Originally published as JCO Early Release 10.1200/JCO.2007.13.9949 on January 22 2008

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Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy

Stephen Johnston, Maureen Trudeau, Bella Kaufman, Hamouda Boussen, Kimberley Blackwell, Patricia LoRusso, Donald P. Lombardi, Slim Ben Ahmed, Dennis L. Citrin, Michelle L. DeSilvio, Jennifer Harris, Ron E. Westlund, Vanessa Salazar, Tal Z. Zaks, Neil L. Spector

From the Department of Medicine-Breast Unit, Royal Marsden Hospital, London, United Kingdom; Medical Oncology & Hematology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada; Oncology Institute, The Chaim Sheba Medical Center, Tel Hashomer, Israel; Institut Shalah Azaiz, Tunis; Department of Service de Carcinologie Médicale, CHU Farhat Hached, Sousse, Tunisia; Duke University Medical Center, Durham, NC; Karmanos Cancer Institute, Detroit, MI; Washington University Medical Center, St Louis, MO; Midwestern Regional Medical Center, Zion, IL; and Oncology Medicines Development Center, Statistics and Programming, and Biomarker Strategy and Analysis, GlaxoSmithKline, Collegeville, PA

Corresponding author: Neil L. Spector, MD, Duke University Medical Center, 2424 Erwin Road, Hock Plaza Suite 601, Durham, NC, 28807; e-mail: neil.spector{at}duke.edu

Purpose Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity.

Patients and Methods Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2–overexpressing [HER-2+]) or B(HER-2–/EGFR+) and fresh pretreatment tumor biopsies were collected.

Results Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib.

Conclusion Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2–, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.

S.J., M.T., and B.K. contributed equally to this work.

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

published online ahead of print at www.jco.org on January 22, 2008.

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