Cell Lung Cancer PowerPoint Presentation

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Non-small Cell Lung Cancer Eva Szabo, MD Division of Cancer Prevention, NCI

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US Lung Cancer Statistics, 2012Siegel R et al., CA Cancer J Clin 2012;62:10 226,160 estimated new cases 160,340 estimated deaths leading cause of cancer deaths greater than breast+prostate+colon Death rate per 100,000 decreasing (90.56 in 1990; 67.45 in 2006) Incidence finally decreasing in women 16% five year survival 5% in 1950’s, 13% in 1970’s 29% of all male cancer deaths 26% of all female cancer deaths

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Age-adjusted Cancer Death Rates 1930-2007Siegel R et al., CA Cancer J Clin 2011;61:212

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Radiographic Evidence Linking Tobacco Use to Lung Cancer -●McMullen, DM & Cohen GA, NEJM 354:397, 2006 -McMullen, DM & Cohen GA, NEJM 354:397, 2006 Radiographic Evidence Linking Tobacco Use to Lung Cancer

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Risk Factors Tobacco, tobacco, tobacco (85% lung ca.) Including passive smoking Prior aerodigestive malignancy COPD Other exposures Asbestos, radon, polycyclic aromatic hydrocarbons, chromium, nickel, inorganic arsenic – mining, ship building, oil refining Genetic predisposition Familial lung cancer – 6q23-25 (Am J Hum Gen, 9/04) 15q24-25.1 – nicotinic acetylcholine receptor subunits CHRNA3 and CHRNA5, OR=1.3, attributable risk ~14% Amos et al., Nat Gen 2008;40:616, Hung et al. Nature 2008;452;633, Thorgeirsson et al. Nature 2008;452:638 CH3NA3/5 is also susceptibility locus for COPD Pillai et al. PLoS Genet 2009;5:1

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Five-year survival by TNM status in NSCLC (old staging system). ●In stage 1A, TNM classification T1N0M0 the 5 year survival is 61%. ● In stage 1BA, TNM classification T2N0M0 the 5 year survival is 38%.●In stage IIA, TNM classification T1N1M0 the 5 year survival is 34%.●In stage IIB, TNM classification T2N1M0 or T3N1M0 the survival is 24%.●In stage IIIA, TNM classification T1-3NanyM0 or TanyN3M0 the 5 year survival is 13%.●In stage IIIB, TNM classification T4NanyM0 or T3N1M0, the 5 year survival is 5%.●In stage IV, TNM classification TanyNanyM1 the 5 year survival is 1%.

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Pathology: Non-small Cell Lung Cancer ●Adenocarcinoma, inc bronchoalveolar 40% ● Squamous cell carcinoma 20% ● Large cell carcinoma 15% ● Others (carcinoid, etc.) Adenocarcinoma, inc bronchoalveolar 40% Squamous cell carcinoma 20% Large cell carcinoma 15% Others (carcinoid, etc.) Pathology: Non-small Cell Lung Cancer

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Pathology: Small Cell Lung Cancer ● Small cell lung cancer - 20% Small cell lung cancer - 20% Pathology: Small Cell Lung Cancer

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The Continuum of Lung CarcinogenesisOpportunities for Intervention Normal Hyper/Metaplasia Dysplasia Early-Late Cancer

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Treatment Strategies for Lung Cancer Treatment based on stage: Early stage (Stage I) – surgery Early stage (Stage II, IIIA resected)-surgery + adjuvant chemo Regional spread (IIIA/IIIB) – combined modality (chemoradiation, +/- surgery for IIIA) Metastatic (IIIB “wet”/IV)– chemotherapy, radiation as needed for local control, occasional resection of isolated mets Small cell lung cancer: chemotherapy (+thoracic radiation for limited stage; prophylactic cranial radiation to prevent brain mets)

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Personalizing Therapy for NSCLCGenetic Abnormalities in Lung Adenocarcinoma

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Epidermal Growth Factor (EGFR) Signaling

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Advanced Disease: Targeted TherapiesEGFR Inhibition Epidermal growth factor receptor (EGFR) inhibition in advanced NSCLC 10% response rate in advanced disease, 30% prolonged stabilization Survival advantage (erlotinib) Shepherd, F. A. et al. N Engl J Med 2005;353:123-132 Mutually exclusive with K-ras Most benefit for non-smoking related NSCLC, with EGFR mutations (females, adenocarcinomas), but benefit in non-mutated as well Lynch et al., NEJM 350:2129, 2004; Paez et al., Science 304:1497, 2004; Pao et al., PNAS 101:13306, 2004 Mechanisms of secondary resistance to EGFR inhibitors being identified (T790M mutation-50%, Met amplification-20%) Pao et al., PLoS Med 2:e17, 2005; Engelman et al., Science 316:1039, 2007

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Effect of Gefitinib on Progression-free Survival and Overall SurvivalMaemondo M et al. N Engl J Med 2010;362:2380-2388 230 patients, EGFR mutated, randomized to gefitinib or chemo(carbo/taxol)Results:10 vs. 5 mth PFS74% vs 31% response Median survival 30.5 vs 23.6 mths

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EGFR as a Target for NSCLCStandard of Care in 2012 Epidermal growth factor receptor (EGFR) inhibition in advanced NSCLC 10% response rate in advanced disease, 30% prolonged stabilization Survival advantage (erlotinib) Shepherd, F. A. et al. N Engl J Med 2005;353:123-132 Mutually exclusive with K-ras Most benefit for non-smoking related NSCLC, with EGFR mutations (females, adenocarcinomas, Asian) Lynch et al., NEJM 350:2129, 2004; Paez et al., Science 304:1497, 2004; Pao et al., PNAS 101:13306, 2004 Mechanisms of secondary resistance to EGFR inhibitors being identified (T790M mutation-50%, Met amplification-10-20%, others) Pao et al., PLoS Med 2:e17, 2005; Engelman et al., Science 316:1039, 2007 Erlotinib approved as single agent for 2nd and 3rd line treatment of NSCLC Also for maintenance after 1st line non-progression after chemo

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HER2/neu as Target for NSCLCKelly R J et al. JCO 2010;28:e507-e510 50 yo AA nonsmoker with stage IV NSCLC (large cell) in 11/07 Rx with carbo/taxol/bevacizumab (PR), erlotinib (PD), PF-00299804 (pan-HER inh, brief PR) -found to be HER2 amplified -Trastuzumab →PD -Trastuzumab/Vinorelbine→ near CR x 13 months Mutations in kinase domain in 4% NSCLC -Hunter et al., Nature 2004;30:431 Amplification (FISH) in 2-5% -Heinmoller P et al. Clin Cancer Res 2003;9:5283

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ROS1 Rearrangements as a TargetBergethon K et al. J Clin Oncol 2012 epub ahead of print Tyrosine kinase (insulin receptor family)1.7% of NSLC have rearrangments Multiple different partnersOne patient treated with crizotinib had major response, 6+ mths

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Personalizing Therapy for NSCLCGenetic Abnormalities in Lung Squamous Cell Ca. FGFR1 amplification ~22% of squamous cell carcinomas (smokers), not in adenocarcinomas experimental FGFR inhibitors in development Weiss J et al., Sci Transl Med 2010;62:62ra93 DDR2 (discoidin domain receptor 2 tyrosine kinase) mutations in ~4% squamous cell carcinomas Sensitive in vitro to dasatinib Hammerman PS et al., Cancer Discovery 2011;1:OF77

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Current Approach to Metastatic NSCLC Chemotherapy (platinum + another agent) in frontline Rx +/- bevacizumab (angiogenesis inhibitor) Pemetrexed for non-squamous histology If EGFR activating mutation or EML4-ALK translocation, then erlotinib or crizotinib given frontline (or 2nd line) Maintenance chemo – pemetrexed or erlotinib FDA approved Overall survival 13.4 vs. 10.6 mths for all subtypes, 15.5 vs. 10.3 mths for non-squamous histologies (Ciuleanu T et al. Lancet 2009;374:14432) Second line chemo – pemetrexed, taxotere, or erlotinib FDA approved Elderly good performance patients – treat with chemo

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Approaches to reducing cancer morbidity and mortality Prevention (primary, secondary, tertiary) Early detection Better therapeutics

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The Continuum of Lung CarcinogenesisOpportunities for Intervention

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Effect of Smoking Cessation on Lung Cancer DeathsLung Health Study, 14.5 yr F/U

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The use of natural or synthetic agents to suppress or reverse carcinogenesis Cancer Chemoprevention Regress existing neoplastic lesions (treat intraepithelial neoplasia) Prevent development of new neoplastic lesions (preneoplastic and cancer) Suppress recurrence of neoplastic lesions

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Rationale for Lung Cancer Prevention Metastatic cancer is rarely curable US lung cancer 5 yr survival is 15% (5% 1950’s, 13% 1970’s) Cancer is preventable P1, STAR breast cancer prevention trials with tamoxifen and raloxifene (Fisher B et al., JNCI 1998;190:1371; Vogel, VG et al., JAMA 2006;295:2727) Multiple animal studies with multiple agents Long preclinical phase with increasing histologic and molecular abnormalities, identifiable populations at risk

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When is the best time to intervene during lung carcinogenesis? Efficacy of intervention Early stage cancer is more curable than late Are precursor lesions more curable than invasive cancer? Can carcinogen-induced DNA damage be prevented? Toxicity of intervention High toxicity acceptable short-term, in setting of cancer Size of target population Many at risk (smokers), relatively few get cancer/yr Cost (resources, psychological impact, etc.)

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Minimal Requirements for Preventive Strategies Benefit Efficacy in preventing cancer and associated morbidity/mortality Risk Lack of adverse side effects that increase morbidity/mortality from other diseases, short- and long-term (major side effects) Tolerability of intervention (minor side effects affecting compliance)

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Efficacy: How Do We Identify New Agents? Knowledge of mechanism Example: HPV vaccine and cervical cancer Need: understanding molecular pathogenesis Preclinical (in vitro and animal models) Example: NSAID treated carcinogenesis and transgenic models Need: models reflective of complexity of human disease Observational epidemiology (cohort and case-control studies) Example: NSAIDs and colon cancer incidence/mortality Secondary endpoints from clinical trials (including other diseases) Example: Tamoxifen/raloxifene and breast cancer

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Targeting Inflammation for Lung Cancer Prevention: Rationale Animal data showing role for steroids in cancer prevention 1970’s – skin Early 1990’s – lung (oral steroids) Late 1990’s – lung (inhaled steroids) Epidemiology/Human data – Mainly negative (but studies of short exposure duration) VA cohort with COPD (n=10,474) – HR 0.39 (95% CI, 0.16-0.96) Parimon T et al., AJRCCM 175:712, 2007

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Effect of Budesonide on Mouse Lung Tumorigenesis Pereira et al., Carcinogenesis 2002

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DCP Phase IIb Trial of Budesonide Lam et al. Clin Cancer Res 10:6502, 2004 ●112 smokers with dysplasia (Bronch)●(Spiral CT) Budesonide vs. Placebo x 6mths (Bronch,Spiral CT) ●1o Endpoint: bronchial dysplasia (#sites/grade)2o Endpoints: multiple biomarkers ● # Screened (sputum): 1040Cancers detected: 13 (3.1%) 112 smokers with dysplasia (Bronch) Budesonide vs. Placebo x 6mths (Bronch, Spiral CT) 1o Endpoint: bronchial dysplasia (#sites/grade) 2o Endpoints: multiple biomarkers (Spiral CT) # Screened (sputum): 1040 Cancers detected: 13 (3.1%) DCP Phase IIb Trial of Budesonide Lam et al. Clin Cancer Res 10:6502, 2004

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Effect of Budesonide on Bronchial Histology %

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Phase IIb Budesonide Chemoprevention TrialPI: Giulia Veronesi, European Institute of Oncology ● 202 participants with persistent spiral CT-detected peripheral nodules (Randomize) ● inhaled budesonide vs. placebo x 1 year ● repeat spiral CT ●Primary endpoint: shrinkage of lung nodules -Primary endpoint: shrinkage of lung nodules Randomize 202 participants with persistent spiral CT-detected peripheral nodules inhaled budesonide vs. placebo x 1 year repeat spiral CT Phase IIb Budesonide Chemoprevention TrialPI: Giulia Veronesi, European Institute of Oncology

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Phase IIb Budesonide Chemoprevention TrialLesion Specific Analysis -Overall response negative, but trend toward regression in non-solid lesions (putative precursors of adenocarcinoma)

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Adenocarcinoma Precursor: Atypical Adenomatous Hyperplasia Natural history unknown Localized ground glass opacities on CT: AAH 25%; bronchoalveolar ca 50%; invasive adenoca 10%; fibrosis 15% (Nakajima et al., J Comput Assist Tomogr 2002;26:323) AAH 63%; bronchoalveolar ca 34%; scar 3% (Ohtsuka et al., Eur J Cardio-Thor Surg 2006;30:160)

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Where do we go from here with steroids? Potential reasons for negative trial Intervention doesn’t work (animal and human data in conflict) Formulation does not penetrate peripherally enough Intervention given too late Intervention focused on wrong cohort (next study to focus on ground glass opacities only) Plan Further molecular characterization of AAH/ground glass opacities Long term follow-up of treated participants

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Table 2. Pooled analysis of the effect of allocation to aspirin on the 20-year risk of death due to cancer during and after the trial treatment periods in the 10 502 patients with scheduled treatment duration of 5 years or longer in the three trials with long-term follow-up,[17], [18] and [19] stratified by type of primary tumour and period of follow-up Analysis limited to patients with scheduled duration of trial treatment or 5 years or longer. n=number of cancer deaths. HR=hazard ratio.* Analysis confined to solid (non-haematological) cancers. Effect of Aspirin on Lung Cancer Mortality-Rothwell et al., Lancet 2011;377:31-individual patient data fromtrials of ASA vs. none-lung: f/u 0-10 yrs 0-20 yrsHR 0.68 0.71 (0.50-0.92, p=0.01) (0.58-0.89, p=0.002)adenocarcinoma only-benefit only after 5 yrs

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myo-Inositol Glucose isomer Source of several second messengers & signaling molecules Dietary sources (grains, beans, fruits, rice) Studied in psychiatric conditions (+/-), diabetic neuropathy(+/-), polycystic ovary syndrome (+)

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Rationale for myo-Inositol in Lung Cancer Prevention Efficacy Multiple animal studies show inhibition of carcinogen induced tumors in mice (40-50%) Estensen and Wattenberg, Carcinogenesis 1993;14:1975 Hecht et al., Carcinogenesis 2002;23:1455 Inhibits carcinogenesis in mainstream/sidestream smoke-exposed A/J mice by 53% Witschi H et al., Carcinogenesis 1999;20:1375 Combination with budesonide  efficacy up to 80% Estensen and Wattenberg, Carcinogenesis 1993;14:1975 Witschi et al. Carcinogenesis 1999;20:1375 Wattenberg et al. Carcinogenesis 2000;21:179 Safety Used in multiple short term trials for psychiatric and diabetic neuropathy indications – no toxicity reported Generally Regarded as Safe (GRAS) by US FDA terminology

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Phase I Study of myo-Inositol in Bronchial Dysplasia-Lam et al., CEBP 2006;15:1526 Phase I study (26 participants) tolerable 18 g/d 91% vs. 48% regression dysplasia, P=0.014 (10 participants) BP↓ ~14 mm Hg, independent of meds

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PI3K pathway activation in the airways of smokers with dysplasia Gustafson A M et al. Sci Transl Med 2010;2:26ra25 -PI3K pathway is activated in smokers with dysplasia in airway p<0.001 -Myo-inositol inhibited PI3K activation in normal bronchial airways in smokers with regression of dysplasia (p=0.04)

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Why is this study so important? Does PI3K activation truly identify smokers at risk for cancer? Easier to get normal brushings than to identify dysplasia (sampling bias); do not remove biomarker with procedure Potential to identify “the right” cohort New potential clinical trial model – pathway analysis pre- and post-treatment, smaller # participants, shorter interventions Identify mechanisms of interventions Needs validation!

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Phase IIb myo-Inositol Chemoprevention TrialPI: Stephen Lam, British Columbia Cancer Agency 30+ pack yr. smokers with dysplasia, age >45-79 N=110(Bronch, Spiral CT) myo-inositol 9g bid vs. placebo x 6 mths (Bronch,Spiral CT) 1o Endpoint: bronchial dysplasia (# sites/grade)2o Endpoints: multiple biomarkers (gene expression) Clinical sites: BCCA, Mayo Clinic, New Mexico VA

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Peroxisome Proliferator-Activated Receptor  (PPAR  ) as a Target for Prevention of Aerodigestive Carcinogenesis Pioglitazone – PPARγ agonist approved for type II DM Rationale: Cell lines – induces growth arrest, differentiation (NSCLC) Animal carcinogenesis models 4-NQO rat tongue model; incidence and multiplicity ↓ 10-fold Yoshida et al., Cancer Sci 94:365, 2003 Epidemiology 33% ↓ lung cancer in diabetics using TZDs (RR=0.67; 95% CI, 0.51-0.87); Nonsignificant decrease in colon and prostate cancer Govindarajan et al. JCO 2007;25:1476-81 41-55%↓ HNSCC in diabetics using TZDs Govindarajan R et al. JCO 2007;25:63s

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Pioglitazone in Oral Leukoplakia DCP phase IIa clinical trial - 22 pts., 81% clinical response rate, 79% average ↓size F. Ondrey, U Minn AACR Frontiers Cancer Prev Res, 2007 New trial – phase IIb, 100 person, 6 mths Rx PIs: J Boyle, MSKCC and F Ondrey, U Minn pre post

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Effect of PPARγ Agonists on NSCLC: Animal Models Treatment: -tumor volume ↓ 66.7%-growth delay 104 days Prevention Vinyl carbamate-treated mice 56-64% ↓ in tumor burden in wildtype and p53 mutant animals Ming You et al. Mol Cancer Ther 2010;9:30742

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Current Pioglitazone Clinical Trials (NCI sponsored) Phase IIb oral leukoplakia Pioglitazone 45 mg qd vs placebo x6 months 100 participants; 11 sites 1o Endpoint: clinical and pathologic response PIs: Jay Boyle, MSKCC and Frank Ondrey, UMinn Pilot trial presurgical NSCLC trial Pioglitazone 45 mg qd for 2-6 weeks prior to definitive surgery 20 participants; biomarker endpoints PI: Dennis Wigle, Mayo

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The Continuum of Lung CarcinogenesisOpportunities for Intervention Normal Hyper/Metaplasia Dysplasia Early-Late Cancer

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“For it happens…that in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure.”-N. Machiavelli, The Prince

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Issues in Lung Cancer Screening Lead-time bias=earlier diagnosis but no postponement of death (survival appears longer) Length bias=diagnosis of more indolent disease with longer preclinical phase (better prognosis, better outcome) Overdiagnosis=identification of clinically unimportant lesions that would not be diagnosed otherwise Morbidity/mortality/cost of screening and subsequent work-up

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PLCO CXR Randomized Trial - MortalityOken, M. M. et al. JAMA 2011;306:1865-1873 154,901 participants, PA CXR vs. usual care x 4 screens, 13 yr f/u

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Lung Cancer Screening TrialsX-ray, Sputum Cytology

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Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer

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“An ounce of preventionis worth a pound of cure” -Benjamin Franklin