Skip to main content

Advertisement

Log in

Interleukin-6, multidrug resistance protein-1 expression and response to paclitaxel in women with metastatic breast cancer: results of cancer and leukemia group B trial 159806

  • Original Paper
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Several reports have suggested that breast cancer patients with elevated serum levels of interleukin-6 (IL-6) have a worse prognosis than patients with lower levels. We have studied IL-6 in breast cancer cell lines and have shown that autocrine production of IL-6 can confer multi-drug resistance in vitro by inducing multidrug resistance gene-1 transcription with subsequent overexpression of P-glycoprotein (PGP). Both IL-6 and PGP expression can be measured in malignant cells using immunohistochemical (IHC) techniques. We hypothesized that patients whose tumors expressed higher amounts of IL-6 or PGP would be less likely to respond to paclitaxel, an agent affected by the PGP pathway. If so, then IL-6 could serve as a predictive factor for paclitaxel sensitivity. Both IL-6 and PGP expression were measured in patients treated in a randomized trial that compared three doses of single agent paclitaxel (175, 210, and 250 mg/m2 over 3 h every 3 weeks) in 469 women with metastatic breast cancer (CALGB 9342). No difference in complete and partial response was found among the three treatment arms. Tissue blocks in this trial were analyzed for IL-6 (154 patients) and PGP (149 patients) in paraffin-embedded sections from tumor samples; clinical characteristics of these patients were similar to the total sample of 469 patients. There were no significant differences among IL-6 or PGP scores whether measured as continuous or dichotomous variables, or by other scoring, and response to paclitaxel. In multivariate analysis neither IL-6 nor PGP was a significant predictor of time to progression or overall survival. IHC expression of IL-6 and PGP levels in tumor cells is not a predictive marker for response to paclitaxel in women with metastatic breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Reference

  1. Miller KD, Sledge GW Jr (1999) Taxanes in the treatment of breast cancer: a prodigy comes of age. Cancer Invest 17:121–136

    Article  PubMed  CAS  Google Scholar 

  2. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S et’al (2003) Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983

    Article  PubMed  CAS  Google Scholar 

  3. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ et’al (2003) Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431–1439

    Article  PubMed  CAS  Google Scholar 

  4. Conze D, Weiss L, Regen PS, Bhushan A, Weaver D, Johnson P, et’al (2001) Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res 61:8851–8858

    PubMed  CAS  Google Scholar 

  5. Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN et’al (2004) Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342. J Clin Oncol 22:2061–2068

    Article  PubMed  CAS  Google Scholar 

  6. Markowska J, Wiktorowicz K, Szewierski Z, Madry R (1995) The value of determining the interleukin-6 levels in epithelial ovarian cancer. Ann N Y Acad Sci. 762:446–449

    Article  PubMed  CAS  Google Scholar 

  7. Scambia G, Testa U, Panici PB, Martucci R, Foti E, Petrini M et’al (1994) Interleukin-6 serum levels in patients with gynecological tumors. Int J Cancer 57:318–323

    PubMed  CAS  Google Scholar 

  8. Scambia G, Testa U, Benedetti PP, Foti E, Martucci R, Gadducci A et’al (1995) Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer 71:354–356

    PubMed  CAS  Google Scholar 

  9. Yanagawa H, Sone S, Takahashi Y, Haku T, Yano S, Shinohara T et’al (1995) Serum levels of interleukin-6 in patients with lung cancer. Br J Cancer 71:1095–1098

    PubMed  CAS  Google Scholar 

  10. Twillie DA, Eisenberger MA, Carducci MA, Hseih WS, Kim WY, Simons JW (1995) Interleukin-6: a candidate mediator of human prostate cancer morbidity. Urology 45:542–549

    Article  PubMed  CAS  Google Scholar 

  11. Kozlowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ (2003) Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. Rocz Akad Med Bialymst 48:82–84

    PubMed  CAS  Google Scholar 

  12. Kuang Y, Zhang Z, Zhang X (1998) Interleukin-6 and its soluble receptors in human breast cancer. Zhonghua Zhong Liu Za Zhi 20:305–307

    PubMed  CAS  Google Scholar 

  13. Benoy I, Salgado R, Colpaert C, Weytjens R, Vermeulen PB, Dirix LY (2002) Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients. Clin Breast Cancer 2:311–315

    Article  PubMed  CAS  Google Scholar 

  14. Niitsu N, Okamato M, Nakamine H, Yoshino T, Tamaru J, Nakamura S et’al (2002) Simultaneous elevation of the serum concentrations of vascular endothelial growth factor and interleukin-6 as independent predictors of prognosis in aggressive non-Hodgkinȁ9s lymphoma. Eur J Haematol 68:91–100

    Article  PubMed  CAS  Google Scholar 

  15. Salgado R, Junius S, Benoy I, Van Dam P, Vermeulen P, Van Marck E et’al (2003) Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer 103:642–646

    Article  PubMed  CAS  Google Scholar 

  16. Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW (2004) Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 23:2934–2949

    Article  PubMed  CAS  Google Scholar 

  17. Bergman PJ (2003) Mechanisms of anticancer drug resistance. Vet Clin North Am Small Anim Pract 33:651–667

    Article  PubMed  Google Scholar 

  18. DeMichele A, Martin AM, Mick R, Gor P, Wray L, Klein-Cabral M et’al (2003) Interleukin-6-174G→C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res 63:8051–8056

    PubMed  CAS  Google Scholar 

  19. Trock BJ, Leonessa F, Clarke R (1997) Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 89:917–931

    Article  PubMed  CAS  Google Scholar 

  20. Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58

    Article  PubMed  CAS  Google Scholar 

  21. Perou CM, Sorlie T, Eisen MB, van de RM, Jeffrey SS, Rees CA et’al (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  PubMed  CAS  Google Scholar 

  22. Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et’al (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–5685

    Article  PubMed  CAS  Google Scholar 

  23. Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Tham YL et’al (2005) Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol 23:1169–1177

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The following institutions participated in this study:

CALGB Statistical Center, Durham, NC–Stephen George, Ph.D., supported by CA33601.

Dana Farber-Partners, Boston, MA–George P Canellos, M.D., supported by CA32291.

Dartmouth Medical School - Norris Cotton Cancer Center, Lebanon, NH–Marc S. Ernstoff, M.D., supported by CA04326.

Duke University Medical Center, Durham, NC–Jeffrey Crawford, M.D., supported by CA47577.

Evanston Northwestern Healthcare CCOP, Evanston, IL–Gershon Y. Locker, M.D.

Georgetown University Medical Center, Washington, DC, Edward Gelmann, M.D., supported by CA77597.

Green Mountain Oncology Group CCOP, Bennington, VT–L. Herbert Maurer, M.D., supported by CA35091.

Massachusetts General Hospital, Boston, MA–Michael L. Grossbard, M.D., supported by CA12449.

Mount Sinai School of Medicine, New York, NY–Lewis R. Silverman, M.D., supported by CA04457.

Rhode Island Hospital, Providence, RI–William Sikov, M.D., supported by CA08025.

Roswell Park Cancer Institute, Buffalo, NY–Ellis Levine, M.D., supported by CA02599.

Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, NC–James N. Atkins, M.D., supported by CA45808.

Southern Nevada Cancer Research Foundation CCOP, Las Vegas, NV–John Ellerton, M.D., supported by CA35421.

State University of New York Upstate Medical University, Syracuse, NY–Stephen L. Graziano, M.D., supported by CA21060.

Syracuse Hematology-Oncology Assoc. CCOP, Syracuse, NY–Jeffrey Kirshner, M.D., supported by CA45389.

University of California at San Diego, San Diego, CA–Joanne Mortimer, M.D., supported by CA11789.

University of California at San Francisco, San Francisco, CA–Alan P. Venook, M.D., supported by CA60138.

University of Chicago, Chicago, IL –Gini Fleming, M.D., supported by CA41287.

University of Iowa, Iowa City, IA–Gerald Clamon, MD, supported by CA47642.

University of Massachusetts Medical Center, Worcester, MA–William V. Walsh, M.D., supported by CA37135.

University of Minnesota, Minneapolis, MN–Bruce A Peterson, M.D., supported by CA16450.

University of Missouri/Ellis Fischel Cancer Center, Columbia, MO–Michael C Perry, M.D., supported by CA12046.

University of North Carolina at Chapel Hill, Chapel Hill, NC–Thomas C. Shea, M.D., supported by CA47559.

Vermont Cancer Center, Burlington, VT–Hyman B. Muss, M.D., supported by CA77406.

Wake Forest University School of Medicine, Winston-Salem, NC–David D Hurd, M.D., supported by CA03927.

Walter Reed Army Medical Center, Washington, DC–Thomas Reid, M.D., supported by CA26806.

Washington University School of Medicine, St. Louis, MO–Nancy Bartlett, M.D., supported by CA77440.

Author information

Authors and Affiliations

Authors

Consortia

Corresponding author

Correspondence to Hyman Muss.

Additional information

The research for CALGB 159806 was supported, in part, by grants from the National Cancer Institute: CA31946 to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman) and by CA77406, CA33601, CA32291, CA47559, CA47577, CA04457, CA45808, CA21060, CA41287, and CA77651. This research was also supported by the Breast Cancer Research Foundation, New York, NY

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rincon, M., Broadwater, G., Harris, L. et al. Interleukin-6, multidrug resistance protein-1 expression and response to paclitaxel in women with metastatic breast cancer: results of cancer and leukemia group B trial 159806. Breast Cancer Res Treat 100, 301–308 (2006). https://doi.org/10.1007/s10549-006-9251-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-006-9251-7

Keywords

Navigation