To date, no comprehensive prognostic or predictive marker profiling analysis has been performed in association with the age of patients with breast cancer. In the present study, 632 breast cancer tissue samples were analyzed for expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), B-cell lymphoma (Bcl)-2 protein, HER2 gene amplification, proliferation [as evaluated by proliferating cell nuclear antigen (PCNA) and Ki-67 index], tumor grade, histological type and molecular subtype. The data revealed correlations with the age of patients. A statistically significant positive correlation was identified between patient age and expression of ER (P<0.0001). There was no significant association between patient age and PR, HER2 protein expression, HER2 gene amplification or PCNA. A significant negative correlation between age and Ki-67 expression (P<0.0001) as well as grade of tumor (P=0.007) was identified. The spectrum of molecular subtypes differed according to age (P=0.0003). The highest incidence of aggressive triple-negative and HER2-positive breast cancer was present in patients aged between 20 and 39 years. Luminal A subtype was the most frequent cancer subtype in patients from age 40 onwards, where proliferation activity declined with age and expression of hormone receptors increased along with Bcl-2 expression. Aggressive forms of breast cancer were more common in younger patients. Prognostic and predictive markers have a complex age-specific distribution. The findings of less aggressive luminal A and B subtypes in older patients, and the positive correlation with ER, PR and Bcl-2 expression reveal the potential efficacy of Bcl-2 as a marker of hormone responsiveness in these patients.

Department of Clinical and Molecular Pathology Faculty of Medicine and Dentistry Palacky University CZ 775 15 Olomouc Czech Republic

Institute of Molecular and Translational Medicine Faculty of Medicine and Dentistry Palacky University CZ 775 15 Olomouc Czech Republic

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Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de Vijver MJ. International Agency for Research on Cancer. Lyon: 2012. WHO Classification of Tumours of the Breast. DOI

Clarke CA, Keegan TH, Yang J, Press DJ, Kurian AW, Patel AH, Lacey JV., Jr Age-specific incidence of breast cancer subtypes: Understanding the black-white crossover. J Natl Cancer Inst. 2012;104:1094–1101. doi: 10.1093/jnci/djs264. PubMed DOI PMC

Kurian AW, Fish K, Shema SJ, Clarke CA. Lifetime risks of specific breast cancer subtypes among women in four racial/ethnic groups. Breast Cancer Res. 2010;12:R99. doi: 10.1186/bcr2780. PubMed DOI PMC

Olsson HL, Ingvar C, Bladström A. Hormone replacement therapy containing progestins and given continuously increases breast carcinoma risk in Sweden. Cancer. 2003;97:1387–1392. doi: 10.1002/cncr.11205. PubMed DOI

Clavel-Chapelon F, Hill C. Hormone replacement therapy in menopause and risk of breast cancer. Presse Med. 2000;29:1688–1693. (In French) PubMed

Bae JM, Kim EH. Hormone replacement therapy and risk of breast cancer in Korean women: A quantitative systematic review. J Prev Med Public Health. 2015;48:225–230. doi: 10.3961/jpmph.15.046. PubMed DOI PMC

Predná L, Habánová M, Sláviková E, Wyka J. Hormonal contraceptives and hormone replacement therapy as a possible factor of breast cancer. Rocz Panstw Zakl Hig. 2015;66:269–274. PubMed

Orecchioni S, Reggiani F, Talarico G, Bertolini F. Mechanisms of obesity in the development of breast cancer. Discov Med. 2015;20:121–128. PubMed

Bertolini F. Adipose tissue and breast cancer progression: A link between metabolism and cancer. Breast. 2013;22:S48–S49. doi: 10.1016/j.breast.2013.07.009. (Suppl 2) PubMed DOI

Bertolini F, Petit JY, Kolonin MG. Stem cells from adipose tissue and breast cancer: Hype, risks and hope. Br J Cancer. 2015;112:419–423. doi: 10.1038/bjc.2014.657. PubMed DOI PMC

Jayasekara H, MacInnis RJ, Room R, English DR. Long-term alcohol consumption and breast, upper aero-digestive tract and colorectal cancer risk: A systematic review and meta-Analysis. Alcohol Alcohol. 2016;51:315–330. doi: 10.1093/alcalc/agv110. PubMed DOI

van den Broek AJ, Schmidt MK, van't Veer LJ, Tollenaar RA, van Leeuwen FE. Worse breast cancer prognosis of BRCA1/BRCA2 mutation carriers: What's the evidence? A systematic review with meta-analysis. PLoS One. 2015;10:e0120189. doi: 10.1371/journal.pone.0120189. PubMed DOI PMC

Llort G, Peris M, Blanco I. Hereditary breast and ovarian cancer: Primary and secondary prevention for BRCA1 and BRCA2 mutation carriers. Med Clin (Barc) 2007;128:468–476. doi: 10.1157/13100569. (In Spanish) PubMed DOI

Calderon-Margalit R, Paltiel O. Prevention of breast cancer in women who carry BRCA1 or BRCA2 mutations: A critical review of the literature. Int J Cancer. 2004;112:357–364. doi: 10.1002/ijc.20429. PubMed DOI

Olsen CM, Wilson LF, Nagle CM, Kendall BJ, Bain CJ, Pandeya N, Webb PM, Whiteman DC. Cancers in Australia in 2010 attributable to insufficient physical activity. Aust N Z J Public Health. 2015;39:458–463. doi: 10.1111/1753-6405.12469. PubMed DOI PMC

Drooger JC, Hooning MJ, Seynaeve CM, Baaijens MH, Obdeijn IM, Sleijfer S, Jager A. Diagnostic and therapeutic ionizing radiation and the risk of a first and second primary breast cancer, with special attention for BRCA1 and BRCA2 mutation carriers: A critical review of the literature. Cancer Treat Rev. 2015;41:187–196. doi: 10.1016/j.ctrv.2014.12.002. PubMed DOI

Tang J, Fernandez-Garcia I, Vijayakumar S, Martinez-Ruis H, Illa-Bochaca I, Nguyen DH, Mao JH, Costes SV, Barcellos-Hoff MH. Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors. Stem Cells. 2014;32:649–661. doi: 10.1002/stem.1533. PubMed DOI

Clemons M, Loijens L, Goss P. Breast cancer risk following irradiation for Hodgkin's disease. Cancer Treat Rev. 2000;26:291–302. doi: 10.1053/ctrv.2000.0174. PubMed DOI

Haffty BG. Radiation therapy and the risk of contralateral breast cancer. Int J Radiat Oncol Biol Phys. 2003;56:920–921. doi: 10.1016/S0360-3016(03)00204-9. PubMed DOI

Kato I, Tominaga S, Suzuki T. Factors related to late menopause and early menarche as risk factors for breast cancer. Jpn J Cancer Res. 1988;79:165–172. doi: 10.1111/j.1349-7006.1988.tb01573.x. PubMed DOI PMC

Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader N, Tatalovich Z, Cho H, et al. SEER Cancer Statistics Review, 1975–2007. Bethesda, MD: National Cancer Institute; 2010.

Diab SG, Elledge RM, Clark GM. Tumor characteristics and clinical outcome of elderly women with breast cancer. J Natl Cancer Inst. 2000;92:550–556. doi: 10.1093/jnci/92.7.550. PubMed DOI

Jenkins EO, Deal AM, Anders CK, Prat A, Perou CM, Carey LA, Muss HB. Age-specific changes in intrinsic breast cancer subtypes: A focus on older women. Oncologist. 2014;19:1076–1083. doi: 10.1634/theoncologist.2014-0184. PubMed DOI PMC

Walter LC, Covinsky KE. Cancer screening in elderly patients: A framework for individualized decision making. JAMA. 2001;285:2750–2756. doi: 10.1001/jama.285.21.2750. PubMed DOI

Benz CC. Impact of aging on the biology of breast cancer. Crit Rev Oncol Hematol. 2008;66:65–74. doi: 10.1016/j.critrevonc.2007.09.001. PubMed DOI PMC

Ihemelandu CU, Leffall LD, Jr, Dewitty RL, Naab TJ, Mezghebe HM, Makambi KH, Adams-Campbell L, Frederick WA. Molecular breast cancer subtypes in premenopausal and postmenopausal African-American women: Age-specific prevalence and survival. J Surg Res. 2007;143:109–118. doi: 10.1016/j.jss.2007.03.085. PubMed DOI

Eppenberger-Castori S, Moore DH, Jr, Thor AD, Edgerton SM, Kueng W, Eppenberger U, Benz CC. Age-associated biomarker profiles of human breast cancer. Int J Biochem Cell Biol. 2002;34:1318–1330. doi: 10.1016/S1357-2725(02)00052-3. PubMed DOI

Quong J, Eppenberger-Castori S, Moore D, III, Scott GK, Birrer MJ, Kueng W, Eppenberger U, Benz CC. Age-dependent changes in breast cancer hormone receptors and oxidant stress markers. Breast Cancer Res Treat. 2002;76:221–236. doi: 10.1023/A:1020886801674. PubMed DOI

Camerlingo R, Ferraro GA, De Francesco F, Romano M, Nicoletti G, Di Bonito M, Rinaldo M, D'Andrea F, Pirozzi G. The role of CD44+/CD24-/low biomarker for screening, diagnosis and monitoring of breast cancer. Oncol Rep. 2014;31:1127–1132. PubMed

Gudadze M, Kankava Q, Mariamidze A, Burkadze G. Features of CD44+/CD24-low phenotypic cell distribution in relation to predictive markers and molecular subtypes of invasive ductal carcinoma of the breast. Georgian Med News. 2014;228:81–87. PubMed

Eroles P, Bosch A, Pérez-Fidalgo JA, Lluch A. Molecular biology in breast cancer: Intrinsic subtypes and signaling pathways. Cancer Treat Rev. 2012;38:698–707. doi: 10.1016/j.ctrv.2011.11.005. PubMed DOI

Morrison DH, Rahardja D, King E, Peng Y, Sarode VR. Tumour biomarker expression relative to age and molecular subtypes of invasive breast cancer. Br J Cancer. 2012;107:382–387. doi: 10.1038/bjc.2012.219. PubMed DOI PMC

Park S, Koo JS, Kim MS, Park HS, Lee JS, Lee JS, Kim SI, Park BW. Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry. Breast. 2012;21:50–57. doi: 10.1016/j.breast.2011.07.008. PubMed DOI

Reis-Filho JS, Tutt AN. Triple negative tumours: A critical review. Histopathology. 2008;52:108–118. doi: 10.1111/j.1365-2559.2007.02889.x. PubMed DOI

Rakha EA, Ellis IO. Triple-negative/basal-like breast cancer: Review. Pathology. 2009;41:40–47. doi: 10.1080/00313020802563510. PubMed DOI

Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12:R68. doi: 10.1186/bcr2635. PubMed DOI PMC

Santos C, Sanz-Pamplona R, Nadal E, Grasselli J, Pernas S, Dienstmann R, Moreno V, Tabernero J, Salazar R. Intrinsic cancer subtypes-next steps into personalized medicine. Cell Oncol (Dordr) 2015;38:3–16. doi: 10.1007/s13402-014-0203-7. PubMed DOI

Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, 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. Arch Pathol Lab Med. 2014;138:241–256. doi: 10.5858/arpa.2013-0953-SA. PubMed DOI PMC

LSI Her-2/neu (Orange)/CEP 17 (Green) Users guide. Olomouc; Czech Republic: 2006. Intellmed s.r.o.

Anders CK, Hsu DS, Broadwater G, Acharya CR, Foekens JA, Zhang Y, Wang Y, Marcom PK, Marks JR, Febbo PG, 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. doi: 10.1200/JCO.2007.14.2471. PubMed DOI

de Kruijf EM, Bastiaannet E, Rubertá F, de Craen AJ, Kuppen PJ, Smit VT, van de Velde CJ, Liefers GJ. Comparison of frequencies and prognostic effect of molecular subtypes between young and elderly breast cancer patients. Mol Oncol. 2014;8:1014–1025. doi: 10.1016/j.molonc.2014.03.022. PubMed DOI PMC

Jenkins EO, Deal AM, Anders CK, Prat A, Perou CM, Carey LA, Muss HB. Age-specific changes in intrinsic breast cancer subtypes: A focus on older women. Oncologist. 2014;19:1076–1083. doi: 10.1634/theoncologist.2014-0184. PubMed DOI PMC

Prat A, Carey LA, Adamo B, Vidal M, Tabernero J, Cortés J, Parker JS, Perou CM, Baselga J. Molecular features and survival outcomes of the intrinsic subtypes within HER2-positive breast cancer. J Natl Cancer Inst. 2014;106:dju152. doi: 10.1093/jnci/dju152. PubMed DOI PMC

Park YH, Lee SJ, Jung HA, Kim SM, Kim MJ, Kil WH, Lee JE, Nam SJ, Ahn JS, Im YH. Prevalence and clinical outcomes of young breast cancer (YBC) patients according to intrinsic breast cancer subtypes: Single institutional experience in Korea. Breast. 2015;24:213–217. doi: 10.1016/j.breast.2015.01.012. PubMed DOI

Merino D, Lok SW, Visvader JE, Lindeman GJ. Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer. Oncogene. 2016;35:1877–1887. doi: 10.1038/onc.2015.287. PubMed DOI

Dawson SJ, Makretsov N, Blows FM, Driver KE, Provenzano E, Le Quesne J, Baglietto L, Severi G, Giles GG, McLean CA, et al. BCL2 in breast cancer: A favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received. Br J Cancer. 2010;103:668–675. doi: 10.1038/sj.bjc.6605736. PubMed DOI PMC

Choi JE, Kang SH, Lee SJ, Bae YK. Prognostic significance of Bcl-2 expression in non-basal triple negative breast cancer patients treated with anthracycline-based chemotherapy. Tumour Biol. 2014;35:12255–12263. doi: 10.1007/s13277-014-2534-4. PubMed DOI

Bouchalova K, Kharaishvili G, Bouchal J, Vrbkova J, Megova M, Hlobilkova A. Triple negative breast cancer-BCL2 in prognosis and prediction. Review. Curr Drug Targets. 2014;15:1166–1175. doi: 10.2174/1389450115666141106151143. PubMed DOI

Bouchalova K, Svoboda K, Kharaishvili G, Vrbkova J, Bouchal J, Trojanec R, Koudelakova V, Radova L, Cwiertka K, Hajduch M, Kolar Z. BCL2 is an independent predictor of outcome in basal-like triple-negative breast cancers treated with adjuvant anthracycline-based chemotherapy. Tumour Biol. 2015;36:4243–4252. doi: 10.1007/s13277-015-3061-7. PubMed DOI

Perillo B, Sasso A, Abbondanza C, Palumbo G. 17beta-estradiol inhibits apoptosis in MMCF-7 cells, including bcl-2 expression via two estrogen-responsive elements present in the coding sequence. Mol Cell Biol. 2000;20:2890–2901. doi: 10.1128/MCB.20.8.2890-2901.2000. PubMed DOI PMC

Certo M, Del Gaizo Moore V, Nishino M, Wei G, Korsmeyer S, Armstrong SA, Letai A. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell. 2015;9:351–365. doi: 10.1016/j.ccr.2006.03.027. PubMed DOI

Honma N, Horii R, Ito Y, Saji S, Younes M, Iwase T, Akiyama F. Differences in clinical importance of Bcl-2 in breast cancer according to hormone receptor status or adjuvant endocrine therapy. BMC Cancer. 2015;15:698. doi: 10.1186/s12885-015-1686-y. PubMed DOI PMC

Seong MK, Lee JY, Byeon J, Sohn YJ, Seol H, Lee JK, Kim EK, Kim HA, Noh WC. Bcl-2 is a highly significant prognostic marker of hormone-receptor-positive, human epidermal growth factor receptor-2-negative breast cancer. Breast Cancer Res Treat. 2015;150:141–148. doi: 10.1007/s10549-015-3305-7. PubMed DOI