Abstract P1-11-16: Her2/neu Overexpressing Breast Cancer Patients Retain an Immunological Proficiency Compromised in Her2/neu-Negative Cases

Abstract

Abstract Although breast cancers overexpressing HER2/neu are associated with a worse prognosis, a high rate of complete responses is usually induced in these patients by current therapeutic strategies, such as Trastuzumab, that also directly mediates antibody-dependent cellular cytotoxicity and possesses immunomodulating properties. Moreover, other chemotherapeutics used in this setting, i.e. doxorubicin and Taxol, were shown to enhance antigen-specific immune responses. On these grounds, a thorough evaluation of the immunologic profile of breast cancer patients may be helpful to predict clinical responses to such therapies. We therefore analyzed at diagnosis different immunological parameters of patients with locally advanced HER2+ (n=18) and HER2- (n=30) breast cancer eligible for neoadjuvant chemotherapy, respectively treated with weekly Paclitaxel (80 mg/mq/ev) and Trastuzumab (4mg/kg/ev day 1 followed by 2 mg/kg/ev weekly), or Epirubicin (90 mg/mq/ev) and Docetaxel (75mg/mq/ev) every 3 weeks. Immunophenotyping of circulating immune cells disclosed several differences in HER2- cases as compared with HER2+ patients and healthy controls (n=20). In particular, HER2- patients showed a higher percentage of NK and B cells (10.2 and 10.0%, respectively) and a lower CD4/CD8 T cell ratio (1.8; with a prevalence of naïve and central memory cells in the CD8+ population) if compared to HER2+ patients (NK 5.8%, B cells 8.2%, and CD4/CD8=2.3) and healthy controls (NK 5.5%, B cells 7.7%, and CD4/CD8=2.2). In addition, HER2- cases had higher numbers of circulating CD4+ regulatory T cells (1.6% FoxP3+CD25+CD127- of CD4+ T cells) with respect to donors (0.9%). Moreover, IFN-gamma ELISPOT assay demonstrated spontaneous T cell responses to a broad spectrum of HLA-A*0201-restricted peptides derived from breast cancer-associated antigens (HER2/neu, MUC-1, mammaglobin-A, Taxol resistance-associated gene-3, survivin, and Bcl-xL) in both groups of tumour patients, although the extent of these responses was usually higher in HER2+ cases. Finally, a multiparametric evaluation of the serum levels of 9 different cytokines revealed a comparable profile in HER2+ cases and in controls, whereas HER2- patients showed significantly lower cytokine amounts compared to healthy donors (IL-2, IL-6, and IL-8) and to HER2+ breast cancers (IL-6, IL-8, and IL-10). Preliminary data revealed a pathological complete response (pCR) in 44.4% of HER2+ patients (8/18), compared to 16.7% of the HER2- arm (5/30). These results are consistent with a retained immunologic proficiency of HER2+ patients, showing an innate tumor-specific immune response. Such features may at least partly account for the clinical benefit of drugs acting through, but also promoting, immunemediated effects. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-16.