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In Reply:

Section of Oncology-Hematology, Department of Internal Medicine, University of Nebraska Medical Center; and Department of Internal Medicine, Omaha VA Medical Center, Omaha, NE

Abe E. Sahmoun

Department of Internal Medicine, University of North Dakota School of Medicine, Fargo, ND

Anil Potti

Divisions of Hematology and Oncology, Duke University Medical Center, Durham, NC

We thank Negaard et al for their interesting hypothesis to explain our findings that use of hormone-replacement therapy (HRT) is associated with a decreased survival in women with lung cancer.¹ As the authors have pointed out, there is considerable evidence for the role of HRT in suppression of tissue factor pathway inhibitor (TFPI). For instance, in a randomized controlled study, Bladbjerg et al² found that concentrations of TFPI were significantly lower in women receiving HRT as compared with controls, and this in turn may be responsible for the increased thrombotic risk seen with HRT.

However, the role of TFPI in carcinogenesis is less clear. As Negaard et al have mentioned, there is evidence that TFPI may have antiangiogenic properties³ and inhibit metastatic spread of tumors.⁴ Similarly, Rollin et al⁵ found that decreased TFPI-2 gene expression and hypermethylation were more frequently associated with stages III or IV non–small-cell lung cancer. In our study, however, we did not find any difference in the stage at presentation for women who used HRT as compared with those who did not use HRT. Therefore, our findings cannot be explained by advanced stage at diagnosis.¹ In another study, Lakka et al⁶ transfected the human lung cancer cell line A549, which produces high levels of TFPI-2, with a vector capable of expressing an antisense transcript complementary to the full-length TFPI-2 mRNA. They found that although the levels of TFPI-2 mRNA and protein were significantly less in antisense clones than in the parental and vector controls, the invasive potential of the antisense clones was significantly greater, thereby suggesting that TFPI was critical for the invasion and metastasis of lung cancer.

Thus, although inhibition of TFPI by HRT is an exciting possible explanation for our findings, we believe that there may be other mechanisms involved that could also be responsible for the less favorable outcomes seen in women with lung cancer who were also using HRT.

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. 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]

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

4. 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]

5. Rollin J, Iochmann S, Blechet C, et al: Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer. Br J Cancer 92:775-783, 2005[CrossRef][Medline]

6. Lakka SS, Konduri SD, Mohanam S, et al: In vitro modulation of human lung cancer cell line invasiveness by antisense cDNA of tissue factor pathway inhibitor-2. Clin Exp Metastasis 18:239-244, 2000[CrossRef][Medline]

Related Correspondence

• Decreased Lung Cancer Survival With Hormone-Replacement Therapy: Caused by a Decreased Tissue Factor Pathway Inhibitor Level?
  Helene F.S. Negaard, Anette L. Eilertsen, Anders Dahm, Per O. Iversen, Bjørn Østenstad, and Per M. Sandset
  JCO 2006 24: 2683-2684 [Full Text]

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