (p = 0.0045), or nonadenocarcinoma (p = 0.0151) patients. There was no difference in the survival of patients with mutated or wild-type EGFR (p = 0.2159). There was no difference in progression-free survival of first-line chemotherapy between patients with wild-type or mutation in EGFR (6.6 months versus 6.1 months).
There is a nonstatistically significant trend toward a higher chemotherapy response rate in patients with mutated EGFR than those with wild-type EGFR. EGFR gene mutation is not a predictive biomarker for progression-free and overall survival to cytotoxic chemotherapy in East Asians with advanced non-small cell lung cancer.
No preview · Article · Sep 2010 · Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: Gefitinib and cetuximab are both epidermal growth factor receptor (EGFR) target therapies used to treat patients with non-small-cell lung cancer (NSCLC) with different mechanisms. To clarify the effectiveness of cetuximab after failure of gefitinib treatment, we investigated the clinical features of patients with NSCLC who received cetuximab-containing chemotherapy after failure of gefitinib.
We analyzed the clinical data and mutational studies of patients with NSCLC in the National Taiwan University Hospital who had received gefitinib and, after failure of gefitinib, cetuximab-containing chemotherapy.
Fifteen patients who received cetuximab-containing chemotherapy after failure of gefitinib were identified. Four were responders to gefitinib therapy, and 3 were responders to cetuximab-containing chemotherapy. Ten were sequenced for EGFR and KRAS mutations. Six of the 10 patients had EGFR mutations, and all 10 patients had wild-type (WT) KRAS. In the 4 patients who had the gefitinib-resistant EGFR T790M mutation, 2 were responders to cetuximab-containing chemotherapy. The other cetuximab responder had WT EGFR.
Cetuximab might add benefit in treatment after failure of gefitinib, regardless of EGFR mutational status. Treatment with cetuximab should be further explored, even in patients who have previously received gefitinib treatment.
No preview · Article · Jul 2010 · Clinical Lung Cancer
[Show abstract][Hide abstract] ABSTRACT: Tyrosine kinase inhibitors of the epidermal growth factor receptor, gefitinib and erlotinib, have changed the treatment paradigm of advanced non-small cell lung cancer (NSCLC). Many phase II or III studies have proven the efficacy of gefitinib or erlotinib as the first-line, second-line, or third-line treatment. However, it is not clear whether gefitinib or erlotinib has different activities in advanced NSCLC patients with different clinicopathological features or at different stages. We review the published clinical trials that used gefitinib or erlotinib in NSCLC and compare their efficacy. The selection criteria and efficacy measurement in these trials that might affect the final results of the studies are listed and discussed. The adequate-powered, direct comparisons of gefitinib against erlotinib under the same clinical scenarios are lacking. There is no evidence at present that the efficacy of these two agents in NSCLC is different.
Full-text · Article · Jun 2010 · Discovery medicine