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