Abstract S3-01: IMENEO: International MEta-analysis of circulating tumor cell detection in early breast cancer patients treated by NEOadjuvant chemotherapy

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<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<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<0.0001), DDFS (HR=2.4 [1.9-3.1], p<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<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<0.0001, No pCR HR=6.2 [3.7-11] p<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.

Limited Sensitivity of Circulating Tumor DNA Detection by Droplet Digital PCR in Non-Metastatic Operable Gastric Cancer Patients

“…Only one study analyzed the monitoring of ctDNA in gastric cancers (other than the detection of methylation in cell-free circulating DNA (cfcDNA)), and showed that three out of 10 patients (30%) with TP53 mutations in primary tumors showed detectable TP53 mutation levels in the preoperative setting [24]. In our study, the 20% detection rate of ctDNA before therapy appears to be lower than that reported in other non-metastatic cancer types, despite using the same approach and ddPCR technique as those reported in other studies from our laboratory [13,17,20,25]. The lower detection rate in the present study could be explained by the systematic laparoscopic assessment of peritoneal metastasis, combined with extensive imaging workup to detect metastasis.…”

“…Circulating tumor biomarkers have demonstrated their clinical validity in several non-metastatic cancer types either as baseline prognostic biomarkers, as a monitoring tool during preoperative chemotherapy and/or as a way to detect minimal residual disease [6,7,8,9,10,11,12,13,14,15,16,17,18,19,20].…”

Exploring the Immunological Profile in Breast Cancer: Recent Advances in Diagnosis and Prognosis through Circulating Tumor Cells

“…As detailed in the previous section, cancer immunotherapies, including CTLA-4 and PD-1/PD-L1 inhibitors, have shown substantial clinical benefits [150,179]. An interesting study established a platform for culturing autologous tumor organoids with peripheral blood lymphocytes to evaluate and stimulate tumor-specific T cell responses to epithelial cancers.…”

Early stage breast cancer treatment and prognostic factors

“…In univariate analyses, ≥1 CTC at baseline was a prognostic factor for overall survival (HR = 2.6 [1.9–3.4], p < 0.0001), distant disease-free survival (HR = 2.4 [1.9–3.1], p < 0.0001), and for locoregional relapse-free interval (HR = 1.8 [1.2–2.7], p = 0.001). In multivariate analyses, baseline CTC detection was an independent prognostic factor for OS, DDFS, and LRFI, together with pCR, cT, cN, and tumor subtype, which shows that CTC are a prognostic biomarker in early breast cancer treated by neoadjuvant chemotherapy with a high level of evidence [ 18 ].…”