Validation of a 46 gene expression signature in early-stage non-small-cell lung cancer
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Lung Cancer Presentation by Dr. Edward Kim, Dr. Raphael Bueno and Jennifer Saam at the 15th WCLC in Sydney, Australia
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Validation of a 46 gene expression signature in early-stage non-small-cell lung cancer
- 1. Validation of a 46-gene expression signature in early-stage non-small-cell lung cancer Edward S. Kim, MD Chair, Solid Tumor Oncology and Investigational Therapeutics Donald S. Kim Distinguished Chair for Cancer Research Levine Cancer Institute Carolinas HealthCare System Raphael Bueno, MD Associate Chief, Thoracic Surgery Brigham and Women's Hospital Professor of Surgery Harvard Medical School Jennifer Saam, PhD Medical Science Liaison for Personalized Medicine Medical Services, Myriad Genetic Laboratories
- 2. Agenda 7:00 AM - 7:25 AM Dr. Edward Kim: Welcome; Integrated Prognosis in Early Stage, Resectable Lung Adenocarcinoma 7:25 AM - 7:50 AM Dr. Raphael Bueno: Validation of a Proliferation-based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma 7:50 AM - 8:00 AM Dr. Jennifer Saam: myPlanTM Lung Cancer Overview
- 3. Integrated Prognosis in Early Stage, Resectable Lung Adenocarcinoma Edward S. Kim, MD Chair, Solid Tumor Oncology and Investigational Therapeutics Donald S. Kim Distinguished Chair for Cancer Research Levine Cancer Institute Carolinas HealthCare System
- 4. Early-Stage Lung Cancer Patients Have Poor Outcomes • 35%-50% recurrence rates even in patients with no nodal or other metastatic involvement at time of surgery • No proven benefit of adjuvant chemotherapy in stage IA patients • One controversial study suggests adjuvant chemotherapy provides benefit in Stage IB patients >4cm • Defined need for objective information to identify early-stage patients at greater or less risk of mortality
- 5. Old Staging vs. New Staging 5th edition • T1 <3 cm • T2 >3 cm 7th edition • T1a <2 cm • T1b >2 to 3 cm • T2a >3 to 5 cm • T2b >5 to 7 cm
- 6. Current Treatment Guidelines for Stage I-II NSCLC IA: CT Observation Surgical Resection IB: CT Observation or adjuvant chemotherapy1 II: Adjuvant chemotherapy 1 High-risk patients are defined by poorly differentiated tumors, vascular invasion, wedge resection, tumors > 4 cm, visceral pleural involvement Pisters KMW, Evans WK, Azzoli CG, et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non–small-cell lung cancer guideline. J Clin Oncol. 2007;25:5506-5518.
- 7. Treatment Dilemma Is there benefit to molecular understanding of the aggressiveness of early stage lung cancer?
- 8. Cell Cycle Progression (CCP) Score • RNA expression profile of cell cycle genes measured by multiplex, quantitative RT-PCR • Hypothesis based gene selection • Validated in multiple tumor types – Prostate – Lung – Breast
- 9. Cell Cycle Progression (CCP) Score • Why Cell Cycle Progression Genes? –Cell cycle genes are the major component of most prognostic signatures –Measures cancer aggressiveness based on cell division • CCP Score –RNA expression profile based on: • 31 genes induced during cell cycle • 15 housekeeping genes for normalization –Validated on FFPE preserved surgical specimens –For adenocarcinoma
- 10. Cell Cycle Progression Genes • BUB1B • RRM2 • DLGAP5 • BIRC5 • KIF20A • PLK1 • TOP2A • TK1 • C18orf24 • RAD54L • CDCA3 • CDC20 • ORC6L • CDCA8 • CENPM • RAD51 • CEP55 • DTL • PRC1 • PBK • ASF1B • FOXM1Z • CDzqKN3 • CDC2 • KIF11 • KIAA0101 • NUSAP1 • CENPF • ASPM • MCM10 • PTTG1
- 11. Verification Data: Cohorts (Stage I and II patients) 1. Publicly available microarray data – Director’s consortium (US) N=256 – GSE31210 (Japan) N=204 2. Clinical FFPE samples from surgical resection – MD Anderson cohort N=207 – Institute of European Oncology cohort (Milan, IT) N=174
- 12. Adenocarcinoma Has a Wide CCP Score Distribution CCP Distribution in Adenocarcinoma
- 13. CCP Score Predicts Lung Cancer Death Study N Deaths HR* 95% CI CCP univariate p-values CCP multivariate p-values Director’s Consortium 256 71 2.02 (1.29-3.17) 0.0001 0.002 GSE31210 204 25 2.16 (1.32-3.53) 0.001 0.003 MDACC-IEO 381 62 1.92 (1.18-3.10) 0.0003 0.007 • CCP is significant both as a univariate predictor and in a multivariate model in all three cohorts • CCP provides additional information to usual clinical factors HR are reported for the interquartile range Events are cancer-related death within 5 years of surgery
- 14. Multi Variate Model: MDACC and IEO Combined DS ~ CCP + Age + Gender + Smoking Status + TNM Stage + Adjuvant Treatment + Tumor Size + Pleural Invasion + Cohort + Stage: Treatment Interaction terms for CCP: Stage, and CCP:cohort were tested but were not significant at the 5% level
- 15. MDACC and IEO Combined Deaths: 62/381 Univariate Multivariate Age 0.03 0.12 Gender 0.002 0.01 Smoking 0.32 0.99 Stage 0.004 0.15 Treatment 0.52 0.13 Tumor Size 0.007 0.39 Pleural Inv. 0.01 0.009 Cohort 0.43 0.61 Stage:Treatment NA 0.09 0.0003 0.007 2.10 (1.39-3.17) 1.92 (1.18-3.10) CCP CCP HR* (95% CI) • In this cohort, gender, pleural invasion and CCP are significant in both the univariate and multivariate models * Standardized Hazard Ratio
- 16. CCP Score by Stage stage IA, n=184 stage IB, n=153 stage II, n=44 •There is a wide CCP score distribution across stages •CCP score adds significant information to stage
- 17. Derivation of a Combined Score (CCP+Stage) • Analysis of untreated patients from Director’s Consortium cohort (DCC) and the clinical data set (MDACC/IEO). • The two variables are weighted by the hazard ratios from a Cox PH analysis with 5-year disease-specific survival. Prognostic score = 0.33 * CCP score + 0.52 * stage Stage was used as numerical variable (1=IA, 2=1B, 3=IIA, 4=2B) CONFIDENTIAL
- 18. 5-year Risk of Lung Cancer Specific Mortality Based on Prognostic Score Prognostic Score
- 19. 5-year Lung Cancer Mortality Risk MDACC-IEO NSCLC Cohort Data on file.
- 20. Summary • CCP expression score is prognostic for lung cancer survival in 3 lung adenocarcinoma data sets. • A combination of pathological stage and the CCP expression score, which produces a prognostic score (PS) that is a more effective predictor of post-surgical risk of cancer specific death than pathological stage alone. • A more precise risk assessment can give better guidance in balancing treatment related risks with disease-specific survival.
- 21. Validation of a Proliferation-based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma Raphael Bueno, MD Associate Chief, Thoracic Surgery Brigham and Women's Hospital Professor of Surgery Harvard Medical School
- 22. Methods Design: • Patient clinical and outcome data were blinded. • Pre-determined Statistical Analysis Plan (SAP) archived with files of finalized clinical data and CCP scores prior to unblinding. Patient Population: • Stage I-II NSCLC ADC by 7th edition IASLC staging • Complete surgical resection • No neo-adjuvant treatment • No adjuvant chemotherapy or radiation within 12 weeks of surgery • Brigham and Women’s and Royal Infirmary at Edinburgh (RIE) Samples: • FFPE tumor specimens • Processed in the CLIA-certified laboratory • 650 patients • 152 events
- 23. Demographic Information Table 1. Demographic and clinical data for the two patient cohorts in the validation study * Pleural invasion data were not available for 17 patients.
- 24. CCP and Stage Are Significant Predictors of 5-year Lung Cancer Mortality Table 2. The CCP score is a significant prognostic marker after adjustment for clinical variables. Results from univariate and multivariate Cox proportional hazards analysis. * Hazard ratio is reported per interquartile range of the CCP score. # Hazard ratio is reported per cm, rounded to the nearest mm. Multivariate analysis, and univariate analysis of pleural invasion, included 633 patients with 147 events. All other univariate analyses included 650 patients with 152 events.
- 25. Significance of Prognostic Score Table 3. The Prognostic Score captures significant prognostic information that is not provided by stage alone. Significance of the Prognostic Score and stage in univariate and bivariate models. Analyses included 650 patients with 152 events. * Hazard ratio is reported per interquartile range of the PS score. • Prognostic Score, Combining Stage and CCP Captures Significant Information that is not Captured by Stage Alone • Prognostic score is predictive of 5-year mortality
- 26. 5-year Lung Cancer Mortality as Predicted by the Prognostic Score
- 27. Low versus High Prognostic Score Low PS (n=328) High PS (n=322) P-Value = 3.8 x 10-6 • Patients in the Low PS group had significantly more favorable 5-year survival than patients in the High PS group
- 28. 5-year Lung Cancer Mortality Risk BWH-RIE NSCLC ADC Prognostic Score Risk Stage Min Mean IA 11% 18% IB 17% 28% IIA 27% 42% IIB 38% 60% Max 34% 43% 62% 68%
- 29. Summary • Prognostic Score (PS) was significantly predictive of 5-year lung cancer mortality, and was significantly more predictive than stage alone (P-Value 2.8×10-11) • Patients in the low PS group had significantly more favorable 5-year survival than patients in the high PS group (P-Value = 3.8 x 10-6) Survival Mortality Low Risk 82% 18% High Risk 65% 35% PS Group • PS improves risk stratification compared to pathological stage alone.
- 30. Jennifer Saam, PhD Medical Science Liaison for Personalized Medicine Medical Services, Myriad Genetic Laboratories
- 31. myPlanTM Lung Cancer Overview • myPlanTM Lung Cancer is a RNA expression profile of cell cycle genes measured by multiplex, quantitative RT-PCR, validated for stage I and II non-small cell lung adenocarcinoma without preoperative radiation therapy and /or chemotherapy. • FFPE blocks or slides are sent to Myriad where the analysis is performed in a CLIA-certified laboratory. • Patient results are sent as either a High or Low myPlanTM Lung Cancer Prognostic Score, which predicts the risk of 5-year lung cancer specific mortality. • myPlanTM Lung Cancer will be available in the United States via an early access Clinical Experience Program mid-November 2013.
- 32. Questions?
- 33. Result example
Editor's Notes
- Cisplatin based regimens recommended for adjuvant chemotherapy.
- Is there interest in having more information to make this decision?How involved are patients in making this decision?
- Myriad’s signature was thoughtfully designed rather than based on a signature from a specific cohort. In a comparison of multiple signatures to assess aggressiveness in breast cancer, Mosely et al found that while each signature had different genes, all had a large number of cell cycle genes and these genes gave the each signature most of its power.Myriad has validated the ability of CCP to measure cancer aggressiveness in different tumor types especially prostate, lung and breast.
- This is a list of the cell cycle progression genes included in the CCP RNA expression profile.
- CCP shows a wide distribution in lung cancer indicating it will be able to identify high and low risk patients.
- This equations describes the factors used in the multivariate model.
- This bar chart examines CCP score by stage. While CCP for stage II tumors is shifted to higher scores than iA tumors, there is still substantial overlap, showing that CCP score is adding information to stage.
- To derive the most useful information for physicians and patients, we looked at combining clinical factors with CCP to provide the most prognostic information. We looked at untreated patients from the Director’s Consortium and the clinical data (MDACC/IEO). The most prognostic model combined stage and CCP score as shown in the equation at the bottom of the slide.The algorithm for deriving a combined score was developed from the Director’s cohort microarray data and the training set from MDACC and IEO.CCP and stage from the COX proportional hazard analysis were used to develop a model that would best predict 5-year lung cancer mortality.Stage was used as a numerical value and CCP was used as a continuous variable.This algorithm with be validated in the two current studies the CCP scores from DCC were centered by processing site and scaled by the ratio of standard deviations for the CCP score between the training set and DC cohort.
- This shows the risk curve for 5-year lung cancer mortality using the model combining CCP score and stage. CCP score and stage each contribute about 50% to the model.
- This graph shows stage risk alone along the y-axis and the risk based on the combined score (stage + CCP) along the x-axis. By stage alone all IA patients have a 13% risk (vertical) but by stage + CCP IA patients have a 7%-23% risk (horizontal). In stage IB patients, the light blue squares are tumors over 4 cm. These tumors are spread over the risk showing that size alone is not showing the full picture.
- The patients were from Brigham and Women’s Hospital and the Royal Infirmary at Edinburgh. They were stage I and II patients who were surgically resected and did not have neo-adjuvant or adjuvant treatment.FFPE specimens were used in the RNA expression assay.This validation study was conducted with a pre-determined statistical plan in which patient clinical and outcome data were blinded. This cohort included 650 patients with 152 events of death from lung cancer or death after recurrence from lung cancer.
- This slide provides the demographic information for the 2 cohorts. While the two cohorts are largely similar, the Edinburgh cohort had more stage II patients. The Brigham and Women’s cohort is particularly enriched for stage 1A patients.All patients were untreated in this cohort.
- In this cohort both CCP and stage were significant in the univariate and multivariate analysis.Tumor size was not significant in the multivariate analysis.
- The prognostic score was developed in the previous study presented by Dr. Kim. This slide shows that the prognostic score is predictive of 5 year lung cancer mortality in both the univariate and bi-variate analysis. Stage is no longer significant in the bi-variate analysis because the prognostic score is encompassing the useful information from stage.
- The risk curve was developed from the Brigham and Women’s and Royal Infirmary of Edinburgh cohort based on the algorithm developed in the MDACC and IEO cohorts. This curve shows the risk of 5-year lung cancer mortality based on the prognostic score (which combines stage and CCP). A cutoff between high and low risk was set at about 22% risk of death. This corresponds with riskiest 15% of the stage IA patients which is approximately the percentage of these patients that die within 5 years from lung cancer (although the actually mortality in this cohort is 18%--the cut off was set before the samples were unblinded). The average risk in the low risk group is 18% as compared to 35% in the high risk group.
- Kaplan Meier curve of the low vs. high risk groups. The difference between the groups is significant with p=3.8X10-4. There are 326 patients in the low risk group and 322 patients in the high risk group.
- This slide shows the value CCP adds to stage alone. The blue triangles are stage 1A patients, green squares are stage 1B, yellow squares are 2A and orange asterisks are 2B. By stage alone, the 1A patients have an 18% risk of death from lung cancer within5 years from surgery (y-axis). Adding CCP shows the range of risk in the 1A patients (11-34% in stage 1A patients). Stage 1B patients have a 28% risk based on stage alone but a 17-43% risk when the prognostic score is used. See the table on the next slide. CCP adds to stage alone. The overall risk for stage IA patients in this cohort was 18% but some had an 11% risk and other had a 34% risk.