Originally published as JCO Early Release 10.1200/JCO.2007.13.5939 on January 7 2008

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Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers

Marta Guix, Nara de Matos Granja, Ingrid Meszoely, Theresa B. Adkins, Bobbye M. Wieman, Kerek E. Frierson, Violeta Sanchez, Melinda E. Sanders, Ana M. Grau, Ingrid A. Mayer, Gary Pestano, Yu Shyr, Senthil Muthuswamy, Benjamin Calvo, Helen Krontiras, Ian E. Krop, Mark C. Kelley, Carlos L. Arteaga

From the Departments of Medicine, Pathology, Biostatistics, Surgery, and Cancer Biology, Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN; Ventana Medical Systems, Inc, Tucson, AZ; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; University of Alabama at Birmingham Cancer Center, Birmingham, AL; and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Corresponding author: Carlos L. Arteaga, MD, Division of Oncology, Vanderbilt University Medical Center, 2220 Pierce Ave, 777 PRB, Nashville, TN 37232-6307; e-mail: carlos.arteaga{at}vanderbilt.edu

Purpose To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity.

Patients and Methods Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ER.

Results In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade 2 rash and diarrhea were the main toxicities. Erlotinib inhibited tumor cell proliferation (Ki67), P-EGFR, and P-HER-2. The inhibition of proliferation occurred in estrogen receptor (ER) –positive but not in human epidermal growth factor receptor 2 (HER-2) –positive or triple-negative cancers. Treatment was associated with a significant reduction of P-MAPK, P-Akt, P-S6, and S118 P-ER in hormone receptor–positive cancers.

Conclusion A presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer. EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2–positive or triple-negative breast cancers.

published online ahead of print at www.jco.org on January 7, 2008.

Supported in part by National Institutes of Health Grant No. R01 CA80195 (C.L.A.), Breast Cancer Specialized Program of Research Excellence (SPORE) Grant No. P50 CA98131, Avon-National Cancer Institute Grant No. CA098131-03S1 (C.L.A.), and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant No. P30 CA68485. M.E.S. and I.A.M. are recipients of Vanderbilt Physician-Scientist Development Awards. A grant from Genentech also partially supported the clinical trial.

Presented in part at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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