Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients.

International audienceBackground: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p<0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p<0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit

Recherche de nouveaux chélateurs du manganèse en vue de la détoxication de l'organisme : Études in vivo et in vitro chez le rat

This study dealt with new manganese chelating agents. The first part is devoted to the development of a subchronic intoxication protocol. Rats were intoxicated by intraperitoneal injections, the oral route being not sufficiently effective since less than 2%of the ingested manganese are absorbed. This result suggests that the risks of intoxication by diet are very weak even null. Accumulation of manganese was observed in well-known target issues (spleen, central nervous system, bones, erythrocytes), but also in bone marrow. In our experimental conditions, the presence of manganese in the brain induced no neurochemical or histological modifications. The second part of this work concerns the in vivo study of new chelating agents selected beforehand for their in vitro effectiveness to complex with manganese. The most effective compounds in vitro (polyaminopolycarboxylic acids) caused only a partial detoxification of the organism; they remained without effect on manganese bound to the erythrocytes (haemoglobin). This results led us to the following assumptions : manganese (Mn2+), which chemical properties are close to those of iron (Fe2+), would take the place of this last not only in haemoglobin, that is already known, but also in the cytochromes of the respiratory chain. So, based on the standard redox potentials of the cytochromes containing manganese, it was possible to show the inability of these structures to reduce oxygen. This incomplete oxygen reduction would lead to the formation of free radicals which are capable of accelerating cells aging and oxidizing dopamine in benzoquinones, implied in the neurological symptoms observed in chronic manganismCette étude a porté sur la recherche de nouveaux chélateurs du manganèse. La première partie est consacrée à la mise au point d'un protocole d'intoxication subchronique. La voie intraperitoneale a été retenue pour intoxiquer les rats, la voie orale n'étant pas suffisamment efficace, puisque moins de 2% du manganèse ingéré est absorbé. Ce résultat permet d'en déduire que les risques d'intoxication alimentaire sont très faibles voire nuls. Une accumulation de manganèse a été mise en évidence dans des tissus ciblés déjà connus (rate, système nerveux central, os, globules rouges), mais également dans la moelle osseuse. Dans nos conditions d'intoxication, l'accumulation de manganèse dans le cerveau n'a pas entraîné des modifications neurochimiques et histologiques. La deuxième partie de ce travail porte sur l'étude in vivo de nouveaux chélateurs préalablement sélectionnés, pour leur bon pouvoir complexant vis-à-vis du manganèse, par une étude technique in vitro. Les composés les plus efficaces in vitro (acides polyaminopolycarboxyliques) n'ont provoqué qu'une détoxification partielle de l'organisme; ils sont restés sans effet sur le manganèse fixé dans les globules rouges (hémoglobine). Ces résultats nous ont conduit aux hypothèses suivantes : le manganèse (Mn2+), aux propriétés chimiques voisines de celles du fer (Fe2+), se fixerait à la place de ce dernier non seulement dans l'hémoglobine, ce qui est déjà connu, mais également dans les cytochromes de la chaîne respiratoire. Ce ce fait, en se basant sur les potentiels redox standard des cytochromes contenant du manganèse, il a été possible de montrer l'incapacité de ces structures à réduire l'oxygène. Cette réduction incomplète de l'oxygène conduirait à la formation de radicaux libres qui sont susceptibles d'altérer les cellules et d'oxyder la dopamine en benzoquinones, impliquées dans les symptômes neurologiques observés dans les cas de manganism

Recherche de nouveaux chélateurs du manganèse en vue de la détoxication de l'organisme (Études in vivo et in vitro chez le rat)

METZ-SCD (574632105) / SudocSudocFranceF

Environmental boron exposure and activity of delta-aminolevulinic acid dehydratase (ALA-D) in a newborn population.

Following boron intake, multiple effects have been observed in animal experiments. However, human data is lacking, and no data is available on the ability of boron to accumulate in fetal tissues. Positive responses in animal species suggest that developmental toxicity may be an area of concern in humans, following exposure to boron. Two hypotheses have seemed to account for the multiple effects described in scientific findings. One hypothesis is that boron is a negative regulator that influences a number of metabolic pathways by competitively inhibiting some key enzyme reactions. The other hypothesis is that boron has a role in ionic membrane transport regulations. To better understand boron potential toxicity, the present study examined the relationship between boron exposure and some key enzymes, well-known for their affinity for mineral elements, such as delta-aminolevulinic acid dehydratase (ALA-D), and two fundamental enzymes having a role in ionic membrane transport regulations (Ca-pump and Na(+)K(+)-ATPase). We investigated the potential effects of an environmental boron exposure on the activity of these enzymes in an urban population of 197 "normal" newborns. Environmental boron exposure was assessed in placental tissue. Because of the well-known inhibiting effect of lead on these enzymes, cord blood and placental lead were also analyzed. After adjustment for potential confounders, including lead, placental boron levels were negatively significantly correlated to ALA-D activity while Ca-pump and Na(+)K(+)-ATPase activities did not seem to be affected by the level of boron exposure. Given boron's ability, as a Lewis acid, to complex with hydroxyl groups, we suggest that such a mechanism would explain the inhibiting effect of boron on ALA-D

Lorlatinib for advanced ALK and ROS1+non-small cell lung cancer (NSCLC): Efficacy and treatment sequences in the IFCT-1803 LORLATU expanded access program (EAP) cohort.

International audienc

EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR wild-type pre-treated advanced nonsmall cell lung cancer in daily practice

International audienc

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

International audienceEGFR 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

Long-term effectiveness and treatment sequences in patients with extensive stage small cell lung cancer receiving atezolizumab plus chemotherapy: Results of the IFCT-1905 CLINATEZO real-world study

International audienceBackground: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab, based on landmark clinical trials. Methods: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospective study of patients with extensive-SCLC receiving atezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness, safety and subsequent treatments. Results: The population analyzed included 518 patients who received atezolizumab in 65 participating centers. There were 66.2% male, mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all (95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0–48.0]) for a median duration of 4.9 months (95% CI 4.5–5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4–2.3]). Best objective response was complete and partial in 19 (3.9%) and 378 (77.1%) patients. Stable disease was observed in 50 patients (10.2%). Median follow-up was 30.8 months (95% CI: [29.9–31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1–12.4]), 46.7% (95% CI [42.3–50.9]) and 21.2% (95% CI [17.7–24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0–5.4]), 37.5% (95% CI [33.3–41.7]) and 15.2% (95% CI [12.2–18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0–13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1–21.5]). Three-hundred-and-twenty-six patients (66.4%) received subsequent treatment and 27 (5.2%) were still under atezolizumab at date of last news. Conclusions: IFCT-1905 CLINATEZO shows reproductibility, in real-life, of IMpower-133 survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches, including concurrent radiotherapy and treatment beyond progression