Non Small Cell Lung Cancer: Scientific Discoveries and the Pursuit of Progress

Transcription

1 Non Small Cell Lung Cancer: Scientific Discoveries and the Pursuit of Progress

2 Lung Cancer Accounts for 14% of All New Cancer Diagnoses in the United States 1 Lung cancer is the second most common malignancy in men and women after prostate and breast cancer, respectively. 1 In 2013, approximately 228,190 people will be diagnosed with lung cancer and 159,480 will die from the disease, accounting for about 27% of all U.S. cancer deaths. 1 Surgery, chemotherapy, and radiation the traditional treatments for lung cancer have increased overall survival since the late 1970s. 2 Thanks to the promising new field of molecular medicine, physicians may have an opportunity to further improve survival time. This innovative approach to therapy may help researchers develop effective chemotherapeutic agents, identify cancer genes, and design new treatments for drug-resistant tumors. 2 Cancer burden: By the numbers $12B Amount spent to treat lung cancer in the United States, annually 3 Approximately 7% of men and women born today will be diagnosed with cancer of the lung and bronchus at some point during their lifetime. 5 While sobering, this rate actually represents a decreased incidence of disease since Between 2000 and 2009, the incidence of all lung cancers in men decreased by 2%, with mortality rates decreasing significantly by 2.3%. 7 Although the incidence of all lung cancers remained level among women for the same period, mortality in this group decreased by 0.7%. 7 Furthermore, since 1975, 5-year relative survival rates have increased significantly (P<0.5) from 12% to 16% for all types and all stages of lung cancer. 8 Despite these gains in survival rates, opportunities for improvement remain, especially for non small cell lung cancer (NSCLC). 6 Some of the recent advances in the treatment of lung cancer come from improvements in surgical techniques, the use of combined chemotherapeutic and radiation treatments, and the development of targeted treatments. $39B Amount in lost productivity in the United States due to lung cancer, annually 4 Types of Lung Cancer 1 56% Diagnoses that occur after metastasis 5 Small cell lung cancer (10% to 15% of all lung cancers) 159,000 Number of Americans who die each year from lung cancer 6 Squamous cell carcinoma (25% to 30% of all lung cancers) Evolving Understanding of Lung Cancer All lung cancers are characterized by the uncontrolled growth of epithelial cells in the lungs and tracheobronchial system, but histological analysis has identified four distinct variants of the disease. 6 Adenocarcinoma (about 40% of all lung cancers) Large cell carcinoma (10% to 15% of all lung cancers) NON SMALL CELL LUNG CANCER (85% to 90% of all lung cancers)

3 Evolution of NSCLC Therapy Treatment Landscape Continuing research into signaling Supportive care Surgical resection Radiotherapy Single-agent chemotherapy 9 Single-agent platinum-based chemotherapy 10 Adjunctive chemotherapy and surgical resection Adjunctive chemotherapy and radiotherapy Platinum-based doublet chemotherapy 11 Adjunctive chemotherapy and radiotherapy 12 Targeted therapies including biologic agents 13,14 pathways may uncover new genetic markers and mechanisms of resistance 15,16 Early 1970s Late 1970s and 1980s 1990s 2000s 2010 and Beyond Over the past 3 decades, our understanding of cancer has greatly expanded. Clinicians have benefitted from these discoveries, and have consistently used scientific breakthroughs to design new treatments. Until the middle of the 1970s, therapy for NSCLC was primarily supportive, consisting of radiotherapy, analgesics, and periodic drainage of pleural effusions. These interventions were designed to reduce patients discomfort. 9 During the late 1970s and through the 1980s, studies showed that platinum-based agents offered promise for treating advanced NSCLC, especially when used as an adjunct to surgery and radiotherapy. 13 By the 1990s, these cytotoxic drugs had become the backbone of platinumbased doublet chemotherapy. 16 Patients also benefitted from simultaneous radiation and chemotherapy. 12 By the early 2000s, researchers had developed drugs that targeted signaling pathways known to be involved in the propagation of NSCLC. 12,17 For instance, the development of monoclonal antibodies helped researchers create antiangiogenic drugs that deprived tumors of the oxygen and nutrition they need to grow beyond a certain size. 12,16,18 Treatment regimens combining chemotherapy and monoclonal antibodies remain a viable treatment for solid NSCLC tumors, many of which still have no known genetic drivers. 13,19 Since 2010, the identification of several new genetic mutations has advanced targeted therapy for NSCLC. Researchers hope to develop targeted treatments through signaling pathways that disrupt the earliest stages of malignancy. 16

4 Signaling Pathways May Lead to New Therapeutic Options Researchers have identified several genetic markers associated with all three types of NSCLC all part of a clinical trend called genomic medicine. By combining healthcare and modern human genetics, genomic medicine seeks to identify new treatment targets, identify patients for specific trials, and monitor responses to therapy. 20 As researchers continue to learn more about the relationship between genetic markers and cancer, they come closer to realizing the goal of genomic medicine: delivering customized therapy for clinically distinct diseases. Unknown HER2 PD-1 p53 HER2 is part of the same family of enzymes as EGFR and shares a similar demographic expression with EGFR mutations in lung cancer. However, HER2 mutations do not appear in patients with EGFR mutations, suggesting that HER2 represents an independent signaling pathway. 24 Tumors may follow several signaling pathways to avoid destruction. The PD-1 pathway shields tumor cells from programmed death through the fusion of two proteins. 25 Overexpression of the p53 protein in patients with NSCLC has been linked to aggressive tumor growth. 26

5 Investigators have detected EGFR in 80% to 85% of patients with NSCLC. 21 Mutations in the genes that encode EGFR have been associated with the proliferation of cancer cells. 22 ALK is an oncogene formed by the fusion of two proteins. ALK rearrangements are generally found in people without EGFR mutations. 22 BRAF is a well-known oncogene that directs cell growth. 23 Most extensively studied in skin cancers, BRAF mutations are believed to affect tumor behavior in multiple other sites. EGFR ALK BRAF KRAS ROS1 RET MET Research is still emerging about the natural history of ROS1 fusions, but they appear in populations similar to those with ALK gene rearrangements. It is unknown whether both groups share environmental or genetic risk factors. 27 RET is an established oncogene that was recently reported in a patient diagnosed with NSCLC. 28 Chromosomal rearrangements on the RET gene appear to be independent of EGFR, ALK, and KRAS. Amplification of the MET gene drives invasive NSCLC tumor growth and correlates with poor survival outcomes in NSCLC. 29,30 MET amplification also plays a role in resistance to EGFR inhibitors. 31

6 References: 1. Lung cancer (non-small cell). American Cancer Society Web site. index. Accessed April 17, Lung cancer research. National Foundation for Cancer Research Web site. Accessed April 17, Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: J Natl Cancer Inst. 2011;103: Bradley CJ, Yabroff KR, Dahman B, et al. Productivity costs of cancer mortality in the United States: J Natl Cancer Inst. 2008;100: SEER stat fact sheets. Lung and bronchus. Surveillance Epidemiology and End Results Web site. seer.cancer.gov/statfacts/html/lungb.html. Accessed April 17, Non small cell lung cancer treatment. National Cancer Institute Web site. Accessed April 17, Lung cancer trends. Centers for Disease Control and Prevention Web site. Accessed April 17, Cancer Facts & Figures American Cancer Society Web site. Accessed April 17, Buccheri G. Chemotherapy and survival in non-small cell lung cancer. Chest. 1991;99(6): Johnson David H. Evolution of cisplatin-based chemotherapy in non-small cell lung cancer. Chest. 2000;117(4):133S-137S. 11. Rigas JR. Taxane-platinum combinations in advanced non-small cell lung cancer: a review. Oncologist. 2004;9(suppl2): Progress against lung cancer. CancerProgress.net. cancerprogress.net/downloads/timelines/progress_against_lung_cancer_timeline.pdf. Accessed April 17, DeVita VT, Chu E. A history of cancer chemotherapy. Cancer Res. 2008;68: Stinchcombe TE, Socinski MA. Current treatments for advanced stage non-small cell lung cancer. Proc Am Thorac Soc. 2009;6: Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12: Sun S, Schiller JH, Spinola M, Minna JD. New molecularly targeted therapies for lung cancer. J Clin Invest. 2007;117(10): Veale D, Ashcroft T, Marsh C, Gibson GJ, Harris AL. Epidermal growth factor receptors in non-small cell lung cancer. Br J Cancer. 1987;55: Guilleminault L, Lemarie E, Heuze-Vourc h N. Monoclonal antibodies: an emerging class of therapeutics in non small cell lung cancer. J Cancer Ther. 2012;3: Paik PK, Arcila ME, Fara M, et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J Clin Oncol. 2011;29: Accelerating Progress Against Cancer. American Society of Clinical Oncology Web site. ASCOv2/Department%20Content/Cancer%20Policy%20and%20Clinical%20Affairs/Downloads/Blueprint.pdf. Accessed April 17, NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer V Available at: Accessed April 17, National Comprehensive Cancer Network, To view the most recent and complete version of the Guideline, go online to 22. Brambilla E, Gazdar A. Pathogenesis of lung cancer signaling pathways: roadmap for therapies. Eur Respir J. 2009;33: Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417: Shigematsu H, Takahashi T, Nomura M, et al. Somatic Mutations of the HER2 Kinase Domain in Lung Adenocarcinomas. Cancer Res. 2005;65(5): Beck S. ASCO: programmed death 1 (PD-1) inhibitor one of the most exciting new melanoma agents. Cancer Network.com.http://www.cancernetwork.com/conference-reports/asco2012/melanoma/content/ article/10165/ Accessed April 17, Tsao MS, Aviel-Ronen S, Ding K, et al. Prognostic and predictive importance of p53 and RAS for adjuvant chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25: Bergethon K, Shaw AT, Ou SI, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30: Ju YS, Lee WC, Shin JY, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res. 2012;22: Lutterback B, Zeng Q, Davis LJ, et al. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res. 2007;67: Cappuzzo F, Marchetti A, Skokan M, et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol. 2009;27: Turke AB, et al. Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17(1): Genentech Inc. All rights reserved. TAR /13 013C