Abstract S3-01: IMENEO: International MEta-analysis of circulating tumor cell detection in early breast cancer patients treated by NEOadjuvant chemotherapy
Authors: Bidard F-C , Michiels S , Mueller V , Riethdorf S , Esserman LJ , Lucci A , Naume B , Horiguchi J , Gisbert-Criado R , Sleijfer S , Toi M , Garcia-Saenz JA , Hartkopf A , Generali D , Rothe F , Smerage J , Muinelo L , Stebbing J , Viens P , Magbanua M , Hall CS , Engebråtenm O , Takata D , Vidal-Martínez J , Onstenk W , Fujisawa N , Diaz-Rubio E , Taran F-A , Cappelletti MR , Ignatiadis M , Name N , Proudhon C , Wolf D , Bowman Bauldry J , Borgen E , Nagaoka R , Carañana V , Kraan J , Maestro M , Brucker SY , Weber K , Reyal F , Amara D , Gopalkrishna Karhade M , Ruud Mathiesen R , Tokiniwa H , Llombart-Cussac A , D'Hollander K , Cottu P , Park JW , Loibl S , Pierga J-Y , Pantel K 
Published: March 2017

Abstract
Background
We performed an international meta-analysis of individual patient data to assess the clinical validity of circulating tumor cell (CTC) count in non-metastatic breast cancer (BC) patients (pts) treated by neoadjuvant chemotherapy (NCT).
Methods
A protocol pre-specified the study objectives. We performed a literature & abstracts search up to Dec 2014, then contacted all centers deemed to have eligible data (published or not): early BC pts treated with NCT with CTC count by CellSearch®. The primary endpoint was overall survival (OS); secondary endpoints included distant disease-free survival (DDFS), locoregional relapse-free interval (LRFI) and pathological complete response (pCR). Non-overlapping CTC time points were: baseline (5-0 weeks before NCT), 1-8 weeks after NCT start, 5-0 weeks before surgery and 1-52 weeks after surgery. We used Cox regression models, stratified by study, and the landmark method to establish the prognostic value of CTC count/changes during treatment and survival.
Results
We collected 2,156 individual pt data from 21 studies and 16 centers worldwide.
With ≥1/≥2/≥5 CTC/7.5ml as thresholds, CTC positivity rate was 25/13/6% at baseline, 17/6/3% after NCT start, 15/5/1% before surgery and 11/4/1% after surgery (decrease, p&lt;0.0001). Before NCT, ≥1 CTC was found in 19%, 22%, 24%, 29% and 41% of cT1, T2, T3, T4a-c and T4d BC, respectively (p&lt;0.0001) and was also marginally associated with hormone-receptors negativity (p=0.04). Later CTC detection rates were not associated with any of the baseline characteristics. pCR (assessed in 2,072 pts; ypT0/isN0 used as pCR definition in 92% of pts) was observed in 24% of pts but was not associated with CTC count, at any time point.
301, 418 and 157 events were reported for OS, DDFS and LRFI, respectively. In univariate analyses, ≥1 CTC at baseline was a prognostic factor for OS (HR=2.6 [1.9-3.4], p&lt;0.0001), DDFS (HR=2.4 [1.9-3.1], p&lt;0.0001) and -importantly- for LRFI (HR=1.8 [1.2-2.7], p=0.001). Similar results were obtained using other thresholds (≥2 & ≥5 CTC) and/or later time points (after NCT start, before surgery). There was no interaction between the prognostic impact of CTC count and tumor subtypes. Although rare, pts with persistently elevated CTC count (≥1CTC) before NCT and before surgery (5% of pts) had a worse OS than patients with persistently null CTC count (HR=6.2 [3.4-11], p&lt;0.0001).
Finally, in multivariate analyses, baseline CTC detection (whatever the CTC threshold used : ≥1/≥2/≥5 CTC) was an independent prognostic factor for OS, DDFS and LRFI, together with pCR, cT, cN and tumor subtype, (e.g. for OS: CTC≥2 HR=4.2 [3.0-5.9] p&lt;0.0001, No pCR HR=6.2 [3.7-11] p&lt;0.0001, cT4d HR=2.6 [1.1-6.6] p=0.02, cN+ HR=1.7 [1.2-2.4] p=0.003, triple negative BC HR=3.2 [2.1-5.1]). Similar results were obtained with later time points (after NCT start, before surgery).
Conclusions
Our study demonstrates with the highest level of evidence that CTCs are a prognostic biomarker in early BC treated by NCT. This impact was independent to that of pCR and was observed on OS, DDFS and also -for the first time- on LRFI. CTC count can usefully complement standard prognostic factors and pCR to improve the prognostication of early BC pts.
Citation Format: Bidard F-C, Michiels S, Mueller V, Riethdorf S, Esserman LJ, Lucci A, Naume B, Horiguchi J, Gisbert-Criado R, Sleijfer S, Toi M, Garcia-Saenz JA, Hartkopf A, Generali D, Rothe F, Smerage J, Muinelo L, Stebbing J, Viens P, Magbanua M, Hall CS, Engebråtenm O, Takata D, Vidal-Martínez J, Onstenk W, Fujisawa N, Diaz-Rubio E, Taran F-A, Cappelletti MR, Ignatiadis M, Name N, Proudhon C, Wolf D, Bowman Bauldry J, Borgen E, Nagaoka R, Carañana V, Kraan J, Maestro M, Brucker SY, Weber K, Reyal F, Amara D, Gopalkrishna Karhade M, Ruud Mathiesen R, Tokiniwa H, Llombart-Cussac A, D'Hollander K, Cottu P, Park JW, Loibl S, Pierga J-Y, Pantel K. IMENEO: International MEta-analysis of circulating tumor cell detection in early breast cancer patients treated by NEOadjuvant chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S3-01.