P3-14-25: Neoadjuvant Trastuzumab and Paclitaxel Combination Induces a High Rate of Pathological Complete Responses in Locally Advanced Breast Cancer by Exploiting Host Antitumor Immunity.
Authors: Dolcetti R , Crivellari D , Muraro E , Martorelli D , Miolo G , Lombardi D , Massarut S , Perin T , Talamini R , Turchet E , Comaro E , Carbone A , Veronesi A 
Published: June 2012

Abstract
Background: A phase II study was performed to assess the role of patients’ immune profile in the activity of a trastuzumab-based, non anthracycline containing neoadjuvant chemotherapy (NC) regimen in locally advanced breast cancer (BC) patients (pts).
Methods: Newly diagnosed T2-3 HER2+ BC pts received a 12 week NC with weekly paclitaxel and trastuzumab, which was continued for further 12 weeks before surgery in the absence of progression (PRO). Further 12 weeks of the same therapy was planned after surgery and then trastuzumab alone to 1 year of treatment ± hormonal therapy and radiotherapy. In case of PRO, trastuzumab was discontinued and anthracyclines were planned. Blood samples were collected at diagnosis and every 3 months for 1 year then yearly. The % of NK cells, T cells and Treg cells was evaluated by flow cytometry, and serum levels of 9 cytokines were assessed by SearchLight multiplex array technology. Circulating CD8+ T cells specific for a broad spectrum of tumor-associated antigens (Her2, muc-1, mammaglobin-A, trag-3, survivin, bcl-xL) were enumerated by IFN-γ Elispot and in vitro T-mediated, antibody-dependent cell cytotoxicity (ADCC) was assessed using patients’ PBMCs.
Results: From July 2006, 34 pts were enrolled, median age 46 yrs (range 30–70). Overall objective clinical response rate was 91%, with 53% of pathological complete responses (pCR) and 38% of partial responses. At a median follow-up of 27 months, 4 relapses were noted (1 brain, 1 local breast, 2 bone). No cardiotoxicity occurred. At diagnosis, pts showed an immune profile similar to that of healthy women, whereas higher numbers of Treg cells (p=0.02), NK cells (p=0.03), lower T cell numbers (p&lt;0.01) and lower amounts of serum IL-2, IL-6, and IL-8 were found in a concomitant control group of untreated HER2− pts. Moreover, spontaneous CD8+ T cells specific for all 13 HLA-A*0201 epitopes were observed in the whole series, with numbers usually higher than those observed in HER2− cases. Notably, patients with pCR, unlike those showing partial responses, retained high numbers of epitope-specific CD8+ T cells throughout the NC treatment, particularly versus survivin and mammaglobin-A epitopes. Moreover, pts achieving pCR showed at diagnosis a significantly higher efficiency of trastuzumab-mediated ADCC compared to pts with partial responses (p=0.05). The treatment also induced a progressive increase in the number of NK cells and in the efficiency of trastuzumab-mediated ADCC.
Conclusions: NC with paclitaxel and trastuzumab induces high rates of pCR with no cardiotoxicity. This clinical efficacy is favoured by the retained immunological proficiency of HER2+ pts, who may benefit from the immunological synergism between the two drugs. In fact, the increased number and activation of NK cells promoted by paclitaxel likely favour NK-dependent ADCC responses, known as one of trastuzumab's main mechanisms of action. The possible role of trastuzumab-mediated ADCC in preserving event-free survival and the involvement of paclitaxel in inducing NK cells’ NF-kB nuclear translocation are under evaluation.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-25.