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Decreased Lung Cancer Survival With Hormone-Replacement Therapy: Caused by a Decreased Tissue Factor Pathway Inhibitor Level?

Department of Hematology, Ullevaal University Hospital, NO 0407 Oslo, Norway

Bjørn Østenstad

Department of Oncology, Ullevaal University Hospital, NO 0407 Oslo, Norway

Per M. Sandset

Department of Hematology, Ullevaal University Hospital, NO 0407 Oslo, Norway

To the Editor:

In the January 1, 2006, issue of Journal of Clinical Oncology, Ganti et al¹ reported decreased survival in women with lung cancer who used hormone-replacement therapy (HRT). In the Discussion section and the article's accompanying Editorial,² several explanations of this finding were debated. We put forward the hypothesis that the observed decrease in lung cancer survival might be a result of the effects of HRT on the coagulation system, in particular on the endogenous coagulation inhibitor tissue factor pathway inhibitor (TFPI).

HRT increases the risk of venous thromboembolic disease, partly because of reduced TFPI levels.³ Low levels of TFPI in circulating blood are associated with increased risk of venous thrombosis.⁴

In addition to its role in coagulation, TFPI may have antiangiogenic properties.⁵ There is also evidence that TFPI prevents metastasis.⁶ In a recent randomized clinical trial assigning patients with small-cell lung cancer to chemotherapy alone or chemotherapy with the addition of low molecular weight heparin (LMWH), longer progression-free and improved overall survival were observed among those receiving LMWH.⁷ This effect may be attributed to release of TFPI associated with vascular endothelium to circulating blood induced by LMWH.⁸

HRT has been shown to decrease the protein level of TFPI. Thus, the decrease in TFPI caused by HRT may lead to less antiangiogenic and antimetastatic effects. These findings might partly explain the decreased survival in women with lung cancer observed by Ganti et al.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Ganti AK, Sahmoun AE, Panwalkar AW, et al: Hormone replacement therapy is associated with decreased survival in women with lung cancer. J Clin Oncol 24:59-63, 2006[Abstract/Free Full Text]

2. Siegfried JM: Hormone replacement therapy and decreased lung cancer survival. J Clin Oncol 24:9-10, 2006[Free Full Text]

3. Bladbjerg EM, Madsen JS, Kristensen SR, et al: Effect of long-term hormone replacement therapy on tissue factor pathway inhibitor and thrombin activatable fibrinolysis inhibitor in healthy postmenopausal women: A randomized controlled study. J Thromb Haemost 1:1208-1214, 2003[CrossRef][Medline]

4. Dahm A, Van Hylckama Vlieg A, Bendz B, et al: Low levels of tissue factor pathway inhibitor (TFPI) increase the risk of venous thrombosis. Blood 101:4387-4392, 2003[Abstract/Free Full Text]

5. Mousa S, Mohamed S: Inhibition of endothelial cell tube formation by the low molecular weight heparin, tinzaprin, is mediated by tissue factor pathway inhibitor. Thromb Haemost 92:627-633, 2004[Medline]

6. Amirkhosravi A, Meyer T, Chang JY, et al: Tissue factor pathway inhibitor reduces experimental lung metastasis of B16 melanoma. Thromb Haemost 87:930-936, 2002[Medline]

7. Altinbas M, Coskun HS, Er O, et al: A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost 2:1266-1271, 2004[CrossRef][Medline]

8. Sandset PM, Bendz B, Hansen JB: Physiological function of tissue factor pathway inhibitor and interaction with heparins. Haemostasis 30:48-56, 2000[CrossRef][Medline]

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Related Reply

• In Reply:
  Apar Kishor Ganti, Abe E. Sahmoun, and Anil Potti
  JCO 2006 24: 2684 [Full Text]

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