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Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000147
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Does Surgery Improve Survival of Patients with Malignant Pleural Mesothelioma? A Multicenter Retrospective Analysis of 1365 Consecutive Patients

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To assess the effect of surgical treatment with pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP) on the outcome of patients with malignant pleural mesothelioma (MPM), a multicenter retrospective study of 1365 consecutive patients with MPM was conducted. Patients were given chemotherapy alone (n = 172) or palliative care (n = 690) or surgery (P/D, n = 202 or EPP, n = 301) with or without chemotherapy. Among 16.8% of patients who were alive after a median follow-up of 6.7 years, median survival was 11.7 months for those who received palliative care, 20.5 months for chemotherapy alone, and 18.8 months for P/D and EPP. The 30-day mortality after P/D and EPP was 2.6% and 4.1%, respectively (p = 0.401). Epithelial histology and chemotherapy were independent favorable prognostic factors. Among 131 patients with all the favorable prognostic factors, the findings showed that median survival was similar between those receiving chemotherapy only (18.6 months), P/D (24.6 months), and EPP (20.9 months) (p = 0.596). The authors concluded that, though no significant improvement in patient survival was observed with surgery, further evaluation of the modest benefit after surgery versus chemotherapy is warranted. In addition, investigating MPM patients with good prognostic factors, who receive P/D after induction chemotherapy versus chemotherapy alone, in a large multicenter randomized trial is required. (p. 383)

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BRIEF REPORT

HIP1-ALK, A Novel Fusion Protein Identified in Lung Adenocarcinoma
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In addition to the five fusion proteins anaplastic lymphoma kinase (ALK)–EML4, –TFG, –KIF5B, –KCL1, and –PTPN3 reported to be involved in ALK overexpression and activation in non– small-cell lung cancer, Hong and colleagues discovered a novel fusion gene, huntingtin interacting protein 1 (HIP1)–ALK. Reverse transcriptase polymerase chain reaction and immunohistochemistry were used in the detection of this fusion gene and protein expression, respectively. It was localized to the cytoplasm, mainly in the submembrane area. HIP1 is essential for clathrin trafficking and cell survival in relation to its epsin N-terminal homology–domain. The coiled-coil domain of HIP1 and the juxtamembrane of ALK on the fusion protein demonstrated potential constitutive dimerization and aberrant activation of the ALK tyrosine kinase activity, which could indicate strong transforming potential. This case report presented HIP1–ALK as a novel diagnostic and therapeutic candidate for lung adenocarcinoma, which warrants further studies. (p. 412)

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RANKL Inhibition Blocks Osteolytic Lesions and Reduces Skeletal Tumor Burden in Models of Non–Small-Cell Lung Cancer Bone Metastases

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RANK ligand (RANKL), crucial for osteoclasts and skeletal destruction because of bone metastasis, is believed to be involved in tumor cell–mediated osteolysis, which is yet to be confirmed in the case of non–small-cell lung cancer (NSCLC). The authors evaluated the effects of RANKL inhibition by using human osteoprotegerin-Fc (OPG-Fc), either alone or in combination with docetaxel, on osteolysis, skeletal tumor burden, and survival in two novel mouse models of NSCLC bone metastasis. Mice bearing skeletal NSCLC tumors were treated with OPG-Fc and tumor progression was monitored using radiography, longitudinal bioluminescent imaging, and histology. The results from both NSCLC bone metastasis models showed that RANKL inhibition reduced osteolytic lesions and skeletal tumor progression. This observation was associated with reduced tumor-associated osteoclasts. These findings indicated that RANKL is needed for tumor-mediated osteolytic bone destruction in NSCLC cells in vivo. The effect of RANKL inhibition on skeletal tumor progression could be a result of indirect suppression of tumor-mediated osteoclastogenesis hence blocking the release of growth factors and calcium from the bone microenvironment. In addition, significantly enhanced inhibition of skeletal tumor growth was observed in OPG-Fc plus docetaxel compared with either agent alone. To conclude, this in vivo study provided solid evidence supporting the antitumor effect and a survival advantage of RANKL inhibition in NSCLC. It also indicated the therapeutic potential of targeting bone environment to achieve better outcomes in patient, which warrants further clinical studies. (p. 345)

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Impact of Extratumoral Lymphatic Permeation on Postoperative Survival of Non–Small-Cell Lung Cancer Patients

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Lymphatic permeation has been a prognostic factor for patients with resected non–small-cell lung cancer and the authors set out to evaluate its survival impact in these patients based on its location, which is in this study, in extratumoral area. From the long-term follow-up data (2001–2006), 1069 consecutive patients with resected NSCLC were analyzed and categorized by absence of (ly0), intratumoral (ly1), and extratumoral (ly2) lymphatic permeation. Majority of the patients (79%) showed no lymphatic permeation; 12% were ly1 whereas 9% were ly2. Ly2 has a higher incidence in patients with advanced disease and intrapulmonary metastases, and significantly worse 5-year overall survival rate (34%) versus ly0 (75%, p<0.01) and ly1 (63%, p<0.01). The findings also demonstrated ly2 as an independent poor prognostic factor (hazard ratio, 1.73; p < 0.01). There was no significant difference in overall survival and recurrence-free survival between the different pT status of tumor where ly2 was present: T1 and T2 (p = 0.43 and p = 0.94, respectively) and T3 (p = 0.77 and p = 0.94, respectively). This study demonstrated a marked difference in the adverse prognostic impact of lymphatic permeation based on its intra-/extratumoral locations. It therefore underscores the importance of assessing locations of lymphatic permeation in resected NSCLC patients. (p. 337)

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RESEARCH WATCH

Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer

Although epidermal growth factor receptor (EGFR) mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) are associated with sensitivity to EGFR tyrosine kinase inhibitors (TKIs) in advanced non–small cell lung cancer (NSCLC), EGFR exon 20 insertion mutations are associated with insensitivity to TKIs. This study evaluated the mechanism of this primary resistance by investigating a range of exon 20 insertion mutations in vitro for TKI sensitivity and comparing it with patients’ responses to gefitinib and erlotinib. The findings showed that most of these exon 20 mutations were resistant to EGFR TKIs. Analysis of the crystal structure demonstrated that the TKI-insensitive mutant (D770_N771insNPG) adopts a structure of adenosine triphosphate–binding pocket and the helix, which helps the active kinase conformation, and activates EGFR by not enhancing its affinity for EGFR TKIs. Interestingly, a novel mutation EGFR-A763_Y764insFQEA uncovered in this study was shown to be highly sensitive to EGFR TKIs in vitro. Its presence in NSCLC patients was associated with response to erlotinib. Further evaluation of this mutant revealed an altered structure in area affected by the TKI-sensitive EGFR-L858R. The results of this study demonstrated complex and detailed interplay between EGFR mutations and their response to EGFR TKIs. It also guides the treatment of NSCLC harboring EGFR exon 20 insertion mutations.

Yasuda H, Park E, Yun C-H, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sc Translat Med 2013;5:216ra177.

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Balancing Curability and Unnecessary Surgery in the Context of Computed Tomography Screening for Lung Cancer

This report revealed the findings on surgical management in computed tomography (CT) screening for lung cancers from a large ongoing screening program, International Early Lung Cancer Action Program for the U.S. sites. Of 31,646 baseline and 37,861 annual repeat CT screenings, 492 patients who underwent surgical resection were identified. Of the 89% diagnosed with lung cancer and underwent surgery, 91% had clinical stage I disease. Fifty-four patients with nonmalignant disease had sublobar (48) and lobectomy (6) resection. All 428 lung cancer patients (excluding 9 with typical carcinoids) demonstrated an estimated cure rate of 84% according to the 15-year Kaplan–Meier survival, and 88% for clinical stage I tumor resected within 1 month of diagnosis. When comparing the results before and after the National Lung Screening Trial, there was a significant increase in video-assisted thoracoscopic surgery (from 10% to 34%, p < 0.0001) and sublobar resection (from 22% to 34%, p = 0.01). However, no significant differences were observed in malignant diagnoses, clinical stage I, pathologic stage, tumor size, and cell type. The authors concluded that in CT screening, the frequency and extent of surgery for nonmalignant disease could be reduced and give lung cancer patients undergoing surgery resection a high cure rate.

Flores R, Bauer T, Aye R, et al. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer. J Thorac Cardiovasc Surg, doi:10.1016/j.jtcvs.2013.11.001 (2013).

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Prediction of Survival in Resected Non–Small-Cell Lung Cancer Using a Protein Expression Based Risk Model: Implications for Personalized Chemoprevention and Therapy

The authors developed a novel risk model in predicting recurrence of disease in patients with resected non–small-cell lung cancer by incorporating clinical data and biomarkers from archival tissues (2002–2005). Immunohistochemistry was used to examine expression of 21 proteins relevant to lung carcinogenesis determined in previous studies. The effects of clinical factors and biomarkers on recurrence-free survival (RFS) and overall survival (OS) were estimated by Cox models. After a median follow-up of 5.3 years of 370 patients, median OS is 6.4 years with 209 recurrences or death. The findings revealed enhanced expression of pAMPK, pmTOR, EpCAM, and CASK to be significant predictors for favorable RFS (p<0.05) whereas insulin receptor, CXCR2, and IGF1R were predictors for unfavorable RFS. Also, pAMPK, pmTOR, and EpCAM predicted for favorable OS (p<0.05) whereas CXCR2 and FEN1 for unfavorable OS. The development of this risk model for tumor recurrence and survival in patients with resected NSCLC could help improve personalization of chemoprevention and therapy, for instance, identifying patients with poor prognosis for novel treatments in clinical trials and sparing those with good prognosis from chemotherapy toxicities.

Gold KA, Kim ES, Liu D, et al. Prediction of survival in resected non-small cell lung cancer using a protein-expression based risk model: Implications for personalized chemoprevention and therapy. Clin Canc Res doi:10.1158/1078-0432.CCR-13–1959 (2013).

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Tecemotide (L-BLP25) versus Placebo after Chemoradiotherapy for Stage III Non–Small-Cell Lung Cancer (START): A Randomized, Double-Blind, Phase 3 Trial

A randomized, double-blind phase III (START) was conducted to evaluate tecemotide (MUC1-specific immunotherapy) in improving survival of patients with stage III unresectable non–small-cell lung cancer as a maintenance therapy after chemoradiation. Patients were randomized to tecemotide (829) and placebo (410). The findings showed no significant difference in overall survival between the tecemotide arm and the placebo arm in all patients: 25.6 months tecemotide versus 22.3 months placebo (adjusted hazard ratio [HR] 0.88; p = 0.123). Median overall survival for patients receiving prior concurrent chemoradiotherapy was 30.8 months tecemotide versus 20.6 months placebo (adjusted HR 0·78; p = 0·016), whereas that for patients receiving sequential chemoradiotherapy was 19.4 months tecemotide versus 24.6 months placebo (adjusted HR 1·12; p = 0·38). Grade 3 or 4 and serious adverse events were found in both groups, including dyspnoea, pneumonia and metastasis to central nervous system. No difference was found in immune-related adverse events between the two groups. Although tecemotide administration after chemoradiotherapy did not improve survival in the study population, the authors suggest potential benefits in patients previously receiving concurrent chemoradiotherapy, which warrants further investigation in this population.

Butts C, Socinski MA, Mitchell PL, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 2013;15:59–68.

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NEWS IN BRIEF

AACR-IASLC Joint Conference on the Molecular Origins of Lung Cancer: E-Cigarettes May Lead to Lung Cancer in High-Risk Individuals
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E-cigarettes have been known as a relatively safe alternative to tobacco cigarettes but studies on their effect on lung function and lung carcinogenesis are scarce. A preclinical study investigated human bronchial epithelial cell harboring mutant TP53 and KRAS genes and demonstrated that e-cigarette vapor promoted carcinogenicity of the cells, similar to tobacco smoke. The findings were presented at the AACR-IASLC Joint Conference on the Molecular Origins of Lung Cancer in San Diego. However, cancerous behaviors did not develop in immortalized human bronchial epithelial cells with normal TP53 and KRAS genes exposed to high-nicotine level from e-cigarette vapor, which was toxic to the cells. The preliminary results suggest that e-cigarette vapor is likely to cause lung cancer in former or current smokers who are at high risk for lung cancer because of the presence of mutations. Further studies include analysis of e-cigarettes induced genetic profiles versus those related to lung carcinogenicity to dissect the role of e-cigarette in malignant transformation of lung. The findings should serve as guidance to the Food and Drug Administration on the physiological effects of e-cigarettes.

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AACR-IASLC Joint Conference on the Molecular Origins of Lung Cancer: Improved Outcomes in Advanced Lung Cancer Patients with Imprime PGG Plus Chemotherapy
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Imprime PGG is an immunotherapy that directs the immune system to kill monoclonal antibody targeted cancer cells. High number of antibodies present to bind Imprime PGG to the immune cells leads to the activation of high number of these cells to recognize and kill cancer cells. These antibodies in the serum were quantified and the levels were used to categorize patients as biomarker positive or negative. A phase II study randomized 90 patients with stage IIIB or IV non–small-cell lung cancer to control + cetuximab (n1 = 30), and to Imprime PGG + cetuximab (n = 60). In addition, carboplatin and paclitaxel were given to all patients. In the Imprime PGG arm, 15 were biomarker-positive whereas 31 were biomarker-negative among 46 patients evaluable for endpoints. Median overall survival of the two arms were similar,that is, 11.2 months and 10.2 months, respectively. Within the Imprime PGG arm, biomarker-positive patients showed extended median overall survival of 16.5 months versus 9.1 months in biomarker-negative patients. Furthermore, 17% of these biomarker-positive patients survived for 3 years post-treatment but none of the biomarker-negative patients achieved that. The findings showed that adding Imprime PGG into chemotherapy with carboplatin, paclitaxel, and cetuximab benefited biomarker-positive patients with late-stage non–small-cell lung cancer (improved response rates and overall survival), with a good safety profile (cytotoxics or cetuxima-relevant toxicities: 86% in control arm versus 78% in Imprime PGG arm).

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FDA Grants Dabrafenib Breakthrough Therapy Designation for BRAF-Mutated NSCLC
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Dabrafenib (Tafinlar) has been granted Breakthrough Therapy designation by the Food and Drug Administration for the treatment of patients with metastatic non–small-cell lung cancer harboring BRAF V600E mutation, and have received previous platinum-containing chemotherapy. BRAF V600E mutation is found in approximately 2% of patients with non– small-cell lung cancer. This designation was based on the results from an ongoing phase II trial of dabrafenib in this patient population, which were presented at the 2013 ASCO Annual Meeting.

Copyright © 2014 by the International Association for the Study of Lung Cancer

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