228P - Development of a novel quantitative assay for predicting ADCC, antibody dependent cell mediated cytotoxicity, and prediction of pathological complet...
|Date||30 September 2012|
|Event||ESMO Congress 2012|
|Session||Poster presentation II|
K. Tamura1, M. Yunokawa2, H. Yamamoto3, M. Kodaira4, C. Shimizu2, K. Yonemori4, Y. Fujiwara5, F. Koizumi6
Antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be one of the modes of action for trastuzumab. We have previously reported that FcγRIIIa-158 V/V and FcγRIIa-131 H/H genotypes predicted clinical outcome of trastuzumab in both neoadjuvant and metastatic setting in patients with HER-2 positive breast cancer. The purpose of this study is to directly measure an inter-individual ADCC and to develop a new system for predicting to a clinical effectiveness of trastuzumab.Materials and methods
The stability of the inter-individual differences has been confirmed using peripheral blood mononuclear cells (PBMCs) of 11 healthy volunteers (HVs). Next, we adopted an ex vivo gene expression analysis to identify the molecules which correlate with ADCC activity. We examined the expression change of 14 candidate genes in the 8 HVs after ex vivo exposure to heat-aggregated IgG1 for 4 hr using Hem A (+) system. After identification of the molecules predicting ADCC, we evaluated prospectively whether values of fold increase (FIs) of these the molecules are associated with a pathological complete response (pCR) in 18 patients with HER2 positive breast cancer, who received trastuzumab-based neoadjuvant chemotherapy.Results
FI in expressions of TNFSF15, IL-6, and CxCL3 are significantly correlated with ADCC activity (R = 0.74, R = 0.85, R = 0.87, respectively). Eligible criteria of the prospective comfort include HER2 positive breast cancer, chemotherapy-naïve, measurable disease, PS 0-2 and adequate organ functions. Patients received standard FEC (5-fluorouracil/epirubicin/cyclophosphamide) q3w for 4cycles followed by weekly paclitaxel/trastuzumab for 12 weeks. Patients who achieved a pCR had a higher FI of CXCL-1, CXCL-3, TNFSF-2, and TNFSF-15 than those who did not (p = 0.004, 0.015, =0.0495, and =0.014, respectively).Conclusions
These results suggest the novel quantitative ADCC assay have a potential to predict pCR to trastuzumab-based neoadjuvant chemotherapy.Disclosure
All authors have declared no conflicts of interest.