Genetic and Environmental Determinants in Lung Cancer Progression and Survivorship

1. Genetic and Environmental Determinants in Lung Cancer Progression and Survivorship Ping Yang, M.D., Ph.D.Professor and Consultant Department of Health Sciences ResearchDepartment of MedicineDepartment of Medical GeneticsMayo Comprehensive Cancer Center Mayo Clinic College of Medicine

2. Outline • Overview of lung cancer prognosis • Known determinants of lung cancer survival:environment and genes • Identify and validate new predictors for lung cancer survival:ongoing efforts • Current research using pharmacogenetic-epidemiologic tools: towardsindividualized medicine • Characteristics of long-term survivors:amulti-dimensional approach

3. Acknowledgement: Survivorship Research Team Medical OncologyThoracic SurgeryChest Pathology Alex A. Adjei Mark S. Allen Marie-Christine Aubry James R. Jett Stephen D. Cassivi Aminah Jatoi Claude DeschampsBiostatistics Randolph S. MarksFrancis C. Nichols Sumithra J. Mandrekar Julian R. MolinaPeter C. PairoleroV. Shane Pankratz Victor F. TrastekJeff A. Sloan (QoL expert) Pulmonary Medicine Eric S. EdellMolecular BiologyPsychology David E. Midthun Julie M. CunninghamMatthew M. Clark Wilma L. Lingle Radiation OncologyWanguo LiuPharmocogenomics Yolanda I. Garces Stephen N. Thibodeau Richard M. Weinshilboum BioinformaticsNicotine DependenceChaplain Zhifu SunJon O. EbbertMary E. Johnson George Vasmatzis Oncology NursingEpidemiology Linda Sarna (UCLA) Ping Yang

4. Overview: An Old Story with Continued ChallengeCarcinoma of the Lung and Bronchus • High incidence rate: 12-13% cancer diagnosis in U.S.; >60% diagnosed at a not-curable stage. • High mortality rate: 5-year survival rate is ~15%. • Kills more people than any other cancer: ~30% of all cancer deaths in U.S.

6. Known Predictors of Early-stage Lung Cancer Survival Yang et al., 2004, Modified from Brundage et al. 2002

7. Quantity and Quality of Life Background: A Lung Cancer Research Infrastructure Physical &Psychosocial Status:e.g., symptoms, comorbidity, & supports Health Related Behaviors: e.g.,diet,smoking, & exercise Staging, PS, & Treatment: TNM, surgery, chemotherapy, & radiotherapy Host Factors:e.g.,genetic predisposition anddemo-graphic factors Tumor: e.g., histologic cell type and differentiation grade, biologic & mechanistic genes CHEST, 2006

8. A ProspectivelyFollowed Patient Cohort: Newly Diagnosed Lung Cancer, 1997-Ongoing Identification, Baseline data, Blood/Tissue ~1000 patients each year 6 months follow-up 1 year follow-up Annually after Progression and Death Svobodnik A, et al, 2004; Yang P, et al. 2005.

9. Identifying and Validating NewPrognostic Factors1 of 4 groups Yang et al., 2004, Modified from Brundage et al. 2002

10. Example: treatment of recurrent lung cancer and post-recurrence survival

14. (continued)

17. Post-Recurrence Survival by Risk Score Group RS4 RS: 4-6 RS: 6-8 RS>8 ATS, 2006

18. ATS, 2006

19. Identifying and Validating NewPrognostic Factors2 of 4 groups Yang et al., 2004, Modified from Brundage et al. 2002

21. Survival by Years Since Quit Smoking, WomenAdjusted for age, packs per day, years smoked, histology, grade, stage, and treatment Lung Cancer, 2005

22. Dietary Supplement of Vitamins and Minerals • In general population, ~40% take vitamin/ mineral supplements regularly. • Approximately 80% of cancer patients do so. • Both clinical and laboratory data have shown that certain micronutrients effect the growth of malignant cells: i.e., vitamins and minerals appear to bemodulators of tumor growth. • Are these supplements helping or hurting lung cancer patients?

24. Dietary Supplement of Vitamins and Minerals: NSCLC Multivariable Model-Based Survival Curves P < 0.01 Lung Cancer, 2005

25. Identifying and Validating NewPrognostic Factors3 of 4 groups Yang et al., 2004, Modified from Brundage et al. 2002

26. Chemotherapy & Treatment Outcome • For stage III (and IV) NSCLC and limited stage SCLC, combined modality of concurrent chemo- and radiotherapy is considered as the standard of care. • The goal of such treatment is to improve loco-regional tumor control and minimize metastases without increasing morbidity. • Overall, there is a significant benefit in survival, but only in a subset of 25-30% among all treated. Who and why?

27. Chemotherapy Agents (in %) Used at Mayo Clinic During the Past Eight Years (1997-2004) All Chemotherapy First-Line Subsequent Chemotherapy Chemotherapy Drug Groups Stage III/IV Stage III&IV Stage III&IV NSCLC SCLC NSCLC SCLC NSCLC SCLC Total Count (denominator) 1093 247 1093 247 463 107 Platinum-containing Agents (P) 90.1 94.7 85.7 91.5 51.8 61.7 Taxane-containing agents (T) 76.2 30.8 66.1 10.5 45.8 52.3 Gemcitabine (G) 32.0 4.9 13.0 0 47.5 11.2 EGFR inhibitor (E) 8.0 0 2.7 0 12.5 0 Either P or T 91.7 97.2 88.2 96.4 64.4 84.1 Both P and T 74.7 28.3 63.7 5.7 33.3 29.9 Either P or G 94.0 94.7 91.1 91.5 76.9 68.2 Both P and G 28.2 4.9 7.6 0 22.5 4.7 Either P or E 92.2 94.7 88.2 91.5 59.6 61.7 Both P and E 5.9 0 0.3 0 4.8 0 Either T or G 85.3 31.2 78.0 10.5 77.8 56.1 Both T and G 23.0 4.5 1.1 0 15.6 7.5 Either T or E 79.2 30.8 68.6 10.5 54.0 52.3 Both T and E 4.9 0 0.3 0 4.3 0 Either G or E 35.9 4.9 15.6 0 54.0 11.2 Both G and I 4.1 0 0.1 0 6.0 0 None of the above 3.1 2.8 4.6 3.6 9.7 14.0

28. A BRIEF BACKGROUND • Platinum-based drugs are commonly used in lung cancer chemotherapy. • The glutathione metabolic pathway is directly involved in the inactivation of platinum compounds.

29. The Glutathione Pathway and Its Role in Drug Detoxification – Yang et al., 2006; JCO Glutathione

30. GCLC Gene, Platinum-based Drugs, & Lung Cancer Survival Yang et al., 2005

31. Clinical Implications • Genotypes of glutathione-related enzymes may be used as host factors in predicting patients’ survival after treatment with platinum-based drugs. • The distribution of GCLC repeats marker: GCLC-77: 19% - not use platinum drugs? GCLC-7_: 50% - balancing benefit vs. harm? GCLC-other: 31% - suitable for platinum-drugs? Yang et al., 2005

32. Many Shortcomings Much needed to be done… Other pathways Paradoxical “toxicities” Accurate follow-up data …

33. Identifying and Validating NewPrognostic Factors- 4 - Yang et al., 2004, Modified from Brundage et al. 2002

35. JTCVS., 2006

36. Biological Markers:Promises and Challenges • Treatment response is generally poor. • Limited markers to predict prognosis and apply to individualized management. • Gene expression profiling, “microarray”, has been widely used to search for answers at molecular level for differed lung cancer survival • (Note: DNA microarray measures tens of thousands expressed genes via mRNA simultaneously in tissue or cells)

37. Emerging evidence shows that the accuracy of expression-based outcome prediction varies greatly among studies. Converging questions have been raised from researchers and clinicians: • Why does gene-based prediction vary? • Can DNA expression profiles provide more accurate prediction than conventional predictors? • Are gene panels or molecular signatures independent predictors or merely surrogates of conventional factors?

38. Three Pioneer Studies: Larger Samples in “Top-Tier” Journals • Stanford group (PNAS 2001;98(24):13784-9):56 cases of lung cancer - 41 AD, 16 SCC, 5 LCLC, 5 SCLC • Harvard group (PNAS 2001;98(24):13790-5):186 cases of lung cancer - 127 AD, 21 SCC, 20 carcinoid, 6 SCLC • Michigan group (Nat Med 2002;8:816-24): - 86 cases of lung adenocarcinoma

39. Survival Prediction on Harvard Data From 50 Genes Selected From Michigan Data

40. Survival Curves Predicted by Different Gene Markers on an Independent Sample

41. Comparison of survival predictions by a 50-gene signature and combination of clinical and pathologic variables Sun &Yang, 2006;15:2063-8

43. Outline • Overview of lung cancer prognosis • Known determinants of lung cancer survival:genes and environment • Identify and validate new predictors for lung cancer survival:ongoing efforts • Current research using pharmacogenetic-epidemiologic tools: towardsindividualized medicine • Characteristics of long-term survivors:amulti-dimensional approach

44. A Brief Background • Individuals who are alive over 5 years after a lung cancer diagnosis are referred to as long-term lung cancer (LTLC) survivors. • In the U.S., approximately 26,000 individuals become LTLC survivors annually. • A paucity of information regarding the quality of life (QoL) among LTLC survivors.

45. Longitudinal Evaluation of Quality of Life in Long-Term Lung Cancer SurvivorsA Short story Overall QoL change between two time periods: under 3years and over5years post diagnosis

46. Multi-dimension Follow-up Measures Besides medical records, multiple tools: • SF-8 Health Survey • ECOG* Performance Status Score (*Eastern Cooperative Oncology Group) • Lung Cancer Symptom Scale (LCSS) • Linear Analogue Self-assessment (LASA)(modified for lung cancer patients) • Baecke Questionnaire for Habitual Activities • FACT-SP Spiritual Well Being Assessment • Other tools (diet, sleep, cognitive function, etc)

47. QoL Assessment • Overall QoL was assessed using LCSS-9: - scores 0 (worst) to 100 points (best) - as continuous variable: distance in cm on a VAS a raw score of the total 100 points - as a binary variable a poor QoL defined as <50 points(Sloan, 2004) • Declining QoL was definedas: a 10-point or more decrease between the two time periods

48. A Prospective Lung Cancer Cohort:Long-term Survivors, 2002-2004 N = 2837 N = 448, 15.8% Patients diagnosed 1997-1999 5-year follow-up Annually after

49. Declining Overall QoL Over Time: Higher Proportion with Poor Overall QoL Yang et al., 2005

50. Factors Influencing Overall QoL in Long-term Lung Cancer Survivors Poor QoL at Characteristics<3 year>5 year Age > 75 years Education < 16 years  TNM staging- Stage I Histology-Poorly/un-differentiated  Lung cancer treatment Chemotherapy – Yes  Radiation therapy – Yes  Comorbid conditions COPD  Heart failure  Recurrent/subsequent lung cancer 