Abstract OT1-1-07: Phase II trial of paclitaxel combined with trastuzumab and pertuzumab as preoperative therapy for HER2 positive inflammatory breast cancer
Authors: Overmoyer BA , Regan M , Brugge J , Perou CM , Nakhlis F , Jennifer B , Heather J , Eren YD , Judith H-B , Winer E 
Published: August 2014

Abstract
Background: Inflammatory breast cancer (IBC) is a rare and virulent disease, accounting for 2-5% of breast cancer (BC) in the United States. The molecular analysis of IBC reveals a propensity to segregate into more proliferative intrinsic subtypes, such as HER2 positive (+) (Van Laere, et al, Br Ca Res Treat 2006). Studies demonstrate a 40-50% incidence of HER2+ disease among IBC, which is &gt;2x the incidence in non-IBC (Turpin E, et al, Br Ca Res Treat 2002). The prevalence of HER2+ IBC and the availability of agents targeting the HER2 domain support investigation into the optimal preoperative regimen incorporating HER2 targeting agents. This preoperative trial evaluates combination pertuzumab (P) paclitaxel (T) and trastuzumab (H) in patients (pts) with newly diagnosed HER2+ IBC.
Methods: Pts with HER2+ Stage III (cT4d, any N, M0) IBC (male or female) are eligible if they have not received prior therapy for BC, have adequate organ function, ECOG PS ≤ 1, cardiac ejection fraction ≥ 50%, and willing to undergo 2 research biopsies (bx) of the affected breast for correlative assays. Staging studies, research bx and whole blood sample are obtained at baseline. Pts receive a loading dose of P 840mg and H 4mg/kg IV (day (d) 1, week (wk) 1). On d8, wk2, a 2nd breast bx and whole blood sample are obtained and wkly H 2mg/kg with T 80mg/m2 IV are administered for a total of 16 wks. P 420mg is given concurrently every 21d for 5 doses beginning on d21, wk3. Following adequate tumor response, pts proceed to modified radical mastectomy followed by doxorubicin (A) 60mg/m2 with cyclophosphamide(C) 600mg/m2 every 21d for 4 cycles. Following AC, the chest wall and regional lymph nodes are treated with radiation concurrently with a loading dose of P 840mg and H 8mg/kg followed by P 420mg and H 6mg/kg every 21d for 12 doses. Adjuvant endocrine therapy is given with P and H if estrogen and/or progesterone receptor positive.
Correlatives: To investigate whether the pre-treatment status of the tumor predicts HER2-resistance, next-generation sequencing technology will be employed to explore gene expression patterns including PAM50-based intrinsic subtyping. Both de novo and acquired mechanisms of resistance to HER2 therapy will be explored including analysis of residual disease obtained at mastectomy. Exploration of early adaptive molecular changes seen in d8, wk2 tumor samples will provide information useful in developing improved therapeutic strategies.
Statistics: The primary endpoint is pathologic complete response (pCR) following therapy with PTH. A Simon minimax two-stage design is being used. If the proportion of pts having pCR is ≤ 0.15 then PTH is considered minimally effective, versus alternative hypothesis that PTH is worthy of further study if proportion pCR ≥ 0.40. In the 1st stage, if ≤ 2/16 pts have pCR, the study is stopped; if ≥ 3 pts have pCR, the study proceeds. In the 2nd stage, PTH is rejected if ≤ 7 of 27 pts have a pCR (α = 0.039; β = 0.05). Up to 30 pts will be enrolled. Secondary objectives are disease-free survival, time to tumor failure and overall survival. Time-to-event distributions are summarized using Kaplan-Meier and 2-sided 90% CI for the medians. Clinical trial information: NCT01796197.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-07.