Inequity in access to personalized medicine in France: Evidences from analysis of geo variations in the access to molecular profiling among advanced non-small-cell lung cancer patients: Results from the IFCT Biomarkers France Study

In this article, we studied geographic variation in the use of personalized genetic testing for advanced non-small cell lung cancer (NSCLC) and we evaluated the relationship between genetic testing rates and local socioeconomic and ecological variables. We used data on all advanced NSCLC patients who had a genetic test between April 2012 and April 2013 in France in the frame of the IFCT Biomarqueurs-France study (n = 15814). We computed four established measures of geographic variation of the sex-adjusted rates of genetic testing utilization at the “départment” (the French territory is divided into 94 administrative units called ‘départements’) level. We also performed a spatial regression model to determine the relationship between département-level sex-adjusted rates of genetic testing utilization and economic and ecological variables. Our results are the following: (i) Overall, 46.87% lung cancer admission patients obtained genetic testing for NSCLC; département-level utilization rates varied over 3.2-fold. Measures of geographic variation indicated a relatively high degree of geographic variation. (ii) there was a statistically significant relationship between genetic testing rates and per capita supply of general practitioners, radiotherapists and surgeons (negative correlation for the latter); lower genetic testing rates were also associated with higher local poverty rates. French policymakers should pursue effort toward deprived areas to obtain equal access to personalized medicine for advanced NSCLC patients

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

Cancer du poumon : bio-marqueurs épidémiologiques et théranostiques

Médecin

Mutations rares du gène de l'EGFR dans des cancers bronchiques non à petites cellules (étude rétrospective nationale de 2008 à 2011)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Evaluation de la radio-sensibilité des cancers bronchiques non à petites cellules (CBNPC) en fonction des bio-marqueurs de routine (étude retrospective unicentrique de 157 cas)

STRASBOURG-Medecine (674822101) / SudocSudocFranceF

Approche moléculaire des cancers bronchiques

Le cancer bronchique est la première cause de décès par cancer dans le monde. Nous nous sommes intéressés à la caractérisation moléculaire des différents types histologiques de ce cancer ainsi qu'à la détection de l'ADN plasmatique tumoral. Nous avons pu montrer qu'un panel de 7 microsatellites caractérisait 87% d'une population d'adénocarcinomes avec une association préférentielle d'altérations entre les régions 9p21 et 3p24 ou 9q34, et que l'altération de la région 17q23 serait un marqueur de bon pronostic. L'allélotypage de l'ADN plasmatique de 34 patients avec 12 marqueurs a permis de caractériser la présence d'ADN tumoral chez 88% des patients avec une spécificité de 100%. La présence d'altération de l'ADN plasmatique au niveau du chromosome 9 serait de moins bon pronostic. Des panels restreints de microsatellites seraient informatifs d'un type histologique. La détection de l'altération simultanée de l'un ou l'autre allèle dans des prélèvements appariés résultant d'événements indépendants, révèlerait une hétérogénéité clonale des tumeurs bronchiques. Nous avons vérifié que cette hypothèse pourrait être plus générale en étudiant une population de carcinomes colo-rectaux avec un panel de 33 microsatellites. Ces altérations alternatives s'observent sur de nombreux chromosomes, et pourraient identifier de nouvelles régions oncogéniques. Afin de mieux préciser l'origine des sous-types histologiques, nous avons caractérisé des carcinomes épidermoides et des adénocarcinomes par l'étude de loci contenant certains des gènes de la famille des FGFR/FGF et de c-Met/HGF impliqués dans la morphogénèse broncho-pulmonaire. Nous avons identifié des groupes d'altérations différents entre ces deux sous-types, impliquant notamment le locus 15q13-22 contenant FGF7. L'ensemble de ce travail nous a permis d'approfondir les bases moléculaires de la cancérogenèse bronchique et de proposer un test sensible de détection de cellules tumorales bronchiques applicable au suivi des patientsLung cancer is the leading cause of cancer death in the world. We chosen to realize the molecular characterization of different histological types of lung cancer and the detection of tumor plasma DNA. In a first part, we showed by allelotyping that a panel of 7 markers could characterize 87% of adenocarcinomas, revealing that alteration at 17q23 locus should be a good prognosis marker, and showed significant associations between alteration at locus 9p21 and 3p24 or 9q34. Allelotyping of plasma DNA with an enlarged panel of 12 microsatellites in a cohort of 34 lung cancer patients, could characterize 88% of the patients with a specificity of 100%. Shorter panel of markers could be informative for histological type. Furthermore, plasma DNA alteration of chromosome 9 appeared to be correlated with a poorer survival. Simultaneous alteration of one or the other allele in paired samples resulting from independent events, suggested a clonal tumor heterogeneity. We verified this hypothesis in a cohort of colorectal cancer with paired liver metastasis using a panel of 33 markers. Such alternative alterations could be seen at most of the chromosomes, regions of which could contain oncogenes. Furthermore, we have characterized squamous and adenocarcinoma by studying of loci containing some of genes belonging to FGFR/FGF and c-Met/HGF families involved in lung morphogenesis. Different patterns of alterations appeared between these two groups, particularly including 15q13-22 locus containing FGF7. Then, our study underlines new patterns of molecular alterations in lung carcinogenesis by histological sub-type, and allows us to propose a sensitive test for the detection of lung tumor cells, which could be useful for the follow-up of lung cancer patients.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Régression Bêta PLS

International audienceMany responses, for instance experimental results, yields or economic indices, can be naturally expressed asrates or proportions whose values must lie between zero and one or between any two given values. The Beta regressionoften allows to model these data accurately since the shapes of the densities of Beta laws are very versatile. Yet, asany of the usual regression model, it cannot be applied safely in case of multicollinearity and not at all when themodel matrix is rectangular. These situations are frequently found from chemistry to medicine through economicsor marketing. To circumvent this difficulty, we derived an extension of PLS regression to Beta regression models. It,as well as several other tools, such as cross validation or bootstrap techniques, is available for the R language in theplsRbeta package.De nombreuses variables d'intérêt, comme par exemple des résultats expérimentaux, des rendements ou des indicateurs économiques, s'expriment naturellement sous la forme de taux, de proportions ou d'indices dont les valeurs sont nécessairement comprises entre zéro et un ou plus généralement deux valeurs fixes connues à l'avance. La régression Bêta permet de modéliser ces données avec beaucoup de souplesse puisque les fonctions de densité des lois Bêta peuvent prendre des formes très variées. Toutefois, comme tous les modèles de régression usuels, elle ne peut s'appliquer directement lorsque les prédicteurs présentent des problèmes de multicolinéarité ou pire lorsqu'ils sont plus nombreux que les observations. Ces situations se rencontrent fréquemment de la chimie à la médecine en passant par l'économie ou le marketing. Pour circonvenir cette difficulté, nous formulons une extension de la régression PLS pour les modèles de régression Bêta. Celle-ci, ainsi que plusieurs outils comme la validation croisée et des techniques bootstrap, est disponible pour le langage R dans la bibliothèque plsRbeta

Prognostic and Predictive Biomarkers in the Era of Immunotherapy for Lung Cancer

The therapeutic algorithm of lung cancer has recently been revolutionized by the emergence of immune checkpoint inhibitors. However, an objective and durable response rate remains low with those recent therapies and some patients even experience severe adverse events. Prognostic and predictive biomarkers are therefore needed in order to select patients who will respond. Nowadays, the only validated biomarker is the PD-L1 expression, but its predictive value remains imperfect, and it does not offer any certainty of a sustained response to treatment. With recent progresses in molecular biology, genome sequencing techniques, and the understanding of the immune microenvironment of the tumor and its host, new molecular features have been highlighted. There are evidence in favor of the positive predictive value of the tumor mutational burden, as an example. From the expression of molecular interactions within tumor cells to biomarkers circulating in peripheral blood, many markers have been identified as associated with the response to immunotherapy. In this review, we would like to summarize the latest knowledge about predictive and prognostic biomarkers of immune checkpoint inhibitors efficacy in order to go further in the field of precision immuno-oncology

Direct Targeting <i>KRAS</i> Mutation in Non-Small Cell Lung Cancer: Focus on Resistance

KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to inactive form (GDP-bound). The KRAS mutations favor the active form with inhibition of GTPAse activity. KRAS mutations are often with poor response of EGFR targeted therapies. KRAS mutations are good predictive factor for immunotherapy. The lack of success with direct targeting of KRAS proteins, downstream inhibition of KRAS effector pathways, and other strategies contributed to a focus on developing mutation-specific KRAS inhibitors. KRAS p.G12C mutation is one of the most frequent KRAS mutation in NSCLC, especially in current and former smokers (over 40%), which occurs among approximately 12–14% of NSCLC tumors. The mutated cysteine resides next to a pocket (P2) of the switch II region, and P2 is present only in the inactive GDP-bound KRAS. Small molecules such as sotorasib are now the first targeted drugs for KRAS G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or adaptative mechanisms in either downstream pathways or in newly expressed KRAS G12C mutation