Higher Serum IL-8 is associated with Reduced PFS and OS during Systemic Therapy in Metastatic Breast, Pancreatic and Prostate Cancer: A Retrospective Study in Patients from BOLERO-2 Trial, Pancreatic and Prostate Cancer Cohorts

Micro Abstract: This manuscript reports circulating interleukin 8 (IL-8) biomarker from three large patient cohorts. The study evaluated the clinical utility of higher circulating IL-8 to predict reduced clinical outcome in these 3 large patient cohorts. The analysis represented a variety of common solid cancers treated with conventional cancer therapeutics. The analysis demonstrates the potential of circulating IL-8 as a biomarker of reduced outcome to various conventional and to immune checkpoint inhibitor therapies. Circulating IL-8 may therefore be an important companion biomarker to potentially select cancer patients for IL-8-targeted therapy, in combination with conventional and/or immune checkpoint inhibitor therapy. Background: We present results from serum IL-8 and outcomes from a large, randomized phase III clinical trial in metastatic breast cancer (BOLERO-2), and in pancreatic and prostate cancer cohorts. Methods: Retrospective analysis included patient samples from original phase III randomized, double-blinded, multi-center clinical trial of pancreatic cancer, double-blinded, international, phase III randomized clinical trial that included 724 post-menopausal patients who had HR+ and HER2-negative advanced breast cancer and a cohort of patients with metastatic castration-resistant prostate cancer (mCRPC). Results: Higher categorical IL-8 levels (median cutpoint) were significantly prognostic for shorter OS (median OS: 17.5 vs. 39.2 months; HR=2.47) and for shorter PFS (median PFS: 2.9 vs. 6.8 months; HR=1.84) in BOLERO-2. Similarly, pretreatment serum IL-8 levels in the pancreatic cohort were significantly correlated with overall survival (OS) (HR= 1.004; p=0.012). Furthermore, higher IL-8 levels above the optimal cutpoint in prostate cancer (>23rd percentile) had a median OS of only 12.8 months, compared with IL-8 levels below this cut-point with significantly longer OS of 29.9 months (HR=2.09, p<0.0001). Conclusion: in the BOLERO-2 metastatic breast cancer trial, higher pretreatment serum IL-8 levels predicted for reduced response to both exemestane (hormone therapy) and everolimus (mTOR inhibitor). Similarly, higher pretreatment serum IL-8 predicted reduced response to chemotherapy in pancreatic and chemo- or hormonal therapy in prostate cancer cohorts. Since higher circulating IL-8 predicted reduced response to hormonal and conventional therapies in metastatic breast, pancreatic, and prostate cancers, the significance of serum IL-8 should be further evaluated in these patients.