Somatic profile in lung cancers is associated to reproductive factors in never-smokers women: Results from the IFCT-1002 BioCAST study.

BACKGROUND: Lung cancer in women is on the rise, with a higher proportion occurring in lifelong never-smokers. Lung cancer in never-smokers (LCINS) exhibits a high frequency of driver oncogene alterations. In this study, we aimed to investigate whether exposure to reproductive factors in women with LCINS may modulate the molecular pattern. METHODS: All newly diagnosed LCINSs were included in a prospective, observational study (IFCT-1002 BioCAST). Each patient responded to a questionnaire including reproductive factors. Biomarker test results were also collected. RESULTS: Two hundred and sixty women were included in this analysis, and 166 alterations were characterized. EGFR mutation frequency proved greater among patients with late menarche (74% in age>14 vs. 40% and 41% for 12-14 and ≤12 years, respectively; P=0.020) and tended to decrease with increasingly late age at menopause. In multivariate analysis, EGFR mutation frequency increased by 23% per increment of 1 year of age at menarche (P=0.048), and by 9% for each year at age at first birth (P=0.035). ALK alteration frequency was greater in women with high parity (50% in≥5 vs. 12% and 7% for 1-4 and nulliparity, respectively; P=0.021). CONCLUSION: In a cohort of women LCINSs, female hormonal factors appear to impact molecular pattern.

[MET exon 14 splicing sites mutations: A new therapeutic opportunity in lung cancer]. / Les mutations des sites d'épissage de l'exon 14 de MET. Une nouvelle opportunité thérapeutique dans le cancer du poumon.

The mutations leading to MET exon 14 skipping represent a new class of molecular alterations described in various cancers. These alterations are observed in 2 to 3 % of cases of non-small cell lung cancer (NSCLC). Several cases of NSCLC carrying such alterations and achieving objective response to MET tyrosine kinase inhibitorshave recently been published. This review summarizes the molecular mechanisms responsible for MET exon 14 skipping as well as the consequences of the loss of this exon on receptor activity. We also describe the clinical characteristics of patients with METΔ14 mutations. Finally, we address the issues related to the detection of these mutations in lung cancer, and the need to anticipate resistance to MET inhibitors.

The future: surgical advances in MEN1 therapeutic approaches and management strategies.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary autosomal dominant disorder associated with numerous neuroendocrine tumors (NETs). Recent advances in the management of MEN1 have led to a decrease in mortality due to excess hormones; however, they have also led to an increase in mortality from malignancy, particularly NETs. The main challenges are to localize these tumors, to select those that need therapy because of the risk of aggressive behavior and to select the appropriate therapy associated with minimal morbidity. This must be applied to a hereditary disease with a high risk of recurrence. The overall aim of management in MEN1 is to ensure that the patient remains disease- and symptom-free for as long as possible and maintains a good quality of life. Herein, we review the changes that occurred in the last 20 years in the surgical management of MEN1-associated functional and non-functional pancreatico-duodenal NETs and thymic and bronchial NETs.

Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort.

BACKGROUND: HER2 mutations have been identified as oncogenic drivers in lung cancers and are found in 1-2% of lung adenocarcinomas. There is, to date, no standard of care for these patients. We thus aim to study the therapeutic outcomes of patients harboring HER2 mutations and establish the efficacy of various drug regimens. PATIENTS AND METHODS: This retrospective cohort study in European centers assessed patients with advanced non-small-cell lung cancer (NSCLC), a known HER2 exon-20 insertion, treated with chemotherapy and/or HER2-targeted drugs. RESULTS: We identified 101 eligible patients from 38 centers: median age 61 years (range: 30-87), 62.4% women, 60.4% never-smokers. All tumors were adenocarcinomas. Concomitant EGFR mutations, ALK translocations, and ROS translocations were observed in 5, 1, and 1 patients, respectively. The median number of treatment lines was 3 (range: 1-11). The median overall survival was 24 months. Overall response rate (ORR) and the median progression-free survival (PFS) with conventional chemotherapy (excluding targeted therapies) were 43.5% and 6 months in first-line (n = 93), and 10% and 4.3 months in second-line (n = 52) therapies. Sixty-five patients received HER2-targeted therapies: trastuzumab = 57, neratinib = 14, afatinib = 9, lapatinib = 5, T-DM1 = 1. ORR was 50.9% and PFS was 4.8 months with trastuzumab or T-DM1. CONCLUSION: This series shows the chemosensitivity of HER2-driven NSCLC, and the potential interest of HER2-targeted agents. Our results should help to define the best therapeutic strategy for these patients and to orient future clinical trials.

Necrosis- and apoptosis-related Met cleavages have divergent functional consequences.

Upon activation by its ligand hepatocyte growth factor/scatter factor, the receptor tyrosine kinase Met promotes survival, proliferation, and migration of epithelial cells during embryogenesis. Deregulated Met signaling can also promote cancer progression and metastasis. Met belongs to the functional family of dependence receptors whose activity switches from pro-survival to pro-apoptotic during apoptosis upon caspase cleavage. Although apoptosis resistance is a hallmark of cancer cells, some remain sensitive to other cell death processes, including necrosis induced by calcium stress. The role and fate of Met during necrotic cell death are unknown. Following treatment with calcium ionophores, cell lines and primary cells undergo necrosis, and the full-length Met receptor is efficiently degraded. This degradation is achieved by double cleavage of Met in its extracellular domain by a metalloprotease of the A disintegrin and metalloproteinase (ADAM) family and in its intracellular domain by calpains (calcium-dependent proteases). These cleavages separate the Met extracellular region from its kinase domain, thus preventing Met activity and its potential pro-survival activity. Although the intracellular fragment is very similar to the fragment generated by caspases, it displays no pro-apoptotic property, likely because of the presence of the last few amino acids of Met, known to inhibit this pro-apoptotic function. The fragments identified here are observed in lung tumors overexpressing the Met receptor, along with fragments previously identified, suggesting that proteolytic cleavages of Met are involved in its degradation in tumor tissues. Thus, Met is a modulator of necrosis, able to protect cells when activated by its ligand but efficiently degraded by proteolysis when this process is engaged.

[Reflections on the limits of specific treatments in thoracic oncology]. / Réflexions sur la limitation des soins spécifiques en oncologie thoracique.

The modest impact of specific treatments is a major problem in oncology and particularly for metastatic lung cancer patients. Therapeutic progress achieved by some targeted therapies is, in fact, only relevant for a small proportion of patients. The vast majority of people with this condition are rapidly confronted by the limits of specific therapies and management is or becomes entirely palliative. This article addresses therapeutic limitations in the management of metastatic lung cancer, as well as legislative aspects and guidelines for practitioners when discussing these issues with patients, together with a discussion of the psychological consequences for patients.

Phase I dose-escalation study of oral vinflunine in combination with erlotinib in pre-treated and unselected EGFR patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Erlotinib, the epidermal growth factor receptor tyrosine kinase inhibitor, and the intra-venous vinflunine vinca alkaloid microtubule inhibitor have been shown to be effective in the setting of non-small-cell lung cancer (NSCLC) palliative patients with acceptable toxicities. This phase I study was conducted to determine the maximal tolerated dose (MTD) and the safety of an all-oral combination. A potential pharmacokinetic drug-drug interaction was also investigated. PATIENTS AND METHODS: Patients with unresectable stage IIIB or stage IV NSCLC who failed one or two previous chemotherapy regimens were treated with flat doses of oral vinflunine from day 1 to day 5 and from day 8 to day 12 every 3 weeks and erlotinib daily on a continuous basis. The dose levels of vinflunine/erlotinib were 95/100, 115/100, 115/150 and 135/100 mg. RESULTS: Thirty patients were enroled. The recommended dose was 115/150 mg and the MTD 135/100 mg. Dose-limiting toxicities included grade 3 febrile neutropenia (1 patient) and related death (1 patient). Non-haematologic grade 3/4 toxicities included fatigue, condition aggravated, hypokalaemia, tumour pain, acneiform dermatitis, diarrhoea, hyperbilirubinaemia and pulmonary haemorrhage, in one patient each. Of 25 patients evaluable for tumour response, 2 patients had partial response and 20 patients had stable disease. CONCLUSION: The recommended doses for oral vinflunine and erlotinib combination were, respectively, 115 mg/day from day 1 to day 5 and from day 8 to day 12 every 3 weeks and 150 mg/day. There was no mutual impact on pharmacokinetics. The combination was safe but evaluation in phase II is needed to further refine the activity and toxicity that can be expected with prolonged administration of this dose schedule.

[Anti-Hu antibody syndrome: diagnostic and therapeutic difficulties]. / Syndrome des anticorps anti-Hu: difficultés diagnostiques et thérapeutiques.

INTRODUCTION: Anti-Hu antibody syndrome is a paraneoplastic syndrome usually associated with small cell lung carcinoma which induces various symptoms, particularly neurological ones. CASE REPORT: We describe the case of a 49-year old woman with a small cell lung carcinoma who initially experiences a spontaneous regression but then developed neurological symptoms associated with severe autonomic dysfunction manifesting as chronic intestinal pseudo-obstruction and leading finally to hemodynamic failure. CONCLUSION: Anti-Hu antibody syndrome remains a rare entity. Its diagnosis must be considered in the face of neurologic symptoms associated with small cell lung cancer.

[Bevacizumab in thoracic oncology: results and practical aspects]. / Bévacizumab en oncologie thoracique: résultats et aspects pratiques.

Bevacizumab (Avastin(®)) is the first antiangiogenic therapy approved in non-small cell lung cancer (NSCLC). It is also currently the only agent in this family approved in NSCLC. This review focuses on results of clinical trials assessing bevacizumab in thoracic oncology. It also provides to clinicians practical advices for its prescription.

Cost-effectiveness of three strategies for second-line erlotinib initiation in nonsmall-cell lung cancer: the ERMETIC study part 3.

Several clinical and biological parameters are known to influence the efficacy of second-line erlotinib therapy for nonsmall cell lung cancer (NSCLC), but their medico-economic impact has not been evaluated. The objective of this study was to compare the incremental cost-effectiveness ratios of strategies for second-line erlotinib initiation in NSCLC: clinically guided initiation (nonsmoking females with adenocarcinoma received erlotinib; all other patients received docetaxel) and biologically guided selection (patients with epidermal growth factor receptor (EGFR) mutation received erlotinib; patients with wild-type EGFR or unknown status received docetaxel), compared with initiation with no patient selection (strategy reference). A Markov model was constructed. Outcomes (overall and progression-free survival), transition probabilities and direct medical costs (from the French third-party payer's perspective) were prospectively collected for individual patients treated with either erlotinib or docetaxel, from treatment initiation to disease progression. Published data were used to estimate utilities and post-progression costs. Sensitivity analyses were performed. The biologically and clinically guided strategies were both more efficient (incremental quality-adjusted life-yrs equal to 0.080 and 0.081, respectively) and less expensive (cost decrease equal to €5,020 and €5,815, respectively) than the no-selection strategy, and the biologically guided strategy was slightly less expensive than the clinically guided strategy. Sensitivity analyses confirmed the robustness of the results. The cost-effectiveness of second-line NSCLC treatment is improved when patients are selected on either clinical or biological grounds.

[Pleuro-pulmonary metastases from a malignant mesothelioma of the tunica vaginalis]. / Métastases pleuropulmonaires d'un mésothéliome de la vaginale testiculaire.

INTRODUCTION: Mesothelioma is a malignant tumour of the serous membranes that principally affects the pleura. Peritoneal, pericardial and tunica vaginalis mesothelioma are very rare. CASE REPORT: We report the case of a 65-year-old male with malignant mesothelioma of the tunica vaginalis (MTV). He presented with several local recurrences and, five years after the initial surgery, with pulmonary nodules and a pleural effusion. Pleural biopsies confirmed epithelioid mesothelioma. A diagnosis of pleuro-pulmonary metastases from previous malignant MTV was made. CONCLUSIONS: Malignant MTV is a rare and aggressive tumor with frequent local recurrences and, rarely, visceral metastases. This case report emphasizes the difficulties of the differential diagnosis between pleural mesothelioma and pleural metastases from MTV. The lack of any treatment for metastatic malignant MTV is discussed.

[Stereotactic radiotherapy for lung cancer: Non-invasive real-time tumor tracking]. / Radiothérapie stéréotaxique de carcinomes bronchiques primitifs: suivi non invasif de la cible en temps réel.

PURPOSE: Stereotactic radiation therapy using the CyberKnife(®) has been introduced in France in 2006. Two treatment modalities are currently available: the first one (Synchrony(®)) is a real-time fiducial-based target tracking system, while the other (Xsight Lung Tracking [XLT] System(®)) is completely fiducial-free. PATIENTS AND METHODS: Sixty-eight patients were treated for a pulmonary tumor between June 2007 and November 2009. Since august 2008, the XLT System(®) was used for 26 patients. We report the necessary conditions for the XLT System (position, laterality and size of the tumor), the toxicity and outcome of this treatment. RESULTS: Twenty-two patients were analyzed. Median follow-up was 6 months (min=3; max=16). Local control rate was 100%. The main toxicity was grade grade 1 pulmonary alveolitis (27%). No grade 3 or 4 toxicities were reported. CONCLUSION: The high local control rate and low toxicity obtained with the CyberKnife(®) XLT System(®) suggest that such treatment is an alternative for inoperable patients.

Megestrol acetate versus metronomic cyclophosphamide in patients having exhausted all effective therapies under standard care.

BACKGROUND: To evaluate the antitumour activity and safety of metronomic cyclophosphamide vs megestrol acetate in progressive and advanced cancer patients having exhausted all effective therapies under standard care. METHODS: Patients were randomly assigned to receive orally metronomic cyclophosphamide (50 mg b.i.d) or megestrol acetate (160 mg only daily) until intolerance or progression (RECIST 1.0). The primary efficacy end point was a 2-month progression-free rate (PFR(2m)). According to Optimal Simon's design and the following assumptions, namely, P0=5%, P1=20%, alpha=beta=10%, the treatment is considered as effective if atleast 5 out of 44 patients achieved PFR(2m). RESULTS: Between September 2006 and January 2009, 88 patients were enrolled. Two patients experienced grade 3-4 toxicities in each arm (4%). One toxic death occurred in the megestrol acetate arm as a consequence of thrombosis. The metronomic cyclophosphamide arm reached the predefined level of efficacy with a PFR(2m) rate of 9 out of 44 and a PFR(4m) rate of 5 out of 44. The MA arm failed to achieve the level of efficacy with a PFR(2m) of 4 out of 44 and a PFR(4m) of 1 out of 44. The median overall survival was 195 and 144 days in the metronomic cyclophosphamide arm and megestrol acetate arm, respectively. CONCLUSION: Metronomic cyclophosphamide is well tolerated and provides stable disease in such vulnerable and poor-prognosis cancer patients. This regimen warrants further evaluations.

Inter- and intraobserver consistency in assessing eligibility for bevacizumab (BVZ) in non-small-cell lung cancer (NSCLC) patients with centrally located tumors.

BACKGROUND: Bevacizumab (BVZ) combined with platinum-based therapy is registered for first-line treatment of nonsquamous non-small-cell lung cancer (NSCLC). Patients with centrally located tumors are stated ineligible for BVZ treatment. The goal of this study was to assess the consistency in evaluating eligibility of patients with central tumors for BVZ treatment. MATERIALS AND METHODS: The study group was composed of 150 NSCLC patients with centrally located tumors. Eligibility for BVZ was assessed by chest computed tomography (CT) scan. Eligibility was assessed independently using CT images reviewed on workstations. Inter- and intraobserver variations on 50 randomly extracted patients were estimated through a statistical modeling (multiple correspondence analysis). RESULTS: Discordance in eligibility was found for 82 patients (55%). The interobserver strength of agreement was fair to moderate (average kappa = 0.40). Contrarily, the intraobserver strength of agreement was good to very good (average kappa = 0.74). At multivariate analysis, the risk of discrepancy was essentially related to the assessment of the contact between the tumor and the vessels (odds ratio = 13.3, 95% confidence interval 2.8-62.6, P = 0.001). CONCLUSIONS: The consistency in evaluating eligibility of patients with central tumors for BVZ treatment is weak. The study group indicated more stringent criteria to help physicians in taking the best treatment choice that need however to be prospectively validated.

[Information on head, neck and lung cancers]. / Cancers des voies aérodigestives supérieures et thoraciques: une vision intégrée.

Notable advances have been achieved in head and neck cancer and in lung cancer as regards oncogenesis knowledge and treatment optimization. Multimodal management including molecular targeted therapies have provided a clear benefit in some circumstances. This review provides information on these two primary sites. Some issues are specific (non-tobacco-related carcinogenesis, antiangogenic agents) while some others are shared by both primary sites (oncogenesis, EGFR pathway targeting). Molecular targeted therapies have shifted some treatment algorithms in head and neck cancer (monoclonal antibodies targeting EGFR and radiotherapy in advanced diseases) and in lung cancer as well (1st line anti VEGFR antibodies, EGFR pathway tyrosin-kinase inhibitors as 2nd line treatment for metastatic diseases). Many new prospects are under evaluation (anti-EGFR antibodies, mTOR inhibitors, multi-targets agents, anti-IGFR1 antibodies). Molecular targeted therapies have also generated new protocols for disease evaluation, imaging and bio-clinical monitoring in order to better select patients and improve the outcome.

[Efficacy and tolerance of bevacizumab in non-small cell lung cancer: preliminary report]. / Efficacité et tolérance du bévacizumab dans le traitement du cancer bronchique: expérience préliminaire.

INTRODUCTION: Bevacizumab is an antiangiogenic drug targeting VEGF. Its interest, in combination with chemotherapy, has been demonstrated in two recent trials in metastatic non-small cell lung cancer and its approval is awaited within few weeks. Due its original mechanism of action, bevacizumab has a very specific safety profile and radiological response patterns. METHOD: Based upon selected observations reported from patients included in clinical trials and on recent literature, we bring some clue for a better and safer use of bevacizumab. RESULTS: We report toxicity associated with bevacizumab, especially vascular side-effects and unusual radiological responses. CONCLUSION: Bevacizumab use in NSCLC is associated with some unexpected side effects and responses that worth to be known by pulmonologists. Selections criteria should be rigorously followed.

[Management of non-small cell lung carcinoma following docetaxel-cisplatin. Results of an epidemiologic survey]. / Prise en charge des cancers bronchiques non à petites cellules après docétaxel-cisplatine. Résultats d'une étude observationnelle.

BACKGROUND: The purpose of this epidemiologic survey was to describe the management of second-line therapy for patients with stage IIIB-IV non-small cell lung carcinoma (NSCLC) following docetaxel-cisplatin as first-line therapy. METHODS: Between June 2003 and December 2004, 265 patients were enrolled. The data registered were the choice of cytotoxics, the safety profile, the efficacy and the clinical benefit. RESULTS: Two hundred and sixty one patients were treated with docetaxel-cisplatin as a first-line regimen and 181 received a second line. This second line was a single agent regimen in 58% of cases and a gemcitabine based treatment in 60.8%. The main criterion for the choice of second-line therapy was the safety profile in 34.3% of cases. The overall response rate was 16.6% after the second line and clinical benefit was reported in 43.6% of patients. CONCLUSION: In more than 2/3 of patients with NSCLC the docetaxel-cisplatin combination leaves the opportunity to give a second-line treatment, providing satisfying results in terms of clinical benefit. In this study gemcitabine was the most widely prescribed second-line treatment, mainly as a single agent.