Circulating tumor cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial

Abstract

Background Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. Methods Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. Results All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. Conclusions CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.

Liquid Biopsy: A New Tool for Overcoming CDKi Resistance Mechanisms in Luminal Metastatic Breast Cancer

“…Besides, those patients with ≥5 CTC develop resistance earlier. RB expression was also analysed but there was no correlation with clinical benefit [55]. Although this is the first study reported based on CTCs enumeration or molecular analysis in these patients, a bigger cohort and more analysis are required, as CTC characterisation will increase their clinical utility.…”

Circulating Biomarkers of CDK4/6 Inhibitors Response in Hormone Receptor Positive and HER2 Negative Breast Cancer

“…Additionally, molecular characterization of CTCs might increase their clinical validity [ 71 ]. The prognostic value of CTC was recently analyzed in patients enrolled in a translational sub-study of TREnd [ 30 ]. CTCs count after the first cycle of palbociclib (T1), but not at baseline was prognostic in terms of PFS.…”

“…Indeed, patients with an increase of three or more CTCs at T1 experienced shorter PFS compared to those without increase. Intriguingly, patients whose CTCs showed detectable expression of RB1 at any time-point had better, although not statistically significant, outcomes compared to those with undetectable levels [ 30 ].…”

Circulating Tumor Cells as a Tool to Untangle the Breast Cancer Heterogeneity Issue

“…Another important aspect concerns the opportunity to make serial withdrawals, allowing for the monitoring of the disease during treatment. Changes in CTC count proved to be clinically relevant [ 48 , 49 , 50 ]. In addition, longitudinal evaluation of CTC clusters proved to further improve prognostication as well as therapy monitoring in mBC patients starting first-line chemotherapy [ 51 ].…”

“…As observed in patients diagnosed with ER-positive advanced BC and treated with Palbociclib in the cTREND study, CTC enumeration during treatment can be helpful to identify early-resistance to treatment. In addition, CTC count at progression can serve as a prognostic factor to predict post-palbociclib outcome but CTC enumeration at baseline did not show any significant prognostic value [ 48 ]. However, the raw CTC enumeration does not take into account the status of these cells.…”