Final Report on Real-World Effectiveness of Sequential Afatinib and Osimertinib in EGFR-Positive Advanced Non–Small Cell Lung Cancer: Updated Analysis of the RESET Study / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#This study aimed to report the final analysis of time-on-treatment (TOT) and overall survival (OS) in patients with advanced-stage epidermal growth factor receptor (EGFR)+ non–small cell lung cancer (NSCLC) who received sequential afatinib and osimertinib and to compare the outcomes with other second-line regimens (comparator group). @*Materials and Methods@#In this updated report, the existing medical records were reviewed and rechecked. TOT and OS were updated and analyzed according to clinical features using the Kaplan-Meier method and log-rank test. TOT and OS were compared with those of the comparator group, in which most patients received pemetrexed-based treatments. A multivariable Cox proportional hazard model was used to evaluate features that could affect survival outcomes. @*Results@#The median observation time was 31.0 months. The follow-up period was extended to 20 months. A total of 401 patients who received first-line afatinib were analyzed (166 with T790M+ and second-line osimertinib, and 235 with unproven T790M and other second-line agents). Median TOTs on afatinib and osimertinib were 15.0 months (95% confidence interval [CI], 14.0 to 16.1) and 11.9 months (95% CI, 8.9 to 14.6), respectively. The median OS in the osimertinib group was 54.3 months (95% CI, 46.7 to 61.9), much longer than that in the comparator group. In patients who received osimertinib, the OS was longest with Del19+ (median, 59.1; 95% CI, 48.7 to 69.5). @*Conclusion@#This is one of the largest real-world studies reporting the encouraging activity of sequential afatinib and osimertinib in Asian patients with EGFR+ NSCLC who acquired the T790M mutation, particularly Del19+.

Real-World Study of Osimertinib in Korean Patients with Epidermal Growth Factor Receptor T790M Mutation–Positive Non–Small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Although osimertinib is the standard-of-care treatment of epidermal growth factor receptor (EGFR) T790M mutation–positive non–small cell lung cancer, real-world evidence on the efficacy of osimertinib is not enough to reflect the complexity of the entire course of treatment. Herein, we report on the use of osimertinib in patients with EGFR T790M mutation–positive non–small cell lung cancer who had previously received EGFR tyrosine kinase inhibitor (TKI) treatment in Korea. @*Materials and Methods@#Patients with confirmed EGFR T790M after disease progression of prior EGFR-TKI were enrolled and administered osimertinib 80 mg daily. The primary effectiveness outcome was progression-free survival, with time-to-treatment discontinuation, treatment and adverse effects leading to treatment discontinuation, and overall survival being the secondary endpoints. @*Results@#A total of 558 individuals were enrolled, and 55.2% had investigator-assessed responses. The median progression-free survival was 14.2 months (95% confidence interval [CI], 13.0 to 16.4), and the median time-to-treatment discontinuation was 15.0 months (95% CI, 14.1 to 15.9). The median overall survival was 36.7 months (95% CI, 30.9 to not reached). The benefit with osimertinib was consistent regardless of the age, sex, smoking history, and primary EGFR mutation subtype. However, hepatic metastases at the time of diagnosis, the presence of plasma EGFR T790M, and the shorter duration of prior EGFR-TKI treatment were poor predictors of osimertinib treatment. Ten patients (1.8%), including three with pneumonitis, had to discontinue osimertinib due to severe adverse effects. @*Conclusion@#Osimertinib demonstrated its clinical effectiveness and survival benefit for EGFR T790M mutation–positive in Korean patients with no new safety signals.

Liquid biopsy using extracellular vesicle–derived DNA in lung adenocarcinoma

Blood liquid biopsy has emerged as a way of overcoming the clinical limitations of repeat biopsy by testing for the presence of acquired resistance mutations to therapeutic agents. Despite its merits of repeatability and non-invasiveness, this method is currently only used as a supplemental test due to a relatively low sensitivity rate of 50%–60%, and cannot replace tissue biopsy. The circulating tumor DNAs used in blood liquid biopsies are passive products of fragmented DNA with a short half-life released following tumor cell death; the low sensitivity seen with liquid blood biopsy results from this instability, which makes increasing the sensitivity of this test fundamentally difficult. Extracellular vesicles (EVs) are ideal carriers of cancer biomarkers, as cancer cells secret an abundance of EVs, and the contents of tumor cell-originated EVs reflect the molecular and genetic composition of parental cells. In addition, EV-derived DNAs (EV DNAs) consist of large-sized genomic DNAs and tumor-specific oncogenic mutant DNAs. For these reasons, liquid biopsy using EV DNA has the potential to overcome issues arising from tissue shortages associated with small biopsies, which are often seen in lung cancer patients, and the biopsy product can be used in other diagnostic methods, such as epidermal growth factor receptor (EGFR) mutation testing and next-generation sequencing (NGS). A higher sensitivity can be achieved when EV DNAs obtained from bronchoalveolar lavage fluid (BALF) are used rather than those from blood. BALF, when obtained close to the tumor site, is a promising liquid biopsy tool, as it enables the gathering of both cellular and non-cellular fractions of the tumor microenvironment, and provides increased diagnostic sensitivity when compared to blood.

Liquid biopsy using extracellular vesicle–derived DNA in lung adenocarcinoma

Blood liquid biopsy has emerged as a way of overcoming the clinical limitations of repeat biopsy by testing for the presence of acquired resistance mutations to therapeutic agents. Despite its merits of repeatability and non-invasiveness, this method is currently only used as a supplemental test due to a relatively low sensitivity rate of 50%–60%, and cannot replace tissue biopsy. The circulating tumor DNAs used in blood liquid biopsies are passive products of fragmented DNA with a short half-life released following tumor cell death; the low sensitivity seen with liquid blood biopsy results from this instability, which makes increasing the sensitivity of this test fundamentally difficult. Extracellular vesicles (EVs) are ideal carriers of cancer biomarkers, as cancer cells secret an abundance of EVs, and the contents of tumor cell-originated EVs reflect the molecular and genetic composition of parental cells. In addition, EV-derived DNAs (EV DNAs) consist of large-sized genomic DNAs and tumor-specific oncogenic mutant DNAs. For these reasons, liquid biopsy using EV DNA has the potential to overcome issues arising from tissue shortages associated with small biopsies, which are often seen in lung cancer patients, and the biopsy product can be used in other diagnostic methods, such as epidermal growth factor receptor (EGFR) mutation testing and next-generation sequencing (NGS). A higher sensitivity can be achieved when EV DNAs obtained from bronchoalveolar lavage fluid (BALF) are used rather than those from blood. BALF, when obtained close to the tumor site, is a promising liquid biopsy tool, as it enables the gathering of both cellular and non-cellular fractions of the tumor microenvironment, and provides increased diagnostic sensitivity when compared to blood.

Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for patient with leptomeningeal metastasis of epidermal growth factor receptor mutant non-small cell lung cancer / 영남의대학술지

We report on a 64-year-old man with leptomeningeal metastasis (LM) from an epidermal growth factor receptor (EGFR)-mutated adenocarcinoma of the lung. He was treated with paclitaxel, cisplatin. After completion of chemotherapy, he complained of headache, nausea, and vomiting. EGFR-mutated tumor cells were identified from the cerebrospinal fluid (CSF). Second-line therapy with gefitinib, methotrexate was started. After receiving gefitinib for 4 weeks, he had no more headaches or vomiting. Eleven months after initiation of gefitinib, he developed headache and nausea. Chest computed tomography showed aggravation of bone metastasis. Third-line therapy was started with gemcitabine and carboplatin. Two weeks later, he experienced disorientation. After a fourth relapse within the central nervous system, the therapy was switched to erlotinib and significant improvement of LM was achieved. This case shows that LM can be diagnosed by detecting EGFR mutation in CSF and EGFR tyrosine kinase inhibitors are effective for LM from EGFR mutant non-small cell lung cancer.

Detection of EGFR and KRAS Mutation by Pyrosequencing Analysis in Cytologic Samples of Non-Small Cell Lung Cancer

EGFR and KRAS mutations are two of the most common mutations that are present in lung cancer. Screening and detecting these mutations are of issue these days, and many different methods and tissue samples are currently used to effectively detect these two mutations. In this study, we aimed to evaluate the testing for EGFR and KRAS mutations by pyrosequencing method, and compared the yield of cytology versus histology specimens in a consecutive series of patients with lung cancer. We retrospectively reviewed EGFR and KRAS mutation results of 399 (patients with EGFR mutation test) and 323 patients (patients with KRAS mutation test) diagnosed with lung cancer in Konkuk University Medical Center from 2008 to 2014. Among them, 60 patients had received both EGFR and KRAS mutation studies. We compared the detection rate of EGFR and KRAS tests in cytology, biopsy, and resection specimens. EGFR and KRAS mutations were detected in 29.8% and 8.7% of total patients, and the positive mutation results of EGFR and KRAS were mutually exclusive. The detection rate of EGFR mutation in cytology was higher than non-cytology (biopsy or resection) materials (cytology: 48.5%, non-cytology: 26.1%), and the detection rate of KRAS mutation in cytology specimens was comparable to non-cytology specimens (cytology: 8.3%, non-cytology: 8.7%). We suggest that cytology specimens are good alternatives that can readily substitute tissue samples for testing both EGFR and KRAS mutations. Moreover, pyrosequencing method is highly sensitive in detecting EGFR and KRAS mutations in lung cancer patients.

A Case of Cryptogenic Organizing Pneumonia after Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma / 결핵및호흡기질환

Cryptogenic organizing pneumonia (COP) is an inflammatory lung disease involving the distal bronchioles, respiratory bronchioles, bronchiolar ducts, and alveolae. The etiology is usually unknown; however, there are several known causes and associated systemic diseases. Corticosteroid therapy is the best treatment option and the prognosis of COP is good, with recovery in up to 80% of patients. We described a patient with in-operable hepatocellular carcinoma (HCC) undergoing chemoembolization with doxorubicin in a drug-eluting bead (DEB). COP developed in the patient after chemoembolization but resolved spontaneously in several months.

Bilateral Internal Auditory Canal Metastasis of Non-small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

We report on a patient with brain metastasis involving bilateral internal auditory canal from non-small cell lung cancer (NSCLC). A 49-year-old woman who had been diagnosed with NSCLC (T2aN1M0) complained of persistent vertigo and bilateral tinnitus for three months. The patient had refused all treatments, including surgery and chemotherapy; however, she sought alternative medicine. The patient's hearing loss showed rapid progression bilaterally, and rotatory vertigo with peripheral-type nystagmus developed. Magnetic resonance imaging of the brain showed irregular nodular enhancement within both internal auditory canals with leptomeningeal enhancement and multiple intracranial metastasis. The patient was treated with epidermal growth factor receptor-tyrosine kinase inhibitor, and the tumor showed partial response. This was a rare case of multiple brain metastases involving bilateral internal auditory canal from known NSCLC presenting with vertigo and hearing loss.

The Korean guideline for lung cancer screening

Lung cancer is the leading cause of cancer death in many countries, including Korea. The majority of patients are inoperable at the time of diagnosis because symptoms are typically manifested at an advanced stage. A recent large clinical trial demonstrated significant reduction in lung cancer mortality by using low dose computed tomography (LDCT) screening. A Korean multisociety collaborative committee systematically reviewed the evidences regarding the benefits and harms of lung cancer screening, and developed an evidence-based clinical guideline. There is high-level evidence that annual screening with LDCT can reduce lung cancer mortality and all-cause mortality of high-risk individuals. The benefits of LDCT screening are modestly higher than the harms. Annual LDCT screening should be recommended to current smokers and ex-smokers (if less than 15 years have elapsed after smoking cessation) who are aged 55 to 74 years with 30 pack-years or more of smoking-history. LDCT can discover non-calcified lung nodules in 20 to 53% of the screened population, depending on the nodule positivity criteria. Individuals may undergo regular LDCT follow-up or invasive diagnostic procedures that lead to complications. Radiation-associated malignancies associated with repetitive LDCT, as well as overdiagnosis, should be considered the harms of screening. LDCT should be performed in qualified hospitals and interpreted by expert radiologists. Education and actions to stop smoking must be offered to current smokers. Chest radiograph, sputum cytology at regular intervals, and serum tumor markers should not be used as screening methods. These guidelines may be amended based on several large ongoing clinical trial results.

Bilateral Ovarian Metastases from ALK Rearranged Non-Small Cell Lung Cancer / 결핵및호흡기질환

Anaplastic lymphoma kinase (ALK) rearrangement, is a kind of driver mutation, accounts for 3%-5% of non-small cell lung cancer (NSCLC). NSCLC patients harboring ALK fusion genes have distinct clinical features and good response to ALK inhibitors. Metastasis from lung cancer to the ovary has rarely been known. We report a case of a 54-year-old woman with bilateral ovarian metastases from ALK rearranged NSCLC. She underwent bilateral salpingo-oophorectomy for ovary masses, which were progressed after cytotoxic chemotherapy although primary lung mass was decreased. Histopathological examination of the ovary tumor showed characteristic adenocarcinoma patterns of the lung and ALK rearrangement.

Treatment of Non-small Cell Lung Carcinoma after Failure of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor / Journal of the Korean Cancer Association, 대한암학회지

Since the first description of non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation as a distinct clinical entity, studies have proved EGFR tyrosine kinase inhibitors (TKIs) as a first choice of treatment. The median response duration of TKIs as a first-line treatment for EGFR mutant tumors ranges from 11 to 14 months. However, acquired resistance to EGFR-TKIs is inevitable due to various mechanisms, such as T790M, c-Met amplification, activation of alternative pathways (IGF-1, HGF, PI3CA, AXL), transformation to mesenchymal cell or small cell features, and tumor heterogeneity. Until development of a successful treatment strategy to overcome such acquired resistance, few options are currently available. Here we provide a summary of the therapeutic options after failure of first line EGFR-TKI treatment for NSCLC.

A Case of Congenital Cystic Adenomatoid Malformation Infected with Mycobacterium avium-intracellulare Complex / 결핵및호흡기질환

We present a case of congenital cystic adenomatoid malformation (CCAM) in a 25-year-old male who was presented with chronic cough. Chest radiography revealed an abnormal mass-like shadow in the right lower pulmonary zone. A contrast enhanced computed tomography showed an 11 cm solid, cystic mixed mass on the right lower lobe. A right lower lobectomy was performed by video-assisted thoracoscopic surgery without complications. The gross specimen showed a massive cavitation with multiloculated cysts of varying size, consistent with CCAM, along with noticeable granulomatous inflammation. Non-tuberculosis mycobacteria were isolated from a bronchial wash specimen, and the resected tissue homogenates were positive for Mycobacterium avium-intracellulare complex by polymerase chain reaction.

Annual Change of Peak Expiratory Flow Rate in Asthma and COPD / 결핵및호흡기질환

BACKGROUND: Measurement of peak expiratory flow rate (PEFR) in a follow-up examination for a chronic airway disease is useful because it has the advantages of being a simple measurement and can be repeated during examination. The aim of this study was to examine the annual decrease of PEFR in asthma and chronic obstructive pulmonary disease (COPD) patients and to confirm the factors which influence this decrease. METHODS: From May, 2003 to September, 2010, the annual decrease of PEFR was obtained from asthma and COPD patients attending an outpatient pulmonary clinic. PEFR was measured using a Mini-Wright peak flow meter (Clement Clarke International Ltd. UK), and we conducted an analysis of factors that influence the change of PEFR and its average values. RESULTS: The results showed an annual decrease of 1.70+/-12.86 L/min the asthmatic patients and an annual decrease of 10.3+/-7.32 L/min in the COPD patients. Age and FEV1 were the predictive factors influencing change in asthma, and FEV1 and smoking were the predictive factors influencing change in COPD. CONCLUSION: We confirmed the annual decreasing PEFR in patients with chronic airway disease and identified factors that work in conjunction with FEV1 to influence the change.

Gefitinib in Selected Patients with Pre-Treated Non-Small-Cell Lung Cancer: Results from a Phase IV, Multicenter, Non-Randomized Study (SELINE) / 결핵및호흡기질환

BACKGROUND: This study was designed to analyze the efficacy of gefitinib as a second-line therapy, according to the clinical characteristics in Korean patients with non-small-cell lung cancer (NSCLC). METHODS: In this Phase IV observational study, we recruited patients, previously failed first-line chemotherapy, who had locally advanced or metastatic NSCLC, and who were found to be either epidermal growth factor receptor (EGFR) mutation-positive or satisfied 2 or more of the 3 characteristics: adenocarcinoma, female, and non-smoker. These patients were administered with gefitinib 250 mg/day, orally. The primary endpoints were to evaluate the objective response rate (ORR) and to determine the relationship of ORRs, depending on each patient's characteristics of modified intent-to-treat population. RESULTS: A total of 138 patients participated in this study. One subject achieved complete response, and 42 subjects achieved partial response (ORR, 31.2%). The subgroup analysis demonstrated that the ORR was significantly higher in patients with EGFR mutation-positive, compared to that of EGFR mutation-negative (45.8% vs. 14.0%, p=0.0004). In a secondary efficacy variable, the median progression-free survival (PFS) was 5.7 months (95% confidence interval, 3.9~8.4 months) and the 6-month PFS and overall survival were 49.6% and 87.9%, respectively. The most common reported adverse events were rash (34.4%), diarrhea (26.6%), pruritus (17.5%), and cough (15.6%). CONCLUSION: Gefitinib was observed in anti-tumor activity with favorable tolerability profile as a second-line therapy in these selected patients. When looking at EGFR mutation status, EGFR mutation-positive showed strong association with gefitinib by greater response and prolonged PFS, compared with that of EGFR mutation-negative.

Comparative Analysis of Peptide Nucleic Acid (PNA)-Mediated Real-Time PCR Clamping and DNA Direct Sequencing for EGFR Mutation Detection / 결핵및호흡기질환

BACKGROUND: Although the gold standard method for research trials on epidermal growth factor receptor (EGFR) mutations has been direct sequencing, this approach has the limitations of low sensitivity and of being time-consuming. Peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping is known to be a more sensitive detection tool. The aim of this study was to compare the detection rate of EGFR mutation and EGFR-tyrosine kinase inhibitor (TKI) responsiveness according to EGFR mutation status using both methodologies. METHODS: Clinical specimens from 112 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20, and 21. All clinical data and tumor specimens were obtained from 3 university hospitals in Korea. After genomic DNA was extracted from paraffin-embedded tissue specimens, both PNA-mediated PCR clamping and direct-sequencing were performed. The results and clinical response to EGFR-TKIs were compared. RESULTS: Sequencing revealed a total of 35 (22.9%) mutations: 8 missense mutations in exon 21 and 26 deletion mutations in exon 19. PNA-mediated PCR clamping showed the presence of genomic alterations in 45 (28.3%) samples, including the 32 identified by sequencing plus 13 additional samples (6 in exon 19 and 7 in exon 21). CONCLUSION: PNA-mediated PCR clamping is simple and rapid, as well as a more sensitive method for screening of genomic alterations in EGFR gene compared to direct sequencing. This data suggests that PNA-mediated PCR clamping should be implemented as a useful screening tool for detection of EGFR mutations in clinical setting.

Comparative Analysis of Peptide Nucleic Acid (PNA)-Mediated Real-Time PCR Clamping and DNA Direct Sequencing for EGFR Mutation Detection / 결핵및호흡기질환

BACKGROUND: Although the gold standard method for research trials on epidermal growth factor receptor (EGFR) mutations has been direct sequencing, this approach has the limitations of low sensitivity and of being time-consuming. Peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping is known to be a more sensitive detection tool. The aim of this study was to compare the detection rate of EGFR mutation and EGFR-tyrosine kinase inhibitor (TKI) responsiveness according to EGFR mutation status using both methodologies. METHODS: Clinical specimens from 112 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20, and 21. All clinical data and tumor specimens were obtained from 3 university hospitals in Korea. After genomic DNA was extracted from paraffin-embedded tissue specimens, both PNA-mediated PCR clamping and direct-sequencing were performed. The results and clinical response to EGFR-TKIs were compared. RESULTS: Sequencing revealed a total of 35 (22.9%) mutations: 8 missense mutations in exon 21 and 26 deletion mutations in exon 19. PNA-mediated PCR clamping showed the presence of genomic alterations in 45 (28.3%) samples, including the 32 identified by sequencing plus 13 additional samples (6 in exon 19 and 7 in exon 21). CONCLUSION: PNA-mediated PCR clamping is simple and rapid, as well as a more sensitive method for screening of genomic alterations in EGFR gene compared to direct sequencing. This data suggests that PNA-mediated PCR clamping should be implemented as a useful screening tool for detection of EGFR mutations in clinical setting.

Usefulness of Vibration Response Imaging (VRI) for Pneumonia Patients / 결핵및호흡기질환

BACKGROUND: Pneumonia is commonly seen in outpatient clinics. it is widely known as the most common cause of death from infectious disease. Pneumonia has been diagnosed by its typical symptoms, chest X-ray and blood tests. However, both chest X-rays and blood tests have limitations in diagnosis. Thus primary care clinicians usually have been constrained due to a lack of adequate diagnostic tools. Vibration response imaging (VRI) is a newly emerging diagnostic modality, and its procedure is non-invasive, radiation-free, and easy to handle. This study was designed to evaluate the diagnostic usefulness of the VRI test among pneumonia patients and to consider its correlation with other conventional tests such as Chest X-ray, laboratory tests and clinical symptoms. METHODS: VRI was performed in 46 patients diagnosed with pneumonia in Konkuk University Medical Center. VRI was assessed in a private and quiet room twice: before and after the treatment. Sensors for VRI were placed on a patient's back at regular intervals; they detected pulmonary vibration energy produced when respiration occurred and presented as specific images. Any modifications either in chest X-ray, C-reactive protein (CRP), white blood cell count (WBC) or body temperature were compared with changes in VRI image during a given time course. RESULTS: VRI, chest X-ray and CRP scores were significantly improved after treatment. Correlation between VRI and other tests was not clearly indicated among all patients. But relatively severe pneumonia patients showed correlations between VRI and chest X-ray, as well as between VRI and CRP. CONCLUSION: This study demonstrates that VRI can be safely applied to patients with pneumonia.

A Case of Yellow Nail Syndrome: Misdiagnosis as Congestive Heart Failure / 결핵및호흡기질환

Yellow nail syndrome (YNS) is a rare disorder of unknown cause associated with yellow nails, lymphedema and respiratory manifestations. It was first described by Samman and White in 1964, and to date, approximately 150 cases have been reported. The diagnosis of YNS is essentially a clinical one and based on the presence of characteristic findings. We report a case of YNS of a 62-year-old female who presented with a 4-month history of dyspnea and recurrent pleural effusion. The patient had a 5-year history of leg swelling and dyspnea. She had been managed with medications for congestive heart failure (CHF) for two years and she was referred to our hospital for further evaluation and management.

PNA-Mediated PCR Clamping for the Detection of EGFR Mutations in Non-Small Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: Recent studies have demonstrated that the epidermal growth factor receptor (EGFR) genotype is the most important predictive marker to EGFR-tyrosine kinase inhibitors (TKIs) and first-line gefitinib treatment will be approved in the near future for use in non-small cell lung cancer (NSCLC) patients with the EGFR mutation. Direct sequencing is known to be the standard for detecting EGFR mutations; however, it has limited sensitivity. Peptide nucleic acids (PNA)-mediated PCR clamping method is a newly introduced method for analyzing EGFR mutations with increased sensitivity and stability. METHODS: A total of 71 NSCLC patients were analyzed for EGFR mutations using the PNA-mediated PCR clamping technique. Sixty-nine patients were analyzed for clinicopathologic correlation with EGFR genotype; 2 patients with indeterminate results were excluded. In order to determine EGFR-TKI drug response, 57 patients (42 gefitinib, 15 erlotinib) were included in the analysis. RESULTS: The EGFR mutation rate was 47.8%. Being female, a non-smoker, and having adenocarcinoma were favorable clinicopathologic factors, as expected. However, more than a few smokers (33.3%), male (28.1%), and patients with non-adenocarcinoma (28.6%) had the EGFR mutation. Having a combination of favorable clinicopathologic factors did not increase the EGFR mutation rate significantly. Drug response to EGFR-TKIs showed significant differences depending on the EGFR genotype; ORR was 14.3% for wild type vs 69.0% for mutant type; DCR is 28.6% for wild type vs 96.6% for mutant type. The median EGFR-TKI treatment duration is 7.6 months for mutant type group and 1.4 months for wild type group. CONCLUSION: EGFR genotype determined using the PNA-mediated PCR clamping method is significantly correlated with the clinical EGFR-TKI responses and PNA-mediated PCR.

Molecular Diagnosis in Lung Cancer

The advent of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib has opened a new horizon for the therapeutic options for patients with advanced lung cancer. Treatment paradigms are shifting from cytotoxic chemotherapies to molecular-based targeted therapies. The discovery of somatic mutations in the exons 18 to 21 of the tyrosine kinase (TK) domain of EGFR has revolutionized the understanding of EGFR in lung carcinogenesis and this has opened a new era for the importance of predictive biomarkers to select the treatment of choice and for personalized therapy for lung cancer. Three important EGFR assays are used and these include mutational analysis, fluorescence in situ hybridization and immunohistochemistry. EGFR mutation study seems to be the most important biomarker to predict the response to EGFR-TKI, yet technical standardization for analyzing the status of EGFR mutation is the key factor. Therefore, it is important to standardize the approach and decide which assays are best to predict a patient's response to targeted therapies. It is also essential to determine the most cost-effective way to integrate EGFR molecular assays into clinical practice. This review will address the practical aspects of each of the currently proposed assays that have focused on EFGR mutational analysis and also the other important molecular markers such as k-ras mutation, the EML4-ALK fusion oncogene, ERCC1 and RRM1.