Download PDF
Thromb Haemost 2003; 89(06): 1098-1106
DOI: 10.1055/s-0037-1613413
Cellular Proteolysis and Oncology
Schattauer GmbH

Impact of pretreatment thrombocytosis on survival in primary breast cancer

for the Austrian Breast and Colorectal Cancer Study Group
Susanne Taucher
1   Departments of Surgery, Gynecology and Internal Medicine, University of Vienna Medical School, Vienna, Austria
,
Andreas Salat
1   Departments of Surgery, Gynecology and Internal Medicine, University of Vienna Medical School, Vienna, Austria
,
Michael Gnant
1   Departments of Surgery, Gynecology and Internal Medicine, University of Vienna Medical School, Vienna, Austria
,
Werner Kwasny
2   Department of Surgery, Wiener Neustadt Hospital, Wiener Neustadt; Austria
,
Brigitte Mlineritsch
3   Third Medical Department and Department of Special Gynecology, Salzburg Hospital, Salzburg, Austria
,
Rainer-Christian Menzel
3   Third Medical Department and Department of Special Gynecology, Salzburg Hospital, Salzburg, Austria
,
Marianne Schmid
4   Medical Department and Department of Surgery, University of Graz Medical School, Graz, Austria
,
Michael G. Smola
4   Medical Department and Department of Surgery, University of Graz Medical School, Graz, Austria
,
Michael Stierer
5   Department of Surgery, Hanusch Hospital, Vienna, Austria
,
Christoph Tausch
6   Department of Surgery, BHS Hospital Linz, Austria
,
Arik Galid
1   Departments of Surgery, Gynecology and Internal Medicine, University of Vienna Medical School, Vienna, Austria
,
Günther Steger
1   Departments of Surgery, Gynecology and Internal Medicine, University of Vienna Medical School, Vienna, Austria
,
Raimund Jakesz
1   Departments of Surgery, Gynecology and Internal Medicine, University of Vienna Medical School, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received 02 November 2002

Accepted after revision 14 March 2003

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

Platelet count has been reported to have predictive value in various cancer entities. In the case of breast cancer, evidence about involvement of platelets is still incomplete. Our objective was to assess the influence of pretreatment thrombocytosis on survival and establish its prognostic relevance for breast cancer patients.

We performed a retrospective, multivariate analysis of 4,300 patients with early-stage breast cancer. All subjects participated in one of five prospective, randomized, multicenter trials conducted by the Austrian Breast and Colorectal Cancer Study Group. Thrombocytosis was defined as a platelet count exceeding 400 G/L. Median follow-up was 52 months. Univariate and multiple Cox regression models were calculated for overall survival (OS), breast cancer-related survival and disease-free survival (DFS). Pretreatment thrombocytosis was observed in 161 patients (3.7%). Estimated median OS, breast cancer-related survival and DFS for patients with versus those without thrombocytosis was 71.0 versus 99.5, 72.0 versus 100.9, and 80.4 versus 88.4 months, respectively (p = 0.0054, p = 0.0095, p = 0.0199). A multiple Cox regression model including tumor and nodal status, grading, age, hormone receptor status and pretreatment thrombocytosis identified pretreatment thrombocytosis as an independent predictive factor for OS (p = 0.0064) and breast cancer-related survival (p = 0.0162). Multivariate analysis failed to identify pretreatment thrombocytosis as an independent risk factor for DFS (p = 0.1355).

In our retrospective study, elevated platelet counts at time of diagnosis were associated with poor prognosis in breast cancer. We hypothesize that platelets may contribute to the patho-physiology of hematogenous metastasis.

Keywords

Platelets - thrombocytosis - primary breast cancer - prognosis
 

  • References

  • 1 Blann AD, Lip GY. Virchow’s triad revisited: the importance of soluble coagulation factors, the endothelium, and platelets. Thromb Res 2001; 101: 321-327.
    CrossrefPubMedGoogle Scholar
  • 2 Hejna M, Raderer M, Zielinski CC. Inhibition of metastases by anticoagulants. J Natl Cancer Inst 1999; 91: 22-36.
    CrossrefPubMedGoogle Scholar
  • 3 Honn KV, Tang DG, Chen YQ. Platelets and cancer metastasis: more than an epiphenomenon. Semin Thromb Hemost 1992; 18: 392-415.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Gasic GJ, Gasic TB, Stewart CC. Antimetastatic effects associated with platelet reduction. Proc Natl Acad Sci U S A 1968; 61: 46-52.
    CrossrefPubMedGoogle Scholar
  • 5 Gasic GJ. Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer Metastasis Rev 1984; 3: 99-114.
    CrossrefPubMedGoogle Scholar
  • 6 Karpatkin S, Pearlstein E. Role of platelets in tumor cell metastases. Ann Intern Med 1981; 95: 636-41.
    CrossrefPubMedGoogle Scholar
  • 7 Pearlstein E, Ambrogio C, Karpatkin S. Effect of antiplatelet antibody on the development of pulmonary metastases following injection of CT26 colon adenocarcinoma, Lewis lung carcinoma, and B16 amelanotic melanoma tumor cells into mice. Cancer Res 1984; 44: 3884-7.
    PubMedGoogle Scholar
  • 8 Pinedo HM, Verheul HM, D’Amato RJ, Folkman J. Involvement of platelets in tumour angiogenesis?. Lancet 1998; 352: 1775-7.
    CrossrefPubMedGoogle Scholar
  • 9 Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998; 113: 723-31.
    CrossrefPubMedGoogle Scholar
  • 10 Levin J, Conley C. Thrombocytosis associated with malignant disease. Arch Intern Med 1964; 114: 497-500.
    CrossrefPubMedGoogle Scholar
  • 11 Silvis SE, Turkbas N, Doscherholmen A. Thrombocytosis in patients with lung cancer. Jama 1970; 211: 1852-3.
    CrossrefPubMedGoogle Scholar
  • 12 Engan T, Hannisdal E. Blood analyses as prognostic factors in primary lung cancer. Acta Oncol 1990; 29: 151-4.
    CrossrefPubMedGoogle Scholar
  • 13 Pedersen LM, Milman N. Prognostic significance of thrombocytosis in patients with primary lung cancer. Eur Respir J 1996; 9: 1826-30.
    CrossrefPubMedGoogle Scholar
  • 14 Costantini V, Zacharski LR, Moritz TE, Edwards RL. The platelet count in carcinoma of the lung and colon. Thromb Haemost 1990; 64: 501-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Hernandez E, Lavine M, Dunton CJ, Gracely E, Parker J. Poor prognosis associated with thrombocytosis in patients with cervical cancer. Cancer 1992; 69: 2975-7.
    CrossrefPubMedGoogle Scholar
  • 16 Chalas E, Welshinger M, Engellener W, Chumas J, Barbieri R, Mann WJ. The clinical significance of thrombocytosis in women presenting with a pelvic mass. Am J Obstet Gynecol 1992; 166: 974-7.
    CrossrefPubMedGoogle Scholar
  • 17 Lopes A, Daras V, Cross PA, Robertson G, Beynon G, Monaghan JM. Thrombocytosis as a prognostic factor in women with cervical cancer. Cancer 1994; 74: 90-2.
    CrossrefPubMedGoogle Scholar
  • 18 Nathan FE, Hernandez E, Dunton CJ, Treat J, Switalska HI, Joseph RR, Tuszynski GP. Plasma thrombospondin levels in patients with gynecologic malignancies. Cancer 1994; 73: 2853-8.
    CrossrefPubMedGoogle Scholar
  • 19 Rodriguez GC, Clarke-Pearson DL, Soper JT, Berchuck A, Synan I, Dodge RK. The negative prognostic implications of thrombocytosis in women with stage IB cervical cancer. Obstet Gynecol 1994; 83: 445-8.
    PubMedGoogle Scholar
  • 20 Menczer J, Schejter E, Geva D, Ginath S, Zakut H. Ovarian carcinoma associated thrombocytosis. Correlation with prognostic factors and with survival. Eur J Gynaecol Oncol 1998; 19: 82-4.
    PubMedGoogle Scholar
  • 21 Kerpsack JT, Finan MA. Thrombocytosis as a predictor of malignancy in women with a pelvic mass. J Reprod Med 2000; 45: 929-32.
    PubMedGoogle Scholar
  • 22 Scholz HS, Petru E, Gucer F, Haas J, Tamussino K, Winter R. Preoperative thrombocytosis is an independent prognostic factor in stage III and IV endometrial cancer. Anticancer Res 2000; 20: 3983-5.
    PubMedGoogle Scholar
  • 23 Lavie O, Comerci G, Daras V, Bolger BS, Lopes A, Monaghan JM. Thrombocytosis in women with vulvar carcinoma. Gynecol Oncol 1999; 72: 82-6.
    CrossrefPubMedGoogle Scholar
  • 24 Hefler L, Mayerhofer K, Leibman B, Obermair A, Reinthaller A, Kainz C, Tempfer C. Tumor anemia and thrombocytosis in patients with vulvar cancer. Tumour Biol 2000; 21: 309-14.
    CrossrefPubMedGoogle Scholar
  • 25 Symbas NP, Townsend MF, El-Galley R, Keane TE, Graham SD, Petros JA. Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma. BJU Int 2000; 86: 203-7.
    CrossrefPubMedGoogle Scholar
  • 26 O’Byrne KJ, Dobbs N, Propper D, Smith K, Harris AL. Vascular endothelial growth factor platelet counts, and prognosis in renal cancer. Lancet 1999; 353: 1494-5.
    PubMedGoogle Scholar
  • 27 Monreal M, Fernandez-Llamazares J, Pinol M. et al. Platelet count and survival in patients with colorectal cancer—a preliminary study. Thromb Haemost 1998; 79: 916-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Jakesz R, Hausmaninger H, Kubista E. et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and Fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer-austrian breast and colorectal cancer study group trial 5. J Clin Oncol 2002; 20: 4621-7.
    CrossrefPubMedGoogle Scholar
  • 29 Schmid M, Jakesz R, Samonigg H. et al. Randomized trial of tamoxifen versus tamoxifen plus aminoglutethimide as adjusted treatment in postmenopausal breast cancer patients with hormone receptor positive disease: Austrian Breast and Colorectal Cancer Study Group Trial 6. J Clin Oncol 2003; 21: 924-90.
    PubMedGoogle Scholar
  • 30 Jakesz R. Comparison of pre- vs postoperative chemotherapy in breast cancer patients: four-year results of Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 7. Proc Am Soc Clin Oncol; 2001; 32a abstract 125
    PubMedGoogle Scholar
  • 31 Reiner A, Neumeister B, Spona J, Reiner G, Schemper M, Jakesz R. Immunocytochemical localization of estrogen and progesterone receptor and prognosis in human primary breast cancer. Cancer Res 1990; 50: 7057-61.
    PubMedGoogle Scholar
  • 32 Santhosh-Kumar CR, Yohannan MD, Higgy KE, al-Mashhadani SA. Thrombocytosis in adults: analysis of 777 patients. J Intern Med 1991; 229: 493-5.
    CrossrefPubMedGoogle Scholar
  • 33 Griesshammer M, Bangerter M, Sauer T, Wen-nauer R, Bergmann L, Heimpel H. Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. J Intern Med 1999; 245: 295-300.
    CrossrefPubMedGoogle Scholar
  • 34 Hernandez E, Heller PB, Whitney C, Diana K, Delgado G. Thrombocytosis in surgically treated stage IB squamous cell cervical carcinoma (A Gynecologic Oncology Group study). Gynecol Oncol 1994; 55: 328-32.
    CrossrefPubMedGoogle Scholar
  • 35 Zeimet AG, Marth C, Muller-Holzner E, Daxenbichler G, Dapunt O. Significance of thrombocytosis in patients with epithelial ovarian cancer. Am J Obstet Gynecol 1994; 170: 549-54.
    CrossrefPubMedGoogle Scholar
  • 36 Gastl G, Plante M, Finstad CL, Wong GY, Federici MG, Bander NH, Rubin SC. High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer. Br J Haematol 1993; 83: 433-41.
    CrossrefPubMedGoogle Scholar
  • 37 Ascensao JL, Oken MM, Ewing SL, Goldberg RJ, Kaplan ME. Leukocytosis and large cell lung cancer. A frequent association. Cancer 1987; 60: 903-5.
    CrossrefPubMedGoogle Scholar
  • 38 Olesen LL, Thorshauge H. Thrombocytosis in patients with malignant pleural mesothelioma. Cancer 1988; 62: 1194-6.
    CrossrefPubMedGoogle Scholar
  • 39 Eltabbakh GH, Piver MS, Hempling RE, Recio FO, Intengen ME. Clinical picture, response to therapy, and survival of women with diffuse malignant peritoneal mesothelio-ma. J Surg Oncol 1999; 70: 6-12.
    CrossrefPubMedGoogle Scholar
  • 40 Nakano T, Chahinian AP, Shinjo M, Tonomura A, Miyake M, Togawa N, Ninomiya K, Higashino K. Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma. Br J Cancer 1998; 77: 907-12.
    CrossrefPubMedGoogle Scholar
  • 41 Alexander WS. Thrombopoietin. Growth Factors 1999; 17: 13-24.
    CrossrefPubMedGoogle Scholar
  • 42 Caen JP, Han ZC, Bellucci S, Alemany M. Regulation of megakaryocytopoiesis. Haemo-stasis 1999; 29: 27-40.
    PubMedGoogle Scholar
  • 43 George JN. Platelets. Lancet 2000; 355: 1531-9.
    CrossrefPubMedGoogle Scholar
  • 44 Sungaran R, Chisholm OT, Markovic B, Khachigian LM, Tanaka Y, Chong BH. The role of platelet alpha-granular proteins in the regulation of thrombopoietin messenger RNA expression in human bone marrow stromal cells. Blood 2000; 95: 3094-101.
    PubMedGoogle Scholar
  • 45 Wang JC, Chen C, Novetsky AD, Lichter SM, Ahmed F, Friedberg NM. Blood thrombopoie-tin levels in clonal thrombocytosis and reactive thrombocytosis. Am J Med 1998; 104: 451-5.
    CrossrefPubMedGoogle Scholar
  • 46 Hsu HC, Tsai WH, Jiang ML, Ho CH, Hsu ML, Ho CK, Wang SY. Circulating levels of thrombopoietic and inflammatory cytokines in patients with clonal and reactive thrombocyto-sis. J Lab Clin Med 1999; 134: 392-7.
    CrossrefPubMedGoogle Scholar
  • 47 Sasaki Y, Takahashi T, Miyazaki H, Matsumoto A, Kato T, Nakamura K, Iho S, Okuno Y, Nakao K. Production of thrombopoietin by human carcinomas and its novel isoforms. Blood 1999; 94: 1952-60.
    PubMedGoogle Scholar
  • 48 Uppenkamp M, Makarova E, Petrasch S, Brittinger G. Thrombopoietin serum concentration in patients with reactive and myeloproliferative thrombocytosis. Ann Hematol 1998; 77: 217-23.
    CrossrefPubMedGoogle Scholar
  • 49 Estrov Z, Talpaz M, Mavligit G, Pazdur R, Harris D, Greenberg SM, Kurzrock R. Elevated plasma thrombopoietic activity in patients with metastatic cancer-related thrombocytosis. Am J Med 1995; 98: 551-8.
    CrossrefPubMedGoogle Scholar
  • 50 Blay JY, Rossi JF, Wijdenes J, Menetrier-Caux C, Schemann S, Negrier S, Philip T, Favrot M. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Int J Cancer 1997; 72: 424-30.
    CrossrefPubMedGoogle Scholar
  • 51 Rawle FC, Shields J, Smith SH, Iliescu V, Merkenschlager M, Beverley PC, Callard RE. B cell growth and differentiation induced by supernatants of transformed epithelial cell lines. Eur J Immunol 1986; 16: 1017-9.
    CrossrefPubMedGoogle Scholar
  • 52 Watson JM, Sensintaffar JL, Berek JS, Martinez-Maza O. Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures. Cancer Res 1990; 50: 6959-65.
    PubMedGoogle Scholar
  • 53 Van Meir E, Sawamura Y, Diserens AC, Hamou MF, de Tribolet N. Human glioblasto-ma cells release interleukin 6 in vivo and in vitro. Cancer Res 1990; 50: 6683-8.
    PubMedGoogle Scholar
  • 54 Yanagawa H, Sone S, Takahashi Y, Haku T, Yano S, Shinohara T, Ogura T. Serum levels of interleukin 6 in patients with lung cancer. Br J Cancer 1995; 71: 1095-8.
    CrossrefPubMedGoogle Scholar
  • 55 Schmitter D, Lauber B, Fagg B, Stahel RA. Hematopoietic growth factors secreted by seven human pleural mesothelioma cell lines: interleukin-6 production as a common feature. Int J Cancer 1992; 51: 296-301.
    CrossrefPubMedGoogle Scholar
  • 56 Schuler M, Bruntsch U, Spath-Schwalbe E. et al. Lack of efficacy of recombinant human interleukin-6 in patients with advanced renal cell cancer: results of a phase II study. Eur J Cancer 1998; 34: 754-6.
    CrossrefPubMedGoogle Scholar
  • 57 Verheul HM, Hoekman K, Luykx-de Bakker S. et al. Platelet: transporter of vascular endothelial growth factor. Clin Cancer Res 1997; 3: 2187-90.
    PubMedGoogle Scholar
  • 58 Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, Selby PJ. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer 1998; 77: 956-64.
    CrossrefPubMedGoogle Scholar
  • 59 Wartiovaara U, Salven P, Mikkola H. et al. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 1998; 80: 171-5.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Locopo N, Fanelli M, Gasparini G. Clinical significance of angiogenic factors in breast cancer. Breast Cancer Res Treat 1998; 52: 159-73.
    CrossrefPubMedGoogle Scholar
  • 61 Salven P, Orpana A, Joensuu H. Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. Clin Cancer Res 1999; 5: 487-91.
    PubMedGoogle Scholar
  • 62 Salgado R, Vermeulen PB, Benoy I. et al. Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients. Br J Cancer 1999; 80: 892-7.
    CrossrefPubMedGoogle Scholar