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A PAM50-based Chemo-Endocrine Score for Hormone Receptor-
Positive Breast Cancer with an Intermediate Risk of Relapse
Aleix Prat1,2,3, Ana Lluch4, Arran K. Turnbull5, Anita K. Dunbier6, Lourdes Calvo7, Joan Albanell8, Juan de la Haba-Rodríguez9, Angels Arcusa10, José Ignacio Chacón11, Pedro Sánchez-Rovira12, Arrate Plazaola13, Montserrat Muñoz1,2, Laia Paré3, Joel S. Parker14, Nuria Ribelles15, Begoña Jimenez15, Abdul Aziz Bin Aiderus5, Rosalía Caballero16, Barbara Adamo1,2, Mitch Dowsett17, Eva Carrasco16, Miguel Martín18, J. Michael Dixon5, Charles M. Perou14,19,20 and Emilio Alba15. 1Department of Medical Oncology, Hospital Clínic i Provincial, Barcelona, Spain. 2Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. 3Translational Genomics Group, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain. 4Department of Medical Oncology, Valencia University Hospital, Valencia, Spain. 5University of Edinburgh Cancer, Research UK Centre, Edinburgh. 6Department of Biochemistry, University of Otago, Dunedin, New Zealand. 7Department of Medical Oncology, A Coruña University Hospital Complex, A Coruña, Spain. 8Department of Medical Oncology, Hospital del Mar Medical Research Institute-IMIM and Pompeu Fabra University, Barcelona, Spain. 9Department of Medical Oncology, Biomedical Research Institute-IMIBIC, Reina Sofía Hospital Complex, Córdoba, Spain. 10Department of Medical Oncology, Consorci Sanitari de Terrassa, Barcelona, Spain. 11Department of Medical Oncology, Virgen de la Salud Hospital, Toledo, Spain. 12Department of Medical Oncology, Jaén Hospital Complex, Jaen, Spain. 13Department of Medical Oncology, Onkologikoa, Donostia, Spain. 14Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. 15Department of Medical Oncology, Virgen de la Victoria University Hospital, Málaga, Spain). 16GEICAM (Spanish Breast Cancer Research Group), Madrid, Spain. 17Academic Department of Biochemistry, Royal Marsden Foundation Trust, London, United Kingdom. 18Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain. 19Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. 20Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
#, corresponding author: Aleix Prat, MD PhD Department of Medical Oncology Hospital Clínic de Barcelona Casanova 170, 08036 Barcelona, Spain Email: [email protected] Running Title: PAM50-based Chemo-Endocrine Score. Additional files: One supplemental file. Competing interests. C.M.P is an equity stock holder of BioClassifier LLC and University Genomics. C.M.P. has filed a patent on the PAM50 assay. Uncompensated advisory role of A.P. and M.M. for Nanostring Technologies. The other authors declare that they have no competing interests. Authors contributions. Study conception and design: AP, EA and CMP. Acquisition of data: all authors. Analysis and interpretation of data: all authors. All authors were involved in drafting the article or revising it critically for important intellectual content, and approved the final version of the manuscript.
Key words: breast cancer, PAM50, intrinsic subtype, chemotherapy, predictor
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
centering for intrinsic subtyping calling was not possible30. In this dataset, CES vas
evaluated as a continuous variable since it is not affected by centering.
Combined cohort of primary breast cancer
To evaluate the relationship between PAM50 subtype calls, prognosis (ROR-P) and
CES, we combined PAM50 data from 7 independent and previously reported
cohorts1,2,11,20,31-33 representing a total of 6,007 primary tumor samples. CES was evaluated
in each individual cohort, and a combined matrix was created (Supplemental Material).
Statistical analysis
Biologic analysis of gene lists was performed with DAVID 6.7 annotation tool34
using the 543-gene list as background. Association between the expression of each gene
and Miller-Payne response (3 categories) was assessed by a quantitative Significance
Analysis of Microarrays (SAM)35. In both testing datasets, association between each
variable and pCR or clinical/radiological response was assessed by univariate and
multivariable logistic regression analyses. The predictive performance of CES was
evaluated using receiver operating characteristic (ROC) curve analysis. Estimates of
survival were from the Kaplan-Meier curves and tests of differences by the log-rank test.
Univariate and multivariable Cox-models were used to test the independent prognostic
significance of each variable. Reported P values are two-sided.
Results
GEICAM 2006-03 dataset
Sixty-three pre- and post-menopausal patients were evaluated in this study (Table 1). Most patients presented ductal carcinomas (83%), tumor sizes of 2-5 cm (76%),
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
1. TCGA: Comprehensive molecular portraits of human breast tumours. Nature 490:61-70, 2012 2. Prat A, Cheang MCU, Martín M, Parker JS, Carrasco E, Caballero R, et al: Prognostic Significance of Progesterone Receptor–Positive Tumor Cells Within Immunohistochemically Defined Luminal A Breast Cancer. Journal of Clinical Oncology 31:203-209, 2013 3. Ades F, Zardavas D, Bozovic-Spasojevic I, Pugliano L, Fumagalli D, de Azambuja E, et al: Luminal B Breast Cancer: Molecular Characterization, Clinical Management, and Future Perspectives. Journal of Clinical Oncology 32:2794-2803, 2014 4. Prat A, Perou CM: Deconstructing the molecular portraits of breast cancer. Mol Oncol 5:5-23, 2011 5. Prat A, Ellis MJ, Perou CM: Practical implications of gene-expression-based assays for breast oncologists. Nat Rev Clin Oncol 9:48-57, 2012 6. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al: Molecular portraits of human breast tumours. Nature 406:747 - 752, 2000 7. Martín M, Prat A, Rodríguez-Lescure Á, Caballero R, Ebbert MW, Munárriz B, et al: PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer. Breast Cancer Research and Treatment 138:457-466, 2013 8. Prat A, Carey LA, Adamo B, Vidal M, Tabernero J, Cortés J, et al: Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer. Journal of the National Cancer Institute 106, 2014 9. Usary J, Zhao W, Darr D, Roberts PJ, Liu M, Balletta L, et al: Predicting Drug Responsiveness in Human Cancers Using Genetically Engineered Mice. Clinical Cancer Research 19:4889-4899, 2013 10. von Minckwitz G, Untch M, Blohmer J-U, Costa SD, Eidtmann H, Fasching PA, et al: Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. Journal of Clinical Oncology 30:1796-1804, 2012 11. Prat A, Parker JS, Fan C, Perou CM: PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer. Breast Cancer Research and Treatment 135:301-306, 2012 12. Prat A, Fan C, Fernández A, Hoadley KA, Martinello R, Vidal M, et al: Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Medicine 13:1-11, 2015 13. Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, et al: Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor–Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype—ACOSOG Z1031. Journal of Clinical Oncology 29:2342-2349, 2011 14. Dunbier AK, Anderson H, Ghazoui Z, Salter J, Parker JS, Perou CM, et al: Association between breast cancer subtypes and response to neoadjuvant anastrozole. Steroids 76:736-740, 2011 15. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al: Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Annals of Oncology, 2013
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
16. Alba E, Calvo L, Albanell J, De la Haba JR, Arcusa Lanza A, Chacon JI, et al: Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-II study. Annals of Oncology, 2012 17. Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al: American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Journal of Clinical Oncology 25:118-145, 2006 18. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, et al: A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. The Breast 12:320-327, 2003 19. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, et al: Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotech 26:317-325, 2008 20. Hatzis C, Pusztai L, Valero V, et al.: A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. Jama 305:1873-1881, 2011 21. Prat A, Galván P, Jimenez B, Buckingham W, Jeiranian HA, Schaper C, et al: Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay. Clinical Cancer Research, 2015 22. Dunbier AK, Anderson H, Ghazoui Z, Folkerd EJ, A'Hern R, Crowder RJ, et al: Relationship Between Plasma Estradiol Levels and Estrogen-Responsive Gene Expression in Estrogen Receptor–Positive Breast Cancer in Postmenopausal Women. Journal of Clinical Oncology 28:1161-1167, 2010 23. Smith IE, Walsh G, Skene A, Llombart A, Mayordomo JI, Detre S, et al: A Phase II Placebo-Controlled Trial of Neoadjuvant Anastrozole Alone or With Gefitinib in Early Breast Cancer. Journal of Clinical Oncology 25:3816-3822, 2007 24. Turnbull AK, Arthur LM, Renshaw L, Larionov AA, Kay C, Dunbier AK, et al: Accurate Prediction and Validation of Response to Endocrine Therapy in Breast Cancer. Journal of Clinical Oncology, 2015 25. Fan C, Prat A, Parker JS, Liu Y, Carey LA, Troester MA, et al: Building prognostic models for breast cancer patients using clinical variables and hundreds of gene expression signatures. BMC Medical Genomics 4:1-15, 2011 26. Prat A, Parker JS, Fan C, Cheang MCU, Miller LD, Bergh J, et al: Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen. Annals of Oncology 23:2866-2873, 2012 27. Parker JS, Mullins M, Cheang MCU, Leung S, Voduc D, Vickery T, et al: Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes. J Clin Oncol 27:1160-1167, 2009 28. Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T, et al: A Comparison of PAM50 Intrinsic Subtyping with Immunohistochemistry and Clinical Prognostic Factors in Tamoxifen-Treated Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res 16:5222-5232, 2010 29. Prat A, Lluch A, Albanell J, Barry WT, Fan C, Chacon JI, et al: Predicting response and survival in chemotherapy-treated triple-negative breast cancer. Br J Cancer 111:1532-1541, 2014 30. Prat A, Ellis MJ, Perou CM: Practical implications of gene-expression-based assays for breast oncologists. Nat Rev Clin Oncol 9, 2012
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
31. Curtis C, Shah SP, Chin S-F, Turashvili G, Rueda OM, Dunning MJ, et al: The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486:346-352, 2012 32. Horak CE, Pusztai L, Xing G, Trifan OC, Saura C, Tseng L-M, et al: Biomarker Analysis of Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early-Stage Breast Cancer. Clinical Cancer Research 19:1587-1595, 2013 33. Fan C, Prat A, Parker J, Liu Y, Carey L, Troester M, et al: Building prognostic models for breast cancer patients using clinical variables and hundreds of gene expression signatures. BMC Medical Genomics 4:3, 2011 34. Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, et al: DAVID: database for annotation, visualization, and Integrated discovery. Genome Biol 4:R60, 2003 35. Tusher VG, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98:5116 - 5121, 2001 36. Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DSA, Nobel AB, et al: Concordance among Gene-Expression–Based Predictors for Breast Cancer. New England Journal of Medicine 355:560-569, 2006 37. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al: A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. New England Journal of Medicine 351:2817-2826, 2004 38. Symmans WF, Hatzis C, Sotiriou C, Andre F, Peintinger F, Regitnig P, et al: Genomic Index of Sensitivity to Endocrine Therapy for Breast Cancer. Journal of Clinical Oncology 28:4111-4119, 2010 39. Andre F, Hatzis C, Anderson K, Sotiriou C, Mazouni C, Mejia J, et al: Microtubule-Associated Protein-tau is a Bifunctional Predictor of Endocrine Sensitivity and Chemotherapy Resistance in Estrogen Receptor–Positive Breast Cancer. Clinical Cancer Research 13:2061-2067, 2007 40. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al: A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer. New England Journal of Medicine 351:2817-2826, 2004 41. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, et al: Gene Expression and Benefit of Chemotherapy in Women With Node-Negative, Estrogen Receptor–Positive Breast Cancer. Journal of Clinical Oncology 24:3726-3734, 2006 42. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, et al: Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology, 2016 43. van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AAM, Mao M, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530-536, 2002 44. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al: Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. The Lancet 384:164-172
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092
Published OnlineFirst November 30, 2016.Clin Cancer Res Aleix Prat, Ana Lluch, Arran K Turnbull, et al. RelapseReceptor-Positive Breast Cancer with an Intermediate Risk of A PAM50-based Chemo-Endocrine Score for Hormone
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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on November 30, 2016; DOI: 10.1158/1078-0432.CCR-16-2092