Early Changes in Circulating Tumor Cells Are Associated with Response and Survival Following Treatment of Metastatic Neuroendocrine Neoplasms

Abstract

Purpose: To investigate posttreatment circulating tumor cell (CTC) counts in patients with neuroendocrine neoplasms (NENs) as a predictive biomarker for disease progression and overall survival (OS).Experimental Design: Patients with metastatic NENs commencing therapy were prospectively recruited (n ¼ 138). Blood samples were obtained for evaluation of CTCs using the CellSearch platform and for chromogranin A (CgA) at baseline, three to five (median, 4.3) weeks and 10 to 15 (median 13.7) weeks after commencing therapy. Radiologic response and OS data were collected.Results: There was a significant association between first posttreatment CTC count and progressive disease (PD; P < 0.001). Only 8% of patients with a favorable "CTC response" (0 CTCs at baseline and 0 at first posttreatment time-point; or !50% reduction from baseline) had PD compared with 60% in the unfavorable group (<50% reduction or increase). Changes in CTCs were strongly associated with OS (P < 0.001), the best prognostic group being patients with 0 CTCs before and after therapy; followed by those with !50% reduction in CTCs [hazard ratio (HR), 3.31]; with those with a <50% reduction or increase in CTCs (HR, 5.07) having the worst outcome. In multivariate analysis, changes in CTCs had the strongest association with OS (HR, 4.13; P ¼ 0.0002). Changes in CgA were not significantly associated with survival.Conclusions: Changes in CTCs are associated with response to treatment and OS in metastatic NENs, suggesting CTCs may be useful as surrogate markers to direct clinical decision making.

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…Current strategies to analyze tumor genomes are limited by the need of sufficient amount of good quality tumor tissue. In the future peripheral blood samples (liquid biopsies) containing either circulating tumor cells or circulating cell free DNA might instead be used for recognition of the genomic landscape of the individual tumors (168,169).…”

Ki-67 index and response to chemotherapy in patients with neuroendocrine tumours

“…Improved methods of patient stratification are therefore required in neuroendocrine tumours in order to provide benefit for those who will respond and spare toxicity in those who will not. There is considerable interest in the predictive role of circulating biomarkers, including NETspecific multi-gene transcripts (NET-test) (Modlin et al 2014), cfDNA and CTCs (Khan et al 2016), but further work is required to prospectively validate these markers before they can be used to select patients for chemotherapy (Modlin et al 2014). …”

Circulating tumor cells and miRNAs as prognostic markers in neuroendocrine neoplasms

“…• Significant association (P < 0.001) between the first post-treatment (after 3-5 weeks) CTCs count and progressive disease (PD): PD in 8% of patients with 'favorable count' (0 CTCs at baseline and after treatment, or ≥50% CTCs reduction after treatment) vs 60% in unfavorable group (<50% CTCs reduction or increase) • Changes in CTCs count at the first post-treatment time (after 3-5 weeks) strongly associated with OS (P < 0.001): the best outcome in group with 0 CTCs count at baseline, followed by the group with ≥50% CTCs reduction after treatment (HRs = 3.31; 95% CI = 1.50-7.32) and then the group with <50% CTCs reduction or increase (HRs = 5.07; 95% CI = 2.48-10.38) • In multivariate analysis changes from baseline CTCs count (P = 0.0002) and grade (P = 0.0046) resulted independent prognostic factors Khan et al (2016) 34 Merkel cell carcinomas • Correlation between CTCs positivity (≥1 CTCs) and extent of disease (P = 0.004) • Statistically significant difference in median OS between CTCs positive and CTCs negative samples (P = 0.0003), also in case of regional node metastases (P = 0.015) Blom et al (2014) 30 Merkel cell carcinomas • Significantly higher CTCs count in patients with active disease • Increasing CTCs count associated with development of new metastases Gaiser et al (2015) 59 Small cell lung cancers • Association between CTCs count <2 and prolonged OS and PFS (P ≤ 0.001)…”

“…In addition, the study showed that patients with more than one CTC displayed worse PFS and OS as compared to patients with <1 CTC, independently of other prognostic markers. To clarify whether CTCs may also predict the response to treatment, the same authors (Khan et al 2016) evaluated CTC count before and after treatment in 138 metastatic NEN patients (31 pNEN including 9 G1, 7 G2 and 15 G3; 81 midgut NENs including 48 G1, 28 G2 and 5 G3; 12 lung NENs including 4 G1, 6 G2 and 3 G3) and found that first post-treatment CTC count was significantly associated with progressive disease. Indeed, a better outcome was recorded in patients that did not have CTCs before and after therapy and in patients displaying a >50% reduction in CTC count after treatment.…”