Gérard Zalcman

Nicolas Girard

European Respiratory Review

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EDITORIALTopics in thoracic oncology: from surgical resection tomolecular dissectionNicolas Girard* and Gérard Zalcman#Thoracic malignancies include tumours of the lung,pleura and mediastinum. Among those, lung cancer isby far the most frequent entity, and represents the firstcause of cancer-related death worldwide. The vast majority ofpatients are diagnosed with advanced disease, preventingcurative treatment (mostly consisting of surgical resection withor without adjuvant chemotherapy) from being performed [1].Until recently, the treatment of these patients was confined tocytotoxic chemotherapy, which, over the past years, has beenoptimised through histology-driven decision making of regi-mens, combination with anti-angiogenic agents and developmentof maintenance strategies [1, 2]. The median overall survival ofpatients has been improved from an abyssal 8 months in the late1990s to 15 months in the most recent phase III trials of the 2010s,but novel strategies are clearly needed [2].Meanwhile, major progress has been achieved in the under-standing of the molecular bases of lung cancer. Data fromgenomic, expression, mutational and proteomic profilingstudies have emerged, first for lung adenocarcinoma and morerecently for squamous cell carcinoma [3]. While being con-sidered obscure and out of touch with the overall poor reality ofcancer care in the clinical setting, these data led to theidentification, among the numerous background molecularalterations observed, of specific oncogenic mutations beingnecessary and sufficient to drive tumour formation andmaintenance, the so-called ‘‘addictive’’ mutations [3]. With thedevelopment of agents specifically designed to target these keysignalling pathways, the paradigm is changing from thetraditional view of chemotherapy, which, even if bindingspecific proteins, aims at destroying cancer cells as ‘‘massivedestruction weapons’’, thus producing toxicities to the non-tumoural tissues, leading to the potential inhibition of causativecarcinogenesis processes by targeted, better tolerated agents.Such an approach requires the accurate selection of patientsbased on the molecular characterisation of individual tumours, asthese targeted agents are highly effective, both in terms ofresponse rate and survival, but in specific molecularly definedsubsets of tumours. Lung adenocarcinoma harbouring epidermalgrowth factor receptor mutations are the best illustration of thetherapeutic relevance of such a strategy [4, 5]. More recently,anaplastic lymphoma kinase rearrangements have emerged asanother driver of molecular alteration, predicting the clinicalefficacy of specific inhibitors [5].These developments actually complicate the physician’s decision-making process, especially when acquired resistance to theseagents ultimately emerges, often after months of initiallyefficacious treatment and dramatic tumour response. Besidesmolecular switch towards other oncogenic pathways, histologicso-called ‘‘trans-differentiation’’ of lung adenocarcinoma tumoursto small cell carcinoma has been reported, alternatively explainedby treatment-induced selection of a sub-clone within the initialtumour. This unexpected dynamic of tumour cells, which has notbeen described in other tumour locations, remains to bemolecularly better understood. Moreover, isolated extrathoracicmetastasis, potentially driven by growth of dormant micro-metastasis, may represent a frequent pattern of recurrence inpatients receiving targeted therapies, bringing the issues raised bythe management of oligometastatic disease back up to date. Someof the historical paradigms in lung cancer treatment may bedisregarded, including the immediate switch of regimen at timeof radiological progression, or the absence of re-challenge of oneanti-tumoural agent during disease management.Furthermore, while our knowledge has been increasing withregard to oncogenic mutations, the tumour microenvironmentis emerging as a major player in lung carcinogenesis, both inthe primary tumour and its metastases [6]. Beyond the classicalanalysis of invasion, metastatic and angiogenesis processes,inflammation and immune responses may represent poten-tially relevant therapeutic targets, as shown by recenttherapeutic results of antibodies targeting signalling pathwaysthat negatively regulate immune reactions against cancer cells.Thus, new prognostic and predictive biomarkers are emerging,both for early-stage and advanced tumours.Other intrathoracic malignancies could also benefit from theseconceptual progresses. The management of thymic epithelialtumours is a paradigm of cooperation between clinicians,surgeons and pathologists from establishing the diagnosis toorganising the multimodal therapeutic strategy [7]. Surgery is themainstay of the curative-intent treatment, as complete resectionrepresents the most significantly favourable prognostic factor onoverall survival. Similar to lung cancer, novel strategies are*Dept of Respiratory Medicine, Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, and #Dept ofRespiratory Medicine and Thoracic Oncology, UMR INSERM 1086 Cancers et Préventions, CaenUniversity Hospital, Caen, France.CORRESPONDENCE: N. Girard, Service de Pneumologie U80, Hôpital Louis Pradel, 28 avenuedoyen Lépine, 69677 Lyon, France. E-mail: nicolas.girard@chu-lyon.frPROVENANCE: Submitted article, peer reviewed.Eur Respir Rev 2013; 22: 128, 101–102DOI: 10.1183/09059180.00000413CopyrightERS 2013cEUROPEAN RESPIRATORY REVIEW VOLUME 22 NUMBER 128 101needed, especially for refractory, recurrent tumours and thymiccarcinomas, which carry a poor prognosis. Personalised app-roaches are currently being developed as potentially druggablemolecular targets and are emerging from recent integratedgenomic analyses.Taken together, these developments led us to begin a series onthoracic oncology in the European Respiratory Review [8]. We aimat providing the reader with a complete viewpoint of the hottesttopics, especially regarding the molecular characterisation of lungcancer, while including comprehensive reviews on landmarkareas, such as surgery and echo-endoscopy. Ultimately, ourobjective is to highlight the variety of questions and answers thatmake the management of thoracic malignancies a model ofimplementation and achievement in respiratory medicine andoncology.STATEMENT OF INTERESTConflict of interest information can be found alongside the onlineversion of this article at err.ersjournals.comREFERENCES1 Goldstraw P, Ball D, Jett JR, et al. Non-small-cell lung cancer. Lancet2011; 378: 1727–1740.2 Zalcman G, Bergot E, Lechapt E. Update in non-small cell lungcancer. Eur Respir Rev 2010; 117: 173–185.3 Zalcman G, Bergot E, Creveuil C, et al. Integrating biomarkers intoclinical trials: methodological issues for a new paradigm innonsmall cell lung cancer. Curr Opin Oncol 2011; 23: 106–111.4 Cadranel J, Zalcman G, Sequist L. Genetic profiling and epidermalgrowth factor receptor-directed therapy in nonsmall cell lungcancer. Eur Respir J 2011; 37: 183–193.5 Pao W, Girard N. New driver mutations in non-small-cell lungcancer. Lancet Oncol 2011; 12: 175–180.6 Gao D, Vahdat LT, Wong S, et al. Microenvironment regualtion ofepithelial-mesenchymal transitions in cancer. Cancer Res 2012; 72:4883–4889.7 Girard N. Chemotherapy and targeted therapy agents for thymicmalignancies. Expert Rev Anticancer Ther 2012; 12: 685–695.8 Dooms C, Muylie I, Yserbyt J, et al. Endobronchial ultrasound in themanagement of nonsmall cell lung cancer. Eur Respir Rev 2013; 22:169–177.EDITORIAL: TOPICS IN THORACIC ONCOLOGY N. GIRARD AND G. ZALCMAN102 VOLUME 22 NUMBER 128 EUROPEAN RESPIRATORY REVIEW

Topics in thoracic oncology: from surgical resection to molecular dissection

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Topics in thoracic oncology: from surgical resection to molecular dissection

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