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01-06-2013 | Clinical Trial

Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial

Authors: J. Bjöhle, J. Bergqvist, J. S. Gronowitz, H. Johansson, L. Carlsson, Z. Einbeigi, B. Linderholm, N. Loman, M. Malmberg, M. Söderberg, M. Sundquist, T. M. Walz, M. Fernö, J. Bergh, T. Hatschek

Published in: Breast Cancer Research and Treatment | Issue 3/2013

Abstract

The primary objective was to estimate serum thymidine kinase 1 (TK1) activity, reflecting total body cell proliferation rate including cancer cell proliferation, in women with loco regional inoperable or metastatic breast cancer participating in a prospective and randomized study. Secondary objectives were to analyze TK1 in relation to progression-free survival (PFS), overall survival (OS), therapy response and other tumour characteristics, including CA 15-3, widely used as a standard serum marker for disease progression. TK1 and CA 15-3 were analysed in 198 serum samples collected prospectively from women included in the randomized TEX trial between December 2002 and June 2007. TK1 activity was determined by the ELISA based DiviTum™ assay, and CA 15-3 analyses was generated with the electrochemiluminescence immunoassay Cobas Elecsys CA 15-3 II. High pre-treatment TK1 activity predicted shorter PFS (10 vs. 15 months p = 0.02) and OS (21 vs. 38 months, p < 0.0001), respectively. After adjustment for age, metastatic site and study treatment TK1 showed a trend as predictor of PFS (p = 0.059) and was an independent prognostic factor for OS, (HR 1.81, 95 % confidence interval (CI) 1.26–2.61, p = 0.001). There was a trend of shortened OS for women with high CA 15-3 (p = 0.054) in univariate analysis, but not after adjustment for the above mentioned covariates. Both TK1 (p = 0.0011) and CA 15-3 (p = 0.0004) predicted response to treatment. There were statistically different distributions of TK1 and CA 15-3 in relation to the site of metastases. TK1 activity measured by DiviTum™ predicted therapy response, PFS and OS in loco regional inoperable or disseminated breast cancer. These results suggest that this factor is a useful serum marker. In the present material, a prognostic value of CA 15-3 could not be proven.

Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287–5312PubMedCrossRef

Largillier R, Ferrero JM, Doyen J, Barriere J, Namer M, Mari V, Courdi A, Hannoun-Levi JM, Ettore F, Birtwisle-Peyrottes I et al (2008) Prognostic factors in 1,038 women with metastatic breast cancer. Ann Oncol 19(12):2012–2019PubMedCrossRef

Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V, Jassem J, Kostler WJ, Krainer M, Menard S et al (2009) Third consensus on medical treatment of metastatic breast cancer. Ann Oncol 20(11):1771–1785PubMedCrossRef

Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G (2000) Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat 59(3):271–278PubMedCrossRef

Foukakis T, Fornander T, Lekberg T, Hellborg H, Adolfsson J, Bergh J (2011) Age-specific trends of survival in metastatic breast cancer: 26 years longitudinal data from a population-based cancer registry in Stockholm Sweden. Breast Cancer Res Treat 130(2):553–560PubMedCrossRef

Cheung KL, Graves CR, Robertson JF (2000) Tumour marker measurements in the diagnosis and monitoring of breast cancer. Cancer Treat Rev 26(2):91–102PubMedCrossRef

Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K, Allred DC et al (2011) Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype–ACOSOG Z1031. J Clin Oncol 29(17):2342–2349PubMedCrossRef

Topolcan O, Holubec L Jr (2008) The role of thymidine kinase in cancer diseases. Expert Opin Med diagn 2(2):129–141PubMedCrossRef

Kim SR, Paik S (2011) Genomics of adjuvant therapy for breast cancer. Cancer J 17(6):500–504PubMedCrossRef

10.

Littlefield JW (1966) The use of drug-resistant markers to study the hybridization of mouse fibroblasts. Exp Cell Res 41(1):190–196PubMedCrossRef

11.

Weissman SM, Smellie RM, Paul J (1960) Studies on the biosynthesis of deoxyribonucleic acid by extracts of mammalian cells. IV. The phosphorylation of thymidine. Biochim Biophys Acta 45:101–110PubMedCrossRef

12.

Hu CM, Chang ZF (2007) Mitotic control of dTTP pool: a necessity or coincidence? J Biomed Sci 14(4):491–497PubMedCrossRef

13.

Munch-Petersen B, Cloos L, Jensen HK, Tyrsted G (1995) Human thymidine kinase 1. Regulation in normal and malignant cells. Adv Enzyme Regul 35:69–89PubMedCrossRef

14.

Broet P, Romain S, Daver A, Ricolleau G, Quillien V, Rallet A, Asselain B, Martin PM, Spyratos F (2001) Thymidine kinase as a proliferative marker: clinical relevance in 1,692 primary breast cancer patients. J Clin Oncol 19(11):2778–2787PubMed

15.

Gronowitz JS, Bergstrom R, Nou E, Pahlman S, Brodin O, Nilsson S, Kallander CF (1990) Clinical and serologic markers of stage and prognosis in small cell lung cancer. A multivariate analysis. Cancer 66(4):722–732

16.

Nisman B, Allweis T, Kaduri L, Maly B, Gronowitz S, Hamburger T, Peretz T (2010) Serum thymidine kinase 1 activity in breast cancer. Cancer Biomarkers 7(2):65–72PubMed

17.

Nisman B, Yutkin V, Nechushtan H, Gofrit ON, Peretz T, Gronowitz S, Pode D (2010) Circulating tumor M2 pyruvate kinase and thymidine kinase 1 are potential predictors for disease recurrence in renal cell carcinoma after nephrectomy. Urology 76(2):513.e1–513.e6CrossRef

18.

O’Neill KL, Hoper M, Odling-Smee GW (1992) Can thymidine kinase levels in breast tumors predict disease recurrence? J Natl Cancer Inst 84(23):1825–1828PubMedCrossRef

19.

Svobodova S, Topolcan O, Holubec L, Treska V, Sutnar A, Rupert K, Kormunda S, Rousarova M, Finek J (2007) Prognostic importance of thymidine kinase in colorectal and breast cancer. Anticancer Res 27(4A):1907–1909PubMed

20.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) Statistics Subcommittee of NCIEWGoCD: REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235PubMedCrossRef

21.

Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Soderberg M et al (2012) Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat 131(3):939–947PubMedCrossRef

22.

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRef

23.

WHO (1979) WHO Handbook for reporting results of treatment, 48th edn. World Health Organization, Geneva

24.

Wu BJ, Li WP, Qian C, Ding W, Zhou ZW, Jiang H (2013) Increased serum level of thymidine kinase 1 correlates with metastatic site in patients with malignant melanoma. Tumour Biol 34(2):643–648PubMedCrossRef

25.

Romain S, Spyratos F, Descotes F, Daver A, Rostaing-Puissant B, Bougnoux P, Colonna M, Bolla M, Martin PM (2000) Prognostic of DNA-synthesizing enzyme activities (thymidine kinase and thymidylate synthase) in 908 T1–T2, N0–N1, M0 breast cancers: a retrospective multicenter study. Int J Cancer 87(6):860–868PubMedCrossRef

26.

Korkmaz T, Seber S, Okutur K, Basaran G, Yumuk F, Dane F, Ones T, Polat O, Madenci OC, Demir G et al (2013) Serum thymidine kinase 1 levels correlates with FDG uptake and prognosis in patients with non small cell lung cancer. Biomarkers 18(1):88–94PubMedCrossRef

27.

He Q, Fornander T, Johansson H, Johansson U, Hu GZ, Rutqvist LE, Skog S (2006) Thymidine kinase 1 in serum predicts increased risk of distant or loco-regional recurrence following surgery in patients with early breast cancer. Anticancer Res 26(6C):4753–4759PubMed

28.

Robertson JF, O’Neill KL, Thomas MW, McKenna PG, Blamey RW (1990) Thymidine kinase in breast cancer. Br J Cancer 62(4):663–667PubMedCrossRef

29.

Gronowitz JS (1984) Extracellular expression of TK isozymes in human body fluids, with special reference to herpesvirus diagnostics and use for monitoring of antiviral therapy. In: Sanna A, Morace G (eds.) New Horizons in Microbiology. Amsterdam, Elsevier Science Publishers, p. 273–284

30.

Foekens JA, Romain S, Look MP, Martin PM, Klijn JG (2001) Thymidine kinase and thymidylate synthase in advanced breast cancer: response to tamoxifen and chemotherapy. Cancer Res 61(4):1421–1425PubMed

31.

Nisman B, Allweis T, Kadouri L, Mali B, Hamburger T, Baras M, Gronowitz S, Peretz T (2013) Comparison of diagnostic and prognostic performance of two assays measuring thymidine kinase 1 activity in serum of breast cancer patients. Clin Chem Lab Med 51(2):439–447PubMedCrossRef

32.

Yerushalmi R, Tyldesley S, Kennecke H, Speers C, Woods R, Knight B, Gelmon KA (2012) Tumor markers in metastatic breast cancer subtypes: frequency of elevation and correlation with outcome. Ann Oncol 23(2):338–345PubMedCrossRef

33.

Luporsi E, Andre F, Spyratos F, Martin PM, Jacquemier J, Penault-Llorca F, Tubiana-Mathieu N, Sigal-Zafrani B, Arnould L, Gompel A et al (2012) Ki-67: level of evidence and methodological considerations for its role in the clinical management of breast cancer: analytical and critical review. Breast Cancer Res Treat 132(3):895–915PubMedCrossRef

Title: Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial
Authors: J. Bjöhle
J. Bergqvist
J. S. Gronowitz
H. Johansson
L. Carlsson
Z. Einbeigi
B. Linderholm
N. Loman
M. Malmberg
M. Söderberg
M. Sundquist
T. M. Walz
M. Fernö
J. Bergh
T. Hatschek
Publication date: 01-06-2013
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2013
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-013-2579-x

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