Journal Article
. 2017 Aug;19(1).
doi: 10.1186/s13058-017-0888-4.

Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes

Elsa Curtit 1 Xavier Pivot 2 Julie Henriques 3 Sophie Paget-Bailly 3 Pierre Fumoleau 4 Maria Rios 5 Hervé Bonnefoi 6 Thomas Bachelot 7 Patrick Soulié 8 Christelle Jouannaud 9 Hugues Bourgeois 10 Thierry Petit 11 Isabelle Tennevet 12 David Assouline 13 Marie-Christine Mathieu 14 Jean-Philippe Jacquin 15 Sandrine Lavau-Denes 16 Ariane Darut-Jouve 17 Jean-Marc Ferrero 18 Carole Tarpin 19 Christelle Lévy 20 Valérie Delecroix 21 Véronique Trillet-Lenoir 22 Oana Cojocarasu 23 Jérôme Meunier 24 Jean-Yves Pierga 25 Pierre Kerbrat 26 Céline Faure-Mercier 27 Hélène Blanché 28 Mourad Sahbatou 28 Anne Boland 29 Delphine Bacq 29 Céline Besse 29 Gilles Thomas 30 Jean-François Deleuze 28 Iris Pauporté 27 Gilles Romieu 31 David G Cox 32 
  • PMID: 28830573
  •     50 References
  •     4 citations


Background: Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer.

Methods: A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS.

Results: The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1-97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival.

Conclusions: In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients' outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis.

Trial Registration: PHARE cohort: NCT00381901 , Sept. 26, 2006 - SIGNAL cohort: INCa RECF1098, Jan. 28, 2009.

Keywords: Breast cancer; Genetic variant; Prognosis; Risk score; Single nucleotide polymorphism.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials).
S Gourgou-Bourgade, D Cameron, +42 authors, T S Dabakuyo-Yonli.
Ann Oncol, 2015 Oct 16; 26(12). PMID: 26467471
Association of TP53 codon 72 polymorphism and the outcome of adjuvant therapy in breast cancer patients.
Tatsuya Toyama, Zhenhuan Zhang, +7 authors, Yoshitaka Fujii.
Breast Cancer Res, 2007 Jun 01; 9(3). PMID: 17537232    Free PMC article.
Pitfalls in outcome prediction of breast cancer.
Emad A Rakha.
J Clin Pathol, 2013 Apr 27; 66(6). PMID: 23618694
6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.
Xavier Pivot, Gilles Romieu, +18 authors, PHARE trial investigators.
Lancet Oncol, 2013 Jun 15; 14(8). PMID: 23764181
Highly Cited.
Systematic pathway enrichment analysis of a genome-wide association study on breast cancer survival reveals an influence of genes involved in cell adhesion and calcium signaling on the patients' clinical outcome.
Andrea Woltmann, Bowang Chen, +11 authors, Asta Försti.
PLoS One, 2014 Jun 03; 9(6). PMID: 24886783    Free PMC article.
Common germline polymorphisms associated with breast cancer-specific survival.
Ailith Pirie, Qi Guo, +146 authors, Marjanka K Schmidt.
Breast Cancer Res, 2015 Apr 22; 17. PMID: 25897948    Free PMC article.
The relationship between eight GWAS-identified single-nucleotide polymorphisms and primary breast cancer outcomes.
Soley Bayraktar, Patricia A Thompson, +5 authors, Abenaa M Brewster.
Oncologist, 2013 May 03; 18(5). PMID: 23635555    Free PMC article.
Triple-negative breast cancer.
William D Foulkes, Ian E Smith, Jorge S Reis-Filho.
N Engl J Med, 2010 Nov 12; 363(20). PMID: 21067385
Highly Cited. Review.
Gene-panel sequencing and the prediction of breast-cancer risk.
Douglas F Easton, Paul D P Pharoah, +14 authors, William D Foulkes.
N Engl J Med, 2015 May 28; 372(23). PMID: 26014596    Free PMC article.
Highly Cited.
The complex genetic landscape of familial breast cancer.
Lorenzo Melchor, Javier Benítez.
Hum Genet, 2013 Apr 05; 132(8). PMID: 23552954
Novel genetic markers of breast cancer survival identified by a genome-wide association study.
Xiao Ou Shu, Jirong Long, +13 authors, Wei Zheng.
Cancer Res, 2012 Jan 11; 72(5). PMID: 22232737    Free PMC article.
Are BRCA1- and BRCA2-associated breast cancers different? Prognosis of BRCA1-associated breast cancer.
M Robson.
J Clin Oncol, 2000 Nov 04; 18(21 Suppl). PMID: 11060338
Prognosis of breast cancer in carriers of BRCA1 and BRCA2 mutations.
Dimitrios H Roukos.
N Engl J Med, 2007 Oct 13; 357(15). PMID: 17933033
GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients.
David G Cox, Elsa Curtit, +32 authors, Xavier Pivot.
Oncotarget, 2016 Oct 21; 7(47). PMID: 27764800    Free PMC article.
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.
Trastuzumab in the treatment of breast cancer.
Gabriel N Hortobagyi.
N Engl J Med, 2005 Oct 21; 353(16). PMID: 16236745
Adjuvant early breast cancer systemic therapies according to daily used technologies.
W Jacot, M Gutowski, D Azria, G Romieu.
Crit Rev Oncol Hematol, 2011 Oct 26; 82(3). PMID: 22024387
Polygenes, risk prediction, and targeted prevention of breast cancer.
Paul D P Pharoah, Antonis C Antoniou, Douglas F Easton, Bruce A J Ponder.
N Engl J Med, 2008 Jun 27; 358(26). PMID: 18579814
Highly Cited.
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.
Review of the clinical studies using the 21-gene assay.
Catherine M Kelly, Ellen Warner, +2 authors, Kathleen I Pritchard.
Oncologist, 2010 Apr 28; 15(5). PMID: 20421266    Free PMC article.
A genome-wide association study identifies locus at 10q22 associated with clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients in Japanese.
Kazuma Kiyotani, Taisei Mushiroda, +15 authors, Hitoshi Zembutsu.
Hum Mol Genet, 2011 Dec 20; 21(7). PMID: 22180457
Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study.
Pamela J Goodwin, Kelly-Anne Phillips, +11 authors, Teri A Longacre.
J Clin Oncol, 2011 Dec 08; 30(1). PMID: 22147742
Association of breast cancer risk loci with breast cancer survival.
Myrto Barrdahl, Federico Canzian, +33 authors, Daniele Campa.
Int J Cancer, 2015 Jan 23; 137(12). PMID: 25611573    Free PMC article.
A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
Y Miki, J Swensen, +7 authors, W Ding.
Science, 1994 Oct 07; 266(5182). PMID: 7545954
Highly Cited.
Functional plasminogen activator inhibitor-1 gene variants and breast cancer survival.
Xianglan Zhang, Xiao-Ou Shu, +3 authors, Wei Zheng.
Clin Cancer Res, 2006 Oct 26; 12(20 Pt 1). PMID: 17062678
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.
Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations.
D K Gaffney, R M Brohet, +7 authors, L A Cannon-Albright.
Radiother Oncol, 1998 Jul 31; 47(2). PMID: 9683359
Prospective Clinical Utility Study of the Use of the 21-Gene Assay in Adjuvant Clinical Decision Making in Women With Estrogen Receptor-Positive Early Invasive Breast Cancer: Results From the SWITCH Study.
Joseph Gligorov, Xavier B Pivot, +11 authors, Francilian Breast Intergroup.
Oncologist, 2015 Jun 27; 20(8). PMID: 26112003    Free PMC article.
Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.
Kristen S Purrington, Seth Slettedahl, +164 authors, Fergus J Couch.
Hum Mol Genet, 2014 Jun 15; 23(22). PMID: 24927736    Free PMC article.
Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis.
Zora Baretta, Simone Mocellin, +2 authors, Dezheng Huo.
Medicine (Baltimore), 2016 Oct 18; 95(40). PMID: 27749552    Free PMC article.
Systematic Review.
Identification of novel genetic markers of breast cancer survival.
Qi Guo, Marjanka K Schmidt, +144 authors, Paul D P Pharoah.
J Natl Cancer Inst, 2015 Apr 22; 107(5). PMID: 25890600    Free PMC article.
Prognostic and predictive factors and genetic analysis of early breast cancer.
Miguel Martín, Fernando González Palacios, +2 authors, José Schneider.
Clin Transl Oncol, 2009 Oct 16; 11(10). PMID: 19828405
Patients with a High Polygenic Risk of Breast Cancer do not have An Increased Risk of Radiotherapy Toxicity.
Leila Dorling, Gillian C Barnett, +7 authors, Catharine M West.
Clin Cancer Res, 2015 Oct 30; 22(6). PMID: 26510858    Free PMC article.
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.
Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13.
R Wooster, S L Neuhausen, +7 authors, D Averill.
Science, 1994 Sep 30; 265(5181). PMID: 8091231
Highly Cited.
Genetic susceptibility to breast cancer.
Nasim Mavaddat, Antonis C Antoniou, Douglas F Easton, Montserrat Garcia-Closas.
Mol Oncol, 2010 Jun 15; 4(3). PMID: 20542480    Free PMC article.
Highly Cited. Review.
Challenges in optimizing care in advanced breast cancer patients: Results of an international survey linked to the ABC1 consensus conference.
Susan McCutcheon, Fatima Cardoso.
Breast, 2015 Jul 24; 24(5). PMID: 26202888
The role of genetic breast cancer susceptibility variants as prognostic factors.
Peter A Fasching, Paul D P Pharoah, +96 authors, Marjanka K Schmidt.
Hum Mol Genet, 2012 Apr 26; 21(17). PMID: 22532573    Free PMC article.
Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium.
Annegien Broeks, Marjanka K Schmidt, +152 authors, Montserrat Garcia-Closas.
Hum Mol Genet, 2011 May 21; 20(16). PMID: 21596841    Free PMC article.
Highly Cited.
Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: what's the evidence? A systematic review with meta-analysis.
Alexandra J van den Broek, Marjanka K Schmidt, +2 authors, Flora E van Leeuwen.
PLoS One, 2015 Mar 31; 10(3). PMID: 25816289    Free PMC article.
Systematic Review.
Genetic variants associated with breast size also influence breast cancer risk.
Nicholas Eriksson, Geoffrey M Benton, +5 authors, Joyce Y Tung.
BMC Med Genet, 2012 Jul 04; 13. PMID: 22747683    Free PMC article.
Association of genetic polymorphisms in the VEGF gene with breast cancer survival.
Hua Lu, Xiao-Ou Shu, +6 authors, Wei Zheng.
Cancer Res, 2005 Jun 17; 65(12). PMID: 15958542
A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis.
Sajjad Rafiq, Sofia Khan, +9 authors, Diana Eccles.
PLoS One, 2014 Dec 20; 9(12). PMID: 25526632    Free PMC article.
Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.
Kyriaki Michailidou, Jonathan Beesley, +245 authors, Douglas F Easton.
Nat Genet, 2015 Mar 10; 47(4). PMID: 25751625    Free PMC article.
Highly Cited.
Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage.
J N Marcus, P Watson, +7 authors, H T Lynch.
Cancer, 1996 Feb 15; 77(4). PMID: 8616762
Polymorphisms in XRCC1, XRCC3, and CCND1 and survival after treatment for metastatic breast cancer.
Mary A Bewick, Michael S C Conlon, Robert M Lafrenie.
J Clin Oncol, 2006 Nov 23; 24(36). PMID: 17116943
Identification of inherited genetic variations influencing prognosis in early-onset breast cancer.
Sajjad Rafiq, William Tapper, +8 authors, Diana Eccles.
Cancer Res, 2013 Jan 16; 73(6). PMID: 23319801    Free PMC article.
Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from medellín, Colombia.
Julián Esteban Londoño Hernández, Marcia Llacuachaqui, +8 authors, Steven A Narod.
Hered Cancer Clin Pract, 2014 Apr 20; 12(1). PMID: 24742220    Free PMC article.
A genome-wide association study of prognosis in breast cancer.
Elizabeth M Azzato, Paul D P Pharoah, +8 authors, Peter Kraft.
Cancer Epidemiol Biomarkers Prev, 2010 Mar 25; 19(4). PMID: 20332263    Free PMC article.
Prognostic and predictive indicators in early-stage breast cancer and the role of genomic profiling: Focus on the Oncotype DX® Breast Recurrence Score Assay.
E Curtit, L Mansi, +2 authors, X Pivot.
Eur J Surg Oncol, 2017 Jan 15; 43(5). PMID: 28087099
Prospective association of a genetic risk score with major adverse cardiovascular events in patients with coronary artery disease.
Chen Zhao, Pin Zhu, Qile Shen, Li Jin.
Medicine (Baltimore), 2018 Feb 03; 96(51). PMID: 29390587    Free PMC article.
Risk, Prediction and Prevention of Hereditary Breast Cancer - Large-Scale Genomic Studies in Times of Big and Smart Data.
Marius Wunderle, Gregor Olmes, +16 authors, Peter A Fasching.
Geburtshilfe Frauenheilkd, 2018 Jun 09; 78(5). PMID: 29880983    Free PMC article.
Prognostic values of the inhibitor of DNA‑binding family members in breast cancer.
Xiao-Ling Zhou, De Zeng, +5 authors, Hao-Yu Lin.
Oncol Rep, 2018 Aug 02; 40(4). PMID: 30066902    Free PMC article.
Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field.
Tatiane Yanes, Mary-Anne Young, Bettina Meiser, Paul A James.
Breast Cancer Res, 2020 Feb 19; 22(1). PMID: 32066492    Free PMC article.