Sébastien Couraud

Lung cancer in never smokers--a review.

An estimated 10-25% of lung cancers worldwide occur in never smokers, i.e. individuals having smoked less than 100 cigarettes in their lifetime. Lung cancer in never smokers (LCINS) is more frequent in women, although large geographic variations are found. Histologically, adenocarcinomas predominate. The mere existence of LCINS suggests that risk factors other than smoking must be present. Exposure to environmental tobacco smoke (particularly in women) and exposure to workplace carcinogens (particularly in men) are the two most important alternative risk factors. However, a history of either is absent in more than a third of LCINS. The large proportion of women in LCINS suggest a hormonal element that may interact with other identified factors such as hereditary risks, a history of respiratory infections or disease, exposure to air pollution, cooking and heating fumes, or exposure to ionising radiation. The study of genomic polymorphisms finds constitutive DNA variations across subjects according to their smoking status, particularly in genes coding for enzymes that participate in the metabolism of certain carcinogens, in those coding for DNA repair enzymes, or in genes associated with tobacco addiction, or inflammatory processes. The type of molecular mutation in p53 or KRAS varies with smoking status. EGFR mutations are more frequent in never smokers, as are EML4-ALK fusions. The mutually exclusive nature of certain mutations is a strong argument in favour of separate genetic paths to cancer for ever smokers and never smokers. In the present paper we review current clinical and molecular aspects of LCINS.

BioCAST/IFCT-1002: epidemiological and molecular features of lung cancer in never-smokers

Lung cancer in never-smokers (LCINS) (fewer than 100 cigarettes in lifetime) is considered as a distinct entity and harbours an original molecular profile. However, the epidemiological and molecular features of LCINS in Europe remain poorly understood. All consecutive newly diagnosed LCINS patients were included in this prospective observational study by 75 participating centres during a 14-month period. Each patient completed a detailed questionnaire about risk factor exposure. Biomarker and pathological analyses were also collected. We report the main descriptive overall results with a focus on sex differences. 384 patients were included: 65 men and 319 women. 66% had been exposed to passive smoking (significantly higher among women). Definite exposure to main occupational carcinogens was significantly higher in men (35% versus 8% in women). A targetable molecular alteration was found in 73% of patients (without any significant sex difference): EGFR in 51%, ALK in 8%, KRAS in 6%, HER2 in 3%, BRAF in 3%, PI3KCA in less than 1%, and multiple in 2%. We present the largest and most comprehensive LCINS analysis in a European population. Physicians should track occupational exposure in men (35%), and a somatic molecular alteration in both sexes (73%). Occupational exposure and targetable mutation should be tracked in lung cancer of European never-smokers. http://ow.ly/FB2WS

Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations

INTRODUCTION BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations are identified in approximately 2% of non-small cell lung cancer (NSCLC). Because of the rarity of those mutations, associated clinical features and prognostic significance have not been thoroughly described so far. METHODS Here we took advantage of the French National Cancer Institute Program of systematic molecular profiling of metastatic lung cancer, to collect clinical characteristics and analyze the outcome of consecutive patients with NSCLC harboring BRAF mutations at the Lyon University Hospital laboratory between February 2012 and October 2014. Especially, we compared those variables with that of patients with EGFR-, BRAF-, KRAS-, HER2-, PIK3CA- wild-type NSCLCs. RESULTS Among 2690 patients with genotyped NSCLC during the study period, BRAF mutations were identified in 80 (3%) cases, consisting of V600E substitution in 42 (53%) cases; non-V600E mutation were observed in 38 (48%) cases. Concurrent mutations were not observed in case of BRAF V600 mutation, and were identified in 5 patients with BRAF non-V600E mutations, in all cases consisting of KRAS mutations. Non-V600E mutations were more likely to be observed in smokers, as compared V600E mutations. There was no significant difference in age, histologic type, performance status, and stage at diagnosis between cases of V600E and non-V600E mutations. Overall survival did not significantly differ in BRAF wild-type, V600E, and non-V600E patients. CONCLUSION This one of the largest series of patients with BRAF mutant NSCLC. Our clinical data suggest that BRAF mutations define specific subsets of patients with NSCLC; while their oncogenic nature is yet to be established in lung cancer, especially for non-V600E mutations, the value of BRAF mutations to predict the efficacy of targeted agents remains unclear.

No impact of passive smoke on the somatic profile of lung cancers in never-smokers

EGFR and HER2 mutations and ALK rearrangement are known to be related to lung cancer in never-smokers, while KRAS, BRAF and PIK3CA mutations are typically observed among smokers. There is still debate surrounding whether never-smokers exposed to passive smoke exhibit a “smoker-like” somatic profile compared with unexposed never-smokers. Passive smoke exposure was assessed in the French BioCAST/IFCT-1002 never-smoker lung cancer cohort and routine molecular profiles analyses were compiled. Of the 384 patients recruited into BioCAST, 319 were tested for at least one biomarker and provided data relating to passive smoking. Overall, 219 (66%) reported having been exposed to passive smoking. No significant difference was observed between mutation frequency and passive smoke exposure (EGFR mutation: 46% in never exposed versus 41% in ever exposed; KRAS: 7% versus 7%; ALK: 13% versus 11%; HER2: 4% versus 5%; BRAF: 6% versus 5%; PIK3CA: 4% versus 2%). We observed a nonsignificant trend for a negative association between EGFR mutation and cumulative duration of passive smoke exposure. No association was found for other biomarkers. There is no clear association between passive smoke exposure and somatic profile in lifelong, never-smoker lung cancer. Never-smokers with lung cancer exposed to passive smoke do not have a smoker-like somatic mutation profile http://ow.ly/Eheoi

Immunohistochemistry evaluation of biomarker expression in non-small cell lung cancer (Pharmacogenoscan study)

OBJECTIVES Platinum-based chemotherapy regimens are the standard treatment of non-small cell lung cancer (NSCLC). In this study, our objective was to identify tumor tissue protein biomarkers that might predict a benefit from these treatments. MATERIALS AND METHODS The Pharmacogenoscan study prospectively included consecutive chemotherapy-naive NSCLC patients at any stage between 2005 and 2010 at six hospitals in the Rhône-Alpes-Auvergne region of France. Of the 537 patients in the full analysis set, 460 had a complete histological diagnosis. We used the tumor tissue samples for an immunohistochemical evaluation of eight biomarkers: ERCC1, BRCA1, p53, p27kip1, class III β-tubulin (TUBB3), Bax, Fas, and FasL. We looked for associations between these biomarkers and the disease control rate (DCR) after 2/3 cycles of platinum-based chemotherapy, progression-free survival (PFS), and overall survival (OS). RESULTS A tissue sample adequate for testing at least one biomarker was available for 289 patients. We found no significant association between biomarker expression levels and clinical or pathological variables; TUBB3 showed a trend toward higher expression in adenocarcinomas (P=0.005). For none of the biomarkers were significant associations found between expression level and DCR, PFS, or OS. TUBB3-negative and FasL-negative tumors showed associations of borderline significance with higher DCR. CONCLUSION In a large cohort of patients with predominantly advanced or metastatic NSCLC, none of eight tested immunohistochemical biomarkers predicted the chemotherapy response or survival. Our data indicate limited usefulness of protein biomarkers in metastatic NSCLC and a need for further research based on molecular signatures of greater complexity.

Completion Pneumonectomy in Patients with Cancer: Postoperative Survival and Mortality Factors

Objective: To describe postoperative complications and long-term outcomes of completion pneumonectomy and highlight prognostic factors. Method: We retrospectively reviewed the records of 46 patients (38 men, 8 women) who underwent completion pneumonectomy for lung cancer between 1995 and 2009 in one of two thoracic surgery departments. Most were current or former smokers (n = 41; 89%) and did not undergo chemotherapy (n = 38; 83%) or radiotherapy (83%) before surgery. Results: Complications after surgery were respiratory failure (n = 11; 24.4%), bronchopleural fistula (n = 6; 13%, with no side preference), and empyema (n = 6; 13%). Blood transfusion was necessary for 43% of the cases (n = 20). The day 90 death rate was 15.2% (n = 7). Postoperative staging showed mostly limited disease. Ten patients (21.7%) underwent operation for a second primary cancer, 25 for local recurrence (54.3%), five for microscopically incomplete resection, and six for other reasons. Median overall survival after completion surgery was 30 months (median follow-up: 46.5 months). Among the 15 living patients (33%), 11 are free of disease (24%). In a Cox regression model, factors negatively influencing overall survival were: age older than 65 years (odds ratio [OR] = 2.47; p = 0.012), current smoker status (OR = 2.285; p = 0.033), postoperative pulmonary (OR = 5.144; p = 0.004), cardiac (OR = 3.404; p = 0.033), or parietal wound complications (OR = 5.439; p = 0.016). Conclusion: Despite its increased postoperative complications and mortality compared with standard pneumonectomy, completion pneumonectomy offers encouraging long-term results. Five main factors seem predictive of shorter overall survival.

Somatic alterations in lung cancer: Do environmental factors matter?

Lung cancer is the leading cause of cancer-related death worldwide and smoking tobacco is now definitively established as the dominant risk factor for the malignancy. However, lung cancer can and does occur in never smokers, thus illustrating the existence of other risk factors. Many of these latter are environmental, such as workplace and home carcinogens, air pollution, radon and certain infectious agents. One of the most remarkable advances in thoracic oncology is the recent identification of somatic oncogenic molecular abnormalities, some of which are candidates for targeted therapies. Active smoking is now known to cause a particular somatic profile distinct from that found in never-smokers. This has logically led researchers to consider the possibility that exposure to other lung cancer risk factors may also engender a unique somatic profile. Thus, with the present work, we sought to review current knowledge on somatic profiles in the setting of bronchial cancer (for targetable mutations such as EGFR, ALK, BRAF and HER2, as well as some non-targetable mutations such as TP53, and KRAS) and their associations with environmental risk factors for the malignancy.

Inequalities in lung cancer: a world of EGFR

Epidermal growth factor receptor gene (EGFR) mutation status has emerged as a crucial issue in lung cancer management. Availability and cost of tests and tyrosine kinase inhibitors (TKIs) may vary as a function of country development. We conducted a prospective specialist opinion survey to map EGFR test and EGFR-TKI availability and detect associations with the Human Development Index (HDI). A questionnaire was sent to specialists in thoracic oncology in all United Nations Member States. We obtained responses from 74 countries, comprising 78% of the worldwide population. Nonresponding countries had significantly lower HDI rank than responding countries. EGFR mutation analysis was routinely available in 57 countries (70% of the worldwide population). The cost of the test was <US

Active prospective surveillance study with post-discharge surveillance of surgical site infections in Cambodia

500 in 49 countries (42.5% of the worldwide population). Test availability and cost were both significantly linked to HDI. Erlotinib, gefitinib, afatinib and icotinib were routinely available in 75%, 66%, 31% and 23% of the worldwide population, respectively, also associated with HDI. EGFR mutation testing and EGFR-TKIs are widely accessible in routine practice worldwide. However, there are large discrepancies in access to this innovative treatment path and in its cost for patients as a function of country development. Availability and cost of EGFR tests and TKI drugs are tightly associated with a countrys Human Development Index http://ow.ly/Y79G8

Physicians' Knowledge and Practice of Lung Cancer Screening: A Cross-Sectional Survey Comparing General Practitioners, Thoracic Oncologists, and Pulmonologists in France

Barriers to the implementation of the Centers for Disease Control and Prevention (CDC) guidelines for surgical site infection (SSI) surveillance have been described in resource-limited settings. This study aimed to estimate the SSI incidence rate in a Cambodian hospital and to compare different modalities of SSI surveillance. We performed an active prospective study with post-discharge surveillance. During the hospital stay, trained surveyors collected the CDC criteria to identify SSI by direct examination of the surgical site. After discharge, a card was given to each included patient to be presented to all practitioners examining the surgical site. Among 167 patients, direct examination of the surgical site identified a cumulative incidence rate of 14 infections per 100 patients. An independent review of medical charts presented a sensitivity of 16%. The sensitivity of the purulent drainage criterion to detect SSIs was 83%. After hospital discharge, 87% of the patients provided follow-up data, and nine purulent drainages were reported by a practitioner (cumulative incidence rate: 20%). Overall, the incidence rate was dependent on the surveillance modalities. The review of medical charts to identify SSIs during hospitalization was not effective; the use of a follow-up card with phone calls for post-discharge surveillance was effective.