1 / 20

Quantitative multi-gene RT-PCR assay for recurrence prediction in stage II colon cancer

This study presents a multi-gene expression assay that predicts recurrence risk in stage II colon cancer patients. The selection of genes was based on large studies, and the assay was validated independently in the QUASAR study.

kimberlymurray
Download Presentation

Quantitative multi-gene RT-PCR assay for recurrence prediction in stage II colon cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. A quantitative multi-gene RT-PCR assay for prediction of recurrence in stage II colon cancer: Selection of the genes in 4 large studies and results of the independent, prospectively-designed QUASAR validation study David Kerr1, Richard Gray2, Philip Quirke3, Drew Watson4, Greg Yothers5, Ian Lavery6, Mark Lee4, Michael O'Connell5, Steven Shak4, Norman Wolmark5 and the Genomic Health & QUASAR Colon Teams 1. University of Oxford, Oxford, UK & SIDRA, Qatar; 2. Birmingham Clinical Trials Unit, Birmingham, UK; 3. Leeds Institute of Molecular Medicine, Leeds, UK; 4. Genomic Health, Inc., Redwood City, CA; 5. National Surgical Adjuvant Breast and Bowel Project, Pittsburgh, PA; 6. Cleveland Clinic, Cleveland, OH

  2. Disclosures D. Kerr, consultant, educational grant, Genomic Health, Inc. R. Gray, educational grant, Genomic Health, Inc. P. Quirke, consultant, educational grant, Genomic Health, Inc. D. Watson, employee, Genomic Health, Inc. G. Yothers, consultant, educational grant, Genomic Health, Inc. I.C. Lavery, consultant, educational grant, Genomic Health, Inc. M. Lee, employee, Genomic Health, Inc. M. J. O'Connell, consultant, educational grant, Genomic Health, Inc. S. Shak, employee, Genomic Health, Inc. N. Wolmark, consultant, educational grant, Genomic Health, Inc.

  3. The Need for Individualized Therapy in Stage II Colon Cancer • The challenge: Which stage II colon cancer patients should be treated with adjuvant chemotherapy? • 75-80% cured with surgery alone, but no method to identify them • Benefit of chemotherapy is small* and no consensus in guidelines on who to treat • Chemotherapy has significant toxicity • Today, decision to give chemotherapy subjectively based on: • Clinical/pathologic markers of risk which are inadequate • Not informative for majority of patients • Patient age, co-morbidities, preferences * Lancet 2007 370:2020-9

  4. Stage II Colon Cancer: Overall Goal • To develop and validate a multi-gene expression assay which improves treatment decisions for patients with stage II colon cancer, providing: • Individualized assessment of recurrence risk following surgery • Identification of patients with differential 5FU/LV benefit • Independent clinical value in the context of other measures such as T-stage and MMR/MSI • Optimized for fixed, paraffin-embedded colon tumor tissue

  5. Quencher Reporter Forward Primer Probe Q R Polymerization Reverse Primer R Q Strand Displacement and Cleavage of Probe Q R Polymerization Completed Real-time RT-PCR for RNA Quantification from Fixed Paraffin-Embedded Tumor Tissue Cronin et al. Am J Pathol. 2004;164:35-42.

  6. Development and Validation of a Multi-Gene RT-PCR Colon Cancer Assay Colon Cancer Technical Feasibility Development Studies Surgery Alone NSABP C-01/C-02 (n=270) Cleveland Clinic (n = 765) Development Studies Surgery + 5FU/LV NSABP C-04 (n=308) NSABP C-06 (n=508) Selection of Final Gene List & Algorithm Standardization and Validation of Analytical Methods Clinical Validation Study – Stage II Colon Cancer QUASAR (n=1,436) Test Prognosis and Treatment Benefit

  7. Assessment of 761 Candidate Genes in 1,851 Patients in the Development Studies to Yield Final Pre-specified Assay for Validation in QUASAR 48 Recurrence and 66 Treatment Benefit Genes Significant Across Development Studies Modeling and Analytical Performance FINAL ASSAY 7 Recurrence Genes 6 Treatment Benefit Genes 5 Reference Genes RECURRENCE SCORE (0-100) TREATMENT SCORE (0-100)

  8. QUASAR: Evaluable Stage II Colon Cancer Patients Parent QUASAR study n=3,239 Patients with collected blocks n=2,197 (68%) 707 cases stage III and rectal cancer Confirmed stage II colon cancer n=1,490 (69%) 54 excluded (3.6%): 29 synchronous tumors 8 insufficient tissue 7 identifier queries 6 RNA quality/quantity 4 ineligible histology Final evaluable population n=1,436

  9. QUASAR: Demographics of 1,436 Evaluable Patients Two Arms are Balanced

  10. QUASAR: 5FU/LV Chemotherapy Benefit in the 1,436 Evaluable Stage II Colon Cancer Patients DFS RFI 1.0 1.0 0.8 0.8 0.6 Proportion Event Free 0.6 Proportion Event Free 0.4 0.4 0.2 0.2 Treatment Surgery Chemo Treatment Surgery Chemo 0.0 0.0 0 1 2 3 4 5 0 1 2 3 4 5 Years Years OS 1.0 0.8 0.6 Proportion Event Free 0.4 0.2 Treatment Surgery Chemo 0.0 0 1 2 3 4 5 Years

  11. RECURRENCE SCORE Calculated from Tumor Gene Expression STROMAL FAP INHBA BGN CELL CYCLE Ki-67 C-MYC MYBL2 GADD45B REFERENCE ATP5E GPX1 PGK1 UBB VDAC2 QUASAR: Pre-Specified Primary Endpoint: Recurrence Risk Is there a significant relationship between the risk of recurrence and the pre-specified continuous Recurrence Score in stage II colon cancer patients randomized to surgery alone?

  12. 35% 30% 25% 20% Risk of Recurrence at 3 years 15% 10% 5% | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 0% 0 10 20 30 40 50 60 70 Recurrence Score QUASAR Results: Colon Cancer Recurrence Score Predicts Recurrence Following Surgery Prospectively-Defined Primary Analysis in Stage II Colon Cancer (n=711) p=0.004

  13. QUASAR Results: Recurrence Risk in Pre-specified Recurrence Risk Groups (n=711) 1.0 0.8 0.6 Proportion Event Free 0.4 Kaplan-Meier Estimates (95% CI) of Recurrence Risk at 3 years Recurrence Risk Group 0.2 Low 12% ( 9% -16%) Comparison of High vs. Low Recurrence Risk Groups using Cox Model: HR = 1.47 (p=0.046) Intermediate 18% (13%-24%) High 22% (16%-29%) 0.0 0 1 2 3 4 5 Years

  14. QUASAR Results: Clinical/Pathological Covariates and Recurrence Pre-specified Multivariate Analysis, Surgery Alone Patients (n=605)

  15. QUASAR Results: Recurrence Score and Alternative Endpoints Disease Free Survival Overall Survival

  16. QUASAR Results: Prediction of Differential 5FU/LV Benefit for Treatment Score • Continuous Treatment Score and Treatment Benefit with 5FU/LV • Treatment Score by Treatment Interaction for RFI: interaction p = 0.19 • Selected Secondary Analyses • Treatment Score by Treatment Interaction not significant when adjusted for prognostic covariates • Treatment Score by Treatment Interaction not significant for DFS (interaction p=0.12) or OS (interaction p=0.15)

  17. QUASAR Results: Prediction of Differential 5FU/LV Benefit for Recurrence Score • Secondary Analysis: RS as a predictor of Chemotherapy Benefit: interaction p=0.69 • No significant difference in PROPORTIONAL benefit of chemotherapy was observed at low RS and at high RS

  18. QUASAR Results: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer 45% T4 stage (13%) 40% 35% 30% 25% T3 and MMR proficient (76%) Risk of recurrence at 3 years 20% 15% 10% MMR deficient (11%) 5% 0% 0 10 20 30 40 50 60 70 Recurrence Score NB. 17 patients had both T4 and MMR Deficient tumors and had recurrence risks that were similar to those for patients with T3 and MMR proficient tumors and were not included in the plot

  19. Summary and Conclusions • The prospectively-defined continuous Recurrence Score has been validated as a predictor of recurrence in stage II colon cancer patients following surgery, and provides independent value beyond available measures • A separate score, based on a distinct set of 6 genes, was not validated for prediction of differential 5FU/LV benefit • The continuous RS provides individualized assessment of recurrence risk and will have the greatest clinical utility when used in conjunction with T stage and Mismatch Repair (MMR/MSI), particularly for the majority of patients for whom those markers are uninformative (~70% of pts) • This is the first demonstration that a prospectively defined gene expression assay can independently predict recurrence in colon cancer Implications for Clinical Practice

  20. Acknowledgements • QUASAR Study Team • Laura Magill • Kelly Handley • Zoe Gray • Claire Beaumont • Rachel Midgley • NSABP Study Team • Joe Costantino • Soon Paik • Cleveland Clinic Study Team • Genomic Health Colon Team • Kim Langone • Rick Baehner • Joffre Baker • Margarita Lopatin • Carl Yoshizawa • Wayne Cowens • Lauren Intagliata • Claire Pomeroy • MRC, UK and CRUK for funding QUASAR trial • Patients and investigators who participated in the NSABP, Cleveland Clinic, and QUASAR studies

More Related