Validation of a Histology-Independent Prognostic Gene Signature for Early-Stage, Non–Small-Cell Lung Cancer Including Stage IA Patients
A 15-gene prognostic classifier, developed from mRNA expression profiling of tumor samples collected in the NCIC CTG JB.10 trial, was previously validated in silico in four large public non–small-cell lung cancer (NSCLC) expression data sets. The present study further evaluated its performance in an independent cohort of 181 snap-frozen samples from stage I and II NSCLC patients without adjuvant therapy, collected at the University Health Network, in Toronto, Canada. Five-year overall survival was estimated using the Kaplan–Meier method, and log-rank test was used to assess the prognostic effect of the classifier. High- and low-risk patients were identified by the classifier with significant difference in overall survival (hazard ratio [HR] = 1.92, p = 0.012). This classifier was prognostic for 127 stage I patients (HR = 2.17, p = 0.018), 48 stage IA patients (HR = 5.61; p = 0.014), and both adenocarcinoma and squamous cell carcinoma cases (HR = 1.76, p = 0.058; HR = 4.19, p = 0.045, respectively). The prognostic accuracy of the 15-gene classifier was validated in early-stage NSCLC patients, including stage IA, and in different histological subtypes. The authors suggested its promising potential in identifying patients who will benefit from adjuvant chemotherapy independent of stage and histology. (p. 59)
Erk/MAP-Kinase Signaling Pathway and Neuroendocrine Differentiation of Non–Small-Cell Lung Cancer
The authors set out to determine the molecular pathways involved in neuroendocrine differentiation (NED) of non–small-cell lung cancer (NSCLC) and its clinical significance. Using NSCLC cell line, NCI-H157, they found that activation of Erk1/2-MAPK signal transduction pathway and inhibition of Akt signaling pathway were associated with NED. The findings were further confirmed by using specific Erk1/2-MAPK pathway activator (Pb2+) and inhibitors (siRNA-Erk1/2, and U0126), and Akt pathway inhibitor (LY294002). The Erk1/2-MAPK pathway was found to be essential for NED of NSCLC and was supported by immunohistochemical staining results that showed high positivity of phospho-Erk1/2 in NSCLC tumors with NED versus other neuroendocrine lung tumors. To conclude, this was the first report of a potential role of Erk1/2-MAPK pathway in NED of NSCLC. Further studies are warranted to dissect the pathway and determine molecular targets of the pathway for the treatment of NSCLC with NED. (p. 50)
Large-Scale Screening and Molecular Characterization of EML4-ALK Fusion Variants in Archival Non–Small-Cell Lung Cancer Tumor Specimens Using Quantitative Reverse Transcription Polymerase Chain Reaction Assays
This study aimed to determine and characterize variants of echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion in 7344 formalin-fixed, paraffin-embedded non–small-cell lung cancer (NSCLC) specimens of North American patients by using a panel of quantitative reverse transcription polymerase chain reaction assays. EGFR and KRAS mutation status as well as thymidylate synthase RNA level were also analyzed. The findings revealed 2.7% of cases with an EML4-ALK+ transcript (54.5% of V1, 10.0% of V2, 34.0% of V3, and 1.5% of V5a variants). The majority of EML4-ALK+ NSCLC tumors were adenocarcinoma (94%). Significantly different level of ALK expression was found between different EML4-ALK+ variants and individual tumors. Concurrent EGFR or KRAS mutation was only identified once for each case. Median thymidylate synthase RNA level was significantly lower in EML4-ALK+ NSCLC tumors versus those without EML4-ALK (p<0.001). In conclusion, this panel of reverse transcription polymerase chain reaction assays detects EML4-ALK+ variants and ALK expression in formalin-fixed, paraffin-embedded NSCLC specimens. It might be useful as an addition to the standard fluorescence in situ hybridization assay for improved evaluation of biology and response to ALK inhibitors. (p. 18)
Poor Survival of Early-Stage Lung Carcinoma Predicted by Epigenetic Inactivation of microRNA-34b/c
The microRNA-34b/c (miR-34b/c) targets genes in cell cycle, apoptosis, and invasion in lung adenocarcinoma (AC) and acts as a tumor suppressor. Nadal et al. investigated the clinical impacts of miR-34b/c methylation in patients with early-stage lung AC and the role of miR-34b/c re-expression in lung AC in vitro. Of 15 lung AC cell lines and 140 primary tumors of early-stage lung AC, miR-34b/c methylation was found in 40% cell lines and 46% primary tumors. Significantly decreased miR-34b/c expression was associated with methylated miR-34b/c in cell lines and primary tumors, especially when TP53 mutation was present. Significantly shorter disease-free survival and overall survival were observed in patients with high levels of methylated miR-34b/c versus those with low levels or nonmethylated miR-34b/c. The findings indicated the prognostic value of DNA methylation of miR-34b/c in early-stage lung cancer. Lung AC cell lines with re-expressed miR-34b/c were also less aggressive, with reduced cell proliferation, migration, and invasion.
Nadal E, Chen G, Gallegos M, et al. Epigenetic inactivation of microRNA-34b/c predicts poor disease-free survival in early stage lung adenocarcinoma. Clin Cancer Res, doi:10.1158/1078-0432.ccr-13–0736 (2013).
Adolescents’ Weight and Socioeconomic Status May Affect Their Risk of Developing Esophageal and Gastric Cancer Later in Life
Levi and colleagues from Rabin Medical Center in Israel discovered that overweight adolescents have 2.1-fold higher risk of developing esophageal adenocarcinoma (EAC) later in life compared with those with normal weights, according to their study published in Cancer. A million Israeli adolescent males (average age, 17 years) had their body mass index measured and were followed up for an average of 18.8 years. Participants who later developed cancer were identified from the national cancer registry. Of the 182 cancer cases documented, 52 had combined EAC and gastroesophageal junction adenocarcinoma (GEJAC). The association of increased risk in the combined EAC and GEJAC group with an adolescent body mass index of 85th percentile or more (hazard ratio, 2.1; p=.032) reflected that being overweight and obese could have a huge impact at younger ages and it is unclear whether weight loss would minimize the risk. Further follow-up of the current study is needed to assess whether the association of adolescent overweight is stronger with EAC or GEJAC.
Levi Z, Kark JD, Shamiss A, et al. Body mass index and socioeconomic status measured in adolescence, country of origin, and the incidence of gastroesophageal adenocarcinoma in a cohort of 1 million men. Cancer 2013;119:4086–4093.
New Genetic Variants Identified for Esophageal Cancers
A genome-wide association study published in Nature Genetics demonstrated a link between four genetic variations and the risk of developing esophageal adenocarcinoma and precancerous Barrett’s esophagus. From 2390 cases of esophageal adenocarcinoma, 3175 individuals with precancerous Barrett’s esophagus, and 10,120 controls significant association with three new variants were identified: CRTC1 at chromosome 19, BARX1 at chromosome 9, and FOXP1 at chromosome 3. The fourth variant, FOXF1 at chromosome 16, was previously associated with Barrett’s esophagus and is hereby found to be also linked to esophageal adenocarcinoma. Further studies are warranted to translate this finding into diagnostic and therapeutic measures for esophageal cancers.
Levine DM, Ek WE, Zhang R, et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus. Nat Genet, doi:10.1038/ng.2796. http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.2796.html#supplementary-information (2013).
A Genomics-Based Classification of Human Lung Tumors: The Clinical Lung Cancer Genome Project (CLCGP) and Network Genomic Medicine (NGM)
The authors of this study aim to determine the genome alterations of clinically relevant subgroups in 1255 lung tumors across histological subtypes for genomic lung cancer diagnosis using comprehensive copy number analyses together with focused sequencing and RNA expression analysis. More than half of these tumors harbored at least one oncogenic alteration, to which targeted intervention or personalized therapies were developed and some are being assessed in clinical trials. For instance, EGFR mutations or anaplastic lymphoma kinase rearrangements in squamous cell carcinomas. The findings showed that the pattern of genomic alterations between and within histological subtypes varied significantly. As a result of combined histopathological and genomic analysis, large cell carcinomas were reassigned to therapeutically relevant groups, for example, adenocarcinoma or squamous cell carcinoma. Prospective evaluation of this genomics-based diagnostic algorithm in 5145 lung cancer patients yielded 75% diagnosis, which confirmed the rational reassignment of LC. The diagnostic signature also markedly improved overall survival in patients harboring EGFR mutations or anaplastic lymphoma kinase rearrangement. To conclude, this study provided a blueprint for genomic lung cancer diagnosis and supported the introduction of a molecular diagnosis in combination with specific therapeutic intervention.
Project TCLCG & Network Genomic Medicine A Genomics-Based Classification of Human Lung Tumors. Science Translational Medicine 2013;5:209ra153.
NEWS IN BRIEF
World Conference on Lung Cancer (WCLC) 2013: Treatment with Therapies Matched to Oncogenic Drivers Improves Survival in Patients with Lung Cancers: Results from The Lung Cancer Mutation Consortium (LCMC)
At the plenary session of the World Conference on Lung Cancer 2013, the results from the Lung Cancer Mutation Consortium, in which multiplexed assays were used to detect modifications in 10 oncogenic driver genes to guide clinical decisions on treatments and clinical trials were presented. Of the patients with metastatic lung adenocarcinoma enrolled at 14 Lung Cancer Mutation Consortium sites, 1007 were genotyped for at least one gene and 733 for all 10 genes. Sixty-four percent of the tumors bear an oncogenic driver: KRAS (25%), sensitizing EGFR (17%), anaplastic lymphoma kinase rearrangements (8%), and less than 5% for each of the following: other EGFR, HER2, BRAF, PIK3CA, MET amplification, NRAS, MEK1, and AKT1. Three percent bear more than one driver. The median survivals were 3.5 years for patients with an oncogenic driver treated with genotype-directed therapy, 2.4 years for those with an oncogenic driver without genotype-directed therapy, and 2.1 years for those without any identified oncogenic driver. Multiplexed testing has enabled targeted therapy in 28% of the patients. The findings demonstrated improved survival in lung cancer patients harboring oncogenic drivers treated with matching targeted therapy.
WCLC 2013: Lung Cancer Probability in Subjects with CT-Detected Pulmonary Nodules
Horeweg and colleagues proposed a new and improved nodule management algorithm for lung cancer computed tomography (CT) screening based on lung cancer probability. Diameter, volume, and volume-doubling time (VDT) of 9.681 nodules detected by CT screening was assessed for the calculation of lung cancer probability. Complete lung cancer diagnoses were obtained from the national cancer registry. The results showed that small nodules (volume <100 mm3 or diameter < 5 mm) are not predictive for lung cancer whereas large nodules (volume ≥ 300 mm3 or diameter ≥ 10 mm) call for immediate diagnostic assessment. Volume-doubling time evaluation is required only for nodules of intermediate sizes (volume 100–300 mm3 or diameter 5–10 mm). The authors estimated fewer follow-up CT assessments (29.8%–22.2%) and fewer additional diagnostic evaluation (8.9%–5.3%) with high sensitivity (94.2%) by raising the thresholds for ACCP recommended nodule size for an indeterminate result (4 mm–5 mm) and a positive result (8 mm–10 mm).
WCLC 2013: MesoVATS Trial of Video-Assisted Thoracoscopic Pleurectomy versus Talc Pleurodesis in Malignant Pleural Mesothelioma
The findings from MesoVATS, a multicenter randomized controlled trial of evaluating video-assisted thoracoscopic (VAT) pleurectomy versus talc pleurodesis in controlling pleural effusion and improving survival in patients with malignant pleural mesothelioma (MPM), were presented at the World Conference on Lung Cancer 2013. Patients with more than 18 years of confirmed or suspected MPM with a pleural effusion were enrolled and risk-stratified. Talc pleurodesis involved the use of tube thoracostomy or poudrage at thoracoscopy. VAT pleurectomy involved partial parietal pleurectomy and decortication of the visceral pleura. There were 87 VAT pleurectomies and 88 talc pleurodeses for the main analysis, which included epithelioid disease (84%), IMIG stage 3/4 (78%), and high risk as per EORTC criteria (49%). The results showed significant improved control of pleural effusion (p = 0.008 at 1 month; p = 0.04 at 6 months) and improved quality of life (p = 0.042 at 6 months; p = 0.006 at 12 months) in the VAT pleurectomy group. But the same group did not show improved overall survival (hazard ratio 1.03; p = 0.83), had longer hospital stay (p < 0.001), and experienced more complications (mainly prolonged air leak, p = 0.009). Further subgroup analyses are warranted to determine the intervention that will most benefit patients with MPM.
WCLC 2013: An Intergroup Randomized Phase III Comparison of Standard-Dose (60 Gy) versus High-Dose (74 Gy) Chemoradiotherapy (CRT) +/− Cetuximab (Cetux) for Stage III Non–Small-Cell Lung Cancer (NSCLC): Results on Cetux from RTOG 0617
The RTOG 0617 trial aims to compare the overall survival (OS) of standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy with concurrent chemotherapy, and the addition of cetuximab (cetux) to standard chemoradiotherapy (CRT). It was previously reported that standard-dose and high-dose arms demonstrated median survival times of 28.7 versus 19.5 months and 18-month OS rates of 66.9% versus 53.9%, respectively (hazard ratio, [HR] = 1.56, p = 0.0007). This was an initial report of survival outcome from the addition of cetux to CRT. Patients received concurrent CRT that included carboplatin and paclitaxel, and were randomized to cetux. There were 419 and 465 patients eligible for radiotherapy and cetux analyses with a median follow-up of 18.7 months. The OS data revealed that 74 Gy is not superior to and could be worse than 60 Gy in treating stage III non–small-cell lung cancer patients receiving CRT. The addition of cetux to CRT did not improve survival: There were similar 18-month OS rates (HR = 0.99, p = 0.484) and median survival with and without cetux.