In This Issue
Whole Genome Sequencing Analysis Identifies a Distinctive Mutational Spectrum in an Arsenic-Related Lung Tumor
In an effort to characterize the mutation profile of arsenic-induced lung tumors, Martinez and colleagues analyzed a lung squamous cell carcinoma (LUSC) from a never-smoker who had chronic arsenic exposure but had no family history of lung cancer. Using whole genome sequencing of the arsenic-induced tumor, they found genetic changes common in LUSC (e.g., higher copies at SOX2 locus) as well as alterations that are uncharacteristic of LUSCs: fewer point mutations, increased T>G/A>C mutations, and fewer C>A/G>T transversions. Also, a G>C mutation in TP53, which is rare in lung tumors but occurs in other arsenic-related cancers, was discovered in this case. The authors have identified a distinct mutation profile related to arsenic exposure in an LUSC, therefore suggesting that arsenic induces different molecular mechanisms in lung tumors compared with tobacco- or other carcinogen-induced lung tumors. Further studies on the mutation profiles of other arsenic-related cancers could provide insight for diagnostic and therapeutic target development. (p. 1451)
Radiotherapy for Intubated Patients with Malignant Airway Obstruction
A 10-year retrospective study was conducted on intensive care unit (ICU) patients who received radiotherapy (RT) and required intubation and mechanical ventilation for malignant airway obstruction (MAO). The aim of the study was to evaluate the efficacy of RT in facilitating extubation as a result of MAO and discharge of intubated ICU patients to home. Primary endpoints were overall survival (OS) and extubation success. Secondary endpoints were discharge rates from the ICU and to home. Of 26 patients, 27% were extubated; all were discharged from the ICU and six were discharged home. Median OS of 0.36 months and 6-month OS of 11% were observed. Higher radiation dose was predictive of prolonged OS (hazard ratio per 5 Gy increase: 0.74; p = 0.016) and associated with a trend for increased extubation success (odds ratio per 5 Gy increase: 0.63; p = 0.080). Taken together, this study suggests that RT is not futile for intubated patients with MAO, and could be of value for this population of patients as they are ineligible for bronchoscopic intervention. (p. 1365)
CDKN2A/p16 Inactivation Mechanisms and Their Relationship to Smoke Exposure and Molecular Features in Non–Small-Cell lung Cancer
This study evaluated the association of three CDKN2A (p16) inactivation mechanisms, that is, homozygous deletions, methylation of promoter and point mutations, with its gene products, common genetic mutations (EGFR, KRAS, STK11) and smoking status in 40 cell lines and 45 primary tumor of non–small-cell lung cancer. The data revealed a tight correlation of all p16 inactivating mechanisms with loss of its mRNA and protein expression. The frequencies of p16 inactivation were comparable regardless of EGFR, KRAS, and STK11 mutations. p16 methylation was associated with KRAS mutation but mutually exclusive of EGFR mutation. Meta-analyses to assess the impact of smoke exposure on p16 inactivation demonstrated a modest positive correlation between p16 promoter methylation and smoking. Further studies on the relationship of specific p16 inactivation mechanisms and other environmental and genetic factors are warranted to shed light on the different molecular mechanisms responsible for non–small-cell lung cancer development. (p. 1378)
Prognostic Value of Fibroblast Growth Factor Receptor 1 Gene Locus Amplification in Resected Lung Squamous Cell Carcinoma
Ten percent to 20% of primary lung squamous cell carcinomas (SqCCs) harbor fibroblast growth factor receptor 1 (FGFR1) gene amplification, which has generated immense interest in its role as a potential therapeutic target. In this study, Craddock et al. sought to determine its prognostic value for early-stage SqCC. Tissue microarrays of 147 primary lung SqCCs and 58 matching lymph node metastases were analyzed by fluorescence in situ hybridization to determine abnormal DNA copy number of the FGFR1. The results revealed 18.2% of 121 primary SqCCs harbored FGFR1 amplification. With 97% to 100% concordance rates between primary and matching lymph node metastases, and between two different lymph node metastases, no significant link between FGFR1 copy number abnormalities and clinicopathological factors was found. The authors concluded that FGFR1 amplification is not prognostic in SqCC. (p. 1371)
A Phase II Study with Cetuximab and Radiation Therapy for Patients with Surgically Resectable Esophageal and Gastroesophageal Junction Carcinomas
Becerra at al. present the results of a phase II, open-label, single-arm, multicenter study to assess the efficacy and safety of cetuximab and radiation therapy followed by surgery in patients with resectable esophageal and gastroesophageal junction carcinomas. The primary objective of the study was to evaluate the pathologic complete response (pCR) rate in the primary tumor post treatment. Secondary objectives were to determine the clinical complete and partial response rates, and overall toxicities. Of 39 patients, the majority were men of an average age of 64 years, with performance status of 0 to 1, had adenocarcinoma, and had tumors in the esophagus. More than 5% of patients experienced grade 3 toxicities whereas 2% experienced grade 5 aspiration. Four deaths were reported. The pCR rates resulted from the cetuximab and radiation therapy regimen were comparable with that from chemotherapy and radiation therapy: 36.6% by intention-to-treat, 48% for patients who underwent esophagectomy; 67% for squamous cell carcinomas, and 28% for adenocarcinoma. Higher pCR was linked to early-stage disease (IIA 70%, IIB 29%, III 28%). The findings suggested this regimen to be more tolerable for the study population when compared with preoperative chemotherapy and radiation. (p. 1425)
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ICOGEN: Icotinib Versus Gefitinib in Previously Treated Advanced Non–Small-Cell Lung Cancer
Icotinib, an oral EGFR inhibitor with promising efficacy and safety profile in early clinical trials, was compared with gefitinib for noninferiority in a randomized, double-blinded phase 3 trial for advanced non–small cell lung cancer. Patients with prior platinum-based chemotherapy (n=395) were analyzed, and EGFR status was assessed if tissues were available. The primary endpoint, median progression-free survival, of patients receiving icotinib was 4.6 months versus 3.4 months for those receiving gefitinib. The most common side effects were rash (41% icotinib versus 49% gefitinib) and diarrhea (22% versus 29%). Lower rate of drug-related adverse events was found in patients who were given icotinib. The findings demonstrated that icotinib was noninferior to gefitinib, and suggested icotinib to be a novel therapy for advanced non–small cell lung cancer with prior chemotherapy.
Shi Y, Zhang L, Liu X, et al. Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial. Lanc Oncol 2013;14:953–961.
Multikinase Inhibitor Blocks Tumor Growth and Metastasis in Non–Small-Cell Lung Cancer
Wu et al. conducted in vitro and in vivo analyses of the orally bioavailable oncokinase inhibitor, LY2801653, which also inhibits MET, in non–small-cell lung cancer (NSCLC). Both in vitro and in vivo findings showed that LY2801653 inhibited tumor growth as a single agent (by 37%–90%) or in combination with cisplatin, gemcitabine, or erlotinib (by 67% –86%). It was also shown to block proliferation, anchorage-independent growth, migration, and invasion by disrupting the constitutive activation of MET pathway signaling. The effect of LY2801653 was also observed in an NSCLC orthotopic model: 88% inhibition of primary tumor growth and 65% to 68% inhibition of metastasis. An 87% longer survival time was reported in tumor-bearing animals in MET-dependent model versus the control. However, it inhibited only primary tumor growth and not metastasis in a MET-independent orthotopic model. The evidence supports clinical development of LY2801653 for treatment of NSCLC and the different MET activation status of tumors could be of predictive value.
Wu W, Bi C, Credille K, et al. Inhibition of tumor growth and metastasis in non-small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET. Clin Cancer Res, doi:10.1158/1078-0432.ccr-13–1758 (2013).
Gene Expression and Drug-Sensitivity Data Stratify Squamous Cell Lung Cancer Subtypes
By integrating comprehensive data sets, Wu et al. evaluated 178 squamous cell lung cancer (SqCC) tumor samples in an effort to characterize the molecular features of the four SqCC subtypes (primitive, classical, secretory, and basal), and map them to the specific time points in airway development and their response to therapy. Differential expression of RNAseq data and pathway analysis identified signature gene sets and pathways specific to the SqCC subtypes. The findings suggest the basal subtype to have originated from an earlier differentiation stage than the primitive subtype. It also revealed that the basal and primitive subtypes do not share significant pathways in the same direction, which might explain the prognosis of these subtypes as being opposite to each other. From the analysis of drug-sensitivity data of the SqCC cell lines classified to each of the SqCC subtypes, it was observed that most of them were sensitive to one of five anticancer drugs (Panobinostat, 17-AAG, Irinotecan, Topotecan and Paclitaxel), except for secretory subtype. Basal subtype cell line was sensitive to PF2341066, AZD6244, and PD-0325901. The integration of genomic and drug-sensitivity data for the SqCC subtypes could potentially guide drug repurposing, with the ultimate aim of improving treatment for patients bearing these subtypes.
Wu D, Pang Y, Wilkerson MD, et al. Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity. Br J Cancer, doi:10.1038/bjc.2013.452 (2013).
New Model Accurately Predicts Cancer on First Lung Low-Dose Computed Tomography Scan
A population-based prospective study led by Terry Fox Research Institute has proved that, 9 out of 10 times, their new clinical risk calculator software accurately predicts which nodules detected on first lung low-dose computed tomography (LDCT) scan in high-risk lung cancer patients are benign and malignant. They analyzed two cohorts of data (Pan-Canadian Early Detection of Lung Cancer Study and British Columbia Cancer Agency chemoprevention trials) with a total of 12,029 nodules from 2961 participants, who were current and former smokers, aged 50 to 75 years, and received LDCT screening. Predictors of cancer in the model were older age, female sex, family history of lung cancer, emphysema, larger nodule size, location of the nodule in the upper lobe, part-solid nodule type, lower nodule count, and spiculation. Their parsimonious and full multivariable logistic-regression models demonstrated excellent discrimination and calibration, even for nodules less than 10 mm. The use of this tool in LDCT screening could improve early detection, diagnosis, and treatment of lung cancer as well as reduce costs and risk of mortality as a result of screening.
McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of Cancer in Pulmonary Nodules Detected on First Screening CT. New Engl J Medicine 2013;369:910–919.
NVALT-10 Trial: Erlotinib Alone Versus Erlotinib and Chemotherapy in Relapsed Non–Small-Cell Lung Cancer Patients
In this phase II study, 231 patients with advanced non–small-cell lung cancer who failed first-line chemotherapy were randomized to receive erlotinib alone or erlotinib intercalated with docetaxel for squamous or pemetrexed for nonsquamous (NSQ) patients. Primary endpoint was progression-free survival. The primary endpoint was not met (hazard ratio = 0.76, p=0.06) but a trend of an increase in progression-free survival was observed primarily in the NSQ group treated with pemetrexed and erlotinib. The secondary endpoint, overall survival, was significantly prolonged in patients with NSQ histology in the combination arm (hazard ratio = 0.67, p=0.01). The toxicity greater than grade 2 was significantly higher in the combination arm (55%) versus erlotinib alone (19%); hematological toxicity was only found in the combination arm. Future studies on combination of chemotherapy and erlotinib in which more than four cycles of chemotherapy treatment are warranted to possibly enhance the synergistic effect.
Aerts JG, Codrington H, Lankheet NAG, et al. A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study. Ann Oncol, doi:10.1093/annonc/mdt341 (2013).
NEWS IN BRIEF
Results of the Two Incidence Screenings in the National Lung Screening Trial
In the National Lung Screening Trial, the effect of three rounds of annual screenings (T0, T1, and T2) using low-dose computed tomography (LDCT) was compared with that of chest radiography in reducing mortality from lung cancer. The results from the first two incidence screenings (rounds T1 and T2) were published in the New England Journal of Medicine (N Engl J Med 2013;369:920–931). LDCT was found to be more sensitive than radiography (T1: 94.4%; T2: 93.0% versus T2: 59.6%; T2: 63.9%) but the predictive positive value of LDCT was lower than that of radiography (T1: 2.4%; T2: 5.2% versus T1: 4.4%; T2: 6.7%). In the LDCT group, there was a decrease in the number of advanced lung cancers diagnosed (47.5%) and increase in the number of early-stage lung cancers diagnosed (31.1%) when compared with the radiology group (23.5% and 59.1%, respectively). These findings support the use of LDCT in detecting more lung cancers, especially early-stage tumors that are potentially curable, in high-risk population. Strategies for further improvement of the characteristic performance of LDCT are warranted.
Photo source: Food and Drug Administration
Ganetespib Granted Fast-Track Designation for Non–Small-Cell Lung Adenocarcinoma
The United States Food and Drug Administration has granted fast-track designation to the development of ganetespib, an Hsp90 inhibitor, for combination treatment with docetaxel in patients with metastatic non–small-cell lung cancer who failed one prior chemotherapy regimen. Ganetespib is currently being investigated in the GALAXY-1 Phase IIb/III all-comer trial and the GALAXY-2 Phase 3 trial for patients most likely to benefit from the treatment.
Photo credit: Grumpy-Puddin ( http://www.flickr.com/photos/grumpy-puddin/5161819684/)
First Fully Automated IHC Companion Diagnostic Approved for ALK-Positive Lung Cancer Patients
The Chinese Food and Drug Administration has approved VENTANA ALK immunohistochemistry assay as the first companion diagnostic for ALK-positive patients with non–small-cell lung cancer eligible for treatment with crizotinib, an oral ALK inhibitor. The VENTANA ALK immunohistochemistry assay uses rabbit monoclonal primary antibody to identify ALK-positive patients with non–small-cell lung cancer. It was proved to demonstrate 99.23% concordance with Abbott’s ALK break-apart fluorescence in situ hybridization assay in a retrospective study of 1100 Chinese subjects.
Photo source: www.cancer.gov