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      Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival

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          Abstract

          Background:

          There is limited Indian data on epidermal growth factor receptor (EGFR) gene activating mutations (AMs) prevalence and their clinicopathologic associations. The current study aimed to assess the relationship between EGFR AM and histologic subtypes and their impact on overall survival (OS) in a North Indian cohort.

          Patients and Methods:

          Retrospective analysis of nonsmall cell lung cancer patients who underwent EGFR mutation testing ( n = 186) over 3 years period (2012–2014). EGFR mutations were tested using polymerase chain reaction amplification and direct sequencing. Patients were classified as EGFR AM, EGFR wild type (WT) or EGFR unknown (UKN). Histologically adenocarcinomas (ADC) were further categorized as per the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society-2011 classification.

          Results:

          Overall EGFR AM prevalence was 16.6%. The ratio of exon 19 deletions to exon 21 L858R mutations was 3.17:1. Female sex ( P = 0.002), never smoking status ( P = 0.002), metastatic disease ( P = 0.032), and nonsolid subtype of ADC ( P = 0.001) were associated with EGFR AM on univariate logistic regression analysis (LRA). On multivariate LRA, solid ADC was negatively associated with EGFR AM. Median OS was higher in patients with EGFR AM (750 days) as compared to EGFR-WT (459 days) or EGFR-UKN (291 days) for the overall population and in patients with Stage IV disease (750 days vs. 278 days for EGFR-WT, P = 0.024). On univariate Cox proportional hazard (CPH) analysis, smoking, poor performance status (Eastern Cooperative Oncology Group ≥ 2), EGFR-UKN status, and solid ADC were associated with worse OS while female sex and lepidic ADC had better OS. On multivariate CPH analysis, lepidic ADC (hazard ratio [HR] =0.12) and EGFR-WT/EGFR-UKN (HR = 2.39 and HR = 3.30 respectively) were independently associated with OS in separate analyses.

          Conclusions:

          Histologic subtyping of ADC performed on small biopsies is independently associated with EGFR AM and with better OS. EGFR AM presence is a positive prognostic factor for OS.

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          Most cited references 52

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          International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.

          Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.
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            Screening for epidermal growth factor receptor mutations in lung cancer.

            Activating mutations in the epidermal growth factor receptor gene (EGFR) confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. We evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment. From April 2005 through November 2008, lung cancers from 2105 patients in 129 institutions in Spain were screened for EGFR mutations. The analysis was performed in a central laboratory. Patients with tumors carrying EGFR mutations were eligible for erlotinib treatment. EGFR mutations were found in 350 of 2105 patients (16.6%). Mutations were more frequent in women (69.7%), in patients who had never smoked (66.6%), and in those with adenocarcinomas (80.9%) (P<0.001 for all comparisons). The mutations were deletions in exon 19 (62.2%) and L858R (37.8%). Median progression-free survival and overall survival for 217 patients who received erlotinib were 14 months and 27 months, respectively. The adjusted hazard ratios for the duration of progression-free survival were 2.94 for men (P<0.001); 1.92 for the presence of the L858R mutation, as compared with a deletion in exon 19 (P=0.02); and 1.68 for the presence of the L858R mutation in paired serum DNA, as compared with the absence of the mutation (P=0.02). The most common adverse events were mild rashes and diarrhea; grade 3 cutaneous toxic effects were recorded in 16 patients (7.4%) and grade 3 diarrhea in 8 patients (3.7%). Large-scale screening of patients with lung cancer for EGFR mutations is feasible and can have a role in decisions about treatment. 2009 Massachusetts Medical Society
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              A Prospective, Molecular Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non–Small-Cell Lung Cancer of Adenocarcinoma Histology (PIONEER)

              Introduction: PIONEER (NCT01185314) was a prospective, multinational, epidemiological study of epidermal growth factor receptor (EGFR) mutations in patients from Asia with newly diagnosed advanced lung adenocarcinoma. Methods: Eligible patients (aged ≥20 years) had untreated stage IIIB/IV adenocarcinoma. The EGFR mutation status (primary end point: positive, negative, or undetermined) of tumor samples (biopsy, surgical specimen, or cytology) was determined (Scorpion amplification refractory mutation system). EGFR mutation frequency was calculated and compared between demographic and clinical subgroups. Results: Of 1482 patients from seven Asian regions, 43.4% of patients were female, median age was 60 years (range, 17–94), and 52.6% of patients were never-smokers. EGFR mutation status was evaluable in tumors from 1450 patients (97.8%) (746 [51.4%] positive; 704 [48.6%] negative). Country, sex, ethnicity, smoking status, pack-years (all p 0–10 pack-years, 57.9%; >50 pack-years, 31.4%) (similar trend by sex). Ethnic group (p < 0.001) and pack-years (p < 0.001) had statistically significant associations with mutation frequency (multivariate analysis); sex was not significant when adjusted for smoking status. Conclusion: PIONEER is the first prospective study to confirm high EGFR mutation frequency (51.4% overall) in tumors from Asian patients with adenocarcinoma. The observed high mutation frequency in demographic/clinical subgroups compared with white populations suggests that mutation testing should be considered for all patients with stage IIIB/IV adenocarcinoma, even males and regular smokers, among Asian populations.
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                Author and article information

                Journal
                Lung India
                Lung India
                LI
                Lung India : Official Organ of Indian Chest Society
                Medknow Publications & Media Pvt Ltd (India )
                0970-2113
                0974-598X
                May-Jun 2016
                : 33
                : 3
                : 257-266
                Affiliations
                Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                [1 ] Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                [2 ] Department of Cytology and Gynaecological Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
                Author notes
                Address for correspondence: Dr. Navneet Singh, Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh - 160 012, India. E-mail: singh.navneet@ 123456pgimer.edu.in
                LI-33-257
                10.4103/0970-2113.180801
                4857560
                27185988
                Copyright: © Lung India

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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