THE PROGNOSTIC AND PREDICTIVE VALUE OF KI-67 PROLIFERATION INDEX AND uPA/PAI-1 COMPLEX IN SERUM FOR PATIENTS WITH EARLY INVASIVE BREAST CANCER
Abstract
Introduction: Breast cancer, the most common malignancy in women, represents a significant health issue, and biomarkers such as the Ki-67 index and uPA/PAI-1 complex can provide insight into treatment outcomes and therapeutic response.
Objective: The primary outcome of the study was the assessment of 5-year disease-free survival (DFS), defined as the postoperative period until the occurrence of loco-regional or distant metastases and death from any cause.
Patients and Methods: A retrospective cohort study included 166 patients with early invasive breast cancer, in whom the prognostic and predictive significance of the uPA/PAI-1 complex and Ki-67 biomarkers in surgically treated patients at the Clinic for General and Abdominal Surgery of the University Clinical Center in Sarajevo was evaluated during the period from September 2015 to February 2017.
Results: Univariate regression analysis identified an increased probability of DFS shorter than five years in patients with negative hormone receptors, positive HER-2 receptor, ≥8 positively mph nodes, and a Ki-67 index ≥14% (p<0.05). Multivariate regression analysis revealed that T2 stage, tumor size of 20-50 mm, and a Ki-67 index ≥14% were associated with a higher probability of DFS shorter than five years (p<0.05). The five-year DFS rate was higher in patients with a Ki-67 index <14% compared to those with ≥14% (p=0.011), while there was no difference in five-year DFS among patients with different levels of the uPA/PAI-1 complex (p=0.636).
Conclusion:Our study highlights the importance of the Ki-67 proliferative index as a strong prognostic and predictive factor for DFS in patients operated on for early invasive breast cancer. Additional monitoring and tailored therapeutic strategies may be beneficial in patients with elevated Ki-67 index values, T2 stage, and tumor size of 20-50 mm.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; 71(3):209-49.doi.org/10.3322/caac.21660.
Viale PH. The American Cancer Society's Facts & Figures: 2020 Edition. J Adv Pract Oncol. 2020; 11(2):135-6.doi: 10.6004/jadpro.2020.11.2.1.
Burstein HJ, Curigliano G, Thürlimann B, Weber WP, Poortmans P, Regan M, et al. Customizing local and systemic therapies for women with early breast cancer: The St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol. 2021; 32(10):1216-35.doi: 10.1016/j.annonc.2021.06.023.
Zhu H, Doğan BE. American joint committee on cancer’s staging system for breast cancer, Eighth edition: summary for clinicians. Eur J Breast Health. 2021; 17(3):234-8.doi: 10.4274/ejbh.galenos.2021.2021-4-3.
Hacking SM, Wang Y. Practical issues of Ki-67 evaluation in breast cancer clinical practice. J ClinTransl Res. 2022; 2(2):53–6. doi: 10.14218/JCTP.2022.00012.
Nielsen TO, Leung SCY, Rimm DL, Dodson A, Acs B, Badve S, et al. Assessment of Ki67 in breast cancer: updated recommendations from the International Ki67 in breast cancer working group. J Nat Cancer Inst. 2021; 113(7):808-19.doi: 10.1093/jnci/djaa201.
Simon RM, Paik S, Hayes DF. Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst. 2009; 101(21):1446–52.doi: 10.1093/jnci/djp335.
Duffy MJ, McGowan PM, Harbeck N, Thomssen C, Schmitt M. uPA and PAI-1 as biomarkers in breast cancer: Validated for clinical use in level of evidence 1 studies. Breast Cancer Res. 2014; 16(4): 428. doi: 10.1186/s13058-014-0428-4.
Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007; 25(33):5287–312.doi: 10.1200/JCO.2007.14.2364.
Fabrice A, Nofisat I, Kimberly HA, Barlow WE, Collyar DE, Damodaran S, et al. Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO Guideline update. J Clin Oncol. 2022; 40(16):1816-37.doi: 10.1200/JCO.22.00069.
Nielsen TO, Leung SCY, Rimm DL, Dodson A, Acs B, Badve S, et al. Assessment of Ki67 in breast cancer: updated recommendations from the International Ki67 in breast cancer working group. J Natl Cancer Inst. 2021; 113(7):201.doi: 10.1093/jnci/djaa201.
Krop I, Ismaila N, Andre F, Bast RC, Barlow W, Collyar DE, et al. Use of biomarkers to guide decisions on ad juvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. 2017;35(24):2838–47. doi: 10.1200/JCO.2017.74.0472.
Cuzick J, Dowsett M, Pineda S, Wale C, Salter J, Quinn E, et al. Prognostic value of a combined estrogen receptor, progesterone receptor, ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the genomic health recurrence score in early breast cancer. J Clin Oncol. 2011; 29(32):4273–8.doi:10.1200/JCO.2010.31.2835.
American Cancer Society. Breast-conserving surgery. Available from:URL:https://www.cancer.org/cancer/types/breast-cancer/treatment/surgery-for-breast-cancer/breast-conserving-surgery-lumpectomy.html (date last accessed: Feb 3, 2024).
Pedersen AN, Brünner N, Høyer Hansen G, Hamer P, Jarosz D, Larsen B, et al. Determination of the complex between urokinase and its type-1 inhibitor in plasma from healthy donors and breast cancer patients. Clin Chem. 1999; 45(8):1206-13.doi: 10.1093/clinchem/45.8.1206.
Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ. Panel members. Strategies for subtypes – dealing with the diversity of breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol. 2011; 22(8):1736-47.doi: 10.1093/annonc/mdr304.
American Cancer Society. Mammograms After Breast Cancer Surgery. Available from: URL:https://www.cancer.org/cancer/types/breastcancer/screening-tests-and-earlydetection/mammograms/having-a-mammogram-after-youve-had-breast-cancer-surgery.html (date last accessed: Feb 2, 2024).
Chuanxu L, Xiaorong Z, Yu F, Yanqi W, Hong Z, Ting L. Clinical characteristics and survival outcome of patients with estrogen receptor low positive breast cancer. Breast. 2022; 63:24–8.doi.org/10.1016/j.breast.2022.03.002.
Belete AM, Aynalem YA, Gemeda BN, Demelew TM, Shiferaw WS. The effect of estrogen receptor status on survival in breast cancer patients in Ethiopia. Retrospective cohort study. Breast Cancer (Dove Med Press). 2022;14:153-61. doi: 10.2147/BCTT.S365295.
Nicolini A, Ferrari P, Duffy MJ. Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol. 2018; 52(Pt1):56–73.doi: 10.1016/j.semcancer.2017.08.010.
Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer—major changes in the American Joint Committee on Cancer Eighth Edition Cancer Staging Manual. CA Cancer J Clin. 2017;67(4):290–303.doi: 10.3322/caac.21393.
Van Maaren MC, de Munck L, Strobbe LJA, Sonke GS, Westenend PJ, Smidt ML, et al. Ten-year recurrence rates for breast cancer subtypes in the Netherlands: A large population-based study. Int J Cancer. 2019; 144(2):263–72.doi: 10.1002/ijc.31914.
Tonellotto F, Bergmann A, Abrahão KS, Sales de Aguiar S, Adeodato BM, Thuler LCS. Impact of number of positive lymph nodes and lymph node ratio on survival of women with node-positive breast cancer. Eur J Breast Health. 2019; 15(2):76-84.doi: 10.5152/ejbh.2019.4414.
Sopik V, Narod SA. Therelationship between tumour size, nodal status and distant metastases: on the origins of breast cancer. Breast Cancer ResTreat. 2018;70(3):647-56.doi: 10.1007/s10549-018-4796-9.
Lian W, Fu F, Chen D, Wang C. Effect of node status on breast cancer survival by subtype: a single-center retrospective cohort study. Transl Cancer Res. 2020; 9(10):5900-08.doi: 10.21037/tcr-20-1117.
Al- Azawi SM, Al- Khateeb MM, Raoof HS. Correlation between histological grading and size of breast cancer with axillary lymph node involvement, a continuous retrospective and prospective study. Int J Curr Res. 2019;11(1):688-92.
Zhang X. Molecular classification of breast cancer: relevance and challenges. Arch Pathol Lab Med. 2023; 147(1):46–51.doi: 10.5858/arpa.2022-0070-RA.
Higgins MJ, Stearns V. Understanding resistance to Tamoxifenin hormone receptor-positive breast cancer. Clin Chem. 2009; 55(8):1453–5.
Sean MH, Yihong W. Practical issues of Ki-67 evaluation in breast cancer clinical practice. J Clin Pathol. 2022; 2(2):53–6.doi: 10.14218/JCTP.2022.00012.
Nielsen TO, Leung SCY, Rimm DL, Dodson A, Acs B, Badve S, et al. Assessment of Ki67 in breast cancer: updated recommendations from the international Ki67 in breast cancer working group. J Nat Cancer Inst. 2021; 113(7):808-19.doi: 10.1093/jnci/djaa201.
Davey MG, Hynes SO, Kerin MJ, Miller N, Lowery AJ. Ki-67 as a prognostic biomarker in invasive breast cancer. Cancers. 2021; 13(17):4455. doi: 10.3390/cancers13174455.
Andre F, Ismaila N, Allison KH, Barlow WE, Collyar DE, Damodaran S, et al. Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO guideline update. J Clin Oncol. 2022; 40(16):1816-37.doi: 10.1200/JCO.22.00069.
De Gregorio A, Friedl TWP, Hering E, Widschwendter P, de Gregorio N, Bekes I, et al. Ki67 as proliferative marker in patients with early breast cancer and its association with clinicopathological factors. Oncology. 2020; 99(12):780–9.doi: 10.1159/000517490.
Aman NA, Doukoure B, Koffi KD, Koui BS, Traore ZC, Kouyate M, et al. Immunohistochemical evaluation of Ki-67 and comparison with clinicopathologic factors in breast carcinomas. Asian Pac J Cancer Prev. 2019; 20(1):73–9. doi:10.31557/apjcp.2019.20.1.73.
Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol 2020; 21(11):1443-54.doi: 10.1016/S1470-2045(20)30458-7.
Gluz O, Kuemmel S, Nitz U, Braun M, Lüdtke-Heckenkamp K, von Schumann R, von Schumann R, et al. Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamidein high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol. 2023; 34(6):531-42.doi: 10.1016/j.annonc.2023.04.002.
Ma CX, Suman V, Leitch AM, Sanati S, Vij K, Unzeitig GW, et al. Neoadjuvant chemotherapy response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106). Cancer Res. 2021; 81(4):GS4-05. doi:10.1158/1538-7445.SABCS20-GS4-05.
Harbeck N, Johnston S, Fasching P, Martin M, Toi M, Rastogi P, et al. High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarch E. Cancer Res 2021; 81( 4):PD2-01.
Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): Diagnostic, prognostic, and therapeutic applications. Front Oncol. 2018; 8:24.doi: 10.3389/fonc.2018.00024.
Harbeck N, Schmitt M, Meisner C, Friedel C, Untch M, Schmidt M, et al. Ten-year analysis of the prospective multicentre Chemo-N0 trial validates American Society of Clinical Oncology (ASCO)- recommended biomarkers uPA and PAI-1 for therapy decision making in node-negative breast cancer patients. Eur J Cancer. 2013; 49(8):1825-35.doi: 10.1016/j.ejca.2013.01.007.
Pusina S. Correlation of serum levels of urokinase activation plasminogen (uPA) and its inhibitor (PAI-1) with hormonal and HER-2 status in the early invasive breast cancer. Med Arch. 2018; 72(5): 336-41. doi: 10.5455/medarh.2018.72.335-340.
Boissière-Michot F, Mollevi C, Baecker V, Crapez E, Jacot W. In situ hybridization for the assessment of urokinase plasminogen activator and plasminogen activator inhibitor type 1 in formalin fixed paraffin embedded breast cancer specimens. Int J Mol Med. 2022;49(6):82.doi: 10.3892/ijmm.2022.5138.
Buta M, Džodić R,, Đurišić I, Marković I, Vujasinović T, Markićević M et al. Potential clinical relevance of uPA and PAI-1 levels in node-negative, postmenopausal breast cancer patients bearing histological grade II tumors with ER/PR expression, during an early follow-up.Tumour Biol. 2015;36(10):8193-200.doi: 10.1007/s13277-015-3573-1.
Singer CF, Filipits M, Jahn SW, Abete L, Jakesz R, Greil R, et al. Stromal coexpression of uPA/PAI-1 protein predicts poor disease outcome in endocrine treated postmenopausal patients with receptor-positive early breast cancer. Breast. 2019; 46:101-7.doi: 10.1016/j.breast.2019.05.007.
Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-year risks of breast-cancer recurrence after stopping endocrine therapy at 5 years. N Engl J Med. 2017; 377(19):1836-46.doi: 10.1056/NEJMoa1701830.
Copyright (c) 2024 Sanamed
This work is licensed under a Creative Commons Attribution 4.0 International License.
Journal Sanamed is published under an Open Access license. All its content is available free of charge. Users can read, download, copy, distribute, print, search the full text of articles, as well as establish HTML links to them, without having to seek the consent of the author or publisher.
The right to use content without consent does not release the users from the obligation to give the credit to the journal and its content in a manner described under CC BY.