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

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
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2017

Open Access 01-12-2017 | Research

Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group

Authors: Amanda Psyrri, Konstantine T. Kalogeras, Ralph M. Wirtz, George Kouvatseas, Georgia Karayannopoulou, Anna Goussia, Flora Zagouri, Elke Veltrup, Eleni Timotheadou, Helen Gogas, Angelos Koutras, Georgios Lazaridis, Christos Christodoulou, George Pentheroudakis, Panagiota Economopoulou, Apostolos Laskarakis, Petroula Arapantoni-Dadioti, Anna Batistatou, Maria Sotiropoulou, Gerasimos Aravantinos, Pavlos Papakostas, Paris Kosmidis, Dimitrios Pectasides, George Fountzilas

Published in: Journal of Translational Medicine | Issue 1/2017

Login to get access

Abstract

Background

The shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN.

Methods

Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively.

Results

OPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00–1.59, Wald’s p = 0.050) and OS (HR 1.37, 95% CI 1.05–1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10–1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61–2.05, p = 0.003) in the multivariate analysis.

Conclusions

We showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy.
Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202
Appendix
Available only for authorised users
Literature
1.
2.
Sangaletti S, Tripodo C, Sandri S, Torselli I, Vitali C, Ratti C, Botti L, Burocchi A, Porcasi R, Tomirotti A, et al. Osteopontin shapes immunosuppression in the metastatic niche. Cancer Res. 2014;74:4706–19.CrossRefPubMed
3.
Zduniak K, Agrawal A, Agrawal S, Hossain MM, Ziolkowski P, Weber GF. Osteopontin splice variants are differential predictors of breast cancer treatment responses. BMC Cancer. 2016;16:441.CrossRefPubMedPubMedCentral
4.
Hayes DF, Bast RC, Desch CE, Fritsche H Jr, Kemeny NE, Jessup JM, Locker GY, Macdonald JS, Mennel RG, Norton L, et al. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst. 1996;88:1456–66.CrossRefPubMed
5.
Shi SM, Su ZB, Zhao JJ, Yu DJ, Tu JW, Zhu JQ, Zhao JP, Sheng L, Wang SB, Sheng YJ, et al. Increased osteopontin protein expression may be correlated with poor prognosis in non-small-cell lung cancer: a meta analysis. J Cancer Res Ther. 2016;12:277–82.PubMed
6.
Luo SD, Chen YJ, Liu CT, Rau KM, Chen YC, Tsai HT, Chen CH, Chiu TJ. Osteopontin involves cisplatin resistance and poor prognosis in oral squamous cell carcinoma. Biomed Res Int. 2015;2015:508587.PubMedPubMedCentral
7.
Zhao M, Liang F, Zhang B, Yan W, Zhang J. The impact of osteopontin on prognosis and clinicopathology of colorectal cancer patients: a systematic meta-analysis. Sci Rep. 2015;5:12713.CrossRefPubMedPubMedCentral
8.
Kiss T, Ecsedi S, Vizkeleti L, Koroknai V, Emri G, Kovacs N, Adany R, Balazs M. The role of osteopontin expression in melanoma progression. Tumour Biol. 2015;36:7841–7.CrossRefPubMed
9.
Singhal H, Bautista DS, Tonkin KS, O’Malley FP, Tuck AB, Chambers AF, Harris JF. Elevated plasma osteopontin in metastatic breast cancer associated with increased tumor burden and decreased survival. Clin Cancer Res. 1997;3:605–11.PubMed
10.
Furger KA, Menon RK, Tuck AB, Bramwell VH, Chambers AF. The functional and clinical roles of osteopontin in cancer and metastasis. Curr Mol Med. 2001;1:621–32.CrossRefPubMed
11.
Xu K, Tian X, Oh SY, Movassaghi M, Naber SP, Kuperwasser C, Buchsbaum RJ. The fibroblast Tiam1-osteopontin pathway modulates breast cancer invasion and metastasis. Breast Cancer Res. 2016;18:14.CrossRefPubMedPubMedCentral
12.
Sharon Y, Raz Y, Cohen N, Ben-Shmuel A, Schwartz H, Geiger T, Erez N. Tumor-derived osteopontin reprograms normal mammary fibroblasts to promote inflammation and tumor growth in breast cancer. Cancer Res. 2015;75:963–73.CrossRefPubMed
13.
Bramwell VH, Tuck AB, Chapman JA, Anborgh PH, Postenka CO, Al-Katib W, Shepherd LE, Han L, Wilson CF, Pritchard KI, et al. Assessment of osteopontin in early breast cancer: correlative study in a randomised clinical trial. Breast Cancer Res. 2014;16:R8.CrossRefPubMedPubMedCentral
14.
Thorat D, Sahu A, Behera R, Lohite K, Deshmukh S, Mane A, Karnik S, Doke S, Kundu GC. Association of osteopontin and cyclooxygenase-2 expression with breast cancer subtypes and their use as potential biomarkers. Oncol Lett. 2013;6:1559–64.PubMedPubMedCentral
15.
Patani N, Jiang W, Mokbel K. Osteopontin C mRNA expression is associated with a poor clinical outcome in human breast cancer. Int J Cancer. 2008;122:2646.CrossRefPubMed
16.
Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, et al. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2005;16:1762–71.CrossRefPubMed
17.
Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 2007;18:1133–44.CrossRefPubMed
18.
Fountzilas G, Dafni U, Gogas H, Linardou H, Kalofonos HP, Briasoulis E, Pectasides D, Samantas E, Bafaloukos D, Stathopoulos GP, et al. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Ann Oncol. 2008;19:853–60.CrossRefPubMed
19.
Gogas H, Dafni U, Karina M, Papadimitriou C, Batistatou A, Bobos M, Kalofonos HP, Eleftheraki AG, Timotheadou E, Bafaloukos D, et al. Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat. 2012;132:609–19.CrossRefPubMed
20.
Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, et al. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011;128:447–56.CrossRefPubMed
21.
Fountzilas G, Dafni U, Bobos M, Batistatou A, Kotoula V, Trihia H, Malamou-Mitsi V, Miliaras S, Chrisafi S, Papadopoulos S, et al. Differential response of immunohistochemically defined breast cancer subtypes to anthracycline-based adjuvant chemotherapy with or without paclitaxel. PLoS ONE. 2012;7:e37946.CrossRefPubMedPubMedCentral
22.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Statistics subcommittee of NCIEWGoCD: reporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat. 2006;100:229–35.CrossRefPubMed
23.
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998;4:844–7.CrossRefPubMed
24.
Skacel M, Skilton B, Pettay JD, Tubbs RR. Tissue microarrays: a powerful tool for high-throughput analysis of clinical specimens: a review of the method with validation data. Appl Immunohistochem Mol Morphol. 2002;10:1–6.PubMed
25.
Fountzilas G, Kourea HP, Bobos M, Televantou D, Kotoula V, Papadimitriou C, Papazisis KT, Timotheadou E, Efstratiou I, Koutras A, et al. Paclitaxel and bevacizumab as first line combined treatment in patients with metastatic breast cancer: the Hellenic Cooperative Oncology Group experience with biological marker evaluation. Anticancer Res. 2011;31:3007–18.PubMed
26.
Psyrri A, Kalogeras KT, Kronenwett R, Wirtz RM, Batistatou A, Bournakis E, Timotheadou E, Gogas H, Aravantinos G, Christodoulou C, et al. Prognostic significance of UBE2C mRNA expression in high-risk early breast cancer. A Hellenic Cooperative Oncology Group (HeCOG) Study. Ann Oncol. 2012;23:1422–7.CrossRefPubMed
27.
Fountzilas G, Dafni U, Bobos M, Kotoula V, Batistatou A, Xanthakis I, Papadimitriou C, Kostopoulos I, Koletsa T, Tsolaki E, et al. Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials. BMC Cancer. 2013;13:163.CrossRefPubMedPubMedCentral
28.
Stavridi F, Kalogeras KT, Pliarchopoulou K, Wirtz RM, Alexopoulou Z, Zagouri F, Veltrup E, Timotheadou E, Gogas H, Koutras A, et al. Comparison of the ability of different clinical treatment scores to estimate prognosis in high-risk early breast cancer patients: a Hellenic Cooperative Oncology Group Study. PLoS ONE. 2016;11:e0164013.CrossRefPubMedPubMedCentral
29.
Tuck AB, O’Malley FP, Singhal H, Harris JF, Tonkin KS, Kerkvliet N, Saad Z, Doig GS, Chambers AF. Osteopontin expression in a group of lymph node negative breast cancer patients. Int J Cancer. 1998;79:502–8.CrossRefPubMed
30.
Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–45.CrossRefPubMed
31.
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–95.CrossRefPubMedPubMedCentral
32.
Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, Watson M, Davies S, Bernard PS, Parker JS, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101:736–50.CrossRefPubMedPubMedCentral
33.
Pang H, Lu H, Song H, Meng Q, Zhao Y, Liu N, Lan F, Liu Y, Yan S, Dong X, Cai L. Prognostic values of osteopontin-c, E-cadherin and beta-catenin in breast cancer. Cancer Epidemiol. 2013;37:985–92.CrossRefPubMed
34.
Bartlett JM, Munro AF, Dunn JA, McConkey C, Jordan S, Twelves CJ, Cameron DA, Thomas J, Campbell FM, Rea DW, et al. Predictive markers of anthracycline benefit: a prospectively planned analysis of the UK National Epirubicin Adjuvant Trial (NEAT/BR9601). Lancet Oncol. 2010;11:266–74.CrossRefPubMed
35.
Press MF, Sauter G, Buyse M, Bernstein L, Guzman R, Santiago A, Villalobos IE, Eiermann W, Pienkowski T, Martin M, et al. Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol. 2011;29:859–67.CrossRefPubMed
36.
Bempt IV, Van Loo P, Drijkoningen M, Neven P, Smeets A, Christiaens MR, Paridaens R, De Wolf-Peeters C. Polysomy 17 in breast cancer: clinicopathologic significance and impact on HER-2 testing. J Clin Oncol. 2008;26:4869–74.CrossRef
37.
Sauter G, Lee J, Bartlett JM, Slamon DJ, Press MF. Guidelines for human epidermal growth factor receptor 2 testing: biologic and methodologic considerations. J Clin Oncol. 2009;27:1323–33.CrossRefPubMed
38.
Pentheroudakis G, Kotoula V, Eleftheraki AG, Tsolaki E, Wirtz RM, Kalogeras KT, Batistatou A, Bobos M, Dimopoulos MA, Timotheadou E, et al. Prognostic significance of ESR1 gene amplification, mRNA/protein expression and functional profiles in high-risk early breast cancer: a translational study of the Hellenic Cooperative Oncology Group (HeCOG). PLoS ONE. 2013;8:e70634.CrossRefPubMedPubMedCentral
39.
Pentheroudakis G, Raptou G, Kotoula V, Wirtz RM, Vrettou E, Karavasilis V, Gourgioti G, Gakou C, Syrigos KN, Bournakis E, et al. Immune response gene expression in colorectal cancer carries distinct prognostic implications according to tissue, stage and site: a prospective retrospective translational study in the context of a hellenic cooperative oncology group randomised trial. PLoS ONE. 2015;10:e0124612.CrossRefPubMedPubMedCentral
40.
Hudis CA, Barlow WE, Costantino JP, Gray RJ, Pritchard KI, Chapman JA, Sparano JA, Hunsberger S, Enos RA, Gelber RD, Zujewski JA. Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: the STEEP system. J Clin Oncol. 2007;25:2127–32.CrossRefPubMed
41.
42.
Ortiz-Martinez F, Perez-Balaguer A, Ciprian D, Andres L, Ponce J, Adrover E, Sanchez-Paya J, Aranda FI, Lerma E, Peiro G. Association of increased osteopontin and splice variant-c mRNA expression with HER2 and triple-negative/basal-like breast carcinomas subtypes and recurrence. Hum Pathol. 2014;45:504–12.CrossRefPubMed
43.
Patani N, Jouhra F, Jiang W, Mokbel K. Osteopontin expression profiles predict pathological and clinical outcome in breast cancer. Anticancer Res. 2008;28:4105–10.PubMed
44.
Kendrick N. A gene’s mRNA level does not usually predict its protein level. Madison: Kendricklabscom; 2014.
45.
de Silva Rudland S, Martin L, Roshanlall C, Winstanley J, Leinster S, Platt-Higgins A, Carroll J, West C, Barraclough R, Rudland P. Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer. Clin Cancer Res. 2006;12:1192–200.CrossRefPubMed
46.
47.
Ribeiro-Silva A, Oliveira da Costa JP. Osteopontin expression according to molecular profile of invasive breast cancer: a clinicopathological and immunohistochemical study. Int J Biol Markers. 2008;23:154–60.CrossRefPubMed
48.
Rudland PS, Platt-Higgins A, El-Tanani M, De Silva Rudland S, Barraclough R, Winstanley JH, Howitt R, West CR. Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Res. 2002;62:3417–27.PubMed
49.
Wang X, Chao L, Ma G, Chen L, Tian B, Zang Y, Sun J. Increased expression of osteopontin in patients with triple-negative breast cancer. Eur J Clin Invest. 2008;38:438–46.CrossRefPubMed
50.
Tuck AB, Chambers AF. The role of osteopontin in breast cancer: clinical and experimental studies. J Mammary Gland Biol Neoplasia. 2001;6:419–29.CrossRefPubMed
51.
Xu YY, Zhang YY, Lu WF, Mi YJ, Chen YQ. Prognostic value of osteopontin expression in breast cancer: a meta-analysis. Mol Clin Oncol. 2015;3:357–62.PubMed
52.
El-Tanani M, Fernig DG, Barraclough R, Green C, Rudland P. Differential modulation of transcriptional activity of estrogen receptors by direct protein-protein interactions with the T cell factor family of transcription factors. J Biol Chem. 2001;276:41675–82.CrossRefPubMed
Metadata
Title
Association of osteopontin with specific prognostic factors and survival in adjuvant breast cancer trials of the Hellenic Cooperative Oncology Group
Authors
Amanda Psyrri
Konstantine T. Kalogeras
Ralph M. Wirtz
George Kouvatseas
Georgia Karayannopoulou
Anna Goussia
Flora Zagouri
Elke Veltrup
Eleni Timotheadou
Helen Gogas
Angelos Koutras
Georgios Lazaridis
Christos Christodoulou
George Pentheroudakis
Panagiota Economopoulou
Apostolos Laskarakis
Petroula Arapantoni-Dadioti
Anna Batistatou
Maria Sotiropoulou
Gerasimos Aravantinos
Pavlos Papakostas
Paris Kosmidis
Dimitrios Pectasides
George Fountzilas
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2017
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-017-1134-7

Other articles of this Issue 1/2017

Journal of Translational Medicine 1/2017 Go to the issue

Research

Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy

Research

Transforming growth factor beta (TGF-β) in adolescent chronic fatigue syndrome

Review

Examining clinical similarities between myalgic encephalomyelitis/chronic fatigue syndrome and d-lactic acidosis: a systematic review

Review

Multiple therapeutic effect of endothelial progenitor cell regulated by drugs in diabetes and diabetes related disorder

Research

DCE-MRI of patient-derived xenograft models of uterine cervix carcinoma: associations with parameters of the tumor microenvironment

Research

Analysis of circulating microRNAs in patients with repaired Tetralogy of Fallot with and without heart failure

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits