Journal Article
. 2017 Nov; 19(1):120.
doi: 10.1186/s13058-017-0911-9.

Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up

Hege O Ohnstad 1 Elin Borgen 2 Ragnhild S Falk 3 Tonje G Lien 4 Marit Aaserud 2 My Anh T Sveli 2 Jon A Kyte 5 Vessela N Kristensen 4 Gry A Geitvik 4 Ellen Schlichting 6 Erik A Wist 7 Therese Sørlie 4 Hege G Russnes 2 Bjørn Naume 5 
  • PMID: 29137653
  •     42 References
  •     22 citations


Background: The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) pN0 patients not treated with chemotherapy.

Methods: Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995-1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS).

Results: Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2- patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2- patients) yielded strong prognostic information. Among the HR+/HER2- pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2- pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2- population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%).

Conclusions: The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy.

Keywords: Breast cancer; Follow-up; PAM50; Patient stratification; Risk of recurrence.

Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens.
Torsten Nielsen, Brett Wallden, +7 authors, James Storhoff.
BMC Cancer, 2014 Mar 15; 14. PMID: 24625003    Free PMC article.
Highly Cited.
Identifying clinically relevant prognostic subgroups of postmenopausal women with node-positive hormone receptor-positive early-stage breast cancer treated with endocrine therapy: a combined analysis of ABCSG-8 and ATAC using the PAM50 risk of recurrence score and intrinsic subtype.
M Gnant, I Sestak, +14 authors, J Cuzick.
Ann Oncol, 2015 May 04; 26(8). PMID: 25935792
Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients.
Leilani Morales, Patrick Neven, +7 authors, Robert Paridaens.
Anticancer Drugs, 2004 Oct 21; 15(8). PMID: 15494636
Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence.
Yi Zhang, Catherine A Schnabel, +7 authors, Mark G Erlander.
Clin Cancer Res, 2013 Jun 13; 19(15). PMID: 23757354
Detection of isolated tumor cells in bone marrow in early-stage breast carcinoma patients: comparison with preoperative clinical parameters and primary tumor characteristics.
B Naume, E Borgen, +5 authors, J M Nesland.
Clin Cancer Res, 2001 Dec 26; 7(12). PMID: 11751511
The West German Study Group Breast Cancer Intrinsic Subtype study: a prospective multicenter decision impact study utilizing the Prosigna assay for adjuvant treatment decision-making in estrogen-receptor-positive, HER2-negative early-stage breast cancer.
R Wuerstlein, K Sotlar, +17 authors, N Harbeck.
Curr Med Res Opin, 2016 Mar 15; 32(7). PMID: 26971372
Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015.
A S Coates, E P Winer, +6 authors, Panel Members.
Ann Oncol, 2015 May 06; 26(8). PMID: 25939896    Free PMC article.
Highly Cited.
Detection of isolated tumor cells in bone marrow is an independent prognostic factor in breast cancer.
G Wiedswang, E Borgen, +8 authors, B Naume.
J Clin Oncol, 2003 Sep 16; 21(18). PMID: 12972522
Value of a gene signature assay in patients with early breast cancer and intermediate risk: a single institution retrospective study.
Jacques Bonneterre, Aleix Prat, +2 authors, Sylvia Giard.
Curr Med Res Opin, 2016 Jan 26; 32(5). PMID: 26809116
The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal women with endocrine-responsive early breast cancer.
Martin Filipits, Torsten O Nielsen, +22 authors, Austrian Breast and Colorectal Cancer Study Group.
Clin Cancer Res, 2014 Feb 13; 20(5). PMID: 24520097
Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy.
Mitch Dowsett, Ivana Sestak, +7 authors, Jack Cuzick.
J Clin Oncol, 2013 Jul 03; 31(22). PMID: 23816962
Highly Cited.
Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor-Positive Lymph Node-Negative Early-Stage Breast Cancer.
Ivana Sestak, Yi Zhang, +4 authors, Dennis Sgroi.
Clin Cancer Res, 2016 Jun 03; 22(20). PMID: 27252417
A breast cancer gene signature for indolent disease.
Leonie J M J Delahaye, Caroline A Drukker, +8 authors, Annuska M Glas.
Breast Cancer Res Treat, 2017 Apr 30; 164(2). PMID: 28451965    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.
OPTIMA prelim: a randomised feasibility study of personalised care in the treatment of women with early breast cancer.
Robert C Stein, Janet A Dunn, +14 authors, OPTIMA Trial Management Group.
Health Technol Assess, 2016 Feb 13; 20(10). PMID: 26867046    Free PMC article.
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.
A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors.
Martin Filipits, Margaretha Rudas, +25 authors, EP Investigators.
Clin Cancer Res, 2011 Aug 03; 17(18). PMID: 21807638
Highly Cited.
Combined analysis of vascular invasion, grade, HER2 and Ki67 expression identifies early breast cancer patients with questionable benefit of systemic adjuvant therapy.
Marit Synnestvedt, Elin Borgen, +6 authors, Bjørn Naume.
Acta Oncol, 2012 Sep 01; 52(1). PMID: 22934555
Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer.
Jack Cuzick, Mitch Dowsett, +10 authors, John F Forbes.
J Clin Oncol, 2011 Oct 13; 29(32). PMID: 21990413
Highly Cited.
Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone.
M Gnant, M Filipits, +22 authors, Austrian Breast and Colorectal Cancer Study Group.
Ann Oncol, 2013 Dec 19; 25(2). PMID: 24347518
Highly Cited.
Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group.
Mitch Dowsett, Torsten O Nielsen, +19 authors, International Ki-67 in Breast Cancer Working Group.
J Natl Cancer Inst, 2011 Oct 01; 103(22). PMID: 21960707    Free PMC article.
Highly Cited.
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.
Outcomes in patients with early-stage breast cancer who underwent a 21-gene expression assay.
Carlos H Barcenas, Akshara Raghavendra, +10 authors, Debu Tripathy.
Cancer, 2017 Feb 16; 123(13). PMID: 28199747    Free PMC article.
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.
Fatima Cardoso, Laura J van't Veer, +32 authors, MINDACT Investigators.
N Engl J Med, 2016 Aug 25; 375(8). PMID: 27557300
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.
Adherence to adjuvant hormonal therapy among breast cancer survivors in clinical practice: a systematic review.
Caitlin C Murphy, L Kay Bartholomew, +2 authors, Sally W Vernon.
Breast Cancer Res Treat, 2012 Jun 13; 134(2). PMID: 22689091    Free PMC article.
Highly Cited. Systematic Review.
A standardized method for quantifying proliferation by Ki-67 and cyclin A immunohistochemistry in breast cancer.
Kun Mu, Li Li, +6 authors, Anders Zetterberg.
Ann Diagn Pathol, 2015 Jun 08; 19(4). PMID: 26049669
Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population.
Dennis C Sgroi, Ivana Sestak, +9 authors, Mitch Dowsett.
Lancet Oncol, 2013 Sep 17; 14(11). PMID: 24035531    Free PMC article.
Highly Cited.
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.
Prospective study of the impact of the Prosigna assay on adjuvant clinical decision-making in unselected patients with estrogen receptor positive, human epidermal growth factor receptor negative, node negative early-stage breast cancer.
Miguel Martín, Milagros González-Rivera, +22 authors, Aleix Prat.
Curr Med Res Opin, 2015 Apr 09; 31(6). PMID: 25851308
Development and verification of the PAM50-based Prosigna breast cancer gene signature assay.
Brett Wallden, James Storhoff, +16 authors, Joel S Parker.
BMC Med Genomics, 2015 Aug 25; 8. PMID: 26297356    Free PMC article.
Highly Cited.
Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial.
Christina Davies, Hongchao Pan, +36 authors, Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group.
Lancet, 2012 Dec 12; 381(9869). PMID: 23219286    Free PMC article.
Highly Cited.
The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients.
P Dubsky, J C Brase, +18 authors, Austrian Breast and Colorectal Cancer Study Group (ABCSG).
Br J Cancer, 2013 Oct 26; 109(12). PMID: 24157828    Free PMC article.
Highly Cited.
Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer.
Tara Sanft, Bilge Aktas, +11 authors, Lajos Pusztai.
Breast Cancer Res Treat, 2015 Nov 19; 154(3). PMID: 26578401    Free PMC article.
Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy of hormone-responsive early breast cancer.
E A Perez.
Ann Oncol, 2007 Dec 06; 18 Suppl 8. PMID: 17890211
West German Study Group Phase III PlanB Trial: First Prospective Outcome Data for the 21-Gene Recurrence Score Assay and Concordance of Prognostic Markers by Central and Local Pathology Assessment.
Oleg Gluz, Ulrike A Nitz, +18 authors, Nadia Harbeck.
J Clin Oncol, 2016 Mar 02; 34(20). PMID: 26926676
Highly Cited.
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.
Kathy S Albain, William E Barlow, +20 authors, Breast Cancer Intergroup of North America.
Lancet Oncol, 2009 Dec 17; 11(1). PMID: 20005174    Free PMC article.
Highly Cited.
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials.
Early Breast Cancer Trialists' Collaborative Group (EBCTCG).
Lancet, 2005 May 17; 365(9472). PMID: 15894097
Highly Cited.
Factors predicting late recurrence for estrogen receptor-positive breast cancer.
Ivana Sestak, Mitch Dowsett, +4 authors, Jack Cuzick.
J Natl Cancer Inst, 2013 Sep 14; 105(19). PMID: 24029245    Free PMC article.
Highly Cited.
Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
T Sørlie, C M Perou, +14 authors, A L Børresen-Dale.
Proc Natl Acad Sci U S A, 2001 Sep 13; 98(19). PMID: 11553815    Free PMC article.
Highly Cited.
Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score.
Ivana Sestak, Jack Cuzick, +8 authors, Michael Gnant.
J Clin Oncol, 2014 Oct 22; 33(8). PMID: 25332252
Highly Cited.
Prospective Validation of a 21-Gene Expression Assay in Breast Cancer.
Joseph A Sparano, Robert J Gray, +28 authors, George W Sledge.
N Engl J Med, 2015 Sep 29; 373(21). PMID: 26412349    Free PMC article.
Highly Cited.
An Efficient Feature Selection Strategy Based on Multiple Support Vector Machine Technology with Gene Expression Data.
Ying Zhang, Qingchun Deng, Wenbin Liang, Xianchun Zou.
Biomed Res Int, 2018 Sep 20; 2018. PMID: 30228989    Free PMC article.
Region-specific glucocorticoid receptor promoter methylation has both positive and negative prognostic value in patients with estrogen receptor-positive breast cancer.
Hilary Snider, Brithica Villavarajan, +3 authors, Christopher R Mueller.
Clin Epigenetics, 2019 Nov 05; 11(1). PMID: 31675993    Free PMC article.
CREB1/Lin28/miR-638/VASP Interactive Network Drives the Development of Breast Cancer.
Peng-Chao Hu, Kai Li, +7 authors, Jing-Wei Zhang.
Int J Biol Sci, 2019 Nov 23; 15(12). PMID: 31754343    Free PMC article.
Identification of Breast Cancer Subtype Specific MicroRNAs Using Survival Analysis to Find Their Role in Transcriptomic Regulation.
Michał Denkiewicz, Indrajit Saha, +2 authors, Dariusz Plewczynski.
Front Genet, 2019 Dec 05; 10. PMID: 31798622    Free PMC article.
Deconvolution of the Genomic and Epigenomic Interaction Landscape of Triple-Negative Breast Cancer.
Jiande Wu, Tarun Karthik Kumar Mamidi, Lu Zhang, Chindo Hicks.
Cancers (Basel), 2019 Nov 07; 11(11). PMID: 31683572    Free PMC article.
Avoiding over- and undertreatment in patients with resected node-positive breast cancer with the use of gene expression signatures: are we there yet?
A Matikas, T Foukakis, S Swain, J Bergh.
Ann Oncol, 2019 May 28; 30(7). PMID: 31131397    Free PMC article.
Gene Expression Profiling Tests for Early-Stage Invasive Breast Cancer: A Health Technology Assessment.
Ontario Health (Quality).
Ont Health Technol Assess Ser, 2020 Apr 15; 20(10). PMID: 32284770    Free PMC article.
An estrogen receptor (ER)-related signature in predicting prognosis of ER-positive breast cancer following endocrine treatment.
Jianing Tang, Qiuxia Cui, +3 authors, Gaosong Wu.
J Cell Mol Med, 2019 May 28; 23(8). PMID: 31124293    Free PMC article.
Artificial intelligence in oncology.
Hideyuki Shimizu, Keiichi I Nakayama.
Cancer Sci, 2020 Mar 07; 111(5). PMID: 32133724    Free PMC article.
DGM-CM6: A New Model to Predict Distant Recurrence Risk in Operable Endocrine-Responsive Breast Cancer.
Lei Lei, Xiao-Jia Wang, +2 authors, Yunyun Zhou.
Front Oncol, 2020 Jun 13; 10. PMID: 32528885    Free PMC article.
A subset of activated fibroblasts is associated with distant relapse in early luminal breast cancer.
Claire Bonneau, Antoine Eliès, +9 authors, Fatima Mechta-Grigoriou.
Breast Cancer Res, 2020 Jul 16; 22(1). PMID: 32665033    Free PMC article.
Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer.
Jiande Wu, Tarun K K Mamidi, Lu Zhang, Chindo Hicks.
Int J Genomics, 2020 Jul 30; 2020. PMID: 32724790    Free PMC article.
Machine learning for RNA sequencing-based intrinsic subtyping of breast cancer.
Silvia Cascianelli, Ivan Molineris, +2 authors, Enzo Medico.
Sci Rep, 2020 Aug 23; 10(1). PMID: 32826944    Free PMC article.
The Oncotype Dx Assay in ER-Positive, HER2-Negative Breast Cancer Patients: A Real Life Experience from a Single Cancer Center.
Stephane Thibodeau, Ioannis A Voutsadakis.
Eur J Breast Health, 2019 Jul 18; 15(3). PMID: 31312792    Free PMC article.
Hypercluster: a flexible tool for parallelized unsupervised clustering optimization.
Lili Blumenberg, Kelly V Ruggles.
BMC Bioinformatics, 2020 Oct 01; 21(1). PMID: 32993491    Free PMC article.
Individualized Prediction of Survival by a 10-Long Non-coding RNA-Based Prognostic Model for Patients With Breast Cancer.
Xuemei Yang, Juan Li, +9 authors, Chuanxin Wang.
Front Oncol, 2020 Nov 17; 10. PMID: 33194577    Free PMC article.
Roadmap of DNA methylation in breast cancer identifies novel prognostic biomarkers.
Bernardo P de Almeida, Joana Dias Apolónio, Alexandra Binnie, Pedro Castelo-Branco.
BMC Cancer, 2019 Mar 15; 19(1). PMID: 30866861    Free PMC article.
Attention-Based Multi-NMF Deep Neural Network with Multimodality Data for Breast Cancer Prognosis Model.
Hongling Chen, Mingyan Gao, +2 authors, Xianchun Zou.
Biomed Res Int, 2019 Jun 20; 2019. PMID: 31214619    Free PMC article.
An Improved, Assay Platform Agnostic, Absolute Single Sample Breast Cancer Subtype Classifier.
Mi-Kyoung Seo, Soonmyung Paik, Sangwoo Kim.
Cancers (Basel), 2020 Dec 02; 12(12). PMID: 33255759    Free PMC article.
Survival outcomes are associated with genomic instability in luminal breast cancers.
Lydia King, Andrew Flaus, Emma Holian, Aaron Golden.
PLoS One, 2021 Feb 04; 16(2). PMID: 33534788    Free PMC article.
Risk of recurrence among patients with HR-positive, HER2-negative, early breast cancer receiving adjuvant endocrine therapy: A systematic review and meta-analysis.
Elizabeth M Salvo, Abril Oliva Ramirez, +4 authors, Imtiaz A Samjoo.
Breast, 2021 Mar 08; 57. PMID: 33677313    Free PMC article.
A pharmacophore-based classification better predicts the outcomes of HER2-negative breast cancer patients receiving the anthracycline- and/or taxane-based neoadjuvant chemotherapy.
Xuan Li, Hefen Sun, +3 authors, Wei Jin.
Cancer Med, 2021 Jun 03; 10(13). PMID: 34076352    Free PMC article.