Charles M. Perou, Ph.D. Departments of Genetics and Pathology Lineberger Comprehensive Cancer Center University of North Carolina Chapel Hill, North Carolina, USA Alternate Gene Signatures, or Not
Charles M. Perou Departments of Genetics and Pathology Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Disclosures Equity Interest/Stock = University Genomics/Bioclassifier LLC, GeneCentric Diagnostics Leadership Position = University Genomics/Bioclassifier LLC, GeneCentric Diagnostics Intellectual Property = licensed IP to Bioclassifier and NanoString Technologies, Inc., and to GeneCentric Diagnostics Consultant = Sanofi Aventis, Beckman Coulter, NanoString Technologies, Inc.
Breast Cancer Gene Expression Profiling Tests Include: 1. The PAM50 Intrinsic Subtypes: LumA, LumB, Basal-like, HER2-enriched, Normal-like (Parker et al., JCO 2009) 2. The PAM50 Risk of Recurrence (ROR) (Parker et al., JCO 2009) 3. 21 Gene Recurrence Score (Paik et al., NEJM, 2004) 4. 70 Gene Prognostic Signature (van de Vijver et al., NEJM, 2002) 5. Genomic Grade Index (Sotiriou et al. JNCI 2006) 5. Breast Cancer Index: 2-gene ratio plus 5-gene proliferation (Ma et al., CCR 2008) 6. EndoPredict (Filipits et al., CCR 2011) 7. and many more that can t be covered here. See Prat et al., Nature Reviews Clinical Oncology, 2011
Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes. Parker et al., J Clinical Oncology; 27:1160-1167 2009 1. The qrt-pcr assay consists of 50 genes and 5 centroids (provided at https://genome.unc.edu/) Luminal A 2. The CV classification concordance of the 50 genes by qrt-pcr compared with 2000 genes by microarray was 93% 3. The assay works using RNA from FFPE materials or fresh frozen tissues. Joel Parker
Prognostic Risk Classification Strategy (ROR) Similarity to the subtypes are used as variables in the prognostic model where the outcome is Risk of Relapse (ROR): (Model 1) ROR-S = b 1* Basal + b 2* HER2 + b 3* LumA + b 4* LumB (Model 2) ROR-T = b 1* Basal + b 2* HER2 + b 3* LumA + b 4* LumB + b 5* Size (Model 3) ROR-PT = b 1* Basal + b 2* HER2 + b 3* LumA + b 4* LumB + b 5* Size + b 6* Proliferation Weights for each term are learned from a training data set using a Cox model with Ridge Regression 1 The weighted sum is assigned as the ROR score for a test case and a threshold may be applied for class assignment 1 Ridge regression with Cox model: Tibshirani, Statistics in Medicine 1997 Comparative study: Bovelstad et al. Bioinformatics 2007 Parker et al. J Clin Oncol; 27:1160-1167 2009
Risk Classification by PAM50 ROR T + ER + Grade ROR-S ROR-T ROR-T + Grade ROR-T score N=558 no adjuvant systemic therapy and node negative test cases C-index: FE Harrell et al., JAMA 1982; 247(18). The c-index is the proportion of all pairs of subjects whose survival time can be ordered such that the subject with the higher predicted survival is the one who survived longer (taken from Harrell, Regression Modeling Strategies, Springer Series in Statistics). Parker et al. J Clin Oncol; 27:1160-1167 2009
A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor positive breast cancer Torsten O. Nielsen, Joel S Parker, Samuel Leung, David Voduc, Mark Ebbert, Tammi Vickery, Sherri R. Davies, Jacqueline Snider, Inge J. Stijleman, Jerry Reed, Maggie C.U. Cheang, Elaine R. Mardis, Charles M. Perou, Philip S. Bernard, Matthew J. Ellis, Clinical Cancer Research 2010 FFPE archive with ~20 years of follow up
ER+, tamoxifen treated, node-negative Nielsen et al., CCR 2010
Prognostic Significance of Progesterone Receptor Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer, Prat et al., January 10, 2013 vol. 31 no. 2 203-209 JCO 2012 the new proposed IHC-based definition of Luminal A is ER+ and/or PR+ HER2- Ki67<14% PR>20%
Prognostic Significance of Progesterone Receptor Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer, Prat et al., January 10, 2013 vol. 31 no. 2 203-209 JCO 2012
Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor-Positive Breast Cancer Paik et al., Journal of Clinical Oncology, 24: 1-12 (2006). NSABP B-20 (651 tumor FFPE samples) All Patients RS low = (CMF) RS intermediate RS high
Accrual completed TAILORx on Oct 25 Study Design th 2010 Target: 10,000 expected to report in 2014 Pre-REGISTER ONCOTYPE DX ASSAY REGISTER Specimen Banking TAILORx Study Design ECOG/Inter-group PI: J. A. Sparano Secondary Study Group 1 RS < 11 ~29% of Population Primary Study Group RS 11-25 ~44% of Population Secondary Study Group 2 RS > 25 ~27% of Population ARM A Hormonal Therapy Alone RANDOMIZE Stratification Factors: Tumor Size, Menopausal Status, Planned Chemo, Planned Radiation ARM D Chemotherapy Plus Hormonal Therapy ARM B Hormonal Therapy Alone ARM C Chemotherapy Plus Hormonal Therapy
Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Albain et al., Lancet Oncology, 2010 (SWOG 8814, 376 tumor FFPE samples) Tamoxifen (T) vs. CAFx6 - Tamoxifen (CAF-T)
A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer With Recurrence Score (RS) of 25 or Less. ClinicalTrials.gov Identifier: NCT01272037 Estimated Accrual = 4000
Cost Economic Analysis of 21 Gene RS Using the 21-gene assay to guide adjuvant chemotherapy decision-making in early-stage breast cancer: a cost-effectiveness evaluation in the German setting. Blohmer JU, Rezai M, Kümmel S, Kühn T, Warm M, Friedrichs K, Benkow A, Valentine WJ, Eiermann W. J Med Econ. 2013;16(1):30-40. doi: 10.3111/13696998.2012.722572. Epub 2012 Sep 11. Cost-utility of the 21-gene recurrence score assay in node-negative and node-positive breast cancer. Lamond NW, Skedgel C, Rayson D, Lethbridge L, Younis T. Breast Cancer Res Treat. 2012 Jun;133(3):1115-23. doi: 10.1007/s10549-012-1989-5. Epub 2012 Feb 24. The effect of Oncotype DX recurrence score on treatment recommendations for patients with estrogen receptor-positive early stage breast cancer and correlation with estimation of recurrence risk by breast cancer specialists. Joh JE, Esposito NN, Kiluk JV, Laronga C, Lee MC, Loftus L, Soliman H, Boughey JC, Reynolds C, Lawton TJ, Acs PI, Gordan L, Acs G. Oncologist. 2011;16(11):1520-6. doi: 10.1634/theoncologist.2011-0045. Epub 2011 Oct 20. Breast medical oncologists' use of standard prognostic factors to predict a 21-gene recurrence score. Kamal AH, Loprinzi CL, Reynolds C, Dueck AC, Geiger XJ, Ingle JN, Carlson RW, Hobday TJ, Winer EP, Goetz MP. Oncologist. 2011;16(10):1359-66. doi: 10.1634/theoncologist.2011-0048. Epub 2011 Sep 20. The effects of oncotype DX recurrence scores on chemotherapy utilization in a multi-institutional breast cancer cohort. Ademuyiwa FO, Miller A, O'Connor T, Edge SB, Thorat MA, Sledge GW, Levine E, Badve S. Breast Cancer Res Treat. 2011 Apr;126(3):797-802. doi: 10.1007/s10549-010-1329-6. Epub 2011 Jan 1. CONCLUSIONS: 20-30% of patients have their chemotherapy recommendation changed, typically to not receive chemotherapy. The still controversial suggestion is that this is cost effective in terms of health care costs, improved survival, and for quality-adjusted life expectancy
PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. Bastien et al., BMC Med Genomics. 2012 (n=820)
Responsiveness of intrinsic subtypes to adjuvant anthracycline substitution in the NCIC.CTG MA.5 randomized trial. Cheang et al., Clinical Cancer Res. Apr 15;18(8):2402-12 (2012) CMF vs. CEF CEF better CMF better
PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer. Martin et al., BCRT 2013 GEICAM 9906: FECx6 vs FECx4 plus weekly Paclitaxel (n=820) all patients in CS study all patients by subtype LOW PROLIFERATION (slowest 25% -- First quartile) HIGH PROLIFERATION (other 75%)
Summary 1. Tumor Subtyping is recommended, be it by Gene Expression, or IHC. Only use validated assays 2. Gene expression-based assays are reproducible biomarkers that are providing valuable information for prognosis, and for general chemotherapy sensitivity 3. Gene expression-based assays might provide valuable information for predicting specific chemotherapeutic sensitivity (and schedules) 4. Molecular classifications for prediction are the future, with DNA mutations, copy number, and gene/protein expression being promising methods