Abstract 26P
Background
CDK 4/6i have dramatically improved the outcome of ER+/HER2- MBC, but most patients will eventually experience disease progression (PD). Dysregulation in lipid metabolism and T cell phenotypes may contribute to therapy resistance. We assessed the impact of these factors on patients treated with CDK 4/6i.
Methods
In this study, peripheral blood was collected at baseline from patients (n= 57) candidate to CDK4/6i at Maggiore Hospital, Novara, Italy. Untargeted lipidomic analysis was performed by liquid chromatography and mass spectrometry. FACS analysis was used for T cell subtyping. Association with progression free survival (PFS) was evaluated by Log-rank test and Cox regression. T cell subtypes frequency, according to treatment response (response/stable [PR/SD] vs PD), was assessed by Mann Whitney U and Wilcoxon matched-pairs rank tests in patients with ≥6 months follow-up (n = 25).
Results
High plasma concentrations of sphingomyelin (SM 44:4;3O HR 1.28 [1.05 – 1.55]), phosphatidylethanolamine (PE P-38:1 HR 3.16 [1.18 - 8.48]), N-acylethanolamine (NAE 18:11 HR 1.27 [1.04 - 1.56]) and phosphatidylcholines (PC O-36:4 HR 1.10 [1.03 - 1.18], LPC O-26:1 HR 1.25 [1.04 - 1.50]) were associated with poorer PFS. A similar association was observed in patients with high frequency of exhausted T cells TIGIT+ (HR 1.25 [1.01 - 1.53]) and PD1+ (HR 1.99 [1.18 - 3.34]). All associations remained significant after age and visceral metastases adjustments (Table). In patients with ≥6 months follow-up, more CD4+CD28- T cells were found in the PR/SD group (22.81 ± 15.16 vs 12.53 ± 19.26, p=0.016). In those experiencing early PD, higher level of T cells expressing PD1+ (0.05 ± 0.08 vs 0.15 ± 0.17, p=0.019) and PD1+LAG3+TIGIT+ exhaustion markers (1.13 ± 0.39 vs 2.14 ± 1.22, p=0.016) were observed. Table: 26P
| Multivariate Cox model adjusted for age (<65 vs ≥65) and presence of visceral metastasis | ||
| Plasma lipids (n = 26) | HR (95% CIs) | |
| PC | PC(O-36:4) | 1.14 (1.03 - 1.25) |
| LPC O-26:1 | 1.25 (1.04 - 1.51) | |
| SM | SM 44:4;3O | 1.29 (1.04 - 1.61) |
| PE | PE P-38:1 | 3.23 (1.18 - 8.84) |
| NAE | NAE 18:1 | 1.36 (1.07 - 1.73) |
| T cell populations (n = 33) | HR (95% CIs) | |
| CD3+CD28+TIGIT+ | 1.27 (1.02 - 1.58) | |
| CD4+CD28+PD-1+ | 2.06 (1.16 - 3.66) |
Conclusions
Lipidomic and T cell profiling may help identifying patients developing resistance to CDK4/6i.
Legal entity responsible for the study
A. Gennari.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.