Abstract P3-06-10: Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial
Authors: Christoph Zielinski C , Istvan Lang , Semir Beslija , Zsuzsanna Kahan , Inbar Moshe J , Salomon Stemmer M , Rodica Anghel , Damir Vrbanec , Diethelm Messinger , Thomas Brodowicz 
Published: May 2015

Abstract
Background:
The randomized phase III TURANDOT trial performed by the Central European Cooperative Oncology Group (CECOG) compared first-line BEV + paclitaxel (PAC) vs BEV + CAP in HER2-negative mBC in a prospective randomized trial [Lang, Lancet Oncol 2013]. In this trial, HFS was the most common adverse drug reaction in the BEV + CAP arm. In the present subanalysis, we investigated whether the occurrence of HFS constituted a predictor for improved efficacy of BEV + CAP in the study population randomized to this treatment arm.
Methods:
In the TURANDOT trial, patients with HER2-negative mBC who had received no prior chemotherapy for mBC were randomized to either BEV-PAC (BEV 10 mg/kg d1 & 15 + PAC 90 mg/m2 d1, 8, & 15 q4w) or BEV-CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2 bid d1-14 q3w). Only patients who were randomized to the BEV-CAP arm and received at least one dose of CAP were included in the present analysis. Cox proportional hazard models with time-dependent covariate "HFS of any grade" and "HFS grade" were used to analyze the association between HFS and OS or PFS. In addition, landmark (LM) analyses were performed analyzing the impact of HFS occurrence within the first 3 treatment months on PFS and OS.
Results:
Baseline characteristics of patients with HFS (n=154) versus no HFS (n=123) were well balanced and showed no significant differences. Table 1 shows that with the occurrence of HFS, the hazard for progression or death was reduced by &gt; 40%, while the risk reduction (RR) was &gt;55% for OS. Moreover, with increasing HFS-grade an increasing RR was observed for OS. In patients with and without HFS in the first 3 months, the median PFS after the 3 months LM were 10 and 6.2 months (logrank test p=0.0026), respectively, and the corresponding OS rates at 2 years after the 3 months LM were 63% and 44% (log rank test, p=0.0842), respectively. Updated OS results will be presented at the conference.
Cox Proportional Hazards Models for PFS and OS with HFS as Time-dependent CovariateUnivariateMultivariate*EndpointTime depent variableHazard ratio (95%Cl)p-valueHazard ratio (95%Cl)p-valuePFSHFS(Yes vs No)0.577(0.431,0.772)0.00020.558(0.409,0.760)0.0002HFS Grade 10.639(0.440,0.927)0.01840.536(0.350,0.821)0.0042HFS Grade 20.481(0.321,0.720)0.00040.487(0.320,0.741)0.0008HFS Grade 30.641(0.411,0.999)0.04950.740(0.466,1.178)0.2043OSHFS(Yes vs No)0.417 (0.273, 0.637)&lt;.00010.436 (0.285, 0.666)0.0001HFS Grade 10.568 (0.334, 0.968)0.03750.548 (0.322, 0.934)0.0270HFS Grade 20.417 (0.227, 0.765)0.00480.448 (0.243, 0.824)0.0098HFS Grade 30.220 (0.093, 0.520)0.00060.247 (0.104, 0.586)0.0015* Significant baseline factors in multivariate models: ECOG (0 vs 1-2) in all models, ER/PR status (Any positive vs Other) in both OS models.
Conclusion:
HFS is a strong predictor for prolonged PFS and OS in mBC patients receiving BEV + CAP first-line treatment. Early occurrence of HFS and HFS severity might be used for treatment modifications and patient motivation. Detection of biomarkers for HFS could strengthen this approach.
Citation Format: Zielinski C Christoph, Lang Istvan, Beslija Semir, Kahan Zsuzsanna, Moshe J Inbar, Stemmer M Salomon, Anghel Rodica, Vrbanec Damir, Messinger Diethelm, Brodowicz Thomas. Hand-foot-syndrome (HFS) is a strong predictor for OS and PFS in HER2-negative metastatic breast cancer (mBC) treated with first-line capecitabine (CAP) + bevacizumab (BEV): Results of a subanalysis of the randomized phase III CECOG TURANDOT trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-10.