D. Moro-Sibilot

High-throughput somatic mutation profiling in pulmonary sarcomatoid carcinomas using the LungCarta™ Panel: exploring therapeutic targets

BACKGROUNDnPulmonary sarcomatoid carcinomas (SC) are tumors characterized by poor prognosis and resistance to conventional platinum-based chemotherapy. This study sought to describe the mutational profile of SC using high-throughput genotyping technology.nnnPATIENTS AND METHODSnWe used mass spectrometry to test 114 surgical biopsies from 81 patients with SC for 214 mutations affecting 26 oncogenes and tumor suppressor genes.nnnRESULTSnIn total, 75 (92.6%) patients were smokers. Within the total 81 tumors, 67 distinct somatic alterations were identified, with 56 tumors (69.1%) harboring at least one mutation. The most frequent mutations were KRAS (27.2%), EGFR (22.2%), TP53 (22.2%), STK11 (7.4%), NOTCH1 (4.9%), NRAS (4.9%), and PI3KCA (4.9%). The EGFR mutations were almost always rare mutations (89%). In 32 tumors (39.5%), two or more mutations co-existed, with up to four mutations in a single case. In six different cases, comparative genetic analysis of different histological areas from the same tumor (giant, spindle, or epithelial component) revealed a 61% concordance rate for all the mutations with a 10% detection threshold, compared with 91.7% with a 20% detection threshold.nnnCONCLUSIONnOur results demonstrated a high mutation rate and frequent co-mutations. Despite SC tumors exhibiting a high histological heterogeneity, some intratumoral molecular homogeneity was found. Now with newly developed targeted therapies, SC patients may be eligible for new target mutations, and can now therefore be screened for clinical trials.

Lung Squamous Cell Carcinomas with Basaloid Histology Represent a Specific Molecular Entity

Purpose: The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient. Experimental Design: To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed). Results: Supervised analyses reveal that pure basaloid tumors display a specific mRNA expression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n = 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjusted HR = 2.45; P = 0.000001). Conclusion: This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies. Clin Cancer Res; 20(22); 5777–86. ©2014 AACR.

Quel traitement pour un patient de PS-2/3 ayant un cancer bronchique non à petites cellules (CBNPC)

Resume Les patients porteurs d’un cancer bronchique non a petites cellules (CBNPC) avance, en mauvais etat general sont souvent peu representes dans les essais cliniques. Ceci entraine une definition souvent empirique de leur prise en charge. Plusieurs travaux recents demontrent l’interet de la chimiotherapie chez les patients de PS (performance status) 2, qui ameliore a la fois les symptomes et probablement la survie. En revanche, il persiste un debat sur l’interet d’une monotherapie ou d’une bitherapie dans ce groupe de patients. Les inhibiteurs de tyrosine kinase de l’EGFR ont demontre leur interet chez les patients pretraites, apportant a la fois un benefice clinique et un benefice de survie dans des etudes randomisees qui ont inclus un nombre significatif de patients en mauvais etat general.

Cancer bronchopulmonaire et réanimation

INTRODUCTIONnLung cancer is a disease with a poor prognosis. Therapeutic innovations in oncology and the optimisation of intensive care patient management have improved the prognosis of lung cancer presenting with acute life-threatening respiratory or cardiac emergencies.nnnOBSERVATIONnWe reported on the case of a patient with lung cancer presenting with mildly abundant haemoptysis, who was hospitalised in intensive care. After multidisciplinary discussion, the patient was intubated following recurrent haemorrhage that resulted in respiratory failure. The outcome was favourable. Four months later, this patient was still alive and autonomous.nnnDISCUSSIONnAfter years of pessimism, the medical literature has revealed an improvement in lung cancer patients survival. Respiratory failure and shock are the main reasons for admission to the intensive care unit. The mortality risk factors depend more on acute conditions than on the underlying lung cancer. The patients admission must be made before multiorgan failure occurs, along with the implementation of non invasive therapies. The use of intensive care as a bridge to overcome an acute event is a possible means of caring for the patient.nnnCONCLUSIONnConsideration of the acute event is important when deciding whether to hospitalise a patient with lung cancer in intensive care. An early admission, if indicated, is desirable. The course in the first 72hours provides a good estimation of the patients prognosis and helps to achieve better treatment.

Prise en charge oncologique du patient opéré: chimiothérapie adjuvante, surveillance, traitement des rechutes

Despite recent progress obtained from perioperative chemotherapy and particularly, that demonstrated by the clinical trials on adjuvant chemotherapy, recurrences remain frequent after surgery for non-small cell lung cancer. Research on adjuvant treatments is ongoing, focused on targeted therapies or personalised therapeutic strategies. Other questions remain unanswered and are still investigated in clinical trials by the French Cancer Institute, such as thoracic radiotherapy for N2 disease, surveillance and treatment of recurrences. Although post-surgical surveillance, with or without chemotherapy, may theoretically increase survival by an earlier detection of recurrences, there are no evidence-based data. With the wide use of adjuvant chemotherapy, the profile of recurrences is likely to change and the best chemotherapy for metastatic recurrences remains to be defined.RésuméMalgré les progrès thérapeutiques récents, obtenus avec la chimiothérapie périopératoire, en particulier démontrés par les essais de chimiothérapie adjuvante, les rechutes après chirurgie d’un carcinome bronchique non à petites cellules restent fréquentes. Les efforts de recherche se pousuivent dans le cadre des traitements adjuvants, avec des essais intégrant les thérapeutiques ciblées et évaluant des stratégies thérapeutiques personnalisées. D’autres questions n’ont actuellement aucune réponse et font l’objet d’essais cliniques conduits sous l’égide de l’IFCT, tels que la radiothérapie postopératoire des N2, la surveillance et le traitement des rechutes. La surveillance après chirurgie ± chimiothérapie, bien que théoriquement susceptible d’améliorer la survie par une détection plus précoce des rechutes, ne repose actuellement sur aucune donnée scientifique solide. Avec l’avènement des chimiothérapies périopératoires, le profil des rechutes est susceptible de se modifier, et la meilleure chimiothérapie à délivrer lors de rechutes métastatiques reste à définir.

Nouvelle perspective de traitement dans le cancer bronchique non à petites cellules (CBNPC). Place de l’afatinib : un inhibiteur oral et irréversible de la famille ErbB

Tyrosine kinase inhibitors (TKI) that block epidermal growth factor receptor (EGFR) pathway have demonstrated a clinical benefit for patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. The currently available TKI (gefitinib and erlotinib) are EGFR reversible inhibitors. Afatinib is an oral, irreversible ErbB family blocker that covalently binds and blocks signaling from EGFR (ErbB1), HER2 (ErbB2) and ErbB4. The compound inhibits also the transphosphorylation of ErbB3. With this mode of action, afatinib is thought to have a mechanistic advantage over EGFR blockade alone, in that it provides a sustained, covalent inhibition of ErbB homo- and hetero-dimers. In the pivotal LUX-Lung 3 study, afatinib demonstrated a prolonged progression free survival over standard pemetrexed plus cisplatin chemotherapy (11.1 versus 6.9 months; HR = 0.58, 95% CI: 0.43-0.78; P = 0.001) in EGFR mutation positive NSCLC patients. The compound has recently been granted a marketing authorization (MA) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutation(s) and EGFR TKI-naive. In this paper are summarized the efficacy and safety data in this indication.

Une monstrueuse masse médiastinale

Un jeune homme de 24 ans sans antécédents pathologiques particuliers est traité depuis quelques mois pour un asthme. Il est hospitalisé pour accentuation progressive d’une dyspnée gênante au moindre effort. La radiographie thoracique montre une opacité homogène des deux tiers inférieurs des deux champs pulmonaires réduisant le volume pulmonaire (fig. 1 et 2). Il existe un trouble ventilatoire mixte extrêmement sévère à prédominance restrictive avec un effondrement de la capacité vitale forcée (1,13 litre soit 19 % de la théorique) et du VEMS (0,9 litre soit 19 % de la théorique) à la spiromètrie. La gazométrie artérielle au repos montre une hypoxémie à 7,06 KPa et une hypercapnie à 7,46 KPa à pH normal.

Chimiothérapie pré-opératoire des cancers bronchiques non à petites cellules

Résumé:La survie à 5 ans des CBNPC varie de 9 à 61 %, après résection celle-ci varie selon le stade et peut varier de 25 à 67 %. Dans les stades IIIA (N2) la chirurgie, quoique controversée représente un des traitements de référence. La majorité des CBNPC rechute, soit sous forme métastatique, soit sous forme locale, ce qui rend logique les approches précédant la chirurgie d’une chimiothérapie néo-adjuvante. La majorité des patients recevant un traitement néo-adjuvant bénéficient ensuite d’une résection chirurgicale. Le traitement néo-adjuvant va réduire le volume tumoral et diminuer la dissémination métastatique. Le traitement néo-adjuvant des stades IIIA (N2) est devenu une pratique courante dans la dernière décennie. Les efforts de recherche actuel sont de positionner la place des traitements néo-adjuvants à des stades plus précoces de la maladie ainsi que la place des traitements par chimioradiothérapie avant chirurgie dans le stade IIIA (N2).Abstract:The five-year survival rates for patients with non-small cell lung cancer (NSCLC) ranges from 9 to 61% following resection, depending on clinical stage; survival rates post-surgery (pathologic stage) range from 25 to 67%. Surgical resection remains the standard of care in early stage NSCLC, although the role of surgery in stage IIIA (N2) disease is controversial. Despite resection, the vast majority of lung cancer patients will experience recurrent and/or metastatic disease; therefore, supplementing surgery with neoadjuvant therapy is a rational treatment strategy. From the current data, the vast majority of patients receiving neoadjuvant chemotherapy undergo the planned surgical resection. Neoadjuvant chemotherapy may also downstage the disease before surgery and decrease perioperative tumor seeding. Neoadjuvant chemotherapy in potentially resectable stage IIIA (N2) non-small cell lung cancer (NSCLC) has been widely prescribed in the last decade. Nowadays, the main topics of ongoing clinical research are to assess the role of induction chemotherapy in early stage disease, and the role of induction radiotherapy, as well as definite chemo-radiotherapy in stage IIIA NSCLC. This report reviews these issues and focuses on current treatment options for resectable NSCLC.

Clinical and molecular characteristics of non-small-cell lung cancer (NSCLC) harboring EGFR mutation: results of the nationwide French Cooperative Thoracic Intergroup (IFCT) program

BACKGROUNDnEGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database.nnnPATIENTS AND METHODSnOf 17664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients.nnnRESULTSnEGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], P < 0.0001; exon 21: HR= 0.76 (95% CI: 0.61-0.95), P = 0.002; exon 20: HR= 1.56 (95% CI: 1.02-2.38), P = 0.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HR= 0.62 (95% CI: 0.49-0.78), P < 0.0001; exon 20: HR= 1.46 (95% CI: 0.96-2.21), P = 0.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HR= 0.67 (95% CI: 0.53-0.85), P = 0.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.nnnCONCLUSIONnEGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.BackgroundnEGFR mutations cause inconsistent response to EGFR tyrosine-kinase inhibitors (TKI). To better understand these features, we reviewed all cases of EGFR-mutated non-small-cell lung cancer collected in the Biomarkers France database.nnnPatients and methodsnOf 17u2009664 patients, 1837 (11%) with EGFR-mutated non-small-cell lung cancer were retrospectively analyzed for clinical and molecular characteristics. Results were correlated with survival and treatment response for the 848 stage IV patients.nnnResultsnEGFR exon 18, 19, 20 and 21 mutations were found in 102 (5.5%), 931 (51%), 102 (5.5%) and 702 (38%) patients, respectively. Over 50% of exon 18 and 20 mutated patients were smokers. The median follow-up was 51.7u2009months. EGFR mutation type was prognostic of overall survival (OS) versus wild-type {exon 19: hazard ratio (HR)=0.51 [95% confidence interval (CI): 0.41-0.64], Pu2009<u20090.0001; exon 21: HRu2009=u20090.76 (95% CI: 0.61-0.95), Pu2009=u20090.002; exon 20: HRu2009=u20091.56 (95% CI: 1.02-2.38), Pu2009=u20090.004}. EGFR mutation type was prognostic of progression-free survival versus wild-type [exon 19: HRu2009=u20090.62 (95% CI: 0.49-0.78), Pu2009<u20090.0001; exon 20: HRu2009=u20091.46 (95% CI: 0.96-2.21), Pu2009=u20090.07]. First-line treatment choice did not influence OS in multivariate analysis. First-line TKI predicted improved progression-free survival versus chemotherapy [HRu2009=u20090.67 (95% CI: 0.53-0.85), Pu2009=u20090.001]. OS was longer for del19 versus L858R, which was associated with better OS compared with other exon 21 mutations, including L861Q. TKI improved survival in patients with exon 18 mutations, while chemotherapy was more beneficial for exon 20-mutated patients.nnnConclusionnEGFR mutation type can inform the most appropriate treatment. Therapeutic schedule had no impact on OS in our study, although TKI should be prescribed in first-line considering the risk of missing the opportunity to use this treatment.

Cancers bronchiques oligométastatiques : une survie proche des maladies localement avancées

Contexte Les patients porteurs d’un cancer bronchique non a petites cellules de stade IV ne sont habituellement eligibles qu’a un traitement par chimiotherapie. Les maladies oligo-metastatiques (OM) peuvent beneficier d’un traitement a visee curative au niveau pulmonaire et sur le/les sites metastatiques. Cette etude compare la survie des patients porteurs d’une maladie OM avec metastase unique synchrone a celle des patients des autres stades evolutifs. Methodes Les donnees issues de la reunion de concertation pluridisciplinaire d’oncologie thoracique du CHU de Grenoble entre 1993xa0et 2012xa0ont ete analysees. Les patients de stade IV avec metastase unique synchrone ont ete consideres comme OM. Resultats Les donnees de 4917xa0patients ont ete etudiees (18xa0exclus pour donnees manquantes). Cent dix patients presentaient une metastase unique, 1508xa0etaient de stade I/II, 1769xa0de stade III et 1512xa0de stade IV avec plus d’une metastase. La mediane de survie globale des patients OM etait de 18,8xa0mois [IQR, 9,8–34,6xa0mois]. Elle etait de 6,3xa0mois [IQR, 2,4–14,1xa0mois] pour les patients avec plus d’une metastase et de 15,8xa0mois [IQR, 6,7–40,0xa0mois]) pour les patients de stade III. Parmi les OM, les patients ayant pu etre operes sur les 2xa0sites de facon complete ( n xa0=xa055, 50xa0%) avaient une mediane de survie globale de 25,7xa0mois [IQR 14,1–41,5xa0mois], meilleure que les autres (mediane 12,4xa0mois [IQR 5,2–24,9xa0mois]) ( p xa0=xa010 −3 ). Conclusion La survie des patients porteurs d’un CBNPC avec metastase unique est bien meilleure que celle des patients porteurs d’une maladie avec plus d’une metastase. Cette difference est encore plus marquee si la maladie tumorale est operable sur les 2xa0sites.