Positive Epidermal Growth Factor Receptor Mutation Research Articles

A Case Report of a Metastatic Adenocarcinoma of Lung with Dual Positivity for EGFR Mutation and ALK Fusion

Non-small cell lung cancer ranks among the most lethal cancers worldwide. The rate of epidermal growth factor receptor (EGFR) mutations and echinoderm microtubuleassociated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) gene fusion is the most common in younger age, non-smoking Asian adenocarcinoma lung cancer patients. EGFR mutations and ALK gene rearrangements are known to be mutually exclusive and as mutual causes of resistance to EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs. However, rarely such co-alterations do co-exist in some clinical cases. Here we report a 62 year old male, heavy smoker with cough, hemoptysis and fatigue. Histopathological examination of bronchoscopic guided biopsy showed adenocarcinoma histology. Staging evaluation, he was found to have stage IV disease on positron emission tomography-computed tomography scan. The biopsy blocks tested positive for both EGFR mutation and ALK fusion. Patient was initiated on tablet Gefitinib 250 mg once daily. To the best of our knowledge, there has been no report of dual EGFR mutation and ALK fusion positivity from India.

Epidermal Growth Factor Receptor Mutations: Effect on Volume Doubling Time of Non–Small-Cell Lung Cancer Patients

The purpose of this study was to retrospectively compare the volume doubling time (VDT) on serial computed tomography (CT) of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation with that of NSCLC without the mutation. One hundred and two pathologically proven NSCLCs, including 69 patients with lung adenocarcinoma, were reviewed with helical CT. Each tumor underwent at least two CT scans. The VDT was calculated using a modified Schwartz formula. EGFR mutations at exons 18-21 were determined by common fragment analysis and Cycleave method. The median VDT of all the patients was 188 days. EGFR mutations were noted in 35 of the 102 patients. The VDT in the 35 patients with EGFR mutations (median 676 days) was longer than that in the 67 patients without EGFR mutations (median 139 days) (p <0.001). By histology subtype, the VDT of adenocarcinoma (305 days) was longer than that of squamous cell carcinoma (81 days) and other types (90 days; p <0.001). In NSCLC patients, positive EGFR mutation status may be associated with longer VDT, which seemed to have a slowly progressive and less-aggressive character. More accurate evaluation of VDT may be helpful for understanding the natural history of EGFR mutation-positive NSCLC and treatment with EGFR tyrosine kinase inhibitors.

191P - Experience of Alk Mutation Testing in 3351 Indian Patients of Nsclc

ABSTRACT Aim: In the last decade, we have witnessed a revolution in the molecular genetics of NSCLC (Non Small Cell Lung Cancer). These advances have led to the development of a multitude of prognostic and predictive biomarkers. Somatic mutations in EGFR (Epidermal Growth Factor Receptor) gene & ALK (Anaplastic Lymphoma Kinase) translocation are two “actionable” biomarkers that have passed clinical validation and are incorporated into current treatment paradigms. This abstract contributes towards understanding the epidemiology of ALK mutation in NSCLC patients in India. Methods: This was an observational study within the cohort of NSCLC patients. Pfizer Ltd supported this study as a part of Diagnostic Assistance Program. A total of 3351 patients of lung adenocarcinoma were tested from Jan 2013 to Mar 2014. These samples were collected from various locations across the country. ALK mutation was studied using the FDA approved Vysis ALK Gene Breakapart Probe Kit and the EGFR mutation testing (exons 18-21) was done using PCR followed by bidirectional Sanger's Sequencing. Results: Of the 3351 samples tested, 2146 (64.04%) were male & 1205 (35.96%) were females. Patients ranged in age from 25-90yrs with a median age of 57.94yrs. Biomarker testing for EGFR and ALK was performed on FFPE specimen of patients with confirmed adenocarcinoma histology. ALK testing was performed on 3351 samples and EGFR analysis on 3079. Of samples received for EGFR, 2653 (86.16%) were successfully analyzed & reported, 177 (5.75%) showed unsatisfactory results, and test could not be performed in 249 cases (8.09%). 2810 (83.86%) samples received for ALK testing by FISH could be successfully reported, 287 (8.56%) showed unsatisfactory results and 254 samples (7.58%) could not be tested. Common reasons for unsatisfactory results were presence of high degree of necrosis, scanty tumor or suboptimal fixation. Of the successfully reported cases, 28.19% were positive for presence of EGFR mutations. Mutations were observed in exon 18 (2.27%), exon 19 (72.99%), exon 20 (3.48%) and exon 21 (21.26%). 71 (2.53%) of the 2810 successfully reported cases were found Positive for ALK Gene Rearrangement. None of the samples showed a concomitant mutation. Conclusions: This study on 3351 adenocarcinoma enriched NSCLC patients of Indian origin, shows an ALK positivity of 2.53% & EGFR mutation positivity of 28.19%. Disclosure: All authors declare that he study was funded by Pfizer Ltd as a part of its Diagnostic Assistance Program. Other than that there is no disclosure to declare.

Impact of EGFR mutation status on tumor response and progression free survival after first-line chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis.

Non-small-cell lung cancer (NSCLC) patients harboring sensitive epidermal growth factor receptor (EGFR) mutations derive greater benefits from EGFR-tyrosine kinase inhibitors (EGFR-TKIs) than those with wild type tumors. However, whether EGFR mutation status is associated with the efficacy of cytotoxic chemotherapy or prognosis in advanced NSCLC patients remained controversial. Thus, we sought to conduct a meta-analysis to answer this question. Electronic databases were searched for eligible literatures. The primary outcomes were objective response rate (ORR) and 6-month progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effects model. Subgroup analyses stratified by study types, EGFR mutation detection methods, chemotherapy regimens, and patient origins were proposed. A total of 14 studies involving 1,772 advanced NSCLC patients with known EGFR mutation status who had received first-line chemotherapy were included. Patients with positive EGFR mutation had numerically higher ORR than wild type patients (36.2% vs. 30.1%) without significant differences (OR 1.24, 95% CI, 0.90 to 1.70; P=0.19). However, patients with EGFR mutants had significantly superior 6-month PFS rate than wild-type patients (58.6% vs. 47.2%; OR 1.88, 95% CI, 1.33 to 2.65; P=0.0003). Results of the subgroup analyses were concordant with the overall ones. This comprehensive analysis revealed that advanced NSCLC patients with sensitivity EGFR mutation had higher 6-month PFS rate and potentially greater ORR compared with wild-type patients after first-line chemotherapy. It suggested that EGFR mutation status should be considered a significant factor for patient stratification in evaluating the efficacy of antitumor agents in addition to EGFR-TKIs.

Impact of the epidermal growth factor receptor mutation status on the post-recurrence survival of patients with surgically resected non-small-cell lung cancer.

The impact of epidermal growth factor receptor (EGFR) status and the use of EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy have not been well discussed only in recurrent non-small-cell lung cancer (NSCLC). The purpose of this study was to identify the prognostic factors associated with post-recurrence survival after surgical resection of NSCLC in terms of the EGFR mutation status and the use of EGFR-TKI therapy. From 2000 through 2011, 1237 consecutive patients with NSCLC underwent pulmonary resection at our institution. Of these patients, 280 experienced postoperative recurrence by the end of 2012. We reviewed the cases of recurrence and analysed the predictors and length of post-recurrence survival. The median post-recurrence survival time and the 5-year survival rate of all patients were 25 months and 20.8%, respectively. A multivariate analysis identified the Eastern Cooperative Oncology Group (ECOG) performance status (PS), brain metastasis, number of sites of recurrence and EGFR mutation status to be independent prognostic factors for post-recurrence survival. Among all cases, the median post-recurrence survival time according to the use of EGFR-TKI therapy was as follows: 49 months in the EGFR mutation-positive patients treated with EGFR-TKI therapy, 20 months in the EGFR wild or unknown cases treated with EGFR-TKI therapy and 17 months in the patients not treated with EGFR-TKI therapy. As to EGFR mutation-positive cases, the patients treated with EGFR-TKIs exhibited significantly longer post-recurrence survival time than the patients treated without EGFR-TKIs (49 vs 12 months). It is essential for recurrent NSCLC patients to be examined for the EGFR mutation status. Patients with a positive EGFR mutation status receive significant benefits from EGFR-TKI therapy.

MicroRNA expression profiles associated with survival, disease progression, and response to gefitinib in completely resected non-small-cell lung cancer with EGFR mutation

microRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumor suppressors, the role of microRNAs in mediating cancer progression remains unexplored. And whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in radically resected non-small-cell lung carcinoma (NSCLC) patients still needs to be further validated. Our analyses involved two separated, retrospective cohorts. Firstly, microRNA expression profile was performed in a cohort consisted of 128 radically resected NSCLC patients [60 were positive to epidermal growth factor receptor (EGFR) mutation and 68 were negative] and 32 healthy providers to identify EGFR mutation-related microRNAs and to determine their association with survival. In addition, to validate our findings, we used quantitative reverse transcriptase polymerase chain reaction assays to measure microRNAs and assess their association with disease progression, survival, and response to gefitinib in an independent cohort of 201 patients with EGRF mutation. In radically resected NSCLC patients, the expression levels of miR-21, 10b in patients with EGFR mutation were much higher than those without mutation. We used Cox proportional-hazards regression to evaluate the effect of treatment on survival. In both univariate and multivariate analyses, gefitinib was associated with a significant improvement in overall survival in patients with reduced miR-21 expression. Thus, miR-21 expression emerged as an independent predictor of the response to gefitinib. Additionally, miR-10b is highly expressed in progressive disease compared with complete remission or stable disease (P<0.001). However, miR-21 expression has no significant prognosis for disease progression (P=0.720). Meanwhile, when overall survival was considered as the end point, miR-10b did not have a significant difference between different subgroups (P=0.634). The expression patterns of microRNAs differ significantly between patients with positive and negative EGFR mutation. And the expression status of miR-21 and 10b in such patients is associated with disease progression, survival, and response to adjuvant therapy with gefitinib.

Phase II study of pemetrexed plus intermittent erlotinib combination therapy for pretreated advanced non-squamous non-small cell lung cancer with documentation of epidermal growth factor receptor mutation status

IntroductionErlotinib and pemetrexed have been approved for the second-line and maintenance treatment of non-small cell lung cancer (NSCLC). With the recommended doses determined by our previous phase I study, we conducted a phase II study to evaluate the efficacy and safety of combination of the two agents in pretreated non-squamous NSCLC patients. MethodsThis study was performed in patients with stage IIIB/IV or post-surgically recurrent non-squamous NSCLC whose disease had progressed on or after receiving first-line chemotherapy. Patients received 500mg/m2 of intravenous pemetrexed every 21 days and 150mg of oral erlotinib on days 2–16 until disease progression, unacceptable toxicity, or withdrawal of consent. The expected response rate and threshold were defined as 33.5% and 10%, respectively. Assuming a one-sided alpha of 5%, a power of 80%, the possible deviation from assessment, 26 patients were necessary. ResultsA total of 27 patients, 16 males and 11 females were recruited. Patients had the median age of 70 years (range, 48–80 years) and included 21 stage IV diseases, 22 adenocarcinomas. Epidermal growth factor receptor (EGFR) mutations were examined in all patients. One patient had positive EGFR mutation, but the other 26 patients had wild-type EGFR. The median number of treatment courses was 3 (range, 1 to over 19). The best overall response rate and disease control rate were 11.1% and 63.0%, respectively. The median progression-free survival and overall survival were 2.8 months (95% confidence interval (CI); 1.9–7.5 months) and 15.8 months (95% CI; 9.3 months to not available), respectively. Dermal, hepatic, gastrointestinal and hematological disorders were the frequently observed adverse events. One patient experienced grade 3 drug-induced interstitial lung disease. ConclusionsWe could not demonstrate the add-on effect of intermittent erlotinib on pemetrexed in a second-line setting for patients with non-squamous NSCLC without EGFR mutations.

Correlation of epidermal growth factor receptor (EGFR) mutation profile with computed tomography (CT) imaging features in lung adenocarcinomas.

7542 Background: Imaging studies provide essential clinical information for lung cancer diagnosis, treatment and management. Features such as ground glass opacity (GGO) or internal air bronchogram (IAB), while commonly seen in early stage lung cancer, have minimal clinical implication. By examining a cohort at a single institution, we explored the hypothesis that radiographic characteristics correlates with the molecular signatures. Methods: Since 2009, our institution has prospectively characterized the EGFR status of all non-squamous lung carcinomas. Our inclusion criteria included tumor size &lt; 3 cm and positive EGFR mutation. We randomly selected wild type (WT) patients matched by age and tumor size. The CT imaging of these patients was evaluated by a single radiologist (EO). Results: Imaging features were extracted from 20 WT and 19 EGFR-mutated tumors. Of the EGFR-mutated tumors, 7 had the exon 21 L858R point mutation and 12 had in-frame exon 19 deletion. There were 68% (13) solid nodules in EGFR-mutated and 90% (18) in WT tumors. While solid nodule was the primary feature seen in both WT and EGFR-mutated tumors, exon 21 mutation was associated with mixed ground glass/solid nodule (MGGS) (p = 0.005). This tendency, however, is not present in the exon 19 mutated tumors. No pure GGO was identified in either EGFR or WT group. IAB was present in 62% (24), pleural attachment (PA) in 87% (34), and spiculated (SP) as opposed to lobulated (LO) nodules in 90% (34) of the tumors, which do not differ significantly among groups. Conclusions: Early stage lung adenocarcinomas show a spectrum of imaging features that can be correlated with tumor’s genetic mutations. MGGS is a distinct imaging characteristic differentiating exon 19 and exon 21 EGFR-mutated tumors. [Table: see text]

Clinical significance of BIM deletion polymorphism in non-small cell lung cancer with epidermal growth factor receptor mutation.

11052 Background: Germ line alterations in the proapoptotic protein BCL2-like 11 (BIM) can have a crucial role in how a tumor responds to treatment. To clarify the clinical usefulness of detecting BIM deletion polymorphism in non-small cell lung cancer (NSCLC) with positive epidermal growth factor receptor (EGFR) mutation we examined the prognosis in patients with or without the BIM changes. Methods: Seventy NSCLC patients with positive EGFR mutation treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) between January 2008 and January 2013 were enrolled in this study. BIM deletion polymorphism was analyzed by PCR in 58 peripheral blood samples, 24 formalin-fixed paraffin-embedded (FFPE) slides of surgical specimens (lung tissue in 20, brain tissue in 4), and 12 samples that included both blood and tissue specimens. We performed retrospective analyses on clinical characteristics, response rate and toxicity of EGFR-TKI, and estimated the prognosis in patients with or without BIM deletion polymorphism. Results: BIM deletion polymorphism was present in 13 of 70 patients (18.6%) with homozygous deletion in 1 and heterozygous deletion in 12. There was no discordance between the two types of samples among the 12 patients. There were no significant differences between patients with or without BIM deletion polymorphism on clinical characteristics, response rate to EGFR-TKI and incidence of EGFR-TKI toxicity. Patients with BIM deletion polymorphism showed significantly shorter PFS that in patients without BIM deletion polymorphism (median: 216 days vs. 430 days, p &lt; 0.001). There was no significant difference in OS. In multivariate analyses using the Cox regression model, BIM deletion polymorphism (hazard ratio = 4.2, p&lt; 0.001, 95% CI = 2.026-8.777) was identified as an independent factor for shorter PFS. Conclusions: BIM deletion polymorphism could be detected by PCR on peripheral blood samples and FFPE slides of surgical specimens. BIM deletion polymorphism has emerged as an independent prognostic factor for shorter PFS. Therefore, new treatment strategies should be established for patients with BIM deletion polymorphism.

Epidermal Growth Factor Recetor mutation study for 5 years, in a population of patients with non-small cell lung cancer

IntroductionIn 2006, the Vila Nova de Gaia/Espinho Hospital Centre Pulmonary Oncology Unit started performing EGFR (Epidermal Growth Factor Receptor) mutation sequencing in selected patients with NSCLC and systematically in all patients since 2010, regardless of histology, smoking habits, age or sex. The aim of this study was to characterize the group of patients that carried out the sequencing between 2006-2010, to determine EGFR mutation frequency, to evaluate the overall survival and the survival after the use of tyrosine kinase inhibitors (TKI), in patients who performed this therapy in second and third line, knowing the EGFR mutation status. MethodsDescriptive statistical analysis of patients who did EGFR sequencing in 2006-2010 and of overall survival in patients treated with TKI as 2nd and 3rd line therapy. Record of the material available for analysis and average delay of exam results, according to the material submitted. ResultsThe sequencing was performed in 374 patients, 71,1% males, 67,1% non/ex-smokers, 32,9% smokers, 57,8% adenocarcinoma and 23,5% squamous cell carcinoma (SCC). The mutation was detected in 49 patients (13,1%). In all studied patients, the mutation rate was 9% in males and 23% in females. Median overall survival after erlotinib use of was 14 months for patients with positive EGFR mutation versus 6 months in not mutated patients (p = 0.003). ConclusionOur group had an overall mutation rate of 13.1% with female, non-smokers, adenocarcinoma histology predominance. In selected patients (2006/2009), the mutation rate was 16%, in not selected patients (2010) the mutation rate was 10.4%. This study has permitted a better understanding of the EGFR mutation rate in the Portuguese population as welll as an evaluation of the patients survival after the use of of tyrosine kinase inhibitors, in second and third line therapy with previous knowledge of the EGFR mutational status. Statistical significant differences in survival were found in the two patient groups (EGFR mutated and non mutated).The EGFR mutation research should be performed in all patients with NSCLC, giving the possibility to a considerable number of patients to perform a first line treatment with TKI (EGFR mutated patients) and the advantage of performing other chemotherapy schemes, when progression occurs.

Estudo da mutação do recetor do fator de crescimento epidérmico, durante 5 anos, numa população de doentes com cancro do pulmão de não pequenas células

IntroductionIn 2006, the Vila Nova de Gaia/Espinho Hospital Centre Pulmonary Oncology Unit started performing EGFR (Epidermal Growth Factor Receptor) mutation sequencing in selected patients with NSCLC and systematically in all patients since 2010, regardless of histology, smoking habits, age or sex. The aim of this study was to characterize the group of patients that carried out the sequencing between 2006-2010, to determine EGFR mutation frequency, to evaluate the overall survival and the survival after the use of tyrosine kinase inhibitors (TKI), in patients who performed this therapy in second and third line, knowing the EGFR mutation status. MethodsDescriptive statistical analysis of patients who did EGFR sequencing in 2006-2010 and of overall survival in patients treated with TKI as 2nd and 3rd line therapy. Record of the material available for analysis and average delay of exam results, according to the material submitted. ResultsThe sequencing was performed in 374 patients, 71,1% males, 67,1% non/ex-smokers, 32,9% smokers, 57,8% adenocarcinoma and 23,5% squamous cell carcinoma (SCC). The mutation was detected in 49 patients (13,1%). In all studied patients, the mutation rate was 9% in males and 23% in females. Median overall survival after erlotinib use of was 14 months for patients with positive EGFR mutation versus 6 months in not mutated patients (p = 0.003). ConclusionOur group had an overall mutation rate of 13.1% with female, non-smokers, adenocarcinoma histology predominance. In selected patients (2006/2009), the mutation rate was 16%, in not selected patients (2010) the mutation rate was 10.4%. This study has permitted a better understanding of the EGFR mutation rate in the Portuguese population as welll as an evaluation of the patients survival after the use of of tyrosine kinase inhibitors, in second and third line therapy with previous knowledge of the EGFR mutational status. Statistical significant differences in survival were found in the two patient groups (EGFR mutated and non mutated).The EGFR mutation research should be performed in all patients with NSCLC, giving the possibility to a considerable number of patients to perform a first line treatment with TKI (EGFR mutated patients) and the advantage of performing other chemotherapy schemes, when progression occurs.

Clinical investigation of EGFR mutation detection by pyrosequencing in lung cancer patients

Direct sequencing is the standard method for the detection of epidermal growth factor receptor (EGFR) mutations in lung cancer, however, its relatively low sensitivity limits its clinical use. Pyrosequencing is a bioluminometric, real-time non-electrophoretic DNA sequencing technique with a number of advantages compared with direct sequencing, including higher sensitivity, speed, automation and cost-effectiveness. Clinical specimens from 202 lung cancer patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21 using the pyrosequencing method following genomic DNA extraction from paraffin-embedded tissue specimens. All clinical data and tumor specimens were obtained from the Konkuk University Hospital (Korea) between July 2006 and December 2008. The results and clinical responses to EGFR-tyrosine kinase inhibitors (TKIs) were compared. Overall, EGFR mutation-positive rate was 26.7% (54/202). Activating EGFR mutations were observed more frequently in female (52.1 vs. 13.0%), non-smoking (47.8 vs. 15.8%) and adenocarcinoma (35.2 vs. 5.2%) patients. However, significant numbers of EGFR mutation-positive patients were identified as male, former or current smokers and non-adenocarcinoma patients. The combinations of favorable clinicopathological factors, including female, non-smoking and adenocarcinoma, were not identified to significantly increase the positive EGFR mutation rate (female, 52.1%; female and non-smoker, 52.6%; female, non-smoker and adenocarcinoma, 51.9%). The present findings indicate that EGFR mutation analysis is a highly useful method for the prediction of response to EGFR-TKI and the use of favorable clinicopathological factors to perform this analysis is not suitable. Exon 19 deletion was the most common mutation (63.6%) and exon 21 L858R substitution was measured at 32.7%. The exon 20 T790M mutation was identified in 1 patient prior to EGFR-TKI treatment. EGFR mutation status is associated with response to EGFR-TKI and the overall response rate in patients who have the activating EGFR mutation was 82.4 vs. 5.9% in patients with a wild-type EGFR. The present study demonstrates that EGFR mutations analyzed by the pyrosequencing method are well correlated with clinicopathological parameters and that this method may be useful in the clinical practice.

1340 - Phase II Study of Erlotinib in Japanese Patients with Pretreated EGFR Mutation Positive Non-Small Cell Lung Cancer: Lung Oncology Group in Kyushu, Japan (LOGIK0803)

ABSTRACT Background Erlotinib has been reported to be useful for treating EGFR mutation-positive (EGFR-mt) non-small cell lung cancer (NSCLC) (OPTIMAL ESMO 2010, EURTAC Lancet Oncol. 2012). However, its usefulness had not been investigated in Japanese patients. Hence, we conducted a multicenter phase II study to investigate the efficacy and safety of erlotinib in Japanese patients with pretreated EGFR-mt NSCLC. Methods Erlotinib, 150 mg/day, was orally administered daily to patients with pretreated EGFR-mt (exon 19/21) NSCLC who had not been treated with EGFR-TKIs. The primary endpoint was objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and safety. Results Between April 2009 and January 2011, 26 patients were enrolled from 15 participating centers. The patient characteristics were as follows: median age, 68 years (51 to 79); men/women, 11/15; adenocarcinoma/others, 24/2; nonsmoking/smoking, 20/6; ECOG PS 0/1/2, 16/8/2; exon 19/21, 19/7; and 2nd/3rd line therapy, 25/1. The antitumor effect was as follows: PR, 14 patients; SD, 7 patients; PD, 4 patients; NE, 1 patient; ORR, 54%; and DCR, 81%. The ORR and DCR according to the EGFR status were 47.4%/71.4% (exon 19/21, p = 0.3913) and 73.7%/100% (p = 0.2782), respectively. The PFS was 9.3 months (range, 0.9 to 19.2 mo). Major adverse drug reactions were rash (96%) and hepatic function disorder (40%); most episodes were grade 2 or less, and all were tolerable. No patients developed interstitial lung disease, and there were no treatment-related deaths. Conclusion In this study, the usefulness of erlotinib was investigated prospectively in Japanese patients with pretreated EGFR-mt NSCLC for the first time, and this drug was shown to be effective and tolerable. At this congress, we will report the study results including the ORR and PFS according to the patient characteristics. Disclosure Y. Nakanishi: From Chugai Pharmaceutical, I received 7500 Euro as honoraria on 2011, and 22000 Euro on 2010 and 70000 Euro on 2011 as research grant. Y. Ichinose: I have research funding with Chugai Pharmaceutical company. All other authors have declared no conflicts of interest.

Biomarkers in the selection of maintenance therapy in non-small cell lung cancer.

Long gone are the days where identification of lung cancer as either non-small cell lung or small cell is sufficient to initiate therapy. Today, the optimal treatment of lung cancer hinges not only on accurate histopathologic diagnosis but further tumor description through molecular characterization (1). The importance of molecular testing prior to initiation of therapy is best highlighted by epidermal growth factor receptor (EGFR) mutational analyses. There have been a number of trials that have identified patients who gleaned a greater benefit from EGFR tyrosine kinase inhibitor (TKI) therapy on the basis of EGFR mutation positivity in first, second and third line treatment regimens.

PCN76 Economic Evaluation of the Use of Erlotinib for Non-Small Cell Lung Cancer (NSCLC) With EGFR Mutation in Mexican Public Health Institutions

Assess whether the use of Erlotinib as 1st line treatment in metastatic or advanced Non Small Cell Lung Cancer (NSCLC) patients with Epidermal Growth Factor Receptor (EGFR) mutation positive, is a dominant alternative from the perspective of public health system in Mexico. It was developed a cost-utility analysis using a Markov model with monthly cycles stages: response to treatment, stable disease, disease progression and death in a time horizon of 5 years. The costing method is the direct medical costs and the main outcome measures were QALY's and total cost of treatment per patient. The drugs compared in the study were Erlotinib, Gefitinib and chemotherapy with Gemcitabine plus Carboplatin. Costs are expressed in US dollars. Erlotinib was the alternative that provided a greater number of QALY's (1.49) compared with Gefitinib (1.32) and chemotherapy with Carboplatin (1.07). Furthermore, treatment with Erlotinib was the least expensive with a cost per patient of $51,249 on a horizon of 5 years while the cost of Gefitinib was $ 53,817 per patient and the QT with Gemcitabine + Carboplatin $53,258 per patient. This implies that the dominant treatment for these patients (NSCLC and positive EGFR mutation) is Erlotinib with a cost-effectiveness average of $34,456. The dominance results of treatment with Erlotinib were consistent with sensitivity analysis, which provides robustness to the results. Considering the average annual costs, Erlotinib represents savings for the health sector from $402 (versus Gemcitabine + Carboplatin) to $514 (vs Gefitinib) for each patient according to its comparator in 1 year. Therefore, under the context of public health system in Mexico, treatment with Erlotinib was shown to be a cost-effective treatment and dominant over other treatment alternatives considered in this study for patients with NSCLC and EGFR mutation.

Usefulness of cumulative smoking dose for identifying the EGFR mutation and patients with non‐small‐cell lung cancer for gefitinib treatment

We examined the diagnostic accuracy of the cumulative smoking dose for identifying the epidermal growth factor receptor (EGFR) exon 19 deletion and L858R mutation among Japanese patients with non-small-cell lung cancer (NSCLC). EGFR mutations in exon 19 and exon 21 were determined in 1001 NSCLC patients. A receiver-operating characteristic (ROC) curve methodology was applied to estimate the diagnostic accuracy. EGFR mutations were detected in 314 patients (31.4%). A cumulative smoking dose of less than 13 pack-years (PY) was the optimal cut-off point for predicting a positive EGFR mutation status, producing a balance between the sensitivity (73.5%) and the specificity (77%). The area under the ROC curve was 0.77, indicating that the smoking dose had a moderate diagnostic accuracy. The median survival time or the median progression-free survival time of patients who had smoked less than 13 pack-years (PY) were 18.6 and 6.3 months, respectively, while those of patients with equal to or more than 13 PY were 9.6 and 2.4 months, respectively. The overall survival (OS) and progression-free survival (PFS) rates were significantly different between the two groups (OS: hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.51-0.80, P = 0.0001) (PFS: HR = 0.58, 95% CI = 0.47-0.71, P < 0.0001). Our study indicated that the smoking dose predicted EGFR mutations with a moderate diagnostic accuracy. Thus, patients who have smoked less than 13 PY might be candidates for gefitinib treatment when EGFR mutation status cannot be determined.

EGFR mutations and human papillomavirus in squamous cell carcinoma of tongue and tonsil

10027 Background: Some studies reported the presence of somatic mutation of EGFR in head and neck cancer. Human papillomavirus (HPV) was associated with some types of head and neck cancer. We performed this study to determine clinical significance of EGFR mutation and its association with HPV infection in patients with tongue and tonsil cancer. Methods: We sequenced exons 18–21 of EGFR TK domain and HPV typing was performed using the HPV DNA chip in tissues of patients with tongue and tonsil cancer. Univariate and multivariate analysis was performed. Results: Eighty-one patients were included. We detected EGFR mutation in 10 (12%) patients. Mutation was significantly frequent in never-smoker (21% versus 5%; P = 0.031). The mutation frequency did not differ between tongue and tonsil cancer (12% vs. 13%, respectively; P = 0.978). There was no difference between female and male (12% vs. 14%, respectively; P = 0.754). Eleven of 81 (14%) patients were HPV positive. HPV positivity was more common in young (&lt;60 years) than older (≥60 years) patients (20% vs. 3%, respectively; P = 0.039). Patients with tonsil cancer showed more frequent HPV positivity than tongue cancer (42% vs. 2%, respectively; P &lt; 0.001). There was no association between HPV positivity and EGFR mutation. In terms of disease-free survival, patients with EGFR mutation had better survival independently of stage and primary site (hazard ratio, 0.246; 95% CI, 0.075 to 0.802). Conclusions: We did not find association between EGFR mutation and HPV positivity. Patients with EGFR mutation showed better outcome in tongue and tonsil cancer. These results suggest that EGFR mutation may be a prognostic factor in patients with head and neck cancer. No significant financial relationships to disclose.