The prognostic impact of NKA dynamics in first-line treatment of metastatic colorectal cancer.
Authors: Nederby Line , Raunkilde Louise , Jakobsen Anders , Jensen Lars Henrik , Havelund Birgitte Mayland , Witting Christensen Wen Sara , Hansen Torben 
Published: June 2023

e15514

Background: Metastatic colorectal cancer (mCRC) remains a therapeutic challenge and new markers hold high priority. Natural Killer (NK) cells are immune cells with potent antitumor properties. The association between neoplastic development and level of effector functions of this cell type is well known. Moreover, it is recognized that NK cells are subject to tumor-mediated immune suppression. The present study aimed at elucidating a potential relationship between NK cell activity (NKA) and response to folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) in mCRC. Methods: NKA was analyzed in patients enrolled in a randomized trial of mCRC receiving FOLFOXIRI and either tocotrienol or placebo as first-line treatment. Blood (1 mL) was sampled into NK Vue tubes at baseline and before treatment cycles 2-3, placed at 37°C for 24 hours, and after incubation, the level of interferon-γ (IFNγ) in the plasma was a surrogate measure for NKA. A cutoff of 250 pg/mL IFNγ distinguished normal and low NKA. The endpoints were response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: A total of 70 patients were enrolled in the randomized clinical trial. The results showed that tocotrienol had no effect on either RR (p = 0.62), PFS (p = 0.52), or OS (p = 0.80). Patients were classified into two groups according to the dynamics of NKA measured at the available time points. Patients that dropped from a normal to a low level of NKA in samples taken between baseline and before cycle 3 and patients with continuous low NKA (IFNγ < 250 pg/mL) were categorized as NKA-low. The NKA-high group included patients that increased from an abnormal to a normal level of NKA and patients that remained within the normal range (IFNγ > 250pg/mL) in all available samples. The RR in the two groups were 38% (8/21) and 69% (24/35), respectively (p = 0.0496). The median PFS was 186 days (95% confidence interval (CI) 136-225 days, n = 23) for the NKA-low group and 252 days (95% CI 223-305 days, n = 37) for NKA-high (p = 0.0005). The hazard ratio (HR) was 2.65 (95% CI 1.28-5.50). After adjusting for age, performance status (PS), and tumor location, NKA remained an independent prognostic factor for PFS (HR = 3.32, 95% CI 1.67-6.61, p = 0.001). Median OS was 408 days (95% CI 219-679 days, n = 23) and 1051 days (95% CI 645-1225 days, n = 37), respectively (p = 0.0034). For OS, the NKA-low group also showed a poor prognosis, HR 2.23 (95% CI 1.17-4.25). NKA dynamics remained an independent prognostic marker for OS after adjusting for age, PS, and tumor location (HR = 2.74, 95% CI 1.50-5.03, p = 0.001). Conclusions: The results suggest that NKA dynamics within the first two cycles of treatment may hold relevant prognostic information in first-line treatment of mCRC. The possible causative relationship between NKA and treatment effect needs further elucidation, but calls for experimental trials combining chemotherapy with NK cell therapy in mCRC.