Dataset Information

Chronic Obstructive Pulmonary Disease-Related Non-Small-Cell Lung Cancer Exhibits a Low Prevalence of EGFR and ALK Driver Mutations.

ABSTRACT: Lung cancer and chronic obstructive pulmonary disease (COPD) are two major lung diseases. Epidermal growth factor receptor (EGFR) mutations, v-Ki-ras2 Kirsten rat sarcoma (KRAS) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements represent driver mutations that are frequently assessed on initial evaluation of non-small-cell lung cancer (NSCLC). The present study focused on the expression of driver mutations in NSCLC patients presenting with COPD and further evaluated the association between NSCLC and COPD. Data from 501 consecutive patients with histologically proven recurrent or metastatic NSCLC were analyzed retrospectively. The patients underwent spirometry and genotyping of EGFR, ALK, and KRAS in tissue samples. Patient characteristics and expression of driver mutations were compared between the COPD and non-COPD groups. Among 350 patients with spirometric results, 106 (30.3%) were diagnosed with COPD, 108 (30.9%) had EGFR mutations, 31 (8.9%) had KRAS mutations, and 34 (9.7%) showed ALK rearrangements. COPD was independently associated with lower prevalences of EGFR mutations (95% confidence interval [CI], 0.254-0.931, p = 0.029) and ALK rearrangements (95% CI, 0.065-0.600, p = 0.004). The proportions of EGFR mutations and ALK rearrangements decreased as the severity of airflow obstruction increased (p = 0.001). In never smokers, the prevalence of EGFR mutations was significantly lower in the COPD group than in the non-COPD group (12.7% vs. 49.0%, p = 0.002). COPD-related NSCLC patients exhibited low prevalences of EGFR mutations and ALK rearrangements compared with the non-COPD group. Further studies are required regarding the molecular mechanisms underlying lung cancer associated with COPD.

SUBMITTER: Lim JU

PROVIDER: S-EPMC4640806 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Chronic Obstructive Pulmonary Disease-Related Non-Small-Cell Lung Cancer Exhibits a Low Prevalence of EGFR and ALK Driver Mutations.

Lim Jeong Uk JU Yeo Chang Dong CD Rhee Chin Kook CK Kim Yong Hyun YH Park Chan Kwon CK Kim Ju Sang JS Kim Jin Woo JW Lee Sang Haak SH Kim Seung Joon SJ Yoon Hyoung Kyu HK Kim Tae-Jung TJ Lee Kyo Young KY

PloS one 20151110 11

Lung cancer and chronic obstructive pulmonary disease (COPD) are two major lung diseases. Epidermal growth factor receptor (EGFR) mutations, v-Ki-ras2 Kirsten rat sarcoma (KRAS) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements represent driver mutations that are frequently assessed on initial evaluation of non-small-cell lung cancer (NSCLC). The present study focused on the expression of driver mutations in NSCLC patients presenting with COPD and further evaluated the associati ...[more]

PMID: 26555338

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Project description:This study aimed to identify the computed tomography characteristics of treatment-naïve patients with lung adenocarcinoma and known driver mutations in EGFR, KRAS, or ALK. Patients with advanced lung adenocarcinoma (stage IIIB-IV) and known mutations in EGFR, KRAS, or ALK were assessed. The radiological findings for the main tumor and intra-thoracic status were retrospectively analyzed in each group, and the groups' characteristics were compared. We identified 265 treatment-naïve patients with non-small-cell carcinoma, who had EGFR mutations (n = 159), KRAS mutations (n = 55), or ALK rearrangements (n = 51). Among the three groups, we evaluated only patients with stage IIIB-IV lung adenocarcinoma who had EGFR mutations (n = 126), KRAS mutations (n = 35), or ALK rearrangements (n = 47). We found that ground-glass opacity at the main tumor was significantly more common among EGFR-positive patients, compared to ALK-positive patients (p = 0.009). Lymphadenopathy was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.003). Extranodal invasion was significantly more common among ALK-positive patients, compared to EGFR-positive patients and KRAS-positive patients (p = 0.001 and p = 0.049, respectively). Lymphangitis was significantly more common among ALK-positive patients, compared to EGFR-positive patients (p = 0.049). Pleural effusion was significantly less common among KRAS-positive patients, compared to EGFR-positive patients and ALK-positive patients (p = 0.046 and p = 0.026, respectively). Lung metastases were significantly more common among EGFR-positive patients, compared to KRAS-positive patients and ALK-positive patients (p = 0.007 and p = 0.04, respectively). In conclusion, EGFR mutations were associated with ground-glass opacity, KRAS-positive tumors were generally solid and less likely to metastasize to the lung and pleura, and ALK-positive tumors tended to present with lymphadenopathy, extranodal invasion, and lymphangitis. These mutation-specific imaging characteristics may be related to the biological differences between these cancers.

Project description:IntroductionTargeted somatic genomic analysis (EGFR, anaplastic lymphoma receptor tyrosine kinase gene [ALK], and ROS1) and programmed death ligand 1 (PD-L1) tumor proportion score (TPS) determined by immunohistochemistry (IHC) are used for selection of first-line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported.MethodsWe retrospectively probed the first 71 pairs of patients with lung adenocarcinoma from our institution. They were analyzed for PD-L1 by IHC using the clone 22C3 pharmDx kit (Agilent Technologies, Santa Clara, CA) and evaluated for co-occurrence of genomic aberrations and clinicopathologic characteristics.ResultsSurgical resection specimens, small biopsy (transbronchial or core needle) samples, and cytologic cell blocks (needle aspirates or pleural fluid) were tested. A PD-L1 TPS of at least ≥50% was seen in 29.6% of tumors. Of 19 tumors with EGFR mutations, ALK fluorescence in situ hybridization positivity, or ROS1 fluorescence in situ hybridization positivity, 18 had a PD-L1 TPS less than 50% versus only one tumor with a PD-L1 TPS of at least 50% (p = 0.0073). Tumors with a PD-L1 TPS of at least 50% were significantly associated with smoking status compared with tumors with a PD-L1 TPS less than 50% but were not associated with patient sex, ethnicity, tumor stage, biopsy site, or biopsy type/preparation.ConclusionsPD-L1 IHC can be performed on routine clinical lung cancer specimens. A TPS of at least 50% seldom overlaps with presence of driver oncogenes with approved targeted therapies. Three biomarker-specified groups of advanced lung adenocarcinomas can now be defined, each paired with a specific palliative first-line systemic therapy of proven clinical benefit: (1) EGFR/ALK/ROS1-affected adenocarcinoma paired with a matched tyrosine kinase inhibitor (∼20% of cases), (2) PD-L1-enriched adenocarcinoma (TPS ≥50%) paired with anti-PD-1 pembrolizumab (∼30% of cases), and (3) biomarker-negative (i.e., EGFR/ALK/ROS1/PD-L1-negative) adenocarcinoma paired with platinum doublet chemotherapy with or without bevacizumab (∼50% of cases).

Project description:BackgroundPatients with EGFR-mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes.MethodsFive hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR-mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET-amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR-mutated tumor samples from erlotinib-treated patients.ResultsThirty-six patients (7%) had EGFR-mutations, including 2 with intrinsic resistance mutation p.T790M together with the p.L858R sensitizing mutation and 1 harboring the p.G719C/S768I double-mutation. Twenty-three patients had either locally advanced or advanced disease and received first-line erlotinib-treatment. Concomitant driver mutations were found in 15/21 (71%) of NGS-analyzed TKI-treated NSCLCs, involving in 67% of cases TP53, in 13% CTNNB1, and in 7% KRAS, MET, SMAD4, PIK3CA, FGFR1, FGFR3, NRAS, DDR2, and ERBB4. No ALK-expression was found, whereas MET-overexpression and MET-amplification were observed in 5 and 4 patients, respectively. Objective responses occurred in 17/23 patients (74%), 4 did not respond (17%), and 2 harboring a SMAD4-mutation (p.R135*(stop)) and a FGFR3-mutation (p.D785fs*31), respectively, displayed mixed response with simultaneously progressing and responding tumors (8.7%). Thus, EGFR-mutated tumors harboring co-mutations were not less likely to respond.ConclusionCo-mutations in other cancer-driver genes (oncogenes or tumor suppressor genes) were frequent in EGFR-mutated NSCLCs and few cases harbored concomitant activating and resistance EGFR-mutations before TKI-treatment. Most co-mutations did not impact the response to first-line erlotinib-treatment, but may represent potential additional therapeutic targets.

Dataset Information

Chronic Obstructive Pulmonary Disease-Related Non-Small-Cell Lung Cancer Exhibits a Low Prevalence of EGFR and ALK Driver Mutations.

Publications

Chronic Obstructive Pulmonary Disease-Related Non-Small-Cell Lung Cancer Exhibits a Low Prevalence of EGFR and ALK Driver Mutations.

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