Longitudinal enumeration and cluster evaluation of circulating tumor cells improve prognostication for patients with newly diagnosed metastatic breast cancer in a prospective observational trial

Abstract

BackgroundCirculating tumor cells (CTCs) carry independent prognostic information in patients with metastatic breast cancer (MBC) on different lines of therapy. Moreover, CTC clusters are suggested to add prognostic information to CTC enumeration alone but their significance is unknown in patients with newly diagnosed MBC. We aimed to evaluate whether longitudinal enumeration of circulating tumor cells (CTCs) and CTC clusters could improve prognostication and monitoring of patients with metastatic breast cancer (MBC) starting first-line therapy.MethodsThis prospective study included 156 women with newly diagnosed MBC. CTCs and CTC clusters were detected using CellSearch technology at baseline (BL) and after 1, 3, and 6 months of systemic therapy. The primary end point was progression-free survival (PFS) and the secondary end point overall survival (OS). Median follow-up time was 25 (7–69) months.ResultsThere were 79 (52%) and 30 (20%) patients with ≥ 5 CTCs and ≥ 1 CTC cluster at baseline, respectively; both factors were significantly associated with impaired survival. Landmark analyses based on follow-up measurements revealed increasing prognostic hazard ratios for ≥ 5 CTCs and CTC clusters during treatment, predicting worse PFS and OS. Both factors added value to a prognostic model based on clinicopathological variables at all time points and ≥ 5 CTCs and presence of CTC clusters enhanced the model’s C-index to > 0.80 at 1, 3, and 6 months. Importantly, changes in CTCs during treatment were significantly correlated with survival and patients with a decline from ≥ 5 CTCs at BL to < 5 CTCs at 1 month had a similar odds ratio for progression to patients with < 5 CTCs at BL and 1 month. Stratification of patients based on CTC count and CTC clusters into four groups (0 CTCs, 1–4 CTCs, ≥ 5 CTCs, and ≥ 1 CTC + CTC clusters) demonstrated that patients with CTC clusters had significantly worse survival compared to patients without clusters.ConclusionsLongitudinal evaluation of CTC and CTC clusters improves prognostication and monitoring in patients with MBC starting first-line systemic therapy. The prognostic value increases over time, suggesting that changes in CTC count are clinically relevant. The presence of CTC clusters adds significant prognostic value to CTC enumeration alone.Trial registrationNCT01322893. Registered on 25 March 2011.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0976-0) contains supplementary material, which is available to authorized users.

Liquid biopsies

“…This meta‐analysis, based on 21 studies, has shown that CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by neoadjuvant chemotherapy, and complements current prognostic models based on tumor characteristics and response to therapy . A very recent clinical prospective study that included 156 women with newly diagnosed metastatic breast cancer concluded that longitudinal evaluation of CTC and CTC clusters improves prognostication and monitoring in patients with metastatic breast cancer starting first‐line systemic therapy …”

“…39 A very recent clinical prospective study that included 156 women with newly diagnosed metastatic breast cancer concluded that longitudinal evaluation of CTC and CTC clusters improves prognostication and monitoring in patients with metastatic breast cancer starting first-line systemic therapy. 40 Detection of CTCs using the CellSearch system before neoadjuvant therapy was an independent prognostic factor of impaired clinical outcome, and when combined with pathologic complete response (pCR), it was shown to be helpful to stratify breast cancer patients for therapeutic interventions. 41 In 3173 patients with nonmetastatic (stage I-III) breast cancer, the presence of CTCs was found to be an independent predictor of poor disease-free, overall, breast cancerspecific, and distant disease-free survival.…”

Circulating tumour cell enumeration does not correlate with Miller-Payne grade in a cohort of breast cancer patients undergoing neoadjuvant chemotherapy

“…This is slightly higher than recently reported by Vetter et al, who found 35% of their cohort had clusters present prior to treatment [26], using the Parsortix microfluidic device. Studies using the CellSearch™ system report cluster rates around 20% [27]. Current technologies significantly under-call the number of CTC clusters because few specialised devices exist for their detection.…”

Evolution of Estrogen Receptor Status from Primary Tumors to Metastasis and Serially Collected Circulating Tumor Cells

“…The study was previously described in detail [27,28]. In brief, 168 women with newly diagnosed MBC, previously untreated for metastatic disease, were included in a prospective observational study at Skåne University Hospital and Halmstad County Hospital (ClinicalTrials.gov NCT01322893).…”