Advertisement
Original Research| Volume 84, P278-289, October 2017

Breast cancer in young women and prognosis: How important are proliferation markers?

Published:August 24, 2017DOI:https://doi.org/10.1016/j.ejca.2017.07.044

      Highlights

      • Proliferation markers are highly expressed in young women with breast cancer.
      • Proliferation markers do not have a major prognostic impact in young women.
      • Ki-67 is only prognostic in young women with luminal progesterone receptor–positive (PR+) tumours.
      • The optimal prognostic cut-off for Ki-67 varies by age.
      • Age is an independent prognostic factor only in women with luminal B PR+ tumours.

      Abstract

      Aim

      Compared to middle-aged women, young women with breast cancer have a higher risk of systemic disease. We studied expression of proliferation markers in relation to age and subtype and their association with long-term prognosis.

      Methods

      Distant disease-free survival (DDFS) was studied in 504 women aged <40 years and 383 women aged ≥40 years from a population-based cohort. Information on patient characteristics, treatment and follow-up was collected from medical records. Tissue microarrays were produced for analysis of oestrogen receptor, progesterone receptor (PR), Her2, Ki-67 and cyclins.

      Results

      Young women with luminal tumours had significantly higher expression of Ki-67 and cyclins. Proliferation markers were prognostic only within this subtype. Ki-67 was a prognostic indicator only in young women with luminal PR+ tumours. The optimal cut-off for Ki-67 varied by age. High expression of cyclin E1 conferred a better DDFS in women aged <40 years with luminal PR− tumours (hazard ratio [HR] 0.47 [0.24–0.92]). Age <40 years was an independent risk factor of DDFS exclusively in women with luminal B PR+ tumours (HR 2.35 [1.22–4.50]). Young women with luminal B PR− tumours expressing low cyclin E1 had a six-fold risk of distant disease compared with luminal A (HR 6.21 [2.17–17.6]).

      Conclusions

      The higher expression of proliferation markers in young women does not have a strong impact on prognosis. Ki-67 is only prognostic in the subgroup of young women with luminal PR+ tumours. The only cyclin adding prognostic value beyond subtype is cyclin E1. Age is an independent prognostic factor only in women with luminal B PR+ tumours.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Azim Jr., H.A.
        • Michiels S.
        • Bedard P.L.
        • Singhal S.K.
        • Criscitiello C.
        • Ignatiadis M.
        • et al.
        Elucidating prognosis and biology of breast cancer arising in young women using gene expression profiling.
        Clin Cancer Res. 2012; 18: 1341-1351
        • Fredholm H.
        • Eaker S.
        • Frisell J.
        • Holmberg L.
        • Fredriksson I.
        • Lindman H.
        Breast cancer in young women: poor survival despite intensive treatment.
        PLoS One. 2009; 4e7695
        • Fredholm H.
        • Magnusson K.
        • Lindstrom L.S.
        • Garmo H.
        • Falt S.E.
        • Lindman H.
        • et al.
        Long-term outcome in young women with breast cancer: a population-based study.
        Breast Cancer Res Treat. 2016; 160: 131-143
        • Gnerlich J.L.
        • Deshpande A.D.
        • Jeffe D.B.
        • Sweet A.
        • White N.
        • Margenthaler J.A.
        Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease.
        J Am Coll Surg. 2009; 208: 341-347
        • Partridge A.H.
        • Hughes M.E.
        • Warner E.T.
        • Ottesen R.A.
        • Wong Y.N.
        • Edge S.B.
        • et al.
        Subtype-dependent relationship between young age at diagnosis and breast cancer survival.
        J Clin Oncol. 2016; 34: 3308-3314
        • Kroman N.
        • Jensen M.B.
        • Wohlfahrt J.
        • Mouridsen H.T.
        • Andersen P.K.
        • Melbye M.
        Factors influencing the effect of age on prognosis in breast cancer: population based study.
        BMJ. 2000; 320: 474-478
        • Anders C.K.
        • Hsu D.S.
        • Broadwater G.
        • Acharya C.R.
        • Foekens J.A.
        • Zhang Y.
        • et al.
        Young age at diagnosis correlates with worse prognosis and defines a subset of breast cancers with shared patterns of gene expression.
        J Clin Oncol. 2008; 26: 3324-3330
        • Bharat A.
        • Aft R.L.
        • Gao F.
        • Margenthaler J.A.
        Patient and tumor characteristics associated with increased mortality in young women (< or =40 years) with breast cancer.
        J Surg Oncol. 2009; 100: 248-251
        • Colleoni M.
        • Rotmensz N.
        • Robertson C.
        • Orlando L.
        • Viale G.
        • Renne G.
        • et al.
        Very young women (<35 years) with operable breast cancer: features of disease at presentation.
        Ann Oncol. 2002; 13: 273-279
        • Sabiani L.
        • Houvenaeghel G.
        • Heinemann M.
        • Reyal F.
        • Classe J.M.
        • Cohen M.
        • et al.
        Breast cancer in young women: pathologic features and molecular phenotype.
        Breast. 2016; 29: 109-116
        • Swain S.M.
        • Nunes R.
        • Yoshizawa C.
        • Rothney M.
        • Sing A.P.
        Quantitative gene expression by recurrence score in ER-positive breast cancer, by age.
        Adv Ther. 2015; 32: 1222-1236
        • Ahn S.H.
        • Son B.H.
        • Kim S.W.
        • Kim S.I.
        • Jeong J.
        • Ko S.S.
        • et al.
        Poor outcome of hormone receptor-positive breast cancer at very young age is due to tamoxifen resistance: nationwide survival data in Korea–a report from the Korean Breast Cancer Society.
        J Clin Oncol. 2007; 25: 2360-2368
        • Cancello G.
        • Maisonneuve P.
        • Rotmensz N.
        • Viale G.
        • Mastropasqua M.G.
        • Pruneri G.
        • et al.
        Prognosis and adjuvant treatment effects in selected breast cancer subtypes of very young women (<35 years) with operable breast cancer.
        Ann Oncol. 2010; 21: 1974-1981
        • Tang L.C.
        • Jin X.
        • Yang H.Y.
        • He M.
        • Chang H.
        • Shao Z.M.
        • et al.
        Luminal B subtype: a key factor for the worse prognosis of young breast cancer patients in China.
        BMC Cancer. 2015; 15: 201
        • Morrison D.H.
        • Rahardja D.
        • King E.
        • Peng Y.
        • Sarode V.R.
        Tumour biomarker expression relative to age and molecular subtypes of invasive breast cancer.
        Br J Cancer. 2012; 107: 382-387
        • Cheang M.C.
        • Chia S.K.
        • Voduc D.
        • Gao D.
        • Leung S.
        • Snider J.
        • et al.
        Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer.
        J Natl Cancer Inst. 2009; 101: 736-750
        • Klintman M.
        • Strand C.
        • Ahlin C.
        • Beglerbegovic S.
        • Fjallskog M.L.
        • Grabau D.
        • et al.
        The prognostic value of mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A, and Ki67, alone and in combinations, in node-negative premenopausal breast cancer.
        PLoS One. 2013; 8e81902
        • Sorlie T.
        • Perou C.M.
        • Tibshirani R.
        • Aas T.
        • Geisler S.
        • Johnsen H.
        • et al.
        Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.
        Proc Natl Acad Sci U S A. 2001; 98: 10869-10874
        • Tobin N.P.
        • Lindstrom L.S.
        • Carlson J.W.
        • Bjohle J.
        • Bergh J.
        • Wennmalm K.
        Multi-level gene expression signatures, but not binary, outperform Ki67 for the long term prognostication of breast cancer patients.
        Mol Oncol. 2014; 8: 741-752
        • Coates A.S.
        • Winer E.P.
        • Goldhirsch A.
        • Gelber R.D.
        • Gnant M.
        • Piccart-Gebhart M.
        • et al.
        Tailoring therapies–improving the management of early breast cancer: St Gallen International expert consensus on the primary therapy of early breast cancer 2015.
        Ann Oncol. 2015; 26: 1533-1546
        • Goldhirsch A.
        • Winer E.P.
        • Coates A.S.
        • Gelber R.D.
        • Piccart-Gebhart M.
        • Thurlimann 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.
        Ann Oncol. 2013; 24: 2206-2223
        • Guo L.
        • Liu S.
        • Jakulin A.
        • Yilamu D.
        • Wang B.
        • Yan J.
        Positive expression of cyclin D1 is an indicator for the evaluation of the prognosis of breast cancer.
        Int J Clin Exp Med. 2015; 8: 18656-18664
        • Agarwal R.
        • Gonzalez-Angulo A.M.
        • Myhre S.
        • Carey M.
        • Lee J.S.
        • Overgaard J.
        • et al.
        Integrative analysis of cyclin protein levels identifies cyclin b1 as a classifier and predictor of outcomes in breast cancer.
        Clin Cancer Res. 2009; 15: 3654-3662
        • Rudolph P.
        • Kuhling H.
        • Alm P.
        • Ferno M.
        • Baldetorp B.
        • Olsson H.
        • et al.
        Differential prognostic impact of the cyclins E and B in premenopausal and postmenopausal women with lymph node-negative breast cancer.
        Int J Cancer. 2003; 105: 674-680
        • Strand C.
        • Ahlin C.
        • Bendahl P.O.
        • Fjallskog M.L.
        • Hedenfalk I.
        • Malmstrom P.
        • et al.
        Combination of the proliferation marker cyclin A, histological grade, and estrogen receptor status in a new variable with high prognostic impact in breast cancer.
        Breast Cancer Res Treat. 2012; 131: 33-40
        • Voduc D.
        • Nielsen T.O.
        • Cheang M.C.
        • Foulkes W.D.
        The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype.
        Hum Pathol. 2008; 39: 1431-1437
        • McShane L.M.
        • Altman D.G.
        • Sauerbrei W.
        • Taube S.E.
        • Gion M.
        • Clark G.M.
        • et al.
        REporting recommendations for tumour MARKer prognostic studies (REMARK).
        Eur J Cancer. 2005; 41: 1690-1696
        • von Elm E.
        • Altman D.G.
        • Egger M.
        • Pocock S.J.
        • Gotzsche P.C.
        • Vandenbroucke J.P.
        • et al.
        The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.
        Lancet. 2007; 370: 1453-1457
        • Uhlen M.
        • Fagerberg L.
        • Hallstrom B.M.
        • Lindskog C.
        • Oksvold P.
        • Mardinoglu A.
        • et al.
        Proteomics. Tissue-based map of the human proteome.
        Science. 2015; 347 (1260419)
        • Hammond M.E.
        • Hayes D.F.
        • Dowsett M.
        • Allred D.C.
        • Hagerty K.L.
        • Badve S.
        • et al.
        American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.
        J Clin Oncol. 2010; 28: 2784-2795
        • Prat A.
        • Cheang M.C.
        • Martin M.
        • Parker J.S.
        • Carrasco E.
        • Caballero R.
        • et al.
        Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer.
        J Clin Oncol. 2013; 31: 203-209
        • Li A.Q.
        • Zhou S.L.
        • Li M.
        • Xu Y.
        • Shui R.H.
        • Yu B.H.
        • et al.
        Clinicopathologic characteristics of oestrogen receptor-positive/progesterone receptor-negative/Her2-negative breast cancer according to a novel definition of negative progesterone receptor status: a large population-based study from China.
        PLoS One. 2015; 10e0125067
        • Maisonneuve P.
        • Disalvatore D.
        • Rotmensz N.
        • Curigliano G.
        • Colleoni M.
        • Dellapasqua S.
        • et al.
        Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes.
        Breast Cancer Res. 2014; 16: R65
        • Dowsett M.
        • Nielsen T.O.
        • A'Hern R.
        • Bartlett J.
        • Coombes R.C.
        • Cuzick J.
        • et al.
        Assessment of Ki67 in breast cancer: recommendations from the international Ki67 in breast cancer working group.
        J Natl Cancer Inst. 2011; 103: 1656-1664
        • Honma N.
        • Horii R.
        • Iwase T.
        • Saji S.
        • Younes M.
        • Ito Y.
        • et al.
        Ki-67 evaluation at the hottest spot predicts clinical outcome of patients with hormone receptor-positive/HER2-negative breast cancer treated with adjuvant tamoxifen monotherapy.
        Breast Cancer. 2015; 22: 71-78
        • Gudlaugsson E.
        • Skaland I.
        • Janssen E.A.
        • Smaaland R.
        • Shao Z.
        • Malpica A.
        • et al.
        Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer.
        Histopathology. 2012; 61: 1134-1144
        • Knutsvik G.
        • Stefansson I.M.
        • Aziz S.
        • Arnes J.
        • Eide J.
        • Collett K.
        • et al.
        Evaluation of Ki67 expression across distinct categories of breast cancer specimens: a population-based study of matched surgical specimens, core needle biopsies and tissue microarrays.
        PLoS One. 2014; 9e112121
        • Wolff A.C.
        • Hammond M.E.
        • Hicks D.G.
        • Dowsett M.
        • McShane L.M.
        • Allison K.H.
        • et al.
        Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.
        J Clin Oncol. 2013; 31: 3997-4013
        • Ahlin C.
        • Aaltonen K.
        • Amini R.M.
        • Nevanlinna H.
        • Fjallskog M.L.
        • Blomqvist C.
        Ki67 and cyclin A as prognostic factors in early breast cancer. What are the optimal cut-off values?.
        Histopathology. 2007; 51: 491-498
        • Michalides R.
        • van Tinteren H.
        • Balkenende A.
        • Vermorken J.B.
        • Benraadt J.
        • Huldij J.
        • et al.
        Cyclin A is a prognostic indicator in early stage breast cancer with and without tamoxifen treatment.
        Br J Cancer. 2002; 86: 402-408
        • Mu K.
        • Li L.
        • Yang Q.
        • Yun H.
        • Kharaziha P.
        • Ye D.W.
        • et al.
        A standardized method for quantifying proliferation by Ki-67 and cyclin A immunohistochemistry in breast cancer.
        Ann Diagn Pathol. 2015; 19: 243-248
        • Sun X.
        • Zhangyuan G.
        • Shi L.
        • Wang Y.
        • Sun B.
        • Ding Q.
        Prognostic and clinicopathological significance of cyclin B expression in patients with breast cancer: a meta-analysis.
        Med Baltim. 2017; 96: e6860
        • Li Z.
        • Cui J.
        • Yu Q.
        • Wu X.
        • Pan A.
        • Li L.
        Evaluation of CCND1 amplification and CyclinD1 expression: diffuse and strong staining of CyclinD1 could have same predictive roles as CCND1 amplification in ER positive breast cancers.
        Am J Transl Res. 2016; 8: 142-153
        • Gao S.
        • Ma J.J.
        • Lu C.
        Prognostic value of cyclin E expression in breast cancer: a meta-analysis.
        Tumour Biol. 2013; 34: 3423-3430
        • Sapino A.
        • Marchio C.
        • Senetta R.
        • Castellano I.
        • Macri L.
        • Cassoni P.
        • et al.
        Routine assessment of prognostic factors in breast cancer using a multicore tissue microarray procedure.
        Virchows Arch. 2006; 449: 288-296
        • Batistatou A.
        • Televantou D.
        • Bobos M.
        • Eleftheraki A.G.
        • Kouvaras E.
        • Chrisafi S.
        • et al.
        Evaluation of current prognostic and predictive markers in breast cancer: a validation study of tissue microarrays.
        Anticancer Res. 2013; 33: 2139-2145
        • Kim H.K.
        • Park I.A.
        • Heo D.S.
        • Noh D.Y.
        • Choe K.J.
        • Bang Y.J.
        • et al.
        Cyclin E overexpression as an independent risk factor of visceral relapse in breast cancer.
        Eur J Surg Oncol. 2001; 27: 464-471
        • Lindahl T.
        • Landberg G.
        • Ahlgren J.
        • Nordgren H.
        • Norberg T.
        • Klaar S.
        • et al.
        Overexpression of cyclin E protein is associated with specific mutation types in the p53 gene and poor survival in human breast cancer.
        Carcinogenesis. 2004; 25: 375-380
        • Nielsen N.H.
        • Arnerlov C.
        • Emdin S.O.
        • Landberg G.
        Cyclin E overexpression, a negative prognostic factor in breast cancer with strong correlation to oestrogen receptor status.
        Br J Cancer. 1996; 74: 874-880
        • Hunt K.K.
        • Keyomarsi K.
        Cyclin E as a prognostic and predictive marker in breast cancer.
        Semin Cancer Biol. 2005; 15: 319-326
        • Lundgren C.
        • Ahlin C.
        • Holmberg L.
        • Amini R.M.
        • Fjallskog M.L.
        • Blomqvist C.
        Cyclin E1 is a strong prognostic marker for death from lymph node negative breast cancer. A population-based case-control study.
        Acta Oncol. 2015; 54: 538-544
        • Keyomarsi K.
        • Tucker S.L.
        • Buchholz T.A.
        • Callister M.
        • Ding Y.
        • Hortobagyi G.N.
        • et al.
        Cyclin E and survival in patients with breast cancer.
        N Engl J Med. 2002; 347: 1566-1575
        • Fasching P.A.
        • Heusinger K.
        • Haeberle L.
        • Niklos M.
        • Hein A.
        • Bayer C.M.
        • et al.
        Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment.
        BMC Cancer. 2011; 11: 486
        • Smith M.L.
        • Seo Y.R.
        Sensitivity of cyclin E-overexpressing cells to cisplatin/taxol combinations.
        Anticancer Res. 2000; 20: 2537-2539
        • Hwang T.S.
        • Han H.S.
        • Hong Y.C.
        • Lee H.J.
        • Paik N.S.
        Prognostic value of combined analysis of cyclin D1 and estrogen receptor status in breast cancer patients.
        Pathol Int. 2003; 53: 74-80