Abstract 2140: DNA damage response in circulating tumor cells shows predictive value for metastatic breast cancer patients receiving CDK4/6 inhibitors
Authors: Keup Corinna , Gruber Charlotte , Moukas Stefanos Ioannis , Tewes Mitra , Kolberg Hans-Christian , Kimmig Rainer , Kasimir-Bauer Sabine 
Published: April 2023

Background: Resistance to CDK4/6 inhibitors (CDK4/6i), like Palbociclib and Ribociclib, plus endocrine therapy (TX) is an omnipresent topic for metastatic (M), hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) patients (pts). Circulating tumor cells (CTCs) represent the oncogenic heterogeneity in real time. Here, we aim to identify markers of resistance to CDK4/6i by mRNA profiling of CTCs.

Methods: Blood of 90 HR+/HER2-MBC pts drawn before CDK4/6i plus endocrine TX (baseline: n=57 pts first line; n=33 second or more line pts), 19 HR+/HER2-MBC pts receiving endocrine monoTX (control group) and matched samples of 78/62 of these 109 pts after six months of TX/at progression (PD) were analyzed. Isolation of CTCs was conducted using the AdnaTest EMT2/StemCell Select. Expression profiling was conducted with preamplified cDNA utilizing QuantiNova LNA Probe assays targeting 25 genes. qPCR data were normalized to CD45 and data of 20 healthy female donors. Consumables: QIAGEN, Germany. Only results with Benjamini Hochberg corrected p&lt;0.05 in univariate Cox regression and multivariate Cox regression with non-adjusted p&lt;0.05 are demonstrated.

Results: At baseline, in pts treated with CDK4/6i in the first line, CETN2 (HR 3.6)/MLH3 (HR 4)/E2F1 (HR 5.3) overexpression signals in CTCs correlated significantly with shorter progression-free survival (PFS) and shorter overall survival [(baseline to death, OS) (HR 8.3/HR 4.9/HR 3.8)], whereas ESR1 signals correlated with a shorter OS (HR 4.4). After six months of TX, in CDK4/6i treated pts, CXCR4 and CETN2 signals correlated with a shorter PFS and the signal dynamics from baseline to six months of CXCR4, CETN2 and PCNA also correlated with a shorter PFS. At PD, STAT1 signals were identified as potential Ribociclib specific resistance markers and Hippo pathway inhibition as a potential new approach for postCDK4/6i TX, because TEAD2 and WWTR1 correlated with shorter remaining time to death.

Conclusion: We identified overexpression of transcripts involved in DNA damage response mechanisms (CETN2, MLH3 and/or PCNA) at baseline to have predictive and/or prognostic value in first line CDK4/6i treated pts while signal dynamics of CETN2 and PCNA to six months of TX could serve as monitoring marker in these pts. Currently, further longitudinal blood sampling over the course of treatment is underway to give a deeper insight in resistance development under CDK4/6i treatment.

Citation Format: Corinna Keup, Charlotte Gruber, Stefanos Ioannis Moukas, Mitra Tewes, Hans-Christian Kolberg, Rainer Kimmig, Sabine Kasimir-Bauer. DNA damage response in circulating tumor cells shows predictive value for metastatic breast cancer patients receiving CDK4/6 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2140.