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.
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 humanEGFR 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.
Authors: Wenle Xia; Zuguo Liu; Rongrong Zong; Leihua Liu; Sumin Zhao; Sarah S Bacus; Yubin Mao; Jia He; Julia D Wulfkuhle; Emanuel F Petricoin; Takuya Osada; Xiao-Yi Yang; Zachary C Hartman; Timothy M Clay; Kimberly L Blackwell; Herbert K Lyerly; Neil L Spector Journal: Mol Cancer Ther Date: 2011-06-14 Impact factor: 6.261
Authors: Manabu Kurokawa; Jiyeon Kim; Joseph Geradts; Kenkyo Matsuura; Liu Liu; Xu Ran; Wenle Xia; Thomas J Ribar; Ricardo Henao; Mark W Dewhirst; Wun-Jae Kim; Joseph E Lucas; Shaomeng Wang; Neil L Spector; Sally Kornbluth Journal: Sci Signal Date: 2013-05-07 Impact factor: 8.192
Authors: Dmytro M Havaleshko; Steven Christopher Smith; HyungJun Cho; Sooyoung Cheon; Charles R Owens; Jae K Lee; Lance A Liotta; Virginia Espina; Julia D Wulfkuhle; Emanuel F Petricoin; Dan Theodorescu Journal: Neoplasia Date: 2009-11 Impact factor: 5.715
Authors: Hiroko Masuda; Dongwei Zhang; Chandra Bartholomeusz; Hiroyoshi Doihara; Gabriel N Hortobagyi; Naoto T Ueno Journal: Breast Cancer Res Treat Date: 2012-10-17 Impact factor: 4.872
Authors: M Toi; H Iwata; Y Fujiwara; Y Ito; S Nakamura; Y Tokuda; T Taguchi; Y Rai; K Aogi; T Arai; J Watanabe; T Wakamatsu; K Katsura; C E Ellis; R C Gagnon; K E Allen; Y Sasaki; S Takashima Journal: Br J Cancer Date: 2009-10-20 Impact factor: 7.640