Abstract
Purpose The utility of three different epithelial mRNA markers to detect clinically significant, disseminated tumour cells in bone marrow (BM) was explored. Methods Mammaglobin A (hMAM), trefoil factor 1 (TFF-1) and prostate derived Ets factor (PDEF) mRNA were quantitated by real-time RT-PCR in BM samples from 192 breast cancer patients undergoing surgery (control group: 26 healthy women). Results During a median follow-up of 72 months, four of the five hMAM BM-positive and three of the seven TFF-1 BM-positive patients experienced a systemic relapse. Kaplan-Meier survival analyses demonstrated significantly shorter recurrence-free-, breast-cancer-specific- and overall survival for both hMAM and TFF-1 BM-positive patients. In contrast, PDEF mRNA quantitation did not reveal any significant differences in the survival analyses. Multivariate Cox regression demonstrated hMAM mRNA BM expression to be an independent predictor of both overall- (hazard ratio = 5.896), breast-cancer-specific- (hazard ratio = 10.208) and systemic-recurrence-free survival (hazard ratio = 14.304). TFF-1 status was related to hMAM status (P < 0.001). Conclusion Breast cancer patients with pre-operative elevated BM levels of hMAM and/or TFF-1 mRNA seem to constitute a small group of patients with a very poor prognosis.
Similar content being viewed by others
References
Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802. doi:10.1056/NEJMoa050434
Mitas M, Mikhitarian K, Walters C et al (2001) Quantitative real-time RT-PCR detection of breast cancer micrometastasis using a multigene marker panel. Int J Cancer 93(2):162–171. doi:10.1002/ijc.1312
Bosma AJ, Weigelt B, Lambrechts AC, Verhagen OJ, Pruntel R, Hart AA et al (2002) Detection of circulating breast tumor cells by differential expression of marker genes. Clin Cancer Res 8(6):1871–1877
Zehentner BK, Dillon DC, Jiang Y et al (2002) Application of a multigene reverse transcription-PCR assay for detection of mammaglobin and complementary transcribed genes in breast cancer lymph nodes. Clin Chem 48(8):1225–1231
Varangot M, Barrios E, Sonora C et al (2005) Clinical evaluation of a panel of mRNA markers in the detection of disseminated tumor cells in patients with operable breast cancer. Oncol Rep 14(2):537–545
Benoy IH, Elst H, Van der Auwera I, Van Laere S, van Dam P, Van Marck E et al (2004) Real-time RT-PCR correlates with immunocytochemistry for the detection of disseminated epithelial cells in bone marrow aspirates of patients with breast cancer. Br J Cancer 91(10):1813–1820. doi:10.1038/sj.bjc.6602189
Benoy IH, Elst H, Philips M, Wuyts H, Van Dam P, Scharpe S et al (2006) Real-time RT-PCR detection of disseminated tumour cells in bone marrow has superior prognostic significance in comparison with circulating tumour cells in patients with breast cancer. Br J Cancer 94(5):672–680
Farmen RK, Nordgard O, Gilje B, Shammas FV, Kvaloy JT, Oltedal S et al (2008) Bone marrow cytokeratin 19 mRNA level is an independent predictor of relapse-free survival in operable breast cancer patients. Breast Cancer Res Treat 108(2):251–258. doi:10.1007/s10549-007-9592-x
Benoy IH, Elst H, Philips M, Wuyts H, Van Dam P, Scharpe S et al (2006) Prognostic significance of disseminated tumor cells as detected by quantitative real-time reverse-transcriptase polymerase chain reaction in patients with breast cancer. Clin Breast Cancer 7(2):146–152
Ghadersohi A, Sood AK (2001) Prostate epithelium-derived Ets transcription factor mRNA is overexpressed in human breast tumors and is a candidate breast tumor marker and a breast tumor antigen. Clin Cancer Res 7(9):2731–2738
Turcotte S, Forget MA, Beauseigle D, Nassif E, Lapointe R (2007) Prostate-derived Ets transcription factor overexpression is associated with nodal metastasis and hormone receptor positivity in invasive breast cancer. Neoplasia 9(10):788–796. doi:10.1593/neo.07460
Tozlu S, Girault I, Vacher S, Vendrell J, Andrieu C, Spyratos F et al (2006) Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. Endocr Relat Cancer 13(4):1109–1120. doi:10.1677/erc.1.01120
Mitas M, Mikhitarian K, Hoover L, Lockett MA, Kelley L, Hill A et al (2002) Prostate-Specific Ets (PSE) factor: a novel marker for detection of metastatic breast cancer in axillary lymph nodes. Br J Cancer 86(6):899–904. doi:10.1038/sj.bjc.6600190
Baker M, Gillanders WE, Mikhitarian K, Mitas M, Cole DJ (2003) The molecular detection of micrometastatic breast cancer. Am J Surg 186(4):351–358. doi:10.1016/S0002-9610(03)00262-9
Mikhitarian K, Gillanders WE, Almeida JS, Hebert Martin R, Varela JC, Metcalf JS et al (2005) An innovative microarray strategy identities informative molecular markers for the detection of micrometastatic breast cancer. Clin Cancer Res 11(10):3697–3704. doi:10.1158/1078-0432.CCR-04-2164
Mikhitarian K, Martin RH, Ruppel MB, Gillanders WE, Hoda R, Schutte DH et al (2008) Detection of mammaglobin mRNA in peripheral blood is associated with high grade breast cancer: interrim results of a prospective cohort study. BMC Cancer 8(55)
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072. doi:10.1200/JCO.2004.01.0454
Shammas FV, Van Eekelen JA, Wee L, Heikkila R, Osland A (1999) Sensitive and quantitative one-step polymerase chain reaction using capillary electrophoresis and fluorescence detection for measuring cytokeratin 19 expression. Scand J Clin Lab Invest 59(8):635–642. doi:10.1080/00365519950185139
Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45. doi:10.1093/nar/29.9.e45
Ooka M, Tamaki Y, Sakita I et al (2001) Bone marrow micrometastases detected by RT-PCR for mammaglobin can be an alternative prognostic factor of breast cancer. Breast Cancer Res Treat 67(2):169–175. doi:10.1023/A:1010651632354
Quintela-Fandino M, Lopez JM, Hitt R et al (2006) Breast cancer-specific mRNA transcripts presence in peripheral blood after adjuvant chemotherapy predicts poor survival among high-risk breast cancer patients treated with high-dose chemotherapy with peripheral blood stem cell support. J Clin Oncol 24(22):3611–3618. doi:10.1200/JCO.2005.04.0576
Smid M, Wang Y, Klijn JG, Sieuwerts AM, Zhang Y, Atkins D et al (2006) Genes associated with breast cancer metastatic to bone. J Clin Oncol 24(15):2261–2267. doi:10.1200/JCO.2005.03.8802
Lacroix M (2006) Significance, detection and markers of disseminated breast cancer cells. Endocr Relat Cancer 13(4):1033–1067. doi:10.1677/ERC-06-0001
Gunawardane RN, Sgroi DC, Wrobel CN, Koh E, Daley GQ, Brugge JS (2005) Novel role for PDEF in epithelial cell migration and invasion. Cancer Res 65(24):11572–11580. doi:10.1158/0008-5472.CAN-05-1196
Abdul-Rasool S, Kidson SH, Panieri E, Dent D, Pillay K, Hanekom GS (2006) An evaluation of molecular markers for improved detection of breast cancer metastases in sentinel nodes. J Clin Pathol 59(3):289–297. doi:10.1136/jcp.2005.028357
Acknowledgements
This study was partly financed by the Norwegian Cancer Society.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Tjensvoll, K., Gilje, B., Oltedal, S. et al. A small subgroup of operable breast cancer patients with poor prognosis identified by quantitative real-time RT-PCR detection of mammaglobin A and trefoil factor 1 mRNA expression in bone marrow. Breast Cancer Res Treat 116, 329–338 (2009). https://doi.org/10.1007/s10549-008-0204-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-008-0204-1