Journal Article
. 2016 Dec;23(12).
doi: 10.1158/1078-0432.CCR-16-2092.

A PAM50-Based Chemoendocrine Score for Hormone Receptor-Positive Breast Cancer with an Intermediate Risk of Relapse

Aleix Prat 1 Ana Lluch 2 Arran K Turnbull 3 Anita K Dunbier 4 Lourdes Calvo 5 Joan Albanell 6 Juan de la Haba-Rodríguez 7 Angels Arcusa 8 José Ignacio Chacón 9 Pedro Sánchez-Rovira 10 Arrate Plazaola 11 Montserrat Muñoz 12 Laia Paré 13 Joel S Parker 14 Nuria Ribelles 15 Begoña Jimenez 15 Abdul Aziz Bin Aiderus 3 Rosalía Caballero 16 Barbara Adamo 12 Mitch Dowsett 17 Eva Carrasco 16 Miguel Martín 18 J Michael Dixon 3 Charles M Perou 14 Emilio Alba 15 
  • PMID: 27903675
  •     41 References
  •     9 citations


Purpose: Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified.Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2- disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors.Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine-sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy.Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035-44. ©2016 AACR.

PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.
Miguel Martín, Aleix Prat, +24 authors, Philip S Bernard.
Breast Cancer Res Treat, 2013 Feb 21; 138(2). PMID: 23423445    Free PMC article.
Direct multiplexed measurement of gene expression with color-coded probe pairs.
Gary K Geiss, Roger E Bumgarner, +18 authors, Krassen Dimitrov.
Nat Biotechnol, 2008 Feb 19; 26(3). PMID: 18278033
Highly Cited.
Practical implications of gene-expression-based assays for breast oncologists.
Aleix Prat, Matthew J Ellis, Charles M Perou.
Nat Rev Clin Oncol, 2011 Dec 07; 9(1). PMID: 22143140    Free PMC article.
Highly Cited. Review.
Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer.
Aleix Prat, Maggie Chon U Cheang, +8 authors, Charles M Perou.
J Clin Oncol, 2012 Dec 13; 31(2). PMID: 23233704    Free PMC article.
Highly Cited.
Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy.
Aleix Prat, Cheng Fan, +11 authors, Charles M Perou.
BMC Med, 2015 Dec 20; 13. PMID: 26684470    Free PMC article.
Supervised risk predictor of breast cancer based on intrinsic subtypes.
Joel S Parker, Michael Mullins, +17 authors, Philip S Bernard.
J Clin Oncol, 2009 Feb 11; 27(8). PMID: 19204204    Free PMC article.
Highly Cited.
Association between breast cancer subtypes and response to neoadjuvant anastrozole.
Anita K Dunbier, Helen Anderson, +5 authors, Mitch Dowsett.
Steroids, 2011 Mar 31; 76(8). PMID: 21447351
Molecular portraits of human breast tumours.
C M Perou, T Sørlie, +15 authors, D Botstein.
Nature, 2000 Aug 30; 406(6797). PMID: 10963602
Highly Cited.
Gene expression profiling predicts clinical outcome of breast cancer.
Laura J van 't Veer, Hongyue Dai, +13 authors, Stephen H Friend.
Nature, 2002 Feb 02; 415(6871). PMID: 11823860
Highly Cited.
Luminal B breast cancer: molecular characterization, clinical management, and future perspectives.
Felipe Ades, Dimitrios Zardavas, +6 authors, Martine Piccart.
J Clin Oncol, 2014 Jul 23; 32(25). PMID: 25049332
Highly Cited. Review.
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.
Antonio C Wolff, M Elizabeth H Hammond, +22 authors, College of American Pathologists.
J Clin Oncol, 2006 Dec 13; 25(1). PMID: 17159189
Highly Cited.
Microtubule-associated protein-tau is a bifunctional predictor of endocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer.
Fabrice Andre, Christos Hatzis, +7 authors, Lajos Pusztai.
Clin Cancer Res, 2007 Apr 04; 13(7). PMID: 17404087
A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival.
Keith N Ogston, Iain D Miller, +5 authors, Steven D Heys.
Breast, 2003 Dec 09; 12(5). PMID: 14659147
Highly Cited.
Prediction of Response to Neoadjuvant Chemotherapy Using Core Needle Biopsy Samples with the Prosigna Assay.
Aleix Prat, Patricia Galván, +14 authors, Emilio Alba.
Clin Cancer Res, 2015 Jul 15; 22(3). PMID: 26152740
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.
A Goldhirsch, E P Winer, +5 authors, Panel members.
Ann Oncol, 2013 Aug 07; 24(9). PMID: 23917950    Free PMC article.
Highly Cited.
PAM50 assay and the three-gene model for identifying the major and clinically relevant molecular subtypes of breast cancer.
A Prat, J S Parker, C Fan, C M Perou.
Breast Cancer Res Treat, 2012 Jul 04; 135(1). PMID: 22752290    Free PMC article.
Deconstructing the molecular portraits of breast cancer.
Aleix Prat, Charles M Perou.
Mol Oncol, 2010 Dec 15; 5(1). PMID: 21147047    Free PMC article.
Highly Cited. Review.
Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer.
Christine E Horak, Lajos Pusztai, +6 authors, David Liu.
Clin Cancer Res, 2013 Jan 24; 19(6). PMID: 23340299
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, +12 authors, Matthew J Ellis.
Clin Cancer Res, 2010 Sep 15; 16(21). PMID: 20837693    Free PMC article.
Highly Cited.
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis.
Patricia Cortazar, Lijun Zhang, +34 authors, Gunter von Minckwitz.
Lancet, 2014 Feb 18; 384(9938). PMID: 24529560
Highly Cited. Review.
Concordance among gene-expression-based predictors for breast cancer.
Cheng Fan, Daniel S Oh, +5 authors, Charles M Perou.
N Engl J Med, 2006 Aug 11; 355(6). PMID: 16899776
Highly Cited.
A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer.
Christos Hatzis, Lajos Pusztai, +27 authors, W Fraser Symmans.
JAMA, 2011 May 12; 305(18). PMID: 21558518    Free PMC article.
Highly Cited.
Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer.
Aleix Prat, Lisa A Carey, +6 authors, José Baselga.
J Natl Cancer Inst, 2014 Aug 21; 106(8). PMID: 25139534    Free PMC article.
Highly Cited.
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.
Lyndsay N Harris, Nofisat Ismaila, +11 authors, American Society of Clinical Oncology.
J Clin Oncol, 2016 Feb 10; 34(10). PMID: 26858339    Free PMC article.
Highly Cited. Review.
A phase II placebo-controlled trial of neoadjuvant anastrozole alone or with gefitinib in early breast cancer.
Ian E Smith, Geraldine Walsh, +7 authors, Mitch Dowsett.
J Clin Oncol, 2007 Aug 08; 25(25). PMID: 17679728
DAVID: Database for Annotation, Visualization, and Integrated Discovery.
Glynn Dennis, Brad T Sherman, +4 authors, Richard A Lempicki.
Genome Biol, 2003 May 08; 4(5). PMID: 12734009
Highly Cited.
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.
Matthew J Ellis, Vera J Suman, +17 authors, John A Olson.
J Clin Oncol, 2011 May 11; 29(17). PMID: 21555689    Free PMC article.
Highly Cited.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Relationship between plasma estradiol levels and estrogen-responsive gene expression in estrogen receptor-positive breast cancer in postmenopausal women.
Anita K Dunbier, Helen Anderson, +11 authors, Mitch Dowsett.
J Clin Oncol, 2010 Feb 04; 28(7). PMID: 20124184    Free PMC article.
Accurate Prediction and Validation of Response to Endocrine Therapy in Breast Cancer.
Arran K Turnbull, Laura M Arthur, +7 authors, J Michael Dixon.
J Clin Oncol, 2015 Jun 03; 33(20). PMID: 26033813
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
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.
E Alba, L Calvo, +10 authors, GEICAM.
Ann Oncol, 2012 Jun 08; 23(12). PMID: 22674146
Building prognostic models for breast cancer patients using clinical variables and hundreds of gene expression signatures.
Cheng Fan, Aleix Prat, +4 authors, Charles M Perou.
BMC Med Genomics, 2011 Jan 11; 4. PMID: 21214954    Free PMC article.
Predicting drug responsiveness in human cancers using genetically engineered mice.
Jerry Usary, Wei Zhao, +14 authors, Charles M Perou.
Clin Cancer Res, 2013 Jun 20; 19(17). PMID: 23780888    Free PMC article.
Genomic index of sensitivity to endocrine therapy for breast cancer.
W Fraser Symmans, Christos Hatzis, +13 authors, Lajos Pusztai.
J Clin Oncol, 2010 Aug 11; 28(27). PMID: 20697068    Free PMC article.
Highly Cited.
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
Christina Curtis, Sohrab P Shah, +29 authors, Samuel Aparicio.
Nature, 2012 Apr 24; 486(7403). PMID: 22522925    Free PMC article.
Highly Cited.
Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.
Gunter von Minckwitz, Michael Untch, +14 authors, Sibylle Loibl.
J Clin Oncol, 2012 Apr 18; 30(15). PMID: 22508812
Highly Cited.
Comprehensive molecular portraits of human breast tumours.
Cancer Genome Atlas Network.
Nature, 2012 Sep 25; 490(7418). PMID: 23000897    Free PMC article.
Highly Cited.
Predicting response and survival in chemotherapy-treated triple-negative breast cancer.
A Prat, A Lluch, +35 authors, E Alba.
Br J Cancer, 2014 Aug 08; 111(8). PMID: 25101563    Free PMC article.
Significance analysis of microarrays applied to the ionizing radiation response.
V G Tusher, R Tibshirani, G Chu.
Proc Natl Acad Sci U S A, 2001 Apr 20; 98(9). PMID: 11309499    Free PMC article.
Highly Cited.
Concordance among gene expression-based predictors for ER-positive breast cancer treated with adjuvant tamoxifen.
A Prat, J S Parker, +9 authors, C M Perou.
Ann Oncol, 2012 Apr 26; 23(11). PMID: 22532584    Free PMC article.
Novel Predictors of Breast Cancer Survival Derived from miRNA Activity Analysis.
Vasily N Aushev, Eunjee Lee, +11 authors, Jia Chen.
Clin Cancer Res, 2017 Nov 16; 24(3). PMID: 29138345    Free PMC article.
Luminal A Breast Cancer and Molecular Assays: A Review.
Jennifer J Gao, Sandra M Swain.
Oncologist, 2018 Feb 24; 23(5). PMID: 29472313    Free PMC article.
Current Status of Neoadjuvant Endocrine Therapy in Early Stage Breast Cancer.
Tomás Reinert, Rodrigo Gonçalves, Matthew J Ellis.
Curr Treat Options Oncol, 2018 Apr 18; 19(5). PMID: 29663173
Predictive markers of endocrine response in breast cancer.
Duniya Mosly, Arran Turnbull, +2 authors, Simon Langdon.
World J Exp Med, 2018 Sep 08; 8(1). PMID: 30191138    Free PMC article.
DNA methylation profiles capturing breast cancer heterogeneity.
Xiao Chen, Jianying Zhang, Xiaofeng Dai.
BMC Genomics, 2019 Nov 09; 20(1). PMID: 31699026    Free PMC article.
Oral metronomic vinorelbine combined with endocrine therapy in hormone receptor-positive HER2-negative breast cancer: SOLTI-1501 VENTANA window of opportunity trial.
Barbara Adamo, Meritxell Bellet, +16 authors, Aleix Prat.
Breast Cancer Res, 2019 Sep 20; 21(1). PMID: 31533777    Free PMC article.
Neoadjuvant Therapy for Breast Cancer as a Model for Translational Research.
Cigdem Selli, Andrew H Sims.
Breast Cancer (Auckl), 2019 Mar 01; 13. PMID: 30814840    Free PMC article.
Should a Multigene Signature be Used in all Luminal Early Breast Cancers.
Nawale Hajjaji, Yves Marie Robin, Jacques Bonneterre.
Front Oncol, 2019 Jun 20; 9. PMID: 31214499    Free PMC article.
Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer.
Aranzazu Fernandez-Martinez, Ian E Krop, +16 authors, Lisa A Carey.
J Clin Oncol, 2020 Oct 24; 38(35). PMID: 33095682    Free PMC article.