IN THIS ISSUE
Relationship between EGFR Expression, EGFR Mutation Status, and the Efficacy of Chemotherapy Plus Cetuximab in FLEX Study Patients with Advanced Non–Small-Cell Lung Cancer
Survival benefits of combining cetuximab to chemotherapy were reported in the phase III FLEX trial in patients with advanced non–small-cell lung cancer expressing increased levels of EGFR (immunohistochemistry score of ≥200; scale 0–300). The current analysis was aimed to investigate the effect of tumor EGFR mutation status on the activity of cetuximab–chemotherapy combination observed in the FLEX study population. Efficacy end points such as overall survival time, progression-free survival (PFS) time, objective response, and time-to-treatment failure (TTF) were included. Of the 971 FLEX study patients screened for tumor mutations, EGFR mutations (exons, 18–21) were found in 14% of them. Tumors with EGFR mutations showed improved median survival and response rate versus EGFR wild-type tumors in both chemotherapy plus cetuximab (17.3 versus 9.6 months; 54.5% versus 32.9%) and chemotherapy alone (19.8 versus 9.6 months; 35.8% versus 27.0%). Findings from patients with EGFR wild-type tumors revealed that a survival benefit from the cetuximab–chemotherapy combination was observed in the high EGFR expression group (immunohistochemistry score of ≥200; hazard ratio [HR] 0.79) versus no benefit in the low EGFR expression group (HR, 0.98). PFS and TTF were similar across treatment and EGFR expression groups, whereas higher response rate was found in high expression group in these patients receiving cetuximab–chemotherapy combination versus chemotherapy alone (39.5% versus 27.4%). Findings from relatively small number of patients with EGFR mutations showed that a survival benefit may have derived from cetuximab–chemotherapy combination in the high EGFR expression group. Median survival of this group versus chemotherapy alone was 21.9 versus 19.5 months (HR, 0.74), whereas the same comparison for the low EGFR expression group was 12.3 versus 23.8 months (HR, 1.82). In patients with EGFR mutations, improved PFS, TTF, and response rates were observed across EGFR expression groups receiving cetuximab–chemotherapy combination versus chemotherapy alone. Taken together, EGFR mutation status did not affect the survival advantage of combining cetuximab in first-line chemotherapy for patients with advanced non– small-cell lung cancer expressing high levels of EGFR. High EGFR expression is a potential biomarker in predicting the clinical outcome of this combination treatment in the study population. (p. 717)
Molecular Mechanisms Underlying Oncogenic RET Fusion in Lung Adenocarcinoma
This study analyzed the mechanism of oncogenic RET fusion, which was recognized as a driver mutation for the development of lung adenocarcinoma (LADC). Genomic polymerase chain reaction and a next-generation sequencer were used to analyze genomic segments with breakpoint junctions for RET fusions and to determine the mechanisms for DNA strand breaks and illegitimate joining of DNA ends. Eighteen RET breakpoints were evaluated, of which, 16 were discovered from the 671 LADC cases screened. The finding of the location of 17 of the 18 RET breakpoints in a 2.0-kb region between exon 11 and intron 11 with no breakpoint within four base pair of each other implied that RET fusion could be induced by the generation of DNA strand breaks at nonspecific sites in this region. Simple reciprocal inversion and DNA repair mechanisms (nonhomologous end joining and break-induced replication) that involves illegitimate joining of DNA ends were found to have contributed to 10 of 18 RET fusions in LADC. The results demonstrated multiple mechanisms driving oncogenic RET fusions in LADC, which involves illegitimate repair of DNA strand breaks via different mechanisms to those in papillary thyroid carcinoma. (p. 622)
Outcomes of Unresected Ground-Glass Nodules with Cytology Suspicious for Adenocarcinoma
Gulati et al. conducted a study to compare the clinical outcomes of patients who were resected immediately after abnormal cytology results suspicious for early lung adenocarcinoma and those who selected watchful waiting. Sixty-three patients without prior history of lung adenocarcinoma, who had computer tomography–guided fine-needle aspiration of ground-glass lesions suspicious for early adenocarcinoma, were identified for the study. Of the 16 patients opted to observe their ground-glass lesions with suspicious cytology results, 37.5% eventually had growth or increase in solid component of the ground-glass lesion. Of these, five patients underwent surgical resection or radiation therapy. No distant metastasis or lung cancer–associated deaths were found in the observed group. In 47 patients opted for immediate resection after abnormal cytology results, metastasis (n = 2), new cancers in remaining lung (n = 5), and existing ground-glass lesion progression (n = 3) were observed. This study indicates that watchful waiting after ground-glass lesion biopsy did not show higher metastatic rates or cancer-related deaths and suggests that delayed resection does not deteriorate the outcomes. (p. 685)
ITMIG Consensus Statement on the Use of the WHO Histological Classification of Thymoma and Thymic Carcinoma: Refined Definitions, Histological Criteria and Reporting
The World Health Organization (WHO) classification (2004) assigns thymic epithelial tumors into A, AB, B1, B2, and B3 and (rare other) thymomas and thymic carcinomas (TC) based on fundamental morphological differences. Nevertheless, poor interobserver reproducibility or inconsistencies in some studies prompted the organization of an interdisciplinary panel by the International Thymic Malignancy Interest Group to refine histological criteria while maintaining the WHO classification for better management of morphological overlap between some thymoma subtypes and TC. A team of 18 pathologists, two surgeons, and an oncologist reviewed 72 hematoxylin and eosin–stained and immunohistochemically processed sections of prototypic and difficult-to-classify thymic epithelial tumors (“borderland” and “combined” thymomas and TC) at an international consensus slide workshop. Consensus was achieved on refined criteria for A/AB “borderland,” distinguishing B1, B2, and B3 thymomas, and separation of B3 thymomas from TCs. A new type A thymoma variant, namely “atypical type A thymoma,” has emerged tentatively. New reporting strategies for tumors with more than one histological pattern are recommended. Although the proposed new criteria and guidelines need to be tested and validated in further studies, they set the stage for reproducibility and improvement of the prognostic and predictive values of the WHO classification. (p. 596)
The Potential Effects of Tobacco Control in China: Projections from the China SimSmoke Simulation Model
The authors sought to project the potential impact of complete implementation of tobacco control in China as recommended by the World Health Organization Framework Convention on Tobacco Control via computer simulation model. In a study population of men and women aged 15 to 74 years, current and former smoking prevalence, initiation and cessation rates, and past policy levels were included to predict past smoking rates and project future status quo rates. The model projected future smoking prevalence to decrease from 51.3% (men) or 2.1% (women) in 2015 to 46.5% (men) or 1.3% (women) by 2050. The most efficient tobacco control policy was by raising the tobacco excise tax to 75% of the retails price, resulting in incremental decline by 12.9% in current smoking versus the status quo by 2050. Approximately 40% of incremental decline in smoking versus the status quo, the prevention of approximately 12.8 million smoking attributable deaths, and the loss of 154 million life years by 2050 were projected through complete implementation of all Framework Convention on Tobacco Control policies in China.
Levy D, Rodriguez-Buno RL, Hu TW, Moran AE. The potential effects of tobacco control in China: projections from the China SimSmoke simulation model. BMJ 2014;348:g1134.
Tobacco Control Policies and Their Impacts. Past, Present, and Future
This abstract is drawn from the February 2014 issue of the Annals of the American Thoracic Society and is one of a number of articles in this issue examining the aspects of smoking and tobacco control including e-cigarettes, changing attitudes, and nicotine products. This article is particularly interesting in its review of the impact of tobacco control policies; it reproduces a figure drawn from U.S. Department of Health and Human Science reports, also reproduced in the leading article of this issue, a special article on the Surgeon Generals’ Reports from 1964 to 2014. This figure is reproduced below and is remarkable for the visual presentation of the link between policy introduction and the decline in cigarette smoking. The governmental policies include increasing cigarette price, which effectively encouraged some to quit smoking or cut daily consumption, and discouraged children from smoking initiation. Dramatic impacts from smoke-free workplace policies were also observed: reduced workers’ exposure to cigarette smoke toxins, employers’ costs, and the incidence of acute myocardial infarctions. Future new and radical tobacco control approaches are warranted to ensure continuing success and achieve a smoke-free society.
Noninvasive Detection of Response and Resistance in EGFR-Mutant Lung Cancer Using Quantitative Next-Generation Genotyping of Cell-Free Plasma DNA
This study explored the use of cell-free plasma DNA (cfDNA) genotyping using droplet digital polymerase chain reaction (ddPCR) as a noninvasive assay in identifying biomarkers for accurate diagnosis and monitoring of disease status. ddPCR emulsifies DNA into droplets that are PCR-amplified and fluorescently labeled, followed by reading in an automated droplet flow cytometer to quantify genome prevalence. Plasma was collected from two patient populations: advanced non–small-cell lung cancer (NSCLC) harboring EGFR or KRAS mutation and advanced melanoma with BRAF mutation. Positive and negative controls using cancers with nonoverlapping genotypes were included to evaluate sensitivity and specificity of the assay. Patients with EGFR-mutant NSCLC from a prospective trial of erlotinib were assessed for response and resistance using the assay. The assay identified EGFR L858R and exon 19 deletions in KRAS-mutant lung cancer with high sensitivity and 100% specificity. An area under the curve of 0.80 to 0.94 was achieved in received operative characteristic curve analysis of the assays. Optimal cfDNA concentrations improved the assay sensitivity. In first-line erlotinib treated patients, serial plasma genotyping of EGFR-mutant NSCLC detected pretreatment EGFR mutations, complete plasma response in most cases, and EGFR T790M–mediated acquired resistance up to 16 weeks before radiographic progression. Taken together, noninvasive genotyping of cfDNA via ddPCR has the potential as a clinical diagnostic for personalizing treatment of tumors with defined genotypes, as well as detection of response and resistance.
Oxnard GR, Paweletz CP, Kuang Y, et al. Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res 2014;20:1698–1705, doi:10.1158/1078-0432.ccr-13-2482.
Maintenance Bevacizumab–Pemetrexed after First-Line Cisplatin–Pemetrexed–Bevacizumab for Advanced Nonsquamous Non– Small-Cell Lung Cancer: Updated Survival Analysis of the AVAPERL (MO22089) Randomized Phase III Trial
This report is an independent and updated survival analysis of the AVAPERL randomized phase III trial, in which safety and efficacy of bevacizumab maintenance with or without pemetrexed in advanced nonsquamous non– small-cell lung cancer were evaluated. After first-line treatment with bevacizumab, cisplatin, and pemetrexed, patients with no progressive disease were randomized to bevacizumab or bevacizumab–pemetrexed until progression. The primary end point was progression-free survival. Significantly prolonged progression-free survival, when measured from randomization, was observed in the bevacizumab–pemetrexed arm (n = 128) versus the bevacizumab arm (n = 125) after a median follow-up of 14.8 months (7.4 versus 3.7 months; hazard ratio, 0.57; p < 0.0001). Overall survival (OS) data were available in 58% of all patients, but the increase in OS was not significant with bevacizumab–pemetrexed versus bevacizumab when measured from randomization (17.1 versus 13.2 months; hazard ratio, 0.87; p = 0.29). No report of new adverse events in this updated analysis. The findings demonstrated that maintenance bevacizumab–pemetrexed after the first-line platinum-based therapy in unselected patients with nonsquamous non–small-cell lung cancer with disease control did not achieve a significant improvement in OS versus bevacizumab alone.
Barlesi F, Scherpereel A, Gorbunova V, et al. Maintenance bevacizumab–pemetrexed after first-line cisplatin–pemetrexed–bevacizumab for advanced nonsquamous non–small-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial. Ann Oncol 2014, doi:10.1093/annonc/mdu098.
Tumor Protein Predicts Response to Chemotherapy in Patients with Esophageal Cancer
Bain et al. set out to determine novel predictive biomarkers for chemotherapy response in patients with esophageal adenocarcinoma using gene expression profiling of their tumor biopsies. The discovery cohort consisted of tumor biopsies from 14 patients with tumor, node, metastasis (TNM) stage IB–IV esophageal adenocarcinomas treated with platinum-based chemotherapy. The validation cohort consisted of 154 patients undergone surgery with or without neoadjuvant platinum chemotherapy and 22 gastric adenocarcinoma cell lines. From the analysis of radiological responding and nonresponding patients, gene enrichment of the 520 differentially expressed genes identified the adipocytokine signaling pathway in association with response. Higher leptin expression correlated with chemoresistance in the discovery and validation cohorts (p = 0.011 and p = 0.007, respectively). Similar results were observed in the gastric adenocarcinoma cell lines to cisplatin (p = 0.008), which were further supported by leptin receptor antagonist-mediated enhanced cell line sensitivity to cisplatin. On the other hand, patients with high leptin expression had improved survival regardless of neoadjuvant chemotherapy versus those with low leptin expression. Taken together, tumor leptin expression is a potential predictive marker for chemoresistance and prognostic marker independent of therapy in esophageal adenocarcinoma. Leptin antagonists in clinical use could be potentially explored for novel therapeutic intervention in esophageal adenocarcinoma.
Bain GH, Collie-Duguid E, Murray GI, et al. Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas. Br J Cancer 2014;110:1525–1534, doi:10.1038/bjc.2014.45.
Preoperative Chemotherapy for Non–Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Individual Participant Data
The effect of preoperative chemotherapy for patients with resectable non–small-cell lung cancer was assessed in this systematic review and meta-analysis of individual participant data. Findings from 15 individual randomized controlled trials which involved 2385 patients were combined. Primary outcome was overall survival, that is, the time from randomization until death (any cause) or date of last follow-up for living patients. Secondary outcomes were recurrence-free survival, time to locoregional and distant recurrence, cause-specific survival, complete and overall resection rates, and postoperative mortality. A significant improvement in overall survival (5% at 5 years) from preoperative chemotherapy was observed (hazard ratio [HR] 0·87, p = 0·007), with a 13% decrease in the relative risk of death. It was unclear that this survival benefit could be affected by chemotherapy regimen or schedules, number of drugs, platinum agents used, and postoperative radiotherapy. It was also unclear that the improved survival by preoperative chemotherapy could be associated with specific patients stratified by age, sex, performance status, histology, and clinical stage. Significantly better recurrence-free survival (HR, 0·85, p = 0·002) and time to distant recurrence (HR, 0·69, p < 0·0001) were observed in patients with preoperative chemotherapy, most of which had stage 1B–IIIA. With significantly improved overall survival, recurrence-free survival, and time to distant recurrence in resectable non–small-cell lung cancer, this study suggests that preoperative chemotherapy is a valid option for treating this patient population.
Preoperative chemotherapy for non–small-cell lung cancer: a systematic review and meta-analysis of individual participant data. The Lancet 2014.
NEWS IN BRIEF
Fast-Tracked Approval of Drugs and Tests in Australia
Previously in Australia, it involved two different review processes to list a drug in the Pharmaceutical Benefits Scheme (PBS) and its companion genetic tests in the publication Medicare Benefits Schedule (MBS). The Australian Government subsidizes prescription drugs via the PBS, and lists a variety of subsidized consultations, procedures, and tests in the MBS. A dual-approval process has enabled the listing of two lung cancer drugs, gefitinib and erlotinib, in the PBS and their companion genetic tests in the MBS, in just one review for the first time. This initiative means eligible patients gain quicker access to treatment and the tests at affordable costs. This approach has been welcome by experts, but also warrants further testing for definitive outcomes and close monitoring of the approval process.
Potential Novel Gene Target for Lung Cancer
In a brief report published in the Journal of Clinical Investigation, Imielinski et al. demonstrated the discovery of a new gene mutation that could drive lung cancer growth and development. One patient from the Eastern Cooperative Oncology Group 2501 clinical study with stage IV lung cancer showed a near-complete response to sorafenib within 2 months of treatment and remained progression free for 5 years. A somatic mutation, ARAF S214C, was identified in the cancer genome with increased expression by whole-genome sequencing and RNA sequencing of patient tumor and normal samples. Additional ARAF mutations were found in 1% of an independent cohort of lung adenocarcinoma. A role in transformation of immortalized human airway epithelial cells was demonstrated for the ARAF mutations in a sorafenib-sensitive manner. The findings suggest that mutant ARAF is an oncogenic driver in lung adenocarcinoma and an indicator of sorafenib response.
Patterns Shifted in the Interpretation of Phase III Clinical Trial Outcomes in Advanced Non–Small-Cell Lung Cancer
A study published in Journal of Clinical Oncology analyzed the change in design and interpretation of 203 randomized controlled trials of systemic therapy for advanced non–small-cell lung cancer over the past 30 years. The findings revealed significantly increasing use of progression-free survival as a surrogate for overall survival (13% rise; p = 0.002) as the primary study end point and a decreasing magnitude of survival gain in positive trials (from 3.9 to 2.5 months; p = 0.11) in conjunction with larger clinical trial sample size (median n = 152 to n = 413; p < 0.001). Although the proportion of trials meeting primary end points remained stable, those showing positive outcome with unmet end point increased (from 30% to 53%; p < 0.001). The findings confirm a significant shift in trial design and interpretation of phase III trials in advanced non–small-cell lung cancer over the past 30 years—significant decline in using survival as the primary measure of outcome, and in clinically relevant magnitude of the outcome.
NEW EU LEGISLATION
A new Tobacco Products Directive has been approved by the European Parliament on February 26, 2014 which strengthens the rules on the manufacture, production, and presentation of tobacco products in the EU. A summary press release ( http://europa.eu/rapid/press-release_MEMO-14-134_en.htm) notes that the commission decided to revise previous rules to deal with new scientific evidence, new products (such as e-cigarettes), and varying regulatory approaches by different EU Member States. Most smokers start smoking when very young (particularly younger than 25 years of age); the new rules aim to make tobacco consumption less attractive in the EU for young people. Future cigarette packs will include health warnings (pictures and text); slim “lipstick”-style packs will be banned. Similar rules will apply to roll-your-own tobacco packs although Member States can choose whether such rules apply to “low-use” tobacco products such as pipe tobacco, cigars, cigarillos, and smokeless products. Plain packaging, although not part of the Directive, may emerge to a limited degree at the discretion of Member States. Flavorings (such as menthol) will be banned (for menthol after a 4-year phase-out period). Mandatory and standardized formatting of ingredients is “foreseen” including tar emissions, nicotine, and carbon monoxide for cigarettes. New rules will cover consumer e-cigarettes on the EU market and will include a maximum nicotine concentration, child- and tamper-proof cartridges, tanks and containers of nicotine liquids, health warnings on e-cigarette packs, advance notification of Member States for new products entering the market, annual reports from manufacturers to Member States (on sales volumes, types of users, etc.), and compliance with advertising rules. Oral tobacco will continue to be banned (outside of Sweden which has an exemption). There are tracking and tracing measures to be introduced to address illicit trade. Bans on cross-border distance sales will be at the Member State’s discretion. The new rules are expected to lead to a 2% decrease in tobacco consumption more than 5 years (approximately 2.4 million fewer smokers) with an annual healthcare saving of 506 million euros. The new Directive will take force in May 2014 with a 2-year phase-in period for Member States to bring national legislation into line with the Directive. Further information is available from http://ec.europa.eu;health/tobacco/products/index_en.htm.