Abstract
The purpose of this article is to investigate the prognostic value of the mitotic activity index (MAI) and the presence of disseminated tumor cells (DTCs) in bone marrow (BM), in clinically operable breast cancer patients. We compared routinely assessed MAI, classic prognosticators and BM DTCs, detected by a real-time RT-PCR multimarker assay including cytokeratin 19, mammaglobin A and TWIST1 mRNA, in 179 consecutive patients with operable breast cancer. Over a median follow-up of 96 months (range: 1–126 months), 31 (17.3%) patients experienced a systemic relapse and 26 (14.5%) died of breast cancer-related causes. MAI (≥ 10) was strongly associated with breast cancer-related death in lymph node (LN)-negative patients (hazard ratio (HR): 7.0, confidence interval (CI) 1.74–27.9), whereas both BM DTC-status (HR: 3.3, CI 1.25–8.52) and MAI (HR: 3.1, CI 1.08–8.8) were significant in LN-positive patients. With multivariate Cox regression, MAI was the only significant predictor of breast cancer-specific survival (HR 7.0, CI 1.7–27.9) in LN-negative patients. In LN-positive patients, both BM DTC-status and MAI were strong independent predictors of breast cancer-specific survival (HR 3.3, CI 1.25-8.49 and HR 3.1, CI 1.1–8.9), respectively. Where, however, MAI and BM DTC-status as single parameters were replaced by a combination of these, this showed to be the most significant prognostic marker in both LN-negative (HR 7.7, CI 1.2-50) and LN-positive (HR 6.0, CI 1.4 to 26.4) patients with regard to breast cancer-specific survival. A combination of MAI and BM DTC detection identified both LN-negative and LN-positive breast cancer patients with poor prognosis.
Similar content being viewed by others
References
Boyages J, Chua B, Taylor R, Bilous M, Salisbury E, Wilcken N, Ung O (2002) Use of the St. Gallen classification for patients with node-negative breast cancer may lead to overuse of adjuvant chemotherapy. Br J Surg 89(6):789–796. doi:10.1046/j.1365-2168.2002.02113.x
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.19136709898
Cobleigh MA, Tabesh B, Bitterman P, Baker J, Cronin M, Liu ML, Borchik R, Mosquera JM, Walker MG, Shak S (2005) Tumor gene expression and prognosis in breast cancer patients with 10 or more positive lymph nodes. Clin Cancer Res 11(24 Pt 1):8623–8631. doi:10.1158/1078-0432.CCR-05-0735
Glas AM, Floore A, Delahaye LJ, Witteveen AT, Pover RC, Bakx N, Lahti-Domenici JS, Bruinsma TJ, Warmoes MO, Bernards R, Wessels LF, Van’t Veer LJ (2006) Converting a breast cancer microarray signature into a high-throughput diagnostic test. BMC Genomics 7:278. doi:10.1186/1471-2164-7-278
Farmen RK, Nordgard O, Gilje B, Shammas FV, Kvaloy JT, Oltedal S, Heikkila R (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
Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, Wiedswang G, Solomayer EF, Kundt G, Strobl B, Fehm T, Wong GY, Bliss J, Vincent-Salomon A, Pantel K (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802. doi:10.1056/NEJMoa050434
Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, Riethmuller G, Schlimok G (2000) Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 342(8):525–533
Bidard FC, Vincent-Salomon A, Gomme S, Nos C, de Rycke Y, Thiery JP, Sigal-Zafrani B, Mignot L, Sastre-Garau X, Pierga JY (2008) Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res 14(11):3306–3311. doi:10.1158/1078-0432.CCR-07-4749
Benoy IH, Elst H, Philips M, Wuyts H, Van Dam P, Scharpe S, Van Marck E, Vermeulen PB, Dirix LY (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
Naume B, Wiedswang G, Borgen E, Kvalheim G, Karesen R, Qvist H, Janbu J, Harbitz T, Nesland JM (2004) The prognostic value of isolated tumor cells in bone marrow in breast cancer patients: evaluation of morphological categories and the number of clinically significant cells. Clin Cancer Res 10(9):3091–3097
Baak JP, van Diest PJ, Voorhorst FJ, van der Wall E, Beex LV, Vermorken JB, Janssen EA (2005) Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years. J Clin Oncol 23(25):5993–6001. doi:10.1200/JCO.2005.05.511
Skaland I, van Diest PJ, Janssen EA, Gudlaugsson E, Baak JP (2008) Prognostic differences of World Health Organization-assessed mitotic activity index and mitotic impression by quick scanning in invasive ductal breast cancer patients younger than 55 years. Hum Pathol 39(4):584–590. doi:10.1016/j.humpath.2007.08.016
Baak JP, van Diest PJ, Ariens AT, van Beek MW, Bellot SM, Fijnheer J, van Gorp LH, Kwee WS, Los J, Peterse HC et al (1989) The Multicenter Morphometric Mammary Carcinoma Project (MMMCP). A nationwide prospective study on reproducibility and prognostic power of routine quantitative assessments in The Netherlands. Pathol Res Pract 185(5):664–670
Janssen EA, van Diest PJ, Soiland H, Gudlaugson E, Nysted A, Voorhorst FJ, Vermorken JB, Soreide JA, Baak JP (2006) Success predictors of adjuvant chemotherapy in node-negative breast cancer patients under 55 years. Cell Oncol 28(5–6):295–303
Lende TH, Janssen EA, Gudlaugson E, Voorhorst F, Smaaland R, Van Diest P, Søiland H, Baak JP (2011) In patients younger than age 55 years with lymph node-negative breast cancer, proliferation by mitotic activity index is prognostically superior to adjuvant! J Clin Oncol 29(7):852–858. doi:10.1200/JCO.2009.25.0407
Penault-Llorca F, Andre F, Sagan C, Lacroix-Triki M, Denoux Y, Verriele V, Jacquemier J, Baranzelli MC, Bibeau F, Antoine M, Lagarde N, Martin AL, Asselain B, Roche H (2009) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27(17):2809–2815. doi:10.1200/JCO.2008.18.2808
Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, Magherini E, Mackey J, Martin M, Vogel C (2009) Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. J Clin Oncol 27(8):1168–1176. doi:10.1200/JCO.2008.18.1024
Tjensvoll K, Oltedal S, Farmen RK, Shammas FV, Heikkila R, Kvaloy JT, Gilje B, Smaaland R, Nordgard O (2010) Disseminated tumor cells in bone marrow assessed by TWIST1, cytokeratin 19, and mammaglobin A mRNA predict clinical outcome in operable breast cancer patients. Clin Breast Cancer 10(5):378–384. doi:10.3816/CBC.2010.n.050
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
Tjensvoll K, Gilje B, Oltedal S, Shammas VF, Kvaloy JT, Heikkila R, Nordgard O (2008) 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. doi:10.1007/s10549-008-0204-1
van Diest PJ, Baak JP, Matze-Cok P, Wisse-Brekelmans EC, van Galen CM, Kurver PH, Bellot SM, Fijnheer J, van Gorp LH, Kwee WS et al (1992) Reproducibility of mitosis counting in 2,469 breast cancer specimens: results from the Multicenter Morphometric Mammary Carcinoma Project. Hum Pathol 23(6):603–607
Baak JP, Van Dop H, Kurver PH, Hermans J (1985) The value of morphometry to classic prognosticators in breast cancer. Cancer 56(2):374–382
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 Investig 59(8):635–642
Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273. doi:10.1038/nrc2620
Martin FT, Dwyer RM, Kelly J, Khan S, Murphy JM, Curran C, Miller N, Hennessy E, Dockery P, Barry FP, O’Brien T, Kerin MJ (2010) Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res Treat. doi:10.1007/s10549-010-0734-1
Evdokimova V, Tognon C, Ng T, Sorensen PH (2009) Reduced proliferation and enhanced migration: two sides of the same coin? Molecular mechanisms of metastatic progression by YB-1. Cell Cycle 8(18):2901–2906
Pantel K, Alix-Panabieres C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6(6):339–351. doi:10.1038/nrclinonc.2009.44
Ross JS, Slodkowska EA (2009) Circulating and disseminated tumor cells in the management of breast cancer. Am J Clin Pathol 132(2):237–245. doi:10.1309/AJCPJI7DEOLKCS6F
Riethdorf S, Pantel K (2008) Disseminated tumor cells in bone marrow and circulating tumor cells in blood of breast cancer patients: current state of detection and characterization. Pathobiology 75(2):140–148. doi:10.1159/000123852
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
Acknowledgments
This study was supported by the Norwegian Regional Health Collaboration of Health West, the Norwegian Cancer Society and Stavanger University Hospital.
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
Gilje, B., Nordgård, O., Tjensvoll, K. et al. Mitotic activity and bone marrow micrometastases have independent prognostic value in node positive breast cancer patients. Breast Cancer Res Treat 128, 137–146 (2011). https://doi.org/10.1007/s10549-011-1487-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-011-1487-1