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David Jablons, M.D.Professor and Chief, Section of General Thoracic SurgeryAda Distinguished Professor and Program LeaderThoracic Oncology Laboratory Helen Diller Family Comprehensive Cancer CenterUniversity of California, San FranciscoLarge-Scale International Validation of a qPCR-Based Genetic Assay Prognostic of Survival in Resected Non-Squamous Cell NSCLC

A practical genomic prognostic assay361 stage I-IV non-squamous FFPE samples(UCSF Training Cohort)Measure expression of 14 cancer pathways + reference genes(CLIA-certified Laboratory)

A practical genomic prognostic assay361 stage I-IV non-squamous FFPE samples(UCSF Training Cohort)Measure expression of 14 cancer pathways + reference genes(CLIA-certified Laboratory)L2-penalized Cox Proportional Hazards Modeling

A practical genomic prognostic assay361 stage I-IV non-squamous FFPE samples(UCSF Training Cohort)Measure expression of 14 cancer pathways + reference genes(CLIA-certified Laboratory)L2-penalized Cox Proportional Hazards Modeling

A practical genomic prognostic assay361 stage I-IV non-squamous FFPE samples(UCSF Training Cohort)Measure expression of 14 cancer pathways + reference genes(CLIA-certified Laboratory)L2-penalized Cox Proportional Hazards ModelingIndependent ValidationKaiser Northern California433 stage IChina Clinical Trials Consortium1006 stage I-III

A practical genomic prognostic assay361 stage I-IV non-squamous FFPE samples(UCSF Training Cohort)Measure expression of 14 cancer pathways + reference genes(CLIA-certified Laboratory)L2-penalized Cox Proportional Hazards ModelingIndependent ValidationKaiser Northern California433 stage IChina Clinical Trials Consortium1006 stage I-IIIparaffin-tissues

A practical genomic prognostic assay361 stage I-IV non-squamous FFPE samples(UCSF Training Cohort)Measure expression of 14 cancer pathways + reference genes(CLIA-certified Laboratory)L2-penalized Cox Proportional Hazards ModelingIndependent ValidationKaiser Northern California433 stage IChina Clinical Trials Consortium1006 stage I-IIIqPCRparaffin-tissues

A practical genomic prognostic assay361 stage I-IV non-squamous FFPE samples(UCSF Training Cohort)Measure expression of 14 cancer pathways + reference genes(CLIA-certified Laboratory)L2-penalized Cox Proportional Hazards ModelingIndependent ValidationKaiser Northern California433 stage IChina Clinical Trials Consortium1006 stage I-IIIqPCRparaffin-tissuesblinded

Study Cohorts (n=1800)

UCSF Training CohortKaiser Validation CohortChina Validation CohortEligible Patients3614331006Successful RNA recovery337 (93.4%)420 (97.0%)967 (96.1%)

Age at Resection67.4 (10.5)66.6(9.3)58.3(10.8)Females200 (59.3%)229 (54.5%)366 (37.9%)Smoking HistoryYes224 (66.5%)355 (84.5%)492 (48.9%)No57 (16.9%)36 (8.6%)403 (40.1%)Unknown56 (16.6%)29 (6.9%)72 (7.2%)Median follow-up (months)46.470.037.8Deaths at 5 years139 (41.2%)179 (42.6%)406 (42.0%)HistologyAdenocarcinoma278 (82.5%)325 (77.4%)881 (87.6%)Large Cell17 (5.0%)15 (3.6%)17 (1.7%)Mixed10 (3.0%)15 (3.6%)46 (4.6%)NSCLC NOS32 (9.5%)65 (15.5%)23 (2.3%)AJCC StageI223 (66.2%)420 (100%)471 (46.8%)II41 (12.2%)0222 (22.1%)III58 (17.2%)0266 (26.4%)IV9 (2.7%)00Undetermined6 (1.8%)08 (0.8%)Cohort Mean (Standard Deviation)

Algorithm Development UCSF CohortOverall survival (%):80% versus 35%, based on 14 cancer-related oncogenes

Blinded Assay ValidationKaiser Cohort (n = 420)China Cohort (n = 967) Overall Survival75% versus 48% 80% versus 45%

Stage Independence (China)Stage I disease (low risk = 83.0% [73.889.1]; intermediate risk = 67.7% [54.877.7]; high risk = 64.6% [57.970.5])Stage II disease (low risk = 54.2% [30.173.2]; intermediate risk = 45.8% [26.263.4]; high risk = 38.1% [29.446.8])Stage III disease (low risk = 53.3% [32.670.3]; intermediate risk = 43.3% [27.258.5]; high risk = 24.0% [17.530.9])

Multivariate ModelsKaiser cohort (n = 420)China cohort(n = 967)

PredictorHR95% CILR test p-valueHigh Risk Category*1.931.23-3.040.010Female Sex0.650.48-0.870.004Age (years)1.041.02-1.06

China stage I-IIA (n=540)New TNMM Staging

TNM StageMulti-Gene AssayNew TNMM StageIALow RiskTNMM IAIBLow Risk

IAIntermediate + High RiskTNMM IBIBIntermediate + High RiskIIALow Risk

IIAIntermediate + High RiskTNMM IIA

Conventional StagingNo data support the use of adjuvant treatment in patients with stage IA tumors as defined by conventional criteriaUse of such treatment in patients with stage IB disease is lent support by only controversial evidence

New TNMM StagingThe addition of the molecular assay gave better risk discrimination than did NCCN risk criteria alone

Genetic Assay Outperforms Conventional Methods The molecular assay was the strongest predictor of 5 year mortality compared with standard criteria (sex, age, smoking status, etc)Outperformed the NCCN guidelines used to identify high-risk patients with stage I disease

ConclusionsThere is a clear need to improve NSCLC stagingA robust, practical assay prognostic of survival after resection has been developed using qPCR and paraffin-tissuesThis multi-gene assay has been independently validated in two large international cohortsThe multi-gene assay can outperform conventional risk factors / staging and may lead to personalized therapies for patients with early stage non-squamous NSCLC

Thank youUCSF Thoracic Oncology LaboratoryDavid JablonsMichael MannPatrick PhamMike MulvihillMarc SegalRoshni RayKirk JonesDan RazZhidong XuThierry JahanBiao HeKaiser Northern CaliforniaStephen Van Den EedenCharles QuesenberryLaurel HabelChina Clinical Trials ConsortiumJianxing HeZhi-Hua ZhuWen GaoHuanrong ZhangBo SuQiuhua DengZongfei WangJiangfen ZhouHuiling LiMei-Chun HuangChe-Chung YehPinpoint GenomicsDavid BerrymanJerry HurstFatemeh Zaiei

Sunday, February 12, 2012Hollywood, FloridaCo-ChairsRogerio C Lilenbaum, MDMark A Socinski, MDCo-Chair and ModeratorNeil Love, MDFaculty Walter J Curran Jr, MDDavid Jablons, MDMark G Kris, MDSuresh Ramalingam, MDAlan B Sandler, MD

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