Early Breast Cancer Management following ESMO Guidelines: An Overview

Authors

  • Haleema Sadia ..
  • Rosheen Zahid
  • Hira Ashraf

DOI:

https://doi.org/10.48111/2021.02.05

Keywords:

Early Breast Cancer, ESMO Guidelines, Breast Cancer, Mammography, Breast Conservation, Neoadjuvant Chemotherapy, Radiotherapy

Abstract

Breast cancer is the most prevalent cancer among women and rarely in the male population. With the advent of breast screening programs across the globe, early cancer detection is being done and the patients are increasingly being managed through breast conservation. National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) have provided guidelines to follow to effectively diagnose and amicably manage the cases of early breast cancer with the aim of reduction in mortality rate and enhancing disease-free survival outcomes. This review provides an overview of the management of early breast cancer in light of ESMO Guidelines and the local perspective.

References

Youn HJ, Han W. A review of the epidemiology of breast cancer in Asia: Focus on risk factors. Asian Pacific Journal of Cancer Prevention. 2020;21(4):867-880. doi:10.31557/APJCP.2020.21.4.867

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer. 2010;127(12):2893-2917. doi:10.1002/ijc.25516

DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA: A Cancer Journal for Clinicians. 2017;67(6):439-448. doi:10.3322/caac.21412

Bouchardy C, Fioretta G, Verkooijen HM, et al. Recent increase of breast cancer incidence among women under the age of forty. British Journal of Cancer. 2007;96(11):1743-1746. doi:10.1038/sj.bjc.6603783

Dobi Á, Kelemen G, Kaizer L, Weiczner R, Thurzó L, Kahán Z. Breast cancer under 40 years of age: Increasing number and worse prognosis. Pathology and Oncology Research. 2011;17(2):425-428. doi:10.1007/s12253-010-9305-3

Chen HL, Zhou MQ, Tian W, Meng KX, He HF. Effect of age on breast cancer patient prognoses: A population-based study using the SEER 18 database. PLoS ONE. 2016;11(10):e0165409. doi:10.1371/journal.pone.0165409

McTiernan A. Behavioral Risk Factors in Breast Cancer: Can Risk Be Modified? The Oncologist. 2003;8(4):326-334. doi:10.1634/theoncologist.8-4-326

Autier P, Boniol M, LaVecchia C, et al. Disparities in breast cancer mortality trends between 30 European countries: Retrospective trend analysis of WHO mortality database. BMJ (Online). 2010;341(7768):335. doi:10.1136/bmj.c3620

Allemani C, Weir HK, Carreira H, et al. Global surveillance of cancer survival 1995-2009: Analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). The Lancet. 2015;385(9972):977-1010. doi:10.1016/S0140-6736(14)62038-9

Cancer Screening in Report on the Implementation of the Council Recommendation on Cancer Screening.

European guidelines for breast cancer screening and diagnosis - Publications Office of the EU. Accessed June 26, 2021. https://op.europa.eu/en/publication-detail/-/publication/b7b66c78-e139-11e6-ad7c-01aa75ed71a1

Gøtzsche PC, Nielsen M. Screening for breast cancer with mammography. Cochrane Database of Systematic Reviews. 2009;(4). doi:10.1002/14651858.CD001877.pub3

Lauby-Secretan B, Scoccianti C, Loomis D, et al. Breast-Cancer Screening — Viewpoint of the IARC Working Group. New England Journal of Medicine. 2015;372(24):2353-2358. doi:10.1056/nejmsr1504363

Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG, Wilcox M. The benefits and harms of breast cancer screening: An independent review. British Journal of Cancer. 2013;108(11):2205-2240. doi:10.1038/bjc.2013.177

Warner E, Messersmith H, Causer P, Eisen A, Shumak R, Plewes D. Systematic review: Using magnetic resonance imaging to screen women at high risk for breast cancer. Annals of Internal Medicine. 2008;148(9):671-679. doi:10.7326/0003-4819-148-9-200805060-00007

Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L. European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition - Summary document. Annals of Oncology. 2008;19(4):614-622. doi:10.1093/annonc/mdm481

Paluch-Shimon S, Cardoso F, Sessa C, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO clinical practice guidelines for cancer prevention and screening. Annals of Oncology. 2016;27(suppl 5):v103-v110. doi:10.1093/annonc/mdw327

Treatment by Cancer Type. Accessed June 26, 2021. https://www.nccn.org/guidelines/category_1

Giuliano AE, Connolly JL, Edge SB, et al. Breast Cancer-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA: A Cancer Journal for Clinicians. 2017;67(4):290-303. doi:10.3322/caac.21393

Krop I, Ismaila N, Andre F, et al. 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 focused update. Journal of Clinical Oncology. 2017;35(24):2838-2847. doi:10.1200/JCO.2017.74.0472

Wishart GC, Bajdik CD, Azzato EM, et al. A population-based validation of the prognostic model PREDICT for early breast cancer. European Journal of Surgical Oncology. 2011;37(5):411-417. doi:10.1016/j.ejso.2011.02.001

Ravdin PM, Siminoff LA, Davis GJ, et al. Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. Journal of Clinical Oncology. 2001;19(4):980-991. doi:10.1200/JCO.2001.19.4.980

Blamey RW, Pinder SE, Ball GR, et al. Reading the prognosis of the individual with breast cancer. European Journal of Cancer. 2007;43(10):1545-1547. doi:10.1016/j.ejca.2007.01.003

Cardoso F, Cataliotti L, Costa A, et al. European Breast Cancer Conference manifesto on breast centres/units. In: European Journal of Cancer. Vol 72. Elsevier Ltd; 2017:244-250. doi:10.1016/j.ejca.2016.10.023

Wilson ARM, Marotti L, Bianchi S, et al. The requirements of a specialist Breast Centre. European Journal of Cancer. 2013;49(17):3579-3587. doi:10.1016/j.ejca.2013.07.017

Senkus E, Gomez H, Dirix L, et al. Attitudes of young patients with breast cancer toward fertility loss related to adjuvant systemic therapies. EORTC study 10002 BIG 3-98. Psycho-Oncology. 2014;23(2):173-182. doi:10.1002/pon.3384

Lee SJ, Schover LR, Partridge AH, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. Journal of Clinical Oncology. 2006;24(18):2917-2931. doi:10.1200/JCO.2006.06.5888

Paluch-Shimon S, Pagani O, Partridge AH, et al. ESO-ESMO 3rd international consensus guidelines for breast cancer in young women (BCY3). Breast. 2017;35:203-217. doi:10.1016/j.breast.2017.07.017

Cardoso F, Loibl S, Pagani O, et al. The European Society of Breast Cancer Specialists recommendations for the management of young women with breast cancer. European Journal of Cancer. 2012;48(18):3355-3377. doi:10.1016/j.ejca.2012.10.004

Peccatori FA, Azim JA, Orecchia R, et al. Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2013;24(SUPPL.6). doi:10.1093/annonc/mdt199

Association of Breast Surgery at. Surgical guidelines for the management of breast cancer. European Journal of Surgical Oncology (EJSO). 2009;35:S1-S22. doi:10.1016/j.ejso.2009.01.008

Albornoz CR, Matros E, Lee CN, et al. Bilateral Mastectomy versus Breast-Conserving Surgery for Early-Stage Breast Cancer: The Role of Breast Reconstruction. Plastic and Reconstructive Surgery. 2015;135(6):1518-1526. doi:10.1097/PRS.0000000000001276

Hwang ES, Lichtensztajn DY, Gomez SL, Fowble B, Clarke CA. Survival after lumpectomy and mastectomy for early stage invasive breast cancer: The effect of age and hormone receptor status. Cancer. 2013;119(7):1402-1411. doi:10.1002/cncr.27795

van Maaren MC, de Munck L, de Bock GH, et al. 10 year survival after breast-conserving surgery plus radiotherapy compared with mastectomy in early breast cancer in the Netherlands: a population-based study. The Lancet Oncology. 2016;17(8):1158-1170. doi:10.1016/S1470-2045(16)30067-5

Lagendijk M, van Maaren MC, Saadatmand S, et al. Breast conserving therapy and mastectomy revisited: Breast cancer-specific survival and the influence of prognostic factors in 129,692 patients. International Journal of Cancer. 2018;142(1):165-175. doi:10.1002/ijc.31034

Gentilini OD, Cardoso MJ, Poortmans P. Less is more. Breast conservation might be even better than mastectomy in early breast cancer patients. Breast. 2017;35:32-33. doi:10.1016/j.breast.2017.06.004

Moran MS, Schnitt SJ, Giuliano AE, et al. Society of surgical oncology-American society for radiation oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages i and II invasive breast cancer. International Journal of Radiation Oncology Biology Physics. 2014;88(3):553-564. doi:10.1016/j.ijrobp.2013.11.012

Morrow M, van Zee KJ, Solin LJ, et al. Society of Surgical Oncology–American Society for Radiation Oncology–American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Ductal Carcinoma in Situ. Practical Radiation Oncology. 2016;6(5):287-295. doi:10.1016/j.prro.2016.06.011

Houssami N, MacAskill P, Marinovich ML, et al. Meta-analysis of the impact of surgical margins on local recurrence in women with early-stage invasive breast cancer treated with breast-conserving therapy. European Journal of Cancer. 2010;46(18):3219-3232. doi:10.1016/j.ejca.2010.07.043

Wei CH, Scott AM, Price AN, et al. Psychosocial and Sexual Well-Being Following Nipple-Sparing Mastectomy and Reconstruction. Breast Journal. 2016;22(1):10-17. doi:10.1111/tbj.12542

de La Cruz L, Moody AM, Tappy EE, Blankenship SA, Hecht EM. Overall Survival, Disease-Free Survival, Local Recurrence, and Nipple–Areolar Recurrence in the Setting of Nipple-Sparing Mastectomy: A Meta-Analysis and Systematic Review. Annals of Surgical Oncology. 2015;22(10):3241-3249. doi:10.1245/s10434-015-4739-1

Eriksson M, Anveden L, Celebioglu F, et al. Radiotherapy in implant-based immediate breast reconstruction: Risk factors, surgical outcomes, and patient-reported outcome measures in a large Swedish multicenter cohort. Breast Cancer Research and Treatment. 2013;142(3):591-601. doi:10.1007/s10549-013-2770-0

Chatterjee JS, Lee A, Anderson W, et al. Effect of postoperative radiotherapy on autologous deep inferior epigastric perforator flap volume after immediate breast reconstruction. British Journal of Surgery. 2009;96(10):1135-1140. doi:10.1002/bjs.6693

Gebruers N, Verbelen H, de Vrieze T, Coeck D, Tjalma W. Incidence and time path of lymphedema in sentinel node negative breast cancer patients: A systematic review. Archives of Physical Medicine and Rehabilitation. 2015;96(6):1131-1139. doi:10.1016/j.apmr.2015.01.014

Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): A randomised, multicentre, open-label, phase 3 non-inferiority trial. The Lancet Oncology. 2014;15(12):1303-1310. doi:10.1016/S1470-2045(14)70460-7

Tada K, Ogiya A, Kimura K, et al. Ductal carcinoma in situ and sentinel lymph node metastasis in breast cancer. World Journal of Surgical Oncology. 2010;8(1):1-5. doi:10.1186/1477-7819-8-6

Meretoja TJ, Heikkilä PS, Salmenkivi K, Leidenius MHK. Outcome of patients with ductal carcinoma in situ and sentinel node biopsy. Annals of Surgical Oncology. 2012;19(7):2345-2351. doi:10.1245/s10434-012-2287-5

Hessler LK, Molitoris JK, Rosenblatt PY, et al. Factors Influencing Management and Outcome in Patients with Occult Breast Cancer with Axillary Lymph Node Involvement: Analysis of the National Cancer Database. Annals of Surgical Oncology. 2017;24(10):2907-2914. doi:10.1245/s10434-017-5928-x

Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA - Journal of the American Medical Association. 2017;317(23):2402-2416. doi:10.1001/jama.2017.7112

Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: Meta-analysis of individual patient data for 10 801 women in 17 randomised trials. The Lancet. 2011;378(9804):1707-1716. doi:10.1016/S0140-6736(11)61629-2

Bartelink H, Maingon P, Poortmans P, et al. Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. The Lancet Oncology. 2015;16(1):47-56. doi:10.1016/S1470-2045(14)71156-8

Werkhoven E van, Hart G, Tinteren H van, et al. Nomogram to predict ipsilateral breast relapse based on pathology review from the EORTC 22881-10882 boost versus no boost trial. Radiotherapy and Oncology. 2011;100(1):101-107. doi:10.1016/j.radonc.2011.07.004

McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. The Lancet. 2014;383(9935):2127-2135. doi:10.1016/S0140-6736(14)60488-8

Poortmans P. Postmastectomy radiation in breast cancer with one to three involved lymph nodes: Ending the debate. The Lancet. 2014;383(9935):2104-2106. doi:10.1016/S0140-6736(14)60192-6

Agrawal RK, Aird EGA, Barrett JM, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. The Lancet. 2008;371(9618):1098-1107. doi:10.1016/S0140-6736(08)60348-7

SM B, RK A, EG A, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. The Lancet Oncology. 2008;9(4):331-341. doi:10.1016/S1470-2045(08)70077-9

Whelan TJ, Pignol J-P, Levine MN, et al. Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer. New England Journal of Medicine. 2010;362(6):513-520. doi:10.1056/nejmoa0906260

Rakovitch E, Nofech-Mozes S, Hanna W, et al. Omitting radiation therapy after lumpectomy for pure DCIS does not reduce the risk of salvage mastectomy. Breast. 2018;37:181-186. doi:10.1016/j.breast.2017.07.002

Barbour S, Moore J, Dunn N, et al. Patterns of care for ductal carcinoma in situ of the breast: Queensland’s experience over a decade. Breast. 2017;35:169-176. doi:10.1016/j.breast.2017.07.003

Morrow M, Schnitt SJ, Norton L. Current management of lesions associated with an increased risk of breast cancer. Nature Reviews Clinical Oncology. 2015;12(4):227-238. doi:10.1038/nrclinonc.2015.8

Albain KS, Barlow WE, Ravdin PM, et al. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. The Lancet. 2009;374(9707):2055-2063. doi:10.1016/S0140-6736(09)61523-3

Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. Journal of the American Medical Association. 2006;295(14):1658-1667. doi:10.1001/jama.295.14.1658

M C, AS C, SC D, et al. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. The Lancet. 2008;371(9606):29-40. doi:10.1016/S0140-6736(08)60069-0

Samuel JA, Wilson JW, Bandos H, et al. Abstract S3-02: NSABP B-36: A randomized phase III trial comparing six cycles of 5-fluorouracil (5-FU), epirubicin, and cyclophosphamide (FEC) to four cycles of adriamycin and cyclophosphamide (AC) in patients (pts) with node-negative breast cancer. In: American Association for Cancer Research (AACR); 2015:S3-02-S3-02. doi:10.1158/1538-7445.sabcs14-s3-02

Albain K, Anderson S, Arriagada R, et al. Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. The Lancet. 2012;379(9814):432-444. doi:10.1016/S0140-6736(11)61625-5

Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in early breast Cancer: The ABC Trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). In: Journal of Clinical Oncology. Vol 35. American Society of Clinical Oncology; 2017:2647-2655. doi:10.1200/JCO.2016.71.4147

Citron ML, Berry DA, Cirrincione C, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. Journal of Clinical Oncology. 2003;21(8):1431-1439. doi:10.1200/JCO.2003.09.081

Gray R, Bradley R, Braybrooke J, et al. Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37?298 women with early breast cancer in 26 randomised trials. The Lancet. 2019;393(10179):1440-1452. doi:10.1016/S0140-6736(18)33137-4

Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: Updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. Journal of Clinical Oncology. 2008;26(5):778-785. doi:10.1200/JCO.2007.15.0235

Gianni L, Baselga J, Eiermann W, et al. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European cooperative trial in operable breast cancer. Journal of Clinical Oncology. 2009;27(15):2474-2481. doi:10.1200/JCO.2008.19.2567

Masuda N, Sagara Y, Kinoshita T, et al. Neoadjuvant anastrozole versus tamoxifen in patients receiving goserelin for premenopausal breast cancer (STAGE): A double-blind, randomised phase 3 trial. The Lancet Oncology. 2012;13(4):345-352. doi:10.1016/S1470-2045(11)70373-4

Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. Use of adjuvant bisphosphonates and other bone-modifying agents in breast cancer: A Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology. 2017;35(18):2062-2081. doi:10.1200/JCO.2016.70.7257

Coleman R, Gray R, Powles T, et al. Adjuvant bisphosphonate treatment in early breast cancer: Meta-analyses of individual patient data from randomised trials. The Lancet. 2015;386(10001):1353-1361. doi:10.1016/S0140-6736(15)60908-4

Coleman R, Cameron D, Dodwell D, et al. Adjuvant zoledronic acid in patients with early breast cancer: Final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial. The Lancet Oncology. 2014;15(9):997-1006. doi:10.1016/S1470-2045(14)70302-X

Hadji P, Aapro MS, Body JJ, et al. Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. Journal of Bone Oncology. 2017;7:1-12. doi:10.1016/j.jbo.2017.03.001

Eidtmann H, de Boer R, Bundred N, et al. Efficacy of zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36-month results of the ZO-FAST Study. Annals of Oncology. 2010;21(11):2188-2194. doi:10.1093/annonc/mdq217

Gambardella V, Tarazona N, Cejalvo JM, et al. Personalized medicine: Recent progress in cancer therapy. Cancers. 2020;12(4):1009. doi:10.3390/cancers12041009

Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2019;30(8):1194-1220. doi:10.1093/annonc/mdz173

Ahn S kyung, Jung S-Y. Current Biomarkers for Precision Medicine in Breast Cancer. In: Springer, Singapore; 2021:363-379. doi:10.1007/978-981-32-9620-6_18

Pinker K, Meyer-Baese A, Morris E. and Phenotype Presentation of Breast Cancer with a Special Focus on High-Risk Women. In: Breast MRI for High-Risk Screening. Springer International Publishing; 2020:113-130. doi:10.1007/978-3-030-41207-4_8

Barzaman K, Karami J, Zarei Z, et al. Breast cancer: Biology, biomarkers, and treatments. International Immunopharmacology. 2020;84:106535. doi:10.1016/j.intimp.2020.106535

Harbeck N, Kates RE, Gauger K, et al. Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: Novel tumor-derived factors with a high prognostic and predictive impact in breast cancer. Thrombosis and Haemostasis. 2004;92(REV.):47-53. doi:10.1160/TH03-12-0798

Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: The St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Annals of Oncology. 2017;28(8):1700-1712. doi:10.1093/annonc/mdx308

Park S, Koo JS, Kim MS, et al. Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry. Breast. 2012;21(1):50-57. doi:10.1016/j.breast.2011.07.008

Pan H, Gray R, Braybrooke J, et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. New England Journal of Medicine. 2017;377(19):1836-1846. doi:10.1056/nejmoa1701830

Committee opinion no. 601: Tamoxifen and uterine cancer. Obstetrics and Gynecology. 2014;123(6):1394-1397. doi:10.1097/01.AOG.0000450757.18294.cf

Mustian KM, Alfano CM, Heckler C, et al. Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: A meta-analysis. JAMA Oncology. 2017;3(7):961-968. doi:10.1001/jamaoncol.2016.6914

Downloads

Published

2021-06-30

Issue

Section

Original Research: Systematic Literature Review

How to Cite

Early Breast Cancer Management following ESMO Guidelines: An Overview. (2021). Archives of Surgical Research, 2(2), 20-31. https://doi.org/10.48111/2021.02.05