Circulating tumour cells (CTCs) as biomarkers of resistance to the CDK4/6 inhibitor (CDK4/6i) palbociclib (P) in patients (pts) with ER+/HER2-negative advanced breast cancer (ABC)
Annals of Oncology(2020)
摘要
Resistance to CDK4/6i is inevitable. CTC count is prognostic in ABC, but its role in pts treated with CDK4/6i is not well defined. Genetic loss of RB1 is a known yet infrequent marker of CDK4/6i resistance. We assessed the prognostic role of CTC count and gene-expression (GE) levels of RB1 in CTCs in pts receiving P. The TREnd trial (NCT02549430) randomized pts with endocrine resistant ABC to either P alone or P plus the endocrine therapy received in the prior line of treatment. In TREnd, blood samples were prospectively collected in CellSave® tubes before starting P (T0), after the first cycle (T1) and at disease progression (T2). CTCs were isolated and counted by CellSearch® System (CS) using CellSearchTM Epithelial Cell kit. Samples with ≥5CTCs were sorted by DEPArray system® (DA). RNA extraction and retro-transcription for GE experiments were performed by Cell Lysis Two-Step RT-qPCR. RB1 and GAPDH GE levels were measured by ddPCR, with a multiplex assay with a sensitivity of 30-10 pg of cDNA, set up on three different cell lines sensitive and resistant to P. 46 pts were suitable for CTC analysis. CTC count at T0 did not show significant prognostic value in terms of progression free survival (PFS). However, pts with at least 1 detectable CTC at T1 (n=26) had a worse PFS than those with 0 CTCs (n=16) (p=0.02). Similar results were observed with a cut-off of 5 CTCs (p=0.04). At T1, 7 out of 39 pts had an increase of at least 3 CTCs which proved prognostic (p=0.01). Pts with ≥5CTCs at T2 (n=6/23) who received chemotherapy as post-study treatment had a shorter time to treatment failure (p=0.02). DA sorting was conducted on 20/46 pts and GE data for RB1 were obtained from 19 pts. CTCs showed heterogeneous RB1 expression. Pts with detectable expression of RB1 in at least one time-point had better, but not significant, outcomes than those with undetectable levels. Persistence or an increase in CTCs after one cycle of P may identify pts with worse outcome. High CTC counts at disease progression on P may indicate poor post-treatment prognosis. Measuring RB1 GE levels on CTCs by ddPCR is feasible, but its clinical significance is yet unclear.
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关键词
breast cancer,tumour cells
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