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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Metastasis | Research article

The prognostic value of the Tau protein serum level in metastatic breast cancer patients and its correlation with brain metastases

Authors: Amélie Darlix, Christophe Hirtz, Simon Thezenas, Aleksandra Maceski, Audrey Gabelle, Evelyne Lopez-Crapez, Hélène De Forges, Nelly Firmin, Séverine Guiu, William Jacot, Sylvain Lehmann

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Metastatic breast cancer (MBC) prognosis is variable, depending on several clinical and biological factors. A better prediction of a patient’s outcome could allow for a more accurate choice of treatments. The role of serum biomarkers in predicting outcome remains unclear in this setting. Tau, a microtubule-associated protein, is a neuronal marker that is also expressed in normal breast epithelial cells and cancer cells. Its tissue expression is associated with prognosis in MBC. However, the prognostic value of Tau serum levels in these patients is unknown. We aimed at evaluating the prognostic value of Tau (and other classical biomarkers) in MBC patients, and to assess its association with the presence of brain metastases (BM).

Methods

244 MBC patients treated at our institution (2007–2015) were retrospectively selected. The usual MBC clinical and pathological variables were collected, altogether with CA15–3, CEA and HER2 extra-cellular domain (ECD) serum levels. Tau serum levels were measured with a novel immunoassay (digital ELISA) using Single Molecule Array (Simoa) technology. Overall survival (OS) was estimated with the Kaplan-Meier method. To investigate prognostic factors, a multivariate analysis was performed. Cut-offs were set using the Youden index method associated with receiver-operating characteristics (ROC) curves to evaluate the accuracy of biomarkers to identify patients with BM.

Results

With a median follow-up of 40.8 months, median OS was 15.5 months (95%CI 12.4–20.2). Elevated serum levels of Tau were independently associated with a poor outcome in the whole population as well as in patients with (n = 86) and without BM (n = 158). Median serum Tau levels tended to be higher in patients with BM (p = 0.23). In univariate analysis, patients with BM had an increased risk of serum Tau > 3.17 pg/mL (OR = 2.2, p = 0.049). In multivariate analysis, high values of Tau (OR = 3.98, p = 0.034) accurately identified patients with BM in our cohort.

Conclusions

Tau is a new biomarker of interest in MBC. Its serum level could represent an independent prognostic factor in these patients (both with and without BM). It also seems to be associated with the presence of BM. A validation of these results in an independent set of MBC patients is necessary to confirm these findings.
Appendix
Available only for authorised users
Literature
1.
Chia SK, Speers CH, D'yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2007;110(5):973–9.PubMedCrossRef
2.
Mosconi P, Colozza M, De Laurentiis M, De Placido S, Maltoni M. Survival, quality of life and breast cancer. Ann Oncol. 2001;12(Suppl 3):S15–9.PubMedCrossRef
3.
Andreopoulou E, Hortobagyi GN. Prognostic factors in metastatic breast cancer: successes and challenges toward individualized therapy. J Clin Oncol. 2008;26(22):3660–2.PubMedCrossRef
4.
Largillier R, Ferrero JM, Doyen J, Barriere J, Namer M, Mari V, et al. Prognostic factors in 1,038 women with metastatic breast cancer. Ann Oncol. 2008;19(12):2012–9.PubMedPubMedCentralCrossRef
5.
Lobbezoo DJ, van Kampen RJ, Voogd AC, Dercksen MW, van den Berkmortel F, Smilde TJ, et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome. Breast Cancer Res Treat. 2013;141(3):507–14.PubMedCrossRef
6.
Solomayer EF, Diel IJ, Meyberg GC, Gollan C, Bastert G. Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis. Breast Cancer Res Treat. 2000;59(3):271–8.PubMedCrossRef
7.
Beslija S, Bonneterre J, Burstein HJ, Cocquyt V, Gnant M, Heinemann V, et al. Third consensus on medical treatment of metastatic breast cancer. Ann Oncol. 2009;20(11):1771–5.PubMedCrossRef
8.
Regierer AC, Wolters R, Ufen MP, Weigel A, Novopashenny I, Köhne CH, et al. An internally and externally validated prognostic score for metastatic breast cancer: analysis of 2269 patients. Ann Oncol. 2014;25(3):633–8.PubMedCrossRef
9.
Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271–7.PubMedCrossRef
10.
Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28(1):92–8.PubMedCrossRef
11.
Yamamoto N, Watanabe T, Katsumata N, Omuro Y, Ando M, Fukuda H, et al. Construction and validation of a practical prognostic index for patients with metastatic breast cancer. J Clin Oncol. 1998;16(7):2401–8.PubMedCrossRef
12.
Wyld L, Gutteridge E, Pinder SE, James JJ, Chan SY, Cheung KL, et al. Prognostic factors for patients with hepatic metastases from breast cancer. Br J Cancer. 2003;89(2):284–90.PubMedPubMedCentralCrossRef
13.
Brown JE, Cook RJ, Lipton A, Coleman RE. Serum lactate dehydrogenase is prognostic for survival in patients with bone metastases from breast cancer: a retrospective analysis in bisphosphonate-treated patients. Clin Cancer Res. 2012;18:6348–55.PubMedCrossRef
14.
Bidard FC, Hajage D, Bachelot T, Delaloge S, Brain E, Campone M, et al. Assessment of circulating tumor cells and serum markers for progression-free survival prediction in metastatic breast cancer: a prospective observational study. Breast Cancer Res. 2012;14(1):R29.PubMedPubMedCentralCrossRef
15.
Lee JS, Park S, Park JM, Cho JH, Kim SI, Park BW. Elevated levels of serum tumor markers CA 15-3 and CEA are prognostic factors for diagnosis of metastatic breast cancers. Breast Cancer Res Treat. 2013;141(3):477–84.PubMedCrossRef
16.
Shao Y, Sun X, He Y, Liu C, Liu H. Elevated levels of serum tumor markers CEA and CA15-3 are prognostic parameters for different molecular subtypes of breast Cancer. PLoS One. 2015;10(7):e0133830.PubMedPubMedCentralCrossRef
17.
Darlix A, Lamy PJ, Lopez-Crapez E, Braccini AL, Firmin N, Romieu G, Thezenas S, Jacot W. Serum HER2 extra-cellular domain, S100ß and CA 15-3 levels are independent prognostic factors in metastatic breast cancer patients. BMC Cancer. 2016;16:428.PubMedPubMedCentralCrossRef
18.
Tsé C, Gauchez AS, Jacot W, Lamy PJ. HER2 shedding and serum HER2 extracellular domain: biology and clinical utility in breast cancer. Cancer Treat Rev. 2012;38(2):133–42.PubMedCrossRef
19.
Baselga J, Cortés J, Im SA, Clark E, Ross G, Kiermaier A, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J Clin Oncol. 2014;32(33):3753–61.PubMedCrossRef
20.
Binder LI, Frankfurter A, Rebhun LI. The distribution of tau in the mammalian central nervous system. J Cell Biol. 1985;101(4):1371–8.PubMedCrossRef
21.
22.
Rouzier R, Rajan R, Wagner P, Hess KR, Gold DL, Stec J, Ayers M, Ross JS, Zhang P, Buchholz TA, Kuerer H, Green M, Arun B, Hortobagyi GN, Symmans WF, Pusztai L. Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc Natl Acad Sci U S A. 2005;102(23):8315–20.PubMedPubMedCentralCrossRef
23.
Souter S, Lee G. Microtubule-associated protein tau in human prostate cancer cells: isoforms, phosphorylation, and interactions. J Cell Biochem. 2009;108(3):555–64.PubMedPubMedCentralCrossRef
24.
Baquero MT, Lostritto K, Gustavson MD, Bassi KA, Appia F, Camp RL, Molinaro AM, Harris LN, Rimm DL. Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts. Breast Cancer Res. 2011;13(5):R85.PubMedPubMedCentralCrossRef
25.
Matrone MA, Whipple RA, Thompson K, Cho EH, Vitolo MI, Balzer EM, Yoon JR, Ioffe OB, Tuttle KC, Tan M, Martin SS. Metastatic breast tumors express increased tau, which promotes microtentacle formation and the reattachment of detached breast tumor cells. Oncogene. 2010;29(22):3217–27.PubMedPubMedCentralCrossRef
26.
Bonneau C, Gurard-Levin ZA, Andre F, Pusztai L, Predictive RR. Prognostic value of the TauProtein in breast Cancer. Anticancer Res. 2015;35(10):5179–84.PubMed
27.
Shao YY, Kuo KT, Hu FC, Lu YS, Huang CS, Liau JY, Lee WC, Hsu C, Kuo WH, Chang KJ, Lin CH, Cheng AL. Predictive and prognostic values of tau and ERCC1 in advanced breast cancer patients treated with paclitaxel and cisplatin. Jpn J Clin Oncol. 2010;40(4):286–93.PubMedCrossRef
28.
Sunderland T, Linker G, Mirza N, et al. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA. 2003;289:2094–103.PubMedCrossRef
29.
Riemenschneider M, Wagenpfeil S, Diehl J, et al. Tau and Abeta42 protein in CSF of patients with frontotemporale degeneration. Neurology. 2002;58(11):1622–8.PubMedCrossRef
30.
Bartosik-Psujek H, Archelos JJ. Tau protein and 14-3-3 are elevated in the cerebrospinal fluid of patients with multiple sclerosis ans correlate with intrathecal synthsis of IgG. J Neurol. 2004;251(4):414–20.PubMedCrossRef
31.
Hesse C, Rosengren L, Vanmechelen E, et al. Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. J Alzheimers Dis. 2000;2(3–4):199–206.PubMedCrossRef
32.
Bitsch A, Horn C. Kemmling yet al. Serum tau protein level as a marker of axonal damage in acute ischemic stroke. Eur Neurol. 2002;47(1):45–51.PubMedCrossRef
33.
Shaw GJ, Jauch EC, Zemlan FP. Serum cleaved tau protein levels and clinical outcome in adult patients with closed head injury. Ann Emerg Med. 2002;39:254–7.PubMedCrossRef
34.
Shahim P, Blennow K, Zetterberg H. Tau, s-100 calcium-binding protein B, and neuron-specific enolase as biomarkers of concussion-reply. JAMA Neurol. 2014;71(7):926–7.PubMedCrossRef
35.
Ahmad O, Wardlaw J, Whiteley WN. Correlation of levels of neuronal and glial markers with radiological measures of infarct volume in ischaemic stroke: a systematic review. Cerebrovasc Dis. 2012;33:47–54.PubMedCrossRef
36.
de Bont JM, Vanderstichele H, Reddingius RE, et al. Increased total-tau levels in cerebrospinal fluid of pediatric hydrocephalus and brain tumor patients. Eur J Paediatr Neurol. 2008;12(4):334–41.PubMedCrossRef
37.
Van Gool SW, Van Kerschaver E, Brock P, et al. Disease- and treatment-related elevation of the neurodegenerative marker tau in children with hematological malignancies. Leukemia. 2000;14(12):2076–84.PubMedCrossRef
38.
Darlix A, Lamy PJ, Lopez-Crapez E, Braccini AL, Firmin N, Romieu G, Thézenas S, Jacot W. Serum NSE, MMP-9 and HER2 extracellular domain are associated with brain metastases in metastatic breast cancer patients: predictive biomarkers for brain metastases? Int J Cancer. 2016 Nov 15;139(10):2299–311.PubMedCrossRef
39.
Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol. 2010;28(6):595–9.PubMedPubMedCentralCrossRef
40.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Statistics subcommittee of NCI-EORTC working group on Cancer diagnostics. REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat. 2006;100(2):229–35.PubMedCrossRef
41.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.CrossRef
42.
43.
Subbiah IM, Lei X, Weinberg JS, Sulman EP, Chavez-MacGregor M, Tripathy D, Gupta R, Varma A, Chouhan J, Guevarra RP, Valero V, Gilbert MR, Gonzalez-Angulo AM. Validation and development of a modified breast graded prognostic assessment as a tool for survival in patients with breast Cancer and Brain metastases. J Clin Oncol. 2015;33(20):2239–45.PubMedPubMedCentralCrossRef
44.
Griguolo G, Jacot W, Kantelhardt E, Dieci MV, Bourgier C, Thomssen C, Bailleux C, Miglietta F, Braccini AL, Conte P, Ferrero JM, Guarneri V, Darlix A. External validation of modified breast graded prognostic assessment for breast cancer patients with brain metastases: a multicentric European experience. Breast. 2017;37:36–41.PubMedCrossRef
45.
Cengiz P, Zemlan F, Eickhoff JC, Ellenbogen R, Zimmerman JJ. Increased cerebrospinal fluid cleaved tau protein (C-tau) levels suggest axonal damage in pediatric patients with brain tumors. Childs Nerv Syst. 2015;31(8):1313–9.PubMedCrossRef
46.
Wunderlich MT, Lins H, Skalej M, Wallesch CW, Goertler M. Neuron-specific enolase and tau protein as neurobiochemical markers of neuronal damage are related to early clinical course and long-term outcome in acute ischemic stroke. Clin Neurol Neurosurg. 2006;108:558–63.PubMedCrossRef
47.
Tsukada Y, Fouad A, Pickren JW, Lane WW. Central nervous system metastasis from breast carcinoma. Autopsy study. Cancer. 1983;52(12):2349–54.PubMedCrossRef
48.
Davis FG, Dolecek TA, McCarthy BJ, Villano JL. Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data. Neuro-Oncology. 2012;14(9):1171–7.PubMedPubMedCentralCrossRef
Metadata
Title
The prognostic value of the Tau protein serum level in metastatic breast cancer patients and its correlation with brain metastases
Authors
Amélie Darlix
Christophe Hirtz
Simon Thezenas
Aleksandra Maceski
Audrey Gabelle
Evelyne Lopez-Crapez
Hélène De Forges
Nelly Firmin
Séverine Guiu
William Jacot
Sylvain Lehmann
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5287-z

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue

Research article

High methylation levels of PCDH10 predict poor prognosis in patients with pancreatic ductal adenocarcinoma

Research article

A phase II randomized controlled trial of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy

Research article

Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance

Study protocol

Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment: a study protocol

Research article

Increased PHGDH expression promotes aberrant melanin accumulation

Research article

IL1A polymorphisms is a risk factor for colorectal cancer in Chinese Han population: a case control study
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