Abstract PD6-5: Pooled analysis of circulating tumor cells in metastatic breast cancer: Findings from 1944 individual patients data
Authors: Bidard F-C , Peeters D , Fehm T , Nole F , Gisbert-Criado R , Mavrudis D , Grisanti S , Generali D , Garcia-Saenz JA , Stebbing J , Caldas C , Gazzaniga P , Manso L , Zamarchi R , Antelo M-L , de Mattos-Arruda L , Ignatiadis M , Lebofsky R , van Laere SJ , Meier-Stiegen F , Sandri M-T , Vidal-Martinez J , Politaki E , Consoli F , Bottini A , Diaz-Rubio E , Krell J , Dawson S-J , Raimondi C , Rutten A , Janni W , Munzone E , Caranana V , Agelaki S , Almici C , Dirix L , Solomayer E , Zorzino L , Johannes H , Reis-Filho J , Pantel K , Pierga J-Y , Michiels S 
Published: August 2014

Abstract
Background: Clinical validity of CTCs (CellSearch®) in metastatic breast cancer (MBC) patients has previously been assessed in studies with limited statistical power. We aimed to pool all European studies to obtain high-level evidence on the prognostic value of CTCs, to investigate their effects across different clinico-pathological characteristics and therapies and to further validate the MD Anderson/Institut Curie/Fox Chase CTC-based prognostic nomogram established in first-line treated MBC patients (Giordano et al, Clin Cancer Res 2013).
Material and methods: Methods were predefined in a written protocol. In December 2012, we searched for eligible studies that accrued patients in 2003-2012. We contacted all European laboratories using CellSearch®. We used likelihood ratio tests (LR) in Cox regression models stratified by study to assess the independent prognostic value of CTC when added to a clinicopathological (CP) model for progression-free (PFS) and overall survival (OS). Landmark analyses were used to assess the prognostic effect of early changes in CTC. The CTC-based nomogram (http://cancernomograms.com/CTCOnline.html) score was retrieved for every patient; we calculated C-indices, drew calibration plots and Kaplan-Meier curves according to quintiles of the nomogram score.
Results: We collected individual data of 1944 MBC patients, from 20 different studies (some unpublished), from 17 centers in 7 European countries. We observed 1507 PFS events and 929 deaths. Baseline CTC count was significantly associated with several patient characteristics, such as performance status (PS, p&lt;10-4), synchronous metastasis (p&lt;10- 2) tumor subtype (p&lt;10-4), liver & bone metastases (p&lt;10-4), CEA & CA15-3 levels (p&lt;10-4). The CP model for OS included PS, MBC subtypes, number of previous lines of treatment, patient's age, metastasis-free interval, metastatic sites (p&lt;0.01 for all). In a multivariate analysis containing the CP model parameters and CTC count at baseline, elevated CTC count (≥5) was a significant independent predictor of OS (n = 1444, HR = 2.7, 95%CI [2.2-3.2], LR p&lt;10-4). Baseline serum markers added either no or marginal effect to the CP plus baseline CTC model for OS. In contrast, early changes in CTC status at week 3-5 significantly added prognostic information for OS to the model with CP factors and baseline CTC+ (n = 569, HR = 1.8 [2.2-3.2], LR p&lt;0.001). In the population of interest (MBC treated by first line chemotherapy, n = 402 patients, 176 deaths), the CTC-based nomogram exhibited a good C-index for OS (0.69), was well calibrated and showed clear separation of the survival curves. Additional results, including subgroup analyses by tumor subtype and treatments will be presented at the meeting.
Conclusions: This pooled analysis is the largest study ever reported on CTC in MBC, with a previously unreached statistical power. It provides a clear level-of-evidence 1 on the independent prognostic value of CTCs before and during treatment in MBC. Also, the CTC-based prognostic nomogram is independently validated.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD6-5.