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

Authors:
  • MTMaureen Trudeau
    Maureen Trudeau
  • BKBella Kaufman
    Bella Kaufman
  • HBHamouda Boussen
    Hamouda Boussen
  • KBKimberley Blackwell
    Kimberley Blackwell
  • PLPatricia LoRusso
    Patricia LoRusso
  • DLDonald P. Lombardi
    Donald P. Lombardi
  • SASlim Ben Ahmed
    Slim Ben Ahmed
  • DCDennis L. Citrin
    Dennis L. Citrin
  • MDMichelle L. DeSilvio
    Michelle L. DeSilvio
  • JHJennifer Harris
    Jennifer Harris
  • RWRon E. Westlund
    Ron E. Westlund
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Abstract
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.

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