Epidermal Growth Factor Receptor Mutation-negative Patients Research Articles

Comparison between Vinorelbine–Carboplatin and Vinorelbine–Cisplatin in Stage III–IV EGFR Mutations-Negative NSCLC

Introduction There are a substantial number of lung cancer patients with negative mutations in Indonesia. This type of cancer is deemed to be the major contributor of lung cancer patient’s death. However, reseaerch related to therapy using vinorelbine combined with platinum-based compounds is still scarce in Indonesia. The aim of this study was to compare the efficacy and tolerability between vinorelbine and carboplatin with vinorelbin and cisplatin in stage III-IV epidermal growth factor receptor (EGFR) mutations-negative non-small cell lung cancer (NSCLC). Methods The participants were divided into two groups—group I(vinorelbine–carboplatin) and group II (vinorelbine–cisplatin). The participants were assessed based on several measurement criteria. Not only Eq-5D was performed, but the body weight and response evaluation criteria for solid tumors (RECIST) were also examined. The participants received chemotherapy for four cycles (1 cycle = 21 days). Results The quality of life was considered stable in 60% of group I and 60% of group II (p = 0.255). In both groups, 46.67% of participants had an increased body weight, while the other 20.00% was stable (p = 1.000). In terms of RECIST evaluation after the second cycle, 80.00% of group I and 86.67% of group II were considered to have a stable disease, with 20% of group I and none of group II had partial response (p = 0.027). However, after the fourth cycle, there were no significant difference between the groups (p = 0.734). Conclusion In EGFR mutation-negative NSCLC patients, the combination of vinorelbine and carboplatin showed comparable outcomes to vinorelbine and cisplatin chemotherapy with no significant differences.

Outcomes of Gamma Knife Radiosurgery for Brain Metastases From Anaplastic Lymphoma Kinase Rearrangement-Positive and EGFR Mutation-Positive Non-Small Cell Lung Cancer.

IntroductionThe outcomes after gamma knife radiosurgery (GKRS) were retrospectively analysed in patients with brain metastases from anaplastic lymphoma kinase (ALK) rearrangement-positive and epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) to evaluate the efficacy, safety and difference for overall survival and local tumor control.MethodsThe medical records were retrospectively reviewed of 607 patients (25 ALK-positive, 171 EGFR-positive, and 411 wild type) with 2959 tumors who had undergone GKRS.ResultsThe median overall survival time after initial GKRS was 14 months. Driver gene mutation-positive patients had significantly longer overall survival than wild type patients (p < 0.0001), and ALK-positive patients survived significantly longer than EGFR-positive patients (p = 0.04). Multivariate analysis showed the unfavorable factors significantly affecting overall survival outcomes were older age, lower Karnofsky Performance Status score, multiple intracranial metastases, uncontrolled primary cancer, uncontrolled extracranial metastases, no administration of immune checkpoint inhibitors, and driver gene mutation-negative cases. Seventy-three patients died of uncontrolled brain metastases at a median of 12 months. Driver gene mutations had no influence (p = 0.33), and ALK-positive and EGFR-positive patients showed no significant difference in neurological survival (p = 0.83). A total of 174 patients demonstrated distant brain control failure at a median of 15 months. ALK-positive type was significant compared with EGFR-positive type (p = 0.047), but driver gene mutation-positive and -negative types showed no significant difference in the development of new brain metastases (p = 0.2). The median tumor volume was 1.06 cm3 in the driver gene mutation-positive type and 1.85 cm3 in wild type. The median marginal dose was 20 Gy in both types. The 6-, 12-, and 24-month local tumor control rates were 97.3%, 96.1%, and 95.9%, respectively. Driver gene mutations had a significantly positive impact on local tumor control (p = 0.001), and ALK-positive and EGFR-positive types showed no significant difference (p = 0.95). A total of 193 tumors had radiation injury at a median of 12 months after GKRS. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 8.1%, and 8.7%, respectively. Driver gene mutations significantly induced radiation damage (p = 0.021), and the ALK-positive type was affected more than the EGFR-positive type (p = 0.02).ConclusionsALK rearrangement-positive NSCLC patients tended to have significantly longer survival, but had higher incidence of new intracranial metastases due to long-term survival after GKRS, compared with EGFR mutation-negative and driver gene mutation-negative NSCLC patients. GKRS induced significantly satisfactory local tumor control in driver gene mutation-positive tumors but GKRS-related complication frequency was higher, especially in ALK-positive NSCLC patients. Therefore, more careful imaging follow-up is necessary after GKRS for patients with driver gene mutation-positive NSCLC.

The Prognostic Role of PORT and EGFR Mutation Status in Completely Resected Stage IIIA/N2 Non-Small Cell Lung Cancer Patients with Postoperative Chemotherapy.

Background: The treatment choice for completely resected stage IIIA/N2 non-small cell lung cancer (NSCLC) patients is still controversial now. Our study aims to identify potential prognostic factors in stage IIIA/N2 NSCLC patients with complete surgical resection and postoperative chemotherapy.Methods: In this study, we screened the stage IIIA/N2 NSCLC patients diagnosed in the Affiliated Cancer Hospital of Zhengzhou University from 2015 to 2019. Completely resected patients with postoperative chemotherapy (PCT) were enrolled. The univariate and multivariate COX proportional hazards regression analyses were used to identify the prognostic factors. The Kaplan-Meier survival curve was used to compare the disease-free survival (DFS) and overall survival (OS) in the subgroup analyses.Results: 180 patients were collected, including 142 patients with PCT treatment alone and 38 patients with postoperative radiotherapy (PORT) treatment. The median DFS was 17.8 months (95% CI: 16.5–19.1 months) and the median OS was 50.6 months (47.4–53.9 months) in all the patients. The median DFS of the PORT group was significantly longer than the PCT group (38.7 vs 16.7 months, p < 0.001). Epidermal growth factor receptor (EGFR) mutation-positive patients had a worse DFS compared with EGFR mutation-negative patients (16.8 vs 18.0 months, p = 0.032). Possible prognostic factors were evaluated through univariate COX regression analysis. The further multivariate COX regression analysis showed that patients with PORT (HR: 0.318, 95% CI: 0.185–0.547, p < 0.001), EGFR mutation-negative (HR: 0.678, 95% CI: 0.492–0.990, p = 0.044), T1 (HR: 0.661, 95% CI: 0.472–0.925, p = 0.016), and lobectomy (HR: 0.423, 95% CI: 0.191–0.935, p = 0.034), had better DFS. The only independent prognostic factor of OS was the type of surgery (p = 0.013).Conclusion: PORT might improve the DFS of stage IIIA/N2 NSCLC patients with complete surgical resection and PCT, but it cannot increase OS. Besides, EGFR mutation status, T stage, and type of surgery are possible independent prognostic factors for DFS, and type of surgery is associated with OS. These factors remain to be clarified in further studies.

Detection of epidermal growth factor receptor (EGFR) mutations from preoperative circulating tumor DNA (ctDNA) as a prognostic predictor for stage I-III non-small cell lung cancer (NSCLC) patients with baseline tissue EGFR mutations.

BackgroundPlasma circulating tumor DNA (ctDNA) may be a surrogate, minimally invasive approach to tissue-based epidermal growth factor receptor (EGFR) mutation detection in non-small cell lung cancer (NSCLC) patients. However, the predictive ability of preoperative ctDNA EGFR mutation test on long-term postoperative survival and tumor metastasis development has not been extensively investigated.MethodsStage I–III NSCLC patients with tissue EGFR mutations were enrolled in this study (n=174). The ctDNA EGFR mutations were identified in paired preoperative plasma samples. EGFR mutation testing was performed using Scorpion amplified refractory mutation system (ARMS) technology. The correlation between ctDNA EGFR mutation status and clinicopathologic parameters was analyzed. By combining at least 5 years of follow-up data, we assessed the relationship between ctDNA EGFR mutation status and disease-free survival (DFS) and overall survival (OS).ResultsPlasma-based ctDNA EGFR mutations were detected in 27 patients. The mutation types were exactly matched with those in paired tissue samples. Blood test sensitivity was closely associated with N stages, tumor-node-metastasis (TNM) stages and tumor differentiation (P<0.001). The overall 5-year survival rate was 18.5% versus 76.9% for ctDNA EGFR mutation-positive and ctDNA EGFR mutation-negative patients, respectively. For patients with ctDNA EGFR mutation positive, the median OS and DFS were 29.00±2.55 and 19.00±2.50 months, respectively, which were both significantly better than those in the ctDNA EGFR mutation-negative subgroup (P<0.001). ctDNA EGFR mutation was an independent risk factor of OS and DFS [hazard ratio (HR) 3.289, 95% confidence interval (CI), 1.816–5.956, P<0.001; HR, 4.860, 95% CI, 2.660–8.880, P<0.001]. For stage III patients with exon 19 deletion or L858R mutations in both tissue and plasma samples, tyrosine kinase inhibitor (TKI) therapy showed significantly better OS (P=0.025) and possible DFS benefit (P=0.060) than did chemotherapy.ConclusionsEGFR mutation testing using the Scorpion-ARMS method in preoperative plasma could be a strong predictor for postoperative survival and metastasis of NSCLC patients. Thus, the subset of this population may be benefit from targeted strategies and management.

Results of EGFR Mutations Detected in Pleural Effusion and Its Clinical Significance in 132 Patients with Advanced Non-small Cell Lung Cancer: A Retrospective Study in A Single Center

背景与目的恶性胸腔积液表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变检测缺乏病理质控，导致对检测结果解释及指导临床EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）使用造成困惑。因此，提出质控标准，并按此标准进行胸水EGFR突变检测尤为重要。本研究拟回顾性分析按照严格病理质控标准进行的胸水沉渣切片EGFR基因突变检测结果以及据此结果指导EGFR-TKIs治疗的疗效。方法回顾性分析中国医学科学院北京协和医院病理科2012年1月-2018年6月收到的胸腔积液标本的患者临床资料，其中具有临床资料相对完整，且按照制定的质控标准进行了胸水沉渣石蜡包埋切片EGFR基因突变检测的患者132例。根据EGFR基因突变检测结果，分为阳性组和阴性组，比较不同组别使用EGFR-TKIs的疗效。结果胸腔积液经离心后，沉渣石蜡包埋、切片，HE染色后镜下观察，若肿瘤细胞数目≥100个，即满足病理质控标准，可用于后续EGFR基因突变检测。132例患者中，72例（54.5%）患者胸水中检出EGFR基因突变。72例突变阳性患者中，69例患者使用了EGFR-TKIs。60例EGFR突变阴性患者中，仅15例使用EGFR-TKIs。EGFR突变阳性组的疾病控制率（disease control rate, DCR）为95.8%，中位无疾病进展生存时间（progression-free survival, PFS）为11个月；EGFR突变阴性组的DCR为0%，中位PFS为1个月，两组患者DCR和PFS均有显著差异（P < 0.05）。结论经病理质控的胸水沉渣包埋切片可用于EGFR基因突变检测，其结果可指导临床EGFR-TKIs使用。

Tumour content ratio matters for detecting epidermal growth factor receptor mutation by cobas test in small biopsies; a retrospective study

BackgroundRecent studies indicate the benefit of treatment with osimertinib over that with conventional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for untreated EGFR-mutated non-small cell lung cancer (NSCLC). Cobas ver2 is the only companion diagnostic method for detecting EGFR mutations with osimertinib treatment. We clinically experience false negative cases with this test, but its actual sensitivity is unknown. Moreover, no study has suggested the importance of tumour dissection, and most facilities do not routinely perform them on small biopsies. The purpose of this study was to evaluate the sensitivity of cobas in clinical practice and clarify the role of dissection as a component of the cobas testing.MethodsWe examined 132 patients with EGFR-mutated NSCLC diagnosed by bronchoscopy and confirmed with PCR clamp. Patients were tested with cobas and the EGFR-positive rate was calculated. Samples with undetected EGFR mutations were retested after tumour dissection and the rate of samples whose EGFR mutation was corrected to positive was assessed. To evaluate tumour cellularity, the tumour content ratio was assessed by calculating tumour cell count over the total cell count on the slide.ResultsThe positive rate of EGFR mutation identification was 76% with cobas, although EGFR mutation-negative patients retained responses to TKI therapy equivalent to positive patients did; however, the tumour content ratio of negative samples was significantly lower than that of positive samples. Twenty-nine negative samples underwent dissection and 24% were corrected to positive. Moreover, 53% of the samples with a tumour content ratio below 10% was negative for cobas, but 33% of these turned positive after dissection.ConclusionsCobas had a high false negative rate in clinical practice, and tumour content ratio might be associated with this rate. Dissection could improve the sensitivity of cobas, especially in samples with low tumour cellularity.

Prognostic value of epidermal growth factor receptor mutations and histologic subtypes with lung adenocarcinoma.

The epidermal growth factor receptor (EGFR) mutation status has become one of the most important factors in the treatment of non-small cell lung cancer. However, the relationship between EGFR mutation and the histologic subtype of lung adenocarcinoma remains to be fully elucidated. We examined the relationship between the predominant subtype of adenocarcinoma and the prognosis and investigated the correlation between a new subtype of adenocarcinoma and EGFR mutations. This study included 182 patients with adenocarcinoma who underwent complete resection. The rate of EGFR mutation-positive patients was significantly higher among female patients, never smokers, patients with small tumors (<3cm in size), patients with well-differentiated tumors, and patients with a pStage I classification. The rates of adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant subtype were high in male EGFR mutation-positive patients. The prevalence of the acinar and papillary-predominant subtypes was high among EGFR mutation-positive female patients, as was AIS, MIA, and the lepidic-predominant subtype. The progression-free survival (PFS) of the EGFR mutation-positive patients was significantly better than that of the EGFR mutation-negative patients (75.8 vs 67.1%, p=0.03). However, the multivariate analysis of clinicopathologic and histologic factors did not reveal the prognostic impact of the EGFR mutation status on PFS. The overall survival (OS) of the EGFR mutation-positive patients was significantly better than that of the EGFR mutation-negative patients (93.7 vs 63.4%, p<0.01). However, in the multivariate analysis the EGFR mutation status was not significantly associated with OS.

Utilization of Molecular Testing and Survival Outcomes of Treatment with First- or Second-line Tyrosine Kinase Inhibitors in Advanced Non-small Cell Lung Cancer in a Dutch Population.

Epidermal growth factor receptor (EGFR) mutation testing is standard-of-care for advanced non-small cell lung cancer (NSCLC). Outcomes of second-/third-line compared to first-line tyrosine kinase inhibitors (TKIs) have shown conflicting results. We investigated utilization of molecular diagnostics and the outcomes of treatment with first-/second-line TKIs in patients with advanced NSCLC. Retrospective analysis was carried out of 2,206 patients with stage IIIb/IV NSCLC treated between 2008 and 2014 in four hospitals in the Netherlands. The rate of performing molecular diagnostics increased from 20.8% to 74.4% in the study period. The median overall survival of EGFR mutation-positive patients treated with TKIs was superior compared to EGFR mutation-negative patients treated with chemotherapy (720 vs. 274 days, p<0.0001). No difference in overall survival was found between EGFR mutation-positive patients treated only with TKIs compared to those treated with chemotherapy prior to TKIs, or upon progression under TKIs. The rate of EGFR testing has improved, increasing the number of patients eligible for targeted therapy. Chemotherapy, prior or subsequent to TKIs, for the treatment of EGFR mutation-positive patients, did not result in significantly better overall survival compared to that achieved with TKIs alone.

Post-Progression Survival after EGFR-TKI for Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations.

BackgroundNon-small cell lung cancer (NSCLC) patients that harbor epidermal growth factor receptor (EGFR) mutations benefit from receiving an EGFR-tyrosine kinase inhibitor (TKI); however, post-progression survival (PPS) after EGFR-TKI treatment has not been sufficiently studied.MethodsWe retrospectively reviewed the clinical data from stage IV or recurrent NSCLC patients who harbored EGFR mutations and who received EGFR-TKI as their first-line treatment in our institute between 2009 and 2011.ResultsIn total, 36 patients received EGFR-TKI treatment as their first-line therapy. Of those 36 patients, 30 experienced recurrence and were enrolled in this study. The median progression-free survival (PFS) of these patients was 8.2 months. Twelve patients received EGFR-TKI treatment beyond the diagnosis of progressive disease (PD), and 8 received second-line therapy. The PPS after EGFR-TKI treatment was 9.1 months, and survival after the termination of EGFR-TKI treatment in those patients treated with second-line chemotherapy was 13.9 months. The site of relapse was investigated and PFS in EGFR-TKI-treated patients with relapse in the brain (11.6 months) showed a trend toward a longer PFS compared with patients with relapse at other sites (8.2 months). The median PPS after EGFR-TKI treatment also showed the same trend in each group (12.9 and 9.2 months, respectively).ConclusionsThe PPS after EGFR-TKI treatment failure was 9.1 months, while the survival of patients who underwent second-line chemotherapy after the termination of EGFR-TKI treatment was 13.9 months, comparable with the overall survival of EGFR mutation-negative patients, as previously reported. The prognosis of these NSCLC patients with EGFR mutations varied according to the sites of recurrence after first-line EGFR-TKI treatment. Of particular note was the prognosis of patients with brain metastases, which tended to be better than that of patients with metastases to other sites.

Egfr Ca Repeat Polymorphism Predict Clinical Outcome in Egfr Mutation Positive Nsclc Patients Treated with Erlotinib

Aim: Somatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). However, not all patients with EGFR mutations respond to erlotinib and the duration of the response varies markedly between patients. ACA repeat polymorphism in intron 1 of the EGFR gene influences the transcription of the EGFR gene. Here the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib is evaluated. Methods: The number of CA repeats in the EGFR gene was evaluated in 432 advanced NSCLC patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA ≤16 in any allele) or long alleles (CA > 16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based on the somatic EGFR mutation status. Results: We demonstrate a significant better median progression free survival (HR= 0.39 (0.22-0.70); p = 0.002) and overall survival (HR= 0.43, (0.23-0.78); p = 0.006) in EGFR mutation positive patients (N = 62) harboring a short allele versus a long allele (median follow-up time of 52.2 months). The result remained highlysignificant in a multivariate Cox proportional hazards model. This correlation was not seen in EGFR mutation negative patients. Further, there were an association between having a short allele and developing the L585R mutation in exon 21 and between long allele and exon 20 insertions. Conclusions: We demonstrate that in EGFR mutation positive NSCLC patients treated with erlotinib a low number of CA repeats in intron 1 of the EGFR gene is a predictor for longer progression free survival and overall survival. Disclosure: All authors have declared no conflicts of interest.

EGFR CA repeat polymorphism predict clinical outcome in EGFR mutation positive NSCLC patients treated with erlotinib

ObjectivesSomatic mutations in the epidermal growth factor receptor (EGFR) are predictors of efficacy for treatment with the EGFR tyrosine kinase inhibitor erlotinib in non-small cell lung cancer (NSCLC). A CA repeat polymorphism in intron 1 of the EGFR gene influences the transcription of the EGFR gene. This study evaluates the association between the CA repeat polymorphism and outcome in NSCLC patients treated with erlotinib. Materials and methodsNumber of CA repeats in the EGFR gene was evaluated with PCR-fragment length analysis by capillary electrophoresis in 432 advanced NSCLC patients treated with erlotinib irrespective of EGFR mutation status. Patients were dichotomized into harboring short allele (CA≤16 in any allele) or long alleles (CA>16 in both alleles). Number of repeats was correlated with clinical characteristic and outcome. A subgroup analysis was performed based on the somatic EGFR mutation status. ResultsIn EGFR mutation positive patients (N=62) we demonstrate a significantly higher median progression free survival (HR=0.39 (0.22–0.70); p=0.002) and overall survival (HR=0.43 (0.23–0.78); p=0.006) in patients also harboring a short CA repeat length vs. a long (median follow-up time of 52.2 months). The result remained highly significant in a multivariate Cox proportional hazards model. This correlation was not seen in EGFR mutation negative patients. ConclusionOur study demonstrate that in EGFR mutation positive NSCLC patients treated with erlotinib a low number of CA repeats in intron 1 of the EGFR gene is a predictor for both longer progression free survival and overall survival.

Epidermal Growth Factor Receptor Mutations in 510 Finnish Non–Small-Cell Lung Cancer Patients

Among the driver gene mutations in non-small-cell lung cancer, mutations in epidermal growth factor receptor (EGFR) are the most important because of their predictive role in selecting patients eligible for targeted therapy. Our aim was to study EGFR mutations in a Finnish non-small-cell lung cancer cohort of 528 patients. Mutation testing was conducted on DNA extracted from paraffin-embedded, formalin-fixed tumor material using the following real-time polymerase chain reaction-based kits: Therascreen EGFR PCR Kit and cobas EGFR Mutation Test. EGFR mutation frequency was 11.4% and all positive cases were adenocarcinomas, of which a majority had an acinar predominant pattern. Mutations were seen significantly more often in females and never-smokers than in males and smokers. The most frequent mutations were L858R in exon 21 and deletions in exon 19. Overall survival of the patients, not treated with EGFR inhibitor, did not differ between EGFR mutation-positive and EGFR mutation-negative patients. EGFR mutation profile in this Finnish non-small-cell lung cancer cohort resembles in many respect with that of other Western European cohorts, even though the overall frequency of mutations is slightly higher. We show the occurrence of EGFR mutations in patients with occupational asbestos exposure and also in those diagnosed with chronic obstructive pulmonary disease who have not been often investigated before.

Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma

ObjectivesThe aim of this study is to evaluate the prevalence and prognostic significance of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement in never-smokers with surgically resected lung adenocarcinoma. MethodsWe retrospectively analyzed 162 consecutive never-smokers who underwent curative resection for stage IB to IIIA lung adenocarcinoma at a single institution. We concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes, and investigated ALK rearrangements by fluorescence in situ hybridization assay. ROS1 rearrangement was also determined in all triple (EGFR/KRAS/ALK)-negative tumors. ResultsOf 162 never smokers with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) had ALK and ROS1 rearrangements, respectively. Nineteen of the 74 (25.7%) EGFR and KRAS mutation-negative patients were fusion-positive (ALK or ROS1 fusion). Fusion-positive patients tended to have shorter median disease-free survival (DFS) than fusion-negative patients (28.0 vs. 33.9 months; p=0.128). In multivariate analysis, fusion-positive patients had significantly poorer DFS than fusion-negative patients after adjustment for age, sex, T stage, N stage, and adjuvant chemotherapy use (p=0.022; hazard ratio, 2.11; 95% confidence interval, 1.19–4.30). The first recurrence sites were not significantly different between fusion-positive and fusion-negative patients in this study. ConclusionThis study shows significantly poorer DFS of ALK or ROS1 fusion-positive lung adenocarcinoma in never-smokers after curative surgery.

FDG PET/CT metabolic tumor volume and total lesion glycolysis predict prognosis in patients with advanced lung adenocarcinoma

We investigated fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT)-assessed metabolic tumor volume (MTV) and total lesion glycolysis (TLG) as prognostic factors in lung adenocarcinoma patients. This retrospective study included 106 patients (19 stage I/II and 87 stage III/IV lung adenocarcinoma) who underwent FDG PET/CT before treatment. Standardized uptake value (SUV), MTV, and TLG (MTV×mean SUV) of each malignant lesion were measured. Whole MTV and whole TLG were the summation of all the MTV and TLG values in each patient. Survival analysis and FDG PET/CT parameters regarding epidermal growth factor receptor (EGFR) gene mutation status were evaluated. Univariate survival analysis of stage III/IV patients identified high whole MTV (≥90), high whole TLG (≥600), and stage IV as significant predictors of poor progression-free survival. For overall survival, high whole MTV (≥90), high whole TLG (≥600), EGFR mutation-negative, and stage IV were significant poor prognostic predictors. After multivariate survival analysis, high whole MTV (P=0.001), high whole TLG (P=0.027), and stage IV (P=0.006) were independent predictors of poor progression-free survival. High whole MTV (P<0.001), high whole TLG (P=0.001), and EGFR mutation-negative (P=0.001) were independent prognostic predictors for poor overall survival. In a survival analysis of stage I/II patients, none was an independent prognostic predictor. No significant differences were found in FDG PET/CT parameters for EGFR mutation-negative and EGFR mutation-positive patients. Assessment of MTV and TLG by FDG PET/CT in advanced lung adenocarcinoma patients provides useful information regarding prognosis.

Carcinoembryonic antigen-related cell adhesion molecules as surrogate markers for EGFR inhibitor sensitivity in human lung adenocarcinoma

Background:Lung adenocarcinoma (LADCA) patients with epidermal growth factor receptor (EGFR) mutations are in general associated with relatively high clinical response rate to EGFR-tyrosine kinase inhibitors (TKIs) but not all responded to TKI. It has therefore become important to identify the additional surrogate markers regarding EGFR-TKI sensitivity.Methods:We first examined the effects of EGFR-TKIs, gefitinib and erlotinib, upon cell proliferation of lung adenocarcinoma cell lines. We then evaluated the gene profiles related to EGFR-TKI sensitivity using a microarray analysis. Results of microarray analysis led us to focus on carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, CEACAM 3, 5, 6, 7, and 19, as potential further surrogate markers of EGFR-TKI sensitivity. We then examined the correlation between the status of CEACAM 3, 5, 6, 7, and 19 immunoreactivity in LADCA and clinicopathological parameters of individual cases.Results:In the cases with EGFR mutations, the status of all CEACAMs examined was significantly higher than that in EGFR wild-type patients, but there were no significant differences in the status of CEACAMs between TKI responder and nonresponder among 22 patients who received gefitinib therapy. However, among 115 EGFR mutation-negative LADCA patients, both CEACAM6 and CEACAM3 were significantly associated with adverse clinical outcome (CEACAM6) and better clinical outcome (CEACAM3).Conclusion:CEACAMs examined in this study could be related to the presence of EGFR mutation in adenocarcinoma cells but not represent the effective surrogate marker of EGFR-TKI in LADCA patients. However, immunohistochemical evaluation of CEACAM3/6 in LADCA patients could provide important information on their clinical outcome.

Role of EGFR mutation status in patients with stage III non-squamous non-small cell lung cancer treated with chemoradiotherapy

背景与目的表皮生长因子受体（epidermal growth factor receptor, EGFR）突变状态与Ⅲ期非小细胞肺癌放化疗近期疗效和生存的关系是目前临床研究热点。本研究旨在探讨EGFR突变状态与Ⅲ期非鳞非小细胞肺癌放化疗疗效的关系。方法本研究共计入组187例Ⅲ期非鳞非小细胞肺癌患者，其中87例能够评估放化疗近期疗效和2年生存率，128例患者适合评估一线化疗疗效。采用变性高效液相色谱法检测EGFR基因突变状态。结果EGFR突变阳性患者对联合放化疗的客观缓解率为84.6%（33/39），明显高于EGFR突变阴性患者56.3%（27/48）（P=0.004）。2年生存率EGFR突变阳性患者为53.8%（21/39），EGFR突变阴性患者为50%（24/48），两组在长期生存方面无统计学差异（P=0.871）。结论在Ⅲ期非鳞非小细胞肺癌中，EGFR突变预示更高的放化疗近期疗效，与生存期无关。

Clinicopathologic comparison of resected pulmonary adenocarcinoma according to the EGFR mutation status.

e17524 Background: Gene mutations of epidermal growth factor receptor (EGFR) are largely limited to tumors in never smokers, light smokers, and adenocarcinoma. The presence of this gene mutation is the clinical indication for the administration of EGFR-tyrosine kinase inhibitors. The present study compared the clinicopathologic features of surgical pulmonary adenocarcinoma according to EGFR mutation status. Methods: The medical records of 102 patients with EGFR mutation status-known adenocarcinoma who underwent a complete resection from 2008 through 2010 were reviewed for the clinicopathologic variables. The patients ranged in age from 37 to 85 years old with a mean of 67.3. The male:female ratio was 44:58. The EGFR mutation positive -negative ratio was 45:57. Results: The comparison between the EGFR mutation positive and EGFR mutation negative patients in various clinicopathological variables is summarized in the table.Significant differences were observed in gender, smoking status, pleural invasion, and histological differentiation. No difference was observed in the postoperative recurrence-free survival associated with the EGFR mutation status (p=0.124). Conclusions: No remarkable difference was found in the potential of tumor extension, although there were significant clinicopathologic differences between the patients with an EGFR mutation positive status and those with an EGFR mutation negative status. Variables Positive (n=45) Negative (n=57) P value Age (mean + SD) 66 + 8.5 68 + 9.9 0.374 Gender (female : male) 36 : 9 23 : 34 <0.01 Never smoker : ex-smoker 31 : 14 15 : 42 <0.01 PET-SUVmax (mean + SD) 4.3 + 3.85 5.9 + 4.80 0.112 Diameter (mean + SD) 2.4 + 1.02 2.8 + 1.56 0.084 Vascular invasion (+/-) 12 : 33 18 : 39 0.589 Lymphatic permeation (+/-) 5 : 40 7 : 50 0.856 Pleural invasion (+/-) 4 : 41 15 : 42 0.025 Differentiation (G1/G2/G3) 33 : 11 : 1 29 : 18 : 10 0.018 pT (T1 : T2 : T3-4) 34 : 10 : 1 36 : 19 : 2 0.480 pN (N0 : N1: N2) 37 : 4 : 4 50 : 3 : 4 0.711

A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naïve Patients with Advanced Non–Small Cell Lung Cancer

This multicenter, phase II study evaluates the efficacy and safety of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, plus sorafenib, a multityrosine kinase inhibitor against vascular endothelial growth factor receptors, in patients with previously untreated advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients with stage IIIB/IV NSCLC received erlotinib (150 mg once a day) and sorafenib (400 mg twice a day) until disease progression or unacceptable toxicity. The primary end point was the rate of nonprogression at 6 weeks. Secondary end points included objective response rate (ORR), time to progression, overall survival, and adverse events. Exploratory end points included pretreatment EGFR and KRAS mutation status, pharmacokinetics, and cytochrome P450 polymorphisms. Fifty patients initiated therapy. The nonprogression rate at 6 weeks was 74%: 12 (24%) partial response and 25 (50%) stable disease. Ultimately, the ORR was 28%. Median time to progression was 5.0 months [95% confidence interval (95% CI), 3.2-6.8 months]. Median overall survival was 10.9 months (95% CI, 3.8-18.1 months). Grade 3/4 adverse events included fatigue (16%), hand-foot skin reaction (16%), rash (16%), diarrhea (14%), and hypophosphatemia (42%). There was one treatment-related fatal pulmonary hemorrhage. Patients with wild-type EGFR had a higher ORR (19%) than previously reported for single-agent erlotinib/sorafenib. Erlotinib levels were lowered. This was associated with CYP3A4 polymorphism and was possibly due to sorafenib. Despite a possible drug interaction, sorafenib plus erlotinib has promising clinical activity in patients with stage IIIB/IV NSCLC and has an acceptable safety profile. Further evaluation of this combination as potential salvage therapy in EGFR mutation-negative patients and the possible drug interaction is warranted.

Clinical outcomes of advanced non-small cell lung cancer patients screened for epidermal growth factor receptor gene mutations

To evaluate the relationship between the epidermal growth factor receptor (EGFR) mutation status and the effectiveness of gefitinib monotherapy or chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We retrospectively analyzed a cohort of 100 patients with stage IIIB/IV NSCLC screened for two major EGFR mutations (exon 19 deletions and L858R mutation). Forty-six out of 48 EGFR mutation-positive patients (96%) received gefitinib, whereas only 3 out of 52 EGFR mutation-negative patients (6%) received gefitinib. Favorable objective response rates to gefitinib as first- and second-line treatment (87 and 80%, respectively) were observed in EGFR mutation-positive patients. Overall response rate to chemotherapy as first-line treatment did not differ significantly between patients with EGFR mutations and those without mutation (32 vs. 28%, respectively; P = 0.7198). As to first-line treatment, EGFR mutation-positive patients treated with gefitinib experienced significantly longer progression-free survival (PFS) than did patients who received chemotherapy (median survival, 7.8 months vs. 5.1 months, respectively; P = 0.0323). Similarly, as to second-line treatment, EGFR mutation-positive patients treated with gefitinib had significantly longer PFS than did patients who received chemotherapy (median survival, 6.5 months vs. 4.0 months, respectively; P = 0.0048). Patients with EGFR mutations survived longer than those without EGFR mutations after first-line treatment (median, 24.3 vs. 12.6 months, respectively; P = 0.0029). EGFR mutation-positive patients benefit from either first- or second-line gefitinib monotherapy. Further large-scale prospective studies to confirm this finding are needed.