Tailored therapy in lung cancer

1Division of Thoracic Surgery, Hôpital Maisonneuve Rosemont, University of Montreal, Montreal; 2Division of Respirology, Institut Universitaire de Cardiologie et de Pneumologie de Québec – Laval University, Quebec City, Quebec Correspondence: Dr George Rakovich, Division of Thoracic Surgery, Hôpital Maisonneuve-Rosemont (University of Montreal), 5415 l’Assomption, Montreal, Quebec H1T 2M4. Telephone 514-252-3400, e-mail george.rakovich@umontreal.ca Historically, although several histological subtypes have been recognized, non-small cell lung cancers (NSCLC) were essentially grouped together and considered to be a single disease. Advances in molecular biology, however, have shown that NSCLC actually comprises a genetically diverse group of tumours. Furthermore, molecular analysis has enabled the characterization of individual tumours as well as identification of potential molecular targets for targeted drug therapy (1-3).

Importantly, an analysis of IPASS participants clearly demonstrated the importance of EGFR status on treatment response.Patients with a positive EGFR had a significantly reduced risk of tumour progression or death (HR 0.48; P<0.001) whereas in EGFR-negative patients the risk was increased (HR 2.85; P<0.001); overall, these findings had a major effect on practice, and have led the American Society of Clinical Oncology to recommend testing all patients with advanced disease for a mutant EGFR to offer TKIs as first-line therapy (16).
Encouraging results in advanced disease logically led to the evaluation of TKIs in the adjuvant and neoadjuvant settings.Two phase 3 studies did not find an advantage to TKIs as adjuvant therapy and, in fact, showed a trend toward decreased survival (3).The methodology of these initial studies has been questioned and several randomized controlled trials are currently attempting to resolve this issue.

echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase fusion gene
A second important molecular target in NSCLC is the echinoderm microtubule-associated protein-like 4 (EML-4) and anaplastic lymphoma kinase (ALK) fusion gene (EML4-ALK).The EML4-ALK gene rearrangement acts as an oncogene and is present in 5% to 7% of lung adenocarcinomas; rates are much higher in younger patients, and in light or never-smokers.Crizotinib is a potent and selective oral inhibitor of ALK.Published data from the three crizotinib trials to date show consistently impressive responses and PFS (seven to nine months) in patients with advanced ALK-positive NSCLC (17)(18)(19).Crizotinib was generally well tolerated, with patients mostly experiencing grade 1 or 2 adverse effects (visual disturbances, gastrointestinal disorders).Multiple guidelines state that EML4-ALK testing should be performed in all patients with NSCLC with an adenocarcinoma component, and crizotinib offered to those who test positive (20,21).

Vascular endothelial growth factor
Vascular endothelial growth factor is overexpressed in most human cancers and is generally associated with more aggressive tumour behaviour.Bevacuzimab is a monoclonal antibody that targets vascular endothelial growth factor and, when combined with chemotherapy, was associated with increases in overall survival and PFS in NSCLC in two large phase 3 trials (22,23), although the absolute increases were <2 months.This benefit is limited to nonsquamous focused review ©2013 Pulsus Group Inc.All rights reserved g rakovich, l tremblay.tailored therapy in lung cancer.can respir J 2013;20(5):367-368.
Historically, all non-small cell lung cancers were essentially grouped together and considered to be a single disease.However, it is now recognized that non-small cell lung cancer actually comprises a genetically diverse group of tumours.This, in turn, affords a new opportunity for the development of effective treatments tailored to individual tumours and patients.Advances in molecular biology have made possible the development of drugs against specific molecular targets on cancer cells, most notably the tyrosine kinase inhibitors.The relevant literature and current practice guidelines are discussed.In addition, other related areas of active investigation, including tumour vaccines and pharmacogenetics, are briefly reviewed.
NSCLC because bevacuzimab has been associated with pulmonary hemorrhage in squamous cell lung cancer.
For now, only drugs targeting the EGFR and EML4-ALK have found their way into clinical practice; however, other potential molecular targets are being investigated.In effect, most current research in advanced lung cancer therapy is focusing on such targets.In addition, the recognition of resistance mechanisms to available molecules is the focus of further study.

tuMour Vaccines
The principle of tumour vaccines is to stimulate the development of immunity to specific tumour components.Various techniques have been developed for the harvest and delivery of such component molecules to achieve optimal stimulation of the immune system (24).MAGE-3 and MUC-1 are examples of candidate molecules that have been singled out as being potentially significant.Several phase 3 studies evaluating the efficacy of tumour vaccines in NSCLC are currently underway, both in advanced disease and in the adjuvant setting (24,25).

PharMacogenetics
Although not an analysis of molecular targets per se, pharmacogenetic profiling of tumours may enable customized conventional chemotherapy by choosing a regimen tailored to specific tumour characteristics to increase efficacy and maximize synergy between individual drugs.Several genetic markers have been identified as a way to predict responses to various chemotherapeutic agents including platinum compounds (ERCC1), gemcitabine (RRM1), pemetrexed (TYMS) and taxanes (25).Unfortunately, study results to date have been conflicting and such an approach has yet to be adopted into routine practice.

conclusion
Following the present brief discussion, it is important to recognize that the development of targeted therapy in NSCLC is the direct result of an evolution of our understanding of lung cancer: we now recognize that NSCLC is not one uniform disease but rather comprises a genetically diverse group of tumours.This, in turn, affords a new opportunity to develop effective treatments tailored to individual tumours and patients.The development of molecular agents targeting mutant EGFR and ALK has significantly affected practice, and both of these are now routinely tested for in most specialized centres.Although the impact on survival remains small and often limited to subpopulations of patients, targeted therapy in lung cancer has clearly shown the potential to positively affect oncological outcomes and improve quality of life with minimal toxicity.Future research is key and will, no doubt, focus on the identification of new, broader targets and the development of novel therapeutic agents, conceivably incorporating them into multidrug combinations to increase their efficacy.