Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 4/2011

Open Access 01-08-2011 | Research article

Prospective evaluation of serum tissue inhibitor of metalloproteinase 1 and carbonic anhydrase IX in correlation to circulating tumor cells in patients with metastatic breast cancer

Authors: Volkmar Müller, Sabine Riethdorf, Brigitte Rack, Wolfgang Janni, Peter A Fasching, Erich Solomayer, Bahriye Aktas, Sabine Kasimir-Bauer, Julia Zeitz, Klaus Pantel, Tanja Fehm, the DETECT study group

Published in: Breast Cancer Research | Issue 4/2011

Login to get access

Abstract

Introduction

Circulating tumor cells (CTCs) reflect aggressive tumor behavior by hematogenous tumor cell dissemination. The tissue inhibitor of metalloproteinase 1 (TIMP-1) plays a role in tissue invasion and is also involved in angiogenesis, abrogation of apoptosis and in chemoresistance. Carbonic anhydrase IX (CAIX) is a metalloenzyme involved in cell adhesion, growth and survival of tumor cells. The aim of the study was to investigate whether serum concentrations of TIMP-1 and CAIX are associated with the detection of CTC in metastatic breast cancer.

Methods

Blood was obtained in a prospective multicenter setting from 253 patients with metastatic breast cancer at the time of disease progression. Serum TIMP-1 and CAIX were determined using commercial ELISA-kits (Oncogene Science). CTC were detected with the CellSearch™ system (Veridex).

Results

Five or more CTCs were detected in 122 patients out of 245 evaluable patients (49.8%). Out of 253 metastatic patients 70 (28%) had serum TIMP-1 levels above 454 ng/mL. Serum CAIX was elevated above 506 ng/mL in 90 (35%) patients. Both serum markers had prognostic significance. Median progression free survival (PFS) was 7.2 months with elevated TIMP-1 vs. 11.4 months with non-elevated levels (p < 0.01). OS was 11.5 vs. 19.1 months (p < 0.01). Median PFS was 7.5 months with elevated CAIX vs. 11.7 months with non-elevated levels (p < 0.01), overall survival (OS) was 13.4 months vs. 19.1 months (p < 0.01). In patients with five or more CTCs, serum levels were above the cut-off for CAIX in 47% vs. 25% in those with less than five CTCs (p = 0.01). For TIMP-1, 37% patients with five or more CTCs had elevated serum levels and 17% of patients with less than five CTCs (p = 0.01). Including TIMP-1, CAIX, CTC and established prognostic factors in the multivariate analysis, the presence of CTCs, the therapy line and elevated CAIX remained independent predictors of OS.

Conclusions

Elevated serum levels of the invasion markers TIMP-1 and CAIX in metastatic breast cancer are prognostic markers and are associated with the presence of CTCs. Whether increased secretion of TIMP-1 and/or CAIX might directly contribute to tumor cell dissemination remains to be elucidated in further investigations.

Trial registration

Current Controlled Trials: ISRCTN59722891
Appendix
Available only for authorised users
Literature
1.
Alix-Panabieres C, Riethdorf S, Pantel K: Circulating tumor cells and bone marrow micrometastasis. Clin Cancer Res. 2008, 14: 5013-5021. 10.1158/1078-0432.CCR-07-5125.CrossRefPubMed
2.
Pantel K, Alix-Panabieres C, Riethdorf S: Cancer micrometastases. Nat Rev Clin Oncol. 2009, 6: 339-351. 10.1038/nrclinonc.2009.44.CrossRefPubMed
3.
Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW: Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res. 2006, 12: 4218-4224. 10.1158/1078-0432.CCR-05-2821.CrossRefPubMed
4.
Riethdorf S, Fritsche H, Müller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F, Jackson S, Gornet T, Cristofanilli M, Pantel K: Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch system. Clin Cancer Res. 2007, 13: 920-928. 10.1158/1078-0432.CCR-06-1695.CrossRefPubMed
5.
Bidard FC, Vincent-Salomon A, Sigal-Zafrani B, Dieras V, Mathiot C, Mignot L, Thiery JP, Sastre-Garau X, Pierga JY: Prognosis of women with stage IV breast cancer depends on detection of circulating tumor cells rather than disseminated tumor cells. Ann Oncol. 2008, 19: 496-500.CrossRefPubMed
6.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004, 351: 781-791. 10.1056/NEJMoa040766.CrossRefPubMed
7.
Lipton A, Leitzel K, Chaudri-Ross HA, Evans DB, Ali SM, Demers L, Hamer P, Brown-Shimer S, Pierce K, Gaur V, Carney W: Serum TIMP-1 and response to the aromatase inhibitor letrozole versus tamoxifen in metastatic breast cancer. J Clin Oncol. 2008, 26: 2653-2658. 10.1200/JCO.2007.15.4336.CrossRefPubMed
8.
Wurtz SO, Schrohl AS, Mouridsen H, Brunner N: TIMP-1 as a tumor marker in breast cancer--an update. Acta Oncol. 2008, 47: 580-590. 10.1080/02841860802022976.CrossRefPubMed
9.
Lipton A, Ali SM, Leitzel K, Demers L, Evans DB, Hamer P, Brown-Shimer S, Pierce K, Carney W: Elevated plasma tissue inhibitor of metalloproteinase-1 level predicts decreased response and survival in metastatic breast cancer. Cancer. 2007, 109: 1933-1939. 10.1002/cncr.22637.CrossRefPubMed
10.
Alexander CM, Howard EW, Bissell MJ, Werb Z: Rescue of mammary epithelial cell apoptosis and entactin degradation by a tissue inhibitor of metalloproteinases-1 transgene. J Cell Biol. 1996, 135: 1669-1677. 10.1083/jcb.135.6.1669.CrossRefPubMed
11.
Liu XW, Bernardo MM, Fridman R, Kim HR: Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway. J Biol Chem. 2003, 278: 40364-40372. 10.1074/jbc.M302999200.CrossRefPubMed
12.
Li G, Fridman R, Kim HR: Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. Cancer Res. 1999, 59: 6267-6275.PubMed
13.
Luparello C, Avanzato G, Carella C, Pucci-Minafra I: Tissue inhibitor of metalloprotease (TIMP)-1 and proliferative behaviour of clonal breast cancer cells. Breast Cancer Res Treat. 1999, 54: 235-244. 10.1023/A:1006121129382.CrossRefPubMed
14.
Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K: Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett. 1992, 298: 29-32. 10.1016/0014-5793(92)80015-9.CrossRefPubMed
15.
Bigelow RL, Williams BJ, Carroll JL, Daves LK, Cardelli JA: TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro. Breast Cancer Res Treat. 2009, 117: 31-44. 10.1007/s10549-008-0170-7.CrossRefPubMed
16.
Robertson N, Potter C, Harris AL: Role of carbonic anhydrase IX in human tumor cell growth, survival, and invasion. Cancer Res. 2004, 64: 6160-6165. 10.1158/0008-5472.CAN-03-2224.CrossRefPubMed
17.
Hussain SA, Ganesan R, Reynolds G, Gross L, Stevens A, Pastorek J, Murray PG, Perunovic B, Anwar MS, Billingham L, James ND, Spooner D, Poole CJ, Rea DW, Palmer DH: Hypoxia-regulated carbonic anhydrase IX expression is associated with poor survival in patients with invasive breast cancer. Br J Cancer. 2007, 96: 104-109. 10.1038/sj.bjc.6603530.CrossRefPubMedPubMedCentral
18.
Klatte T, Seligson DB, Rao JY, Yu H, de Martino M, Kawaoka K, Wong SG, Belldegrun AS, Pantuck AJ: Carbonic anhydrase IX in bladder cancer: a diagnostic, prognostic, and therapeutic molecular marker. Cancer. 2009, 115: 1448-1458. 10.1002/cncr.24163.CrossRefPubMed
19.
Loncaster JA, Harris AL, Davidson SE, Logue JP, Hunter RD, Wycoff CC, Pastorek J, Ratcliffe PJ, Stratford IJ, West CM: Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 2001, 61: 6394-6399.PubMed
20.
Swinson DE, Jones JL, Richardson D, Wykoff C, Turley H, Pastorek J, Taub N, Harris AL, O'Byrne KJ: Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol. 2003, 21: 473-482. 10.1200/JCO.2003.11.132.CrossRefPubMed
21.
Liao SY, Darcy KM, Randall LM, Tian C, Monk BJ, Burger RA, Fruehauf JP, Peters WA, Stock RJ, Stanbridge EJ: Prognostic relevance of carbonic anhydrase-IX in high-risk, early-stage cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2010, 116: 452-458. 10.1016/j.ygyno.2009.10.062.CrossRefPubMed
22.
Zavada J, Zavadova Z, Zat'ovicova M, Hyrsl L, Kawaciuk I: Soluble form of carbonic anhydrase IX (CA IX) in the serum and urine of renal carcinoma patients. Br J Cancer. 2003, 89: 1067-1071. 10.1038/sj.bjc.6601264.CrossRefPubMedPubMedCentral
23.
Li G, Feng G, Gentil-Perret A, Genin C, Tostain J: Serum carbonic anhydrase 9 level is associated with postoperative recurrence of conventional renal cell cancer. J Urol. 2008, 180: 510-513. 10.1016/j.juro.2008.04.024. discussion 513-514CrossRefPubMed
24.
Carney WP: Circulating oncoproteins HER2/neu, EGFR and CAIX (MN) as novel cancer biomarkers. Expert Rev Mol Diagn. 2007, 7: 309-319. 10.1586/14737159.7.3.309.CrossRefPubMed
25.
Fehm T, Müller V, Aktas B, Janni W, Schneeweiss A, Stickeler E, Lattrich K, Löhberg C, Solomayer E, Rack B, Riethdorf S, Klein C, Schindlbeck C, Brocker K, Kasimir-Bauer S, Wallwiener D, Pantel K: HER2 status of circulating tumor cells in patients with metastatic breast cancer: a prospective, multicenter trial. Breast Cancer Res Treat. 2010, 124: 403-412. 10.1007/s10549-010-1163-x.CrossRefPubMed
26.
Hayes DF, Ethier S, Lippman ME: New guidelines for reporting of tumor marker studies in breast cancer research and treatment: REMARK. Breast Cancer Res Treat. 2006, 100: 237-238. 10.1007/s10549-006-9253-5.CrossRefPubMed
27.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM: Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005, 97: 1180-1184. 10.1093/jnci/dji237.CrossRefPubMed
28.
Ejlertsen B, Jensen MB, Nielsen KV, Balslev E, Rasmussen BB, Willemoe GL, Hertel PB, Knoop AS, Mouridsen HT, Brunner N: HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients. J Clin Oncol. 2010, 28: 984-990. 10.1200/JCO.2009.24.1166.CrossRefPubMed
29.
Schrohl AS, Meijer-van Gelder ME, Holten-Andersen MN, Christensen IJ, Look MP, Mouridsen HT, Brunner N, Foekens JA: Primary tumor levels of tissue inhibitor of metalloproteinases-1 are predictive of resistance to chemotherapy in patients with metastatic breast cancer. Clin Cancer Res. 2006, 12: 7054-7058. 10.1158/1078-0432.CCR-06-0950.CrossRefPubMed
30.
Wang T, Lv JH, Zhang XF, Li CJ, Han X, Sun YJ: Tissue inhibitor of metalloproteinase-1 protects MCF-7 breast cancer cells from paclitaxel-induced apoptosis by decreasing the stability of cyclin B1. Int J Cancer. 2010, 126: 362-370. 10.1002/ijc.24753.CrossRefPubMed
31.
Klintman M, Ornbjerg Wurtz S, Christensen IJ, Braemer Hertel P, Ferno M, Malmberg M, Mouridsen H, Cold F, Schrohl AS, Foekens JA, Malmstrom P, Brunner N: Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer. Breast Cancer Res Treat. 2008, 121: 365-371.CrossRef
32.
Schrohl AS, Müller V, Christensen IJ, Pantel K, Thomssen C, Bruenner N: A comparative study of tissue inhibitor of metalloproteinases-1 levels in plasma and tumour tissue from patients with primary breast cancer and in plasma from patients with metastatic breast cancer. Tumour Biol. 2008, 29: 181-187. 10.1159/000146863.CrossRefPubMed
33.
Jensen SA, Vainer B, Bartels A, Brunner N, Sorensen JB: Expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) by colorectal cancer cells and adjacent stroma cells--associations with histopathology and patients outcome. Eur J Cancer. 2010, 46: 3233-3242. 10.1016/j.ejca.2010.07.046.CrossRefPubMed
34.
Sorensen NM, Schrohl AS, Jensen V, Christensen IJ, Nielsen HJ, Brunner N: Comparative studies of tissue inhibitor of metalloproteinases-1 in plasma, serum and tumour tissue extracts from patients with primary colorectal cancer. Scand J Gastroenterol. 2008, 43: 186-191. 10.1080/00365520701491355.CrossRefPubMed
35.
Wicha MS, Hayes DF: Circulating Tumor Cells: Not All Detected Cells Are Bad and Not All Bad Cells Are Detected. J Clin Oncol. 2011, 29: 1508-1511. 10.1200/JCO.2010.34.0026.CrossRefPubMed
36.
Ivanov S, Liao SY, Ivanova A, Danilkovitch-Miagkova A, Tarasova N, Weirich G, Merrill MJ, Proescholdt MA, Oldfield EH, Lee J, Zavada J, Waheed A, Sly W, Lerman MI, Stanbridge EJ: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol. 2001, 158: 905-919. 10.1016/S0002-9440(10)64038-2.CrossRefPubMedPubMedCentral
37.
Fang JS, Gillies RD, Gatenby RA: Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol. 2008, 18: 330-337. 10.1016/j.semcancer.2008.03.011.CrossRefPubMedPubMedCentral
38.
Li Y, Tu C, Wang H, Silverman DN, Frost SC: Catalysis and pH control by membrane-associated carbonic anhydrase IX in MDA-MB-231 breast cancer cells. J Biol Chem. 2011, 286: 15789-15796. 10.1074/jbc.M110.188524.CrossRefPubMedPubMedCentral
39.
Dang CV, Resar LM, Emison E, Kim S, Li Q, Prescott JE, Wonsey D, Zeller K: Function of the c-Myc oncogenic transcription factor. Exp Cell Res. 1999, 253: 63-77. 10.1006/excr.1999.4686.CrossRefPubMed
40.
Gatenby RA, Gillies RJ: Glycolysis in cancer: a potential target for therapy. Int J Biochem Cell Biol. 2007, 39: 1358-1366. 10.1016/j.biocel.2007.03.021.CrossRefPubMed
41.
Gatenby RA, Smallbone K, Maini PK, Rose F, Averill J, Nagle RB, Worrall L, Gillies RJ: Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer. 2007, 97: 646-653. 10.1038/sj.bjc.6603922.CrossRefPubMedPubMedCentral
42.
Tripp BC, Smith K, Ferry JG: Carbonic anhydrase: new insights for an ancient enzyme. J Biol Chem. 2001, 276: 48615-48618. 10.1074/jbc.R100045200.CrossRefPubMed
43.
Wykoff CC, Beasley NJ, Watson PH, Turner KJ, Pastorek J, Sibtain A, Wilson GD, Turley H, Talks KL, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL: Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res. 2000, 60: 7075-7083.PubMed
44.
Choschzick M, Woelber L, Hess S, zu Eulenburg C, Schwarz J, Simon R, Mahner S, Jaenicke F, Müller V: Overexpression of carbonic anhydrase IX (CAIX) in vulvar cancer is associated with tumor progression and development of locoregional lymph node metastases. Virchows Arch. 2010, 456: 483-490. 10.1007/s00428-010-0905-9.CrossRefPubMed
45.
Mahner S, Woelber L, Eulenburg C, Schwarz J, Carney W, Jaenicke F, Milde-Langosch K, Müller V: TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients. BMC Cancer. 2010, 10: 139-10.1186/1471-2407-10-139.CrossRefPubMedPubMedCentral
46.
Morsy SM, Badawi AM, Cecchi A, Scozzafava A, Supuran CT: Carbonic anhydrase inhibitors. Biphenylsulfonamides with inhibitory action towards the transmembrane, tumor-associated isozymes IX possess cytotoxic activity against human colon, lung and breast cancer cell lines. J Enzyme Inhib Med Chem. 2009, 24: 499-505. 10.1080/14756360802218441.CrossRefPubMed
47.
Tan EY, Yan M, Campo L, Han C, Takano E, Turley H, Candiloro I, Pezzella F, Gatter KC, Millar EK, O'Toole SA, McNeil CM, Crea P, Segara D, Sutherland RL, Harris AL, Fox SB: The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy. Br J Cancer. 2009, 100: 405-411. 10.1038/sj.bjc.6604844.CrossRefPubMedPubMedCentral
48.
Brennan DJ, Jirstrom K, Kronblad A, Millikan RC, Landberg G, Duffy MJ, Ryden L, Gallagher WM, O'Brien SL: CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance. Clin Cancer Res. 2006, 12: 6421-6431. 10.1158/1078-0432.CCR-06-0480.CrossRefPubMed
49.
Winum JY, Scozzafava A, Montero JL, Supuran CT: Inhibition of carbonic anhydrase IX: a new strategy against cancer. Anticancer Agents Med Chem. 2009, 9: 693-702.CrossRefPubMed
50.
Swietach P, Hulikova A, Vaughan-Jones RD, Harris AL: New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation. Oncogene. 2010, 29: 6509-6521. 10.1038/onc.2010.455.CrossRefPubMed
51.
Lou Y, McDonald PC, Oloumi A, Chia SK, Ostlund C, Ahmadi A, Kyle A, Auf dem Keller U, Leung S, Huntsman DG, Clarke B, Sutherland BW, Waterhouse D, Bally MB, Roskelley CD, Overall CM, Minchinton A, Pacchiano F, Carta F, Scozzafava A, Touisni N, Winum JY, Supuran CT, Dedhar S: Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res. 2011, 71: 3364-3376. 10.1158/0008-5472.CAN-10-4261.CrossRefPubMed
52.
Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y, Horvath S, Leibovich BC, Chopra S, Liao SY, Stanbridge E, Lerman MI, Palotie A, Figlin RA, Belldegrun AS: Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res. 2003, 9: 802-811.PubMed
53.
Woelfle U, Cloos J, Sauter G, Riethdorf L, Janicke F, van Diest P, Brakenhoff R, Pantel K: Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res. 2003, 63: 5679-5684.PubMed
Metadata
Title
Prospective evaluation of serum tissue inhibitor of metalloproteinase 1 and carbonic anhydrase IX in correlation to circulating tumor cells in patients with metastatic breast cancer
Authors
Volkmar Müller
Sabine Riethdorf
Brigitte Rack
Wolfgang Janni
Peter A Fasching
Erich Solomayer
Bahriye Aktas
Sabine Kasimir-Bauer
Julia Zeitz
Klaus Pantel
Tanja Fehm
the DETECT study group
Publication date
01-08-2011
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 4/2011
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2916

Other articles of this Issue 4/2011

Breast Cancer Research 4/2011 Go to the issue

Review

Vitamin D and breast cancer: interpreting current evidence

Research article

Tribbles homolog 3 denotes a poor prognosis in breast cancer and is involved in hypoxia response

Research article

β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib

Editorial

Targeting bone metastases starting from the preneoplastic niche: home sweet home

Viewpoint

Cannibalism, cell survival, and endocrine resistance in breast cancer

Research article

Allele-specific regulation of FGFR2 expression is cell type-dependent and may increase breast cancer risk through a paracrine stimulus involving FGF10
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits