Russian Journal of BiotherapyRussian Journal of BiotherapyРоссийский биотерапевтический журнал1726-97841726-9792Publishing House ABV Press110810.17650/1726-9784-2018-17-1-14-22REVIEWSОБЗОРЫ ЛИТЕРАТУРЫPossibilities of application of genetic and serum oncomarkers in early diagnostics of breast cancerВозможности применения генетических и сывороточных онкомаркеров при ранней диагностике рака молочной железыRyabchikovD. A.РябчиковД. А.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

Денис Анатольевич Рябчиков 

dr.denisr@mail.ruDudinaI. A.ДудинаИ. А.
Russian Federation

Bldg. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

VorotnikovI. K.ВоротниковИ. К.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

DenchikD. A.ДенчикД. А.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

ShusharinA. S.ШушаринА. С.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

AbdullaevaE. I.АбдуллаеваЭ. И.
Russian Federation

Bldg. 2, 8 Trubetskaya St., Moscow 119991

119991 Москва, ул. Трубецкая, 8, стр. 2

N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of RussiaФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава РоссииSechenov UniversityФГАОУ ВО Первый Московский государственный медицинский университет им. И.М. Сеченова Минздрава России (Сеченовский Университет)27022018171142226112018261120182018https://bioterapevt.abvpress.ru/jour/article/view/1108

Currently, mammography is the main screening method for diagnosing breast cancer (BC); but the process of carcinogenesis begins long before the appearance of a visualized tumor. For successful early diagnosis of breast cancer, a systematic approach is required, that includes all stages of tumor development. On the example of BC we consider the possibilities of integrating the recent scientific achievements of oncogenetics and proteomics with standard methods. In this article we investigate the possibilities of using genetic research, serum cancer markers and radiation methods for early diagnosis of BC. This article also presents potential options for managing high-risk development of this disease.

В настоящее время маммография – основной скрининговый метод диагностики рака молочной железы (РМЖ); но процесс канцерогенеза начинается задолго до появления визуализируемого новообразования. Поэтому для успешной ранней диагностики РМЖ у населения необходим системный подход, который будет затрагивать все этапы развития опухоли. В статье на примере РМЖ – социально значимого заболевания – обсуждаются перспективы интеграции недавних научных достижений онкогенетики и протеомики со стандартными методами. Рассмотрены возможности применения генетических исследований, сывороточных онкомаркеров и лучевых методов при ранней диагностике РМЖ, а также представлены потенциальные варианты, которые могут быть использованы при ведении таких пациентов.

breast cancerearly diagnosisoncomarkersscreeningpreventionрак молочной железыранняя диагностикаонкомаркерыскринингпрофилактика1. Социально значимые заболевания населения России в 2016 году (статистические материалы). Под ред. А.Д. Каприна и др. М., 2017.Социально значимые заболевания населения России в 2016 году (статистические материалы). Под ред. А.Д. Каприна и др. М., 2017.2. Рябчиков Д.А., Портной С.М., Воротников И.К., Чхиквадзе Н.В. Прогнозирование эффекта неоадъювантной химиотерапии у больных местнораспространенным раком молочной железы с использованием иммуногистохимических маркеров. Онкогинекология 2012;(3):56–61.Рябчиков Д.А., Портной С.М., Воротников И.К., Чхиквадзе Н.В. Прогнозирование эффекта неоадъювантной химиотерапии у больных местнораспространенным раком молочной железы с использованием иммуногистохимических маркеров. Онкогинекология 2012;(3):56–61.3. Дедов И.И., Тюльпаков А.Н., Чехонин В.П. и др. Персонализированная медицина: современное состояние и перспективы. Вестник Российской академии медицинских наук 2012;67(12):4–12. DOI: http://dx.doi.org/10.15690/vramn. v67i12.474.Дедов И.И., Тюльпаков А.Н., Чехонин В.П. и др. Персонализированная медицина: современное состояние и перспективы. Вестник Российской академии медицинских наук 2012;67(12):4–12. DOI: http://dx.doi.org/10.15690/vramn. v67i12.474.4. Lynch H.T., Snyder C., Lynch J. Hereditary breast cancer: Practical pursuit for clinical translation. Ann Surg Oncol 2012;19(6):1723–31. DOI: 10.1245/s10434-012-2256-z. PMID: 22434244.Lynch H.T., Snyder C., Lynch J. Hereditary breast cancer: Practical pursuit for clinical translation. Ann Surg Oncol 2012;19(6):1723–31. DOI: 10.1245/s10434-012-2256-z. PMID: 22434244.5. Buys S.S., Sandbach J.F., Gammon A. et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017;123(10):1721–30. DOI: 10.1002/cncr.30498. PMID: 28085182.Buys S.S., Sandbach J.F., Gammon A. et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017;123(10):1721–30. DOI: 10.1002/cncr.30498. PMID: 28085182.6. Oldenburg R.A., Meijers-Heijboer H., Cornelisse C.J. et al. Genetic susceptibility for breast cancer: how many more genes to be found? Crit Rev Oncol Hematol 2007;63(2):125–49. DOI: 10.1016/j.critrevonc.2006.12.004. PMID: 17498966.Oldenburg R.A., Meijers-Heijboer H., Cornelisse C.J. et al. Genetic susceptibility for breast cancer: how many more genes to be found? Crit Rev Oncol Hematol 2007;63(2):125–49. DOI: 10.1016/j.critrevonc.2006.12.004. PMID: 17498966.7. Rosenthal E.T., Evans B., Kidd J. et al. Increased identification of candidates for high-risk breast cancer screening through expanded genetic testing. J Am Coll Radiol 2017;14(4):561–8. DOI: 10.1016/j.jacr.2016.10.003. PMID: 28011157.Rosenthal E.T., Evans B., Kidd J. et al. Increased identification of candidates for high-risk breast cancer screening through expanded genetic testing. J Am Coll Radiol 2017;14(4):561–8. DOI: 10.1016/j.jacr.2016.10.003. PMID: 28011157.8. Kleibl Z., Kristensen V.N. Women at high risk of breast cancer: Molecular characteristics, clinical presentation and management. Breast 2016;28:136–44. DOI: 10.1016/j.breast.2016.05.006. PMID: 27318168.Kleibl Z., Kristensen V.N. Women at high risk of breast cancer: Molecular characteristics, clinical presentation and management. Breast 2016;28:136–44. DOI: 10.1016/j.breast.2016.05.006. PMID: 27318168.9. Бит-Сава Е.М., Белогурова М.Б. Наследственный рак молочной железы. Сибирский онкологический журнал 2013;1(55):75–81.Бит-Сава Е.М., Белогурова М.Б. Наследственный рак молочной железы. Сибирский онкологический журнал 2013;1(55):75–81.10. Aysola K., Desai A., Welch C. et al. Triple negative breast cancer – an overview. Hereditary Genet 2013;2013(Suppl 2):001. DOI: 10.4172/2161-1041.S2-001.Aysola K., Desai A., Welch C. et al. Triple negative breast cancer – an overview. Hereditary Genet 2013;2013(Suppl 2):001. DOI: 10.4172/2161-1041.S2-001.11. Lee A.J., Cunningham A.P., Tischkowitz M. et al. Incorporating truncating variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model. Genet Med 2016;18(12):1190–8. DOI: 10.1038/gim.2016.31. PMID: 27464310.Lee A.J., Cunningham A.P., Tischkowitz M. et al. Incorporating truncating variants in PALB2, CHEK2 and ATM into the BOADICEA Breast Cancer Risk Model. Genet Med 2016;18(12):1190–8. DOI: 10.1038/gim.2016.31. PMID: 27464310.12. Любченко Л.Н., Батенева Е.И., Воротников И.К. и др. Наследственный рак молочной железы: генетическая и клиническая гетерогенность, молекулярная диагностика, хирургическая профилактика в группах риска. Успехи молекулярной онкологии 2014;1(2):16–25. DOI: 10.17650/2313-805X.2014.1.2.16-25.Любченко Л.Н., Батенева Е.И., Воротников И.К. и др. Наследственный рак молочной железы: генетическая и клиническая гетерогенность, молекулярная диагностика, хирургическая профилактика в группах риска. Успехи молекулярной онкологии 2014;1(2):16–25. DOI: 10.17650/2313-805X.2014.1.2.16-25.13. Collins I.M., Bickerstaffe A., Ranaweera T. et al. iPrevent®: a tailored, web-based, decision support tool for breast cancer risk assessment and management. Breast Cancer Res Treat 2016;156(1):171–82. DOI: 10.1007/s10549-016-3726-y. PMID: 26909793.Collins I.M., Bickerstaffe A., Ranaweera T. et al. iPrevent®: a tailored, web-based, decision support tool for breast cancer risk assessment and management. Breast Cancer Res Treat 2016;156(1):171–82. DOI: 10.1007/s10549-016-3726-y. PMID: 26909793.14. Ozaki T., Nakagawara A. Role of p53 in cell death and human cancers. Cancers (Basel) 2011;3(1):994–1013. DOI: 10.3390/cancers3010994. PMID: 24212651.Ozaki T., Nakagawara A. Role of p53 in cell death and human cancers. Cancers (Basel) 2011;3(1):994–1013. DOI: 10.3390/cancers3010994. PMID: 24212651.15. Mai P.L., Best A.F., Peters J.A. et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 2016;122(23):3673–81. DOI: 10.1002/cncr.30248. PMID: 27496084.Mai P.L., Best A.F., Peters J.A. et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 2016;122(23):3673–81. DOI: 10.1002/cncr.30248. PMID: 27496084.16. Pederson H.J., Padia S.A., May M., Grobmyer S. Managing patients at genetic risk of breast cancer. Cleve Clin J Med 2016;83(3):199–206. DOI: 10.3949/ccjm.83a.14057. PMID: 26974991.Pederson H.J., Padia S.A., May M., Grobmyer S. Managing patients at genetic risk of breast cancer. Cleve Clin J Med 2016;83(3):199–206. DOI: 10.3949/ccjm.83a.14057. PMID: 26974991.17. Lalloo F., Varley J., Moran A. et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 2006;42(8):1143–50. DOI: 10.1016/j.ejca.2005.11.032. PMID: 16644204.Lalloo F., Varley J., Moran A. et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 2006;42(8):1143–50. DOI: 10.1016/j.ejca.2005.11.032. PMID: 16644204.18. Gonzalez K.D., Noltner K.A., Buzin C.H. et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27(8):1250–6. DOI: 10.1200/JCO.2008.16.6959. PMID: 19204208.Gonzalez K.D., Noltner K.A., Buzin C.H. et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27(8):1250–6. DOI: 10.1200/JCO.2008.16.6959. PMID: 19204208.19. de Jong M.M., Nolte I.M., te Meerman G.J. et al. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J Med Genet 2002;39(4):225–42. PMID: 11950848.de Jong M.M., Nolte I.M., te Meerman G.J. et al. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility. J Med Genet 2002;39(4):225–42. PMID: 11950848.20. Silwal-Pandit L., Vollan H.K., Chin S.F. et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 2014;20(13):3569–80. DOI: 10.1158/1078-0432.CCR-13-2943. PMID: 24803582.Silwal-Pandit L., Vollan H.K., Chin S.F. et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res 2014;20(13):3569–80. DOI: 10.1158/1078-0432.CCR-13-2943. PMID: 24803582.21. Encinas G., Maistro S., Pasini F.S. et al. Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis. Rev Assoc Med Bras (1992) 2015; 61(5):474–83. DOI: 10.1590/1806-9282.61.05.474. PMID: 26603012.Encinas G., Maistro S., Pasini F.S. et al. Somatic mutations in breast and serous ovarian cancer young patients: a systematic review and meta-analysis. Rev Assoc Med Bras (1992) 2015; 61(5):474–83. DOI: 10.1590/1806-9282.61.05.474. PMID: 26603012.22. Hainaut P., Pfeifer G.P. Somatic TP53 mutations in the era of genome sequencing. Cold Spring Harb Perspect Med 2016;6(11). DOI: 10.1101/cshperspect.a026179. PMID: 27503997.Hainaut P., Pfeifer G.P. Somatic TP53 mutations in the era of genome sequencing. Cold Spring Harb Perspect Med 2016;6(11). DOI: 10.1101/cshperspect.a026179. PMID: 27503997.23. Olivier M., Hollstein M., Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2(1):a001008. DOI: 10.1101/cshperspect.a001008. PMID: 20182602.Olivier M., Hollstein M., Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010;2(1):a001008. DOI: 10.1101/cshperspect.a001008. PMID: 20182602.24. Murnyáka B., Hortobágyi T. Immunohist ochemical correlates of TP53 somatic mutations in cancer. Oncotarget 2016;7(40):64910–20. DOI: 10.18632/oncotarget.11912. PMID: 27626311.Murnyáka B., Hortobágyi T. Immunohist ochemical correlates of TP53 somatic mutations in cancer. Oncotarget 2016;7(40):64910–20. DOI: 10.18632/oncotarget.11912. PMID: 27626311.25. Ngeow J., Sesock K., Eng C. Breast cancer risk and clinical implications for germline PTEN mutation carriers. Breast Cancer Res Treat 2017;165(1):1–8. DOI: 10.1007/s10549-015-3665-z. PMID: 26700035.Ngeow J., Sesock K., Eng C. Breast cancer risk and clinical implications for germline PTEN mutation carriers. Breast Cancer Res Treat 2017;165(1):1–8. DOI: 10.1007/s10549-015-3665-z. PMID: 26700035.26. Yakubov E., Ghoochani A., Buslei R. et al. Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency. Oncoscience 2016;3(5–6):149–55. DOI: 10.18632/oncoscience.305. PMID: 27489861.Yakubov E., Ghoochani A., Buslei R. et al. Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency. Oncoscience 2016;3(5–6):149–55. DOI: 10.18632/oncoscience.305. PMID: 27489861.27. Kraus C., Hoyer J., Vasileiou G. et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer 2017;140(1):95–102. DOI: 10.1002/ijc.30428. PMID: 27616075.Kraus C., Hoyer J., Vasileiou G. et al. Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Int J Cancer 2017;140(1):95–102. DOI: 10.1002/ijc.30428. PMID: 27616075.28. Jones S., Hruban R.H., Kamiyama M. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009;324(5924):217. DOI: 10.1126/science.1171202. PMID: 19264984.Jones S., Hruban R.H., Kamiyama M. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009;324(5924):217. DOI: 10.1126/science.1171202. PMID: 19264984.29. Hartley T., Cavallone L., Sabbaghian N. et al. Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada. Hered Cancer Clin Pract 2014;12(1):19. DOI: 10.1186/1897-4287-12-19. PMID: 25225577.Hartley T., Cavallone L., Sabbaghian N. et al. Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada. Hered Cancer Clin Pract 2014;12(1):19. DOI: 10.1186/1897-4287-12-19. PMID: 25225577.30. Antoniou A.C., Casadei S., Heikkinen T. et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014;371:497–506. DOI: 10.1056/NEJMoa1400382. PMID: 25099575.Antoniou A.C., Casadei S., Heikkinen T. et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014;371:497–506. DOI: 10.1056/NEJMoa1400382. PMID: 25099575.31. Janatova M., Kleibl Z., Stribrna J. et al. The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. Cancer Epidemiol Biomarkers Prev 2013;22(12):2323–32. DOI: 10.1158/1055-9965.EPI-13-0745-T. PMID: 24136930.Janatova M., Kleibl Z., Stribrna J. et al. The PALB2 gene is a strong candidate for clinical testing in BRCA1- and BRCA2-negative hereditary breast cancer. Cancer Epidemiol Biomarkers Prev 2013;22(12):2323–32. DOI: 10.1158/1055-9965.EPI-13-0745-T. PMID: 24136930.32. Southey M.C., Teo Z.L., Dowty J.G. et al. A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 2010;12(6):R109. DOI: 10.1186/bcr2796. PMID: 21182766.Southey M.C., Teo Z.L., Dowty J.G. et al. A PALB2 mutation associated with high risk of breast cancer. Breast Cancer Res 2010;12(6):R109. DOI: 10.1186/bcr2796. PMID: 21182766.33. Gatti R., Perlman S. Ataxia-telangiectasia. GeneReviews® 1999. PMID: 20301790.Gatti R., Perlman S. Ataxia-telangiectasia. GeneReviews® 1999. PMID: 20301790.34. Goldgar D.E., Healey S., Dowty J.G. et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011;13(4):R73. DOI: 10.1186/bcr2919. PMID: 21787400.Goldgar D.E., Healey S., Dowty J.G. et al. Rare variants in the ATM gene and risk of breast cancer. Breast Cancer Res. 2011;13(4):R73. DOI: 10.1186/bcr2919. PMID: 21787400.35. Eliade M., Skrzypski J., Baurand A. et al. The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? Oncotarget 2017;8(2):1957–71. DOI: 10.18632/oncotarget.12699. PMID: 27779110.Eliade M., Skrzypski J., Baurand A. et al. The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families? Oncotarget 2017;8(2):1957–71. DOI: 10.18632/oncotarget.12699. PMID: 27779110.36. Tavera-Tapia A., Pérez-Cabornero L., Macías J.A. et al. Almost 2 % of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene. Breast Cancer Res Treat 2017;161(3):597–604. DOI: 10.1007/s10549-016-4058-7. PMID: 27913932.Tavera-Tapia A., Pérez-Cabornero L., Macías J.A. et al. Almost 2 % of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene. Breast Cancer Res Treat 2017;161(3):597–604. DOI: 10.1007/s10549-016-4058-7. PMID: 27913932.37. Fernet M., Moullan N., Lauge A. et al. Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers. Br J Cancer 2004;90(4):866–73. DOI: 10.1038/sj.bjc.6601549. PMID: 14970866.Fernet M., Moullan N., Lauge A. et al. Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers. Br J Cancer 2004;90(4):866–73. DOI: 10.1038/sj.bjc.6601549. PMID: 14970866.38. Cuzick J., Sestak I., Thorat M.A. Impact of preventive therapy on the risk of breast cancer among women with benign breast disease. Breast 2015;24 Suppl 2:51–5. DOI: 10.1016/j.breast.2015.07.013. PMID: 26255741.Cuzick J., Sestak I., Thorat M.A. Impact of preventive therapy on the risk of breast cancer among women with benign breast disease. Breast 2015;24 Suppl 2:51–5. DOI: 10.1016/j.breast.2015.07.013. PMID: 26255741.39. Cuzick J., DeCensi A., Arun B. et al. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol 2011;12(5):496–503. DOI: 10.1016/S1470-2045(11)70030-4. PMID: 21441069.Cuzick J., DeCensi A., Arun B. et al. Preventive therapy for breast cancer: a consensus statement. Lancet Oncol 2011;12(5):496–503. DOI: 10.1016/S1470-2045(11)70030-4. PMID: 21441069.40. Rothwell P.M., Fowkes F.G., Belch J.F. et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377(9759):31–41. DOI: 10.1016/S0140-6736(10)62110-1. PMID: 21144578.Rothwell P.M., Fowkes F.G., Belch J.F. et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377(9759):31–41. DOI: 10.1016/S0140-6736(10)62110-1. PMID: 21144578.41. Shim V., Gauthier M.L., Sudilovsky D. et al. Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium. Cancer Res 2003;63(10):2347–50. PMID: 12750248.Shim V., Gauthier M.L., Sudilovsky D. et al. Cyclooxygenase-2 expression is related to nuclear grade in ductal carcinoma in situ and is increased in its normal adjacent epithelium. Cancer Res 2003;63(10):2347–50. PMID: 12750248.42. Litzenburger B.C., Brown P.H. Advances in preventive therapy for estrogenreceptor-negative breast cancer. Curr Breast Cancer Rep 2014;6(2):96–109. DOI: 10.1007/s12609-014-0144-1. PMID: 24829621.Litzenburger B.C., Brown P.H. Advances in preventive therapy for estrogenreceptor-negative breast cancer. Curr Breast Cancer Rep 2014;6(2):96–109. DOI: 10.1007/s12609-014-0144-1. PMID: 24829621.43. To C., Kim E.-H., Royce D.B. et al. PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice. Cancer Prev Res (Phila) 2014;7(7):698–707. DOI: 10.1158/1940-6207.CAPR-14-0047. PMID: 24817481.To C., Kim E.-H., Royce D.B. et al. PARP inhibitors, veliparib and olaparib, are effective chemopreventive agents for delaying mammary tumor development in BRCA1-deficient mice. Cancer Prev Res (Phila) 2014;7(7):698–707. DOI: 10.1158/1940-6207.CAPR-14-0047. PMID: 24817481.44. Petrucelli N., Daly M.B., Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. GeneReviews® 2016. PMID: 20301425.Petrucelli N., Daly M.B., Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. GeneReviews® 2016. PMID: 20301425.45. Zheng H., Luo R.C. Diagnostic value of combined detection of TPS, CA153 and CEA in breast cancer. Di Yi Jun Yi Da Xue Xue Bao 2005;25(10):1293–4. PMID: 16234113.Zheng H., Luo R.C. Diagnostic value of combined detection of TPS, CA153 and CEA in breast cancer. Di Yi Jun Yi Da Xue Xue Bao 2005;25(10):1293–4. PMID: 16234113.46. Chen Y., Zheng Y.H., Lin Y.Y. et al. Clinical and prognostic significance of preoperative serum CA153, CEA and TPS levels in patients with primary breast cancer. Zhonghua Zhong Liu Za Zhi 2011;33(11):842–6. PMID: 22335950.Chen Y., Zheng Y.H., Lin Y.Y. et al. Clinical and prognostic significance of preoperative serum CA153, CEA and TPS levels in patients with primary breast cancer. Zhonghua Zhong Liu Za Zhi 2011;33(11):842–6. PMID: 22335950.47. Duffy M.J. Serum tumor markers in breast cancer: are they of clinical value? Clin Chem 2006;52(3):345–51. DOI: 10.1373/clinchem.2005.059832. PMID: 16410341.Duffy M.J. Serum tumor markers in breast cancer: are they of clinical value? Clin Chem 2006;52(3):345–51. DOI: 10.1373/clinchem.2005.059832. PMID: 16410341.48. Keyhani M., Nasizadeh S., Dehghannejad A. Serum CA15-3 measurement in breast cancer patients before and after mastectomy. Arch Iranian Med 2005;8(4):263–6.Keyhani M., Nasizadeh S., Dehghannejad A. Serum CA15-3 measurement in breast cancer patients before and after mastectomy. Arch Iranian Med 2005;8(4):263–6.49. Tang S., Zhou F., Sun Y. et al. CEA in breast ductal secretions as a promising biomarker for the diagnosis of breast cancer: a systematic review and metaanalysis. Breast Cancer 2016;23(6): 813–9. DOI: 10.1007/s12282-016-0680-9. PMID: 26898373.Tang S., Zhou F., Sun Y. et al. CEA in breast ductal secretions as a promising biomarker for the diagnosis of breast cancer: a systematic review and metaanalysis. Breast Cancer 2016;23(6): 813–9. DOI: 10.1007/s12282-016-0680-9. PMID: 26898373.50. Ławicki S., Zajkowska M., Głażewska E.K. et al. Plasma levels and diagnostic utility of VEGF, MMP-9, and TIMP-1 in the diagnosis of patients with breast cancer. Onco Targets Ther 2016;9:911–9. DOI: 10.2147/OTT.S99959. PMID: 26966379.Ławicki S., Zajkowska M., Głażewska E.K. et al. Plasma levels and diagnostic utility of VEGF, MMP-9, and TIMP-1 in the diagnosis of patients with breast cancer. Onco Targets Ther 2016;9:911–9. DOI: 10.2147/OTT.S99959. PMID: 26966379.51. Schmidt M., Voelker H.U., Kapp M. et al. Expression of VEGFR-1 (Flt-1) in breast cancer is associated with VEGF expression and with node-negative tumour stage. Anticancer Res 2008;28(3А):1719–24. PMID: 18630531.Schmidt M., Voelker H.U., Kapp M. et al. Expression of VEGFR-1 (Flt-1) in breast cancer is associated with VEGF expression and with node-negative tumour stage. Anticancer Res 2008;28(3А):1719–24. PMID: 18630531.52. Teramoto S., Arihiro K., Koseki M. et al. Role of vascular endothelial growth factor-C and -D mRNA in breast cancer. Hiroshima J Med Sci 2008;57(2):73–8. PMID: 18717190.Teramoto S., Arihiro K., Koseki M. et al. Role of vascular endothelial growth factor-C and -D mRNA in breast cancer. Hiroshima J Med Sci 2008;57(2):73–8. PMID: 18717190.53. Lee K., Kim H., Lee J.H. et al. Retrospective observation on contribution and limitations of screening for breast cancer with mammography in Korea: detection rate of breast cancer and incidence rate of interval cancer of the breast. BMC Womens Health 2016;16(1):72. DOI: 10.1186/s12905-016-0351-1. PMID: 27863517.Lee K., Kim H., Lee J.H. et al. Retrospective observation on contribution and limitations of screening for breast cancer with mammography in Korea: detection rate of breast cancer and incidence rate of interval cancer of the breast. BMC Womens Health 2016;16(1):72. DOI: 10.1186/s12905-016-0351-1. PMID: 27863517.54. Ohuchi N., Suzuki A., Sobue T. et al. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet 2016;387(10016):341–8. DOI: 10.1016/S0140-6736(15)00774-6. PMID: 26547101.Ohuchi N., Suzuki A., Sobue T. et al. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial. Lancet 2016;387(10016):341–8. DOI: 10.1016/S0140-6736(15)00774-6. PMID: 26547101.55. Gagnon J., Lévesque E., Borduas F. et al. Recommendations on breast cancer screening and prevention in the context of implementing risk stratification: impending changes to current policies. Curr Oncol 2016;23(6):e615–25. DOI: 10.3747/co.23.2961. PMID: 28050152.Gagnon J., Lévesque E., Borduas F. et al. Recommendations on breast cancer screening and prevention in the context of implementing risk stratification: impending changes to current policies. Curr Oncol 2016;23(6):e615–25. DOI: 10.3747/co.23.2961. PMID: 28050152.