Background: IL-8 (CXCL8) is a pro-inflammatory cytokine that binds to CXCR1 and CXCR2 receptors and promotes tumor immune escape and progression. High serum IL-8 levels correlate with poor prognosis in many cancers and predict for reduced overall survival (OS) to nivolumab or nivolumab plus ipilimumab in melanoma, lung, and renal cell cancer; and decreased efficacy of atezolizumab in metastatic urothelial and renal-cell cancers. We previously reported the significant prognostic and predictive utility of serum PD-L1 in the CCTG MA.31 breast cancer trial. Here we correlated plasma IL-8 and PD-L1 with OS in metastatic castration-resistant prostate cancer (mCRPC) patients.Methods: 201 chemotherapy-naïve mCRPC patients had EDTA plasma available for retrospective ELLA IL-8 and PD-L1 immunoassay analysis.Findings: The optimal cutpoint for OS was the upper 23rd percentile for both IL-8 and PD-L1. In univariate analysis, higher plasma IL-8 levels were significantly associated with reduced OS at the optimal cutpoint (HR=2.09; p=<.0001; median 12.8 vs 29.9mos). Higher plasma PD-L1 was significant at the optimal cutpoint (HR=1.53; p=0.0162; median 20.5 vs 25.4mos). When plasma IL-8 and PD-L1 levels were combined (at optimal cutpoints), plasma IL-8 high / PD-L1 high patients (n=15) had a significantly shorter OS vs the plasma IL-8 low / PD-L1 low patients (n=123) (HR=4.44; p= <.0001; median 5.8 vs 30.0mos). In multivariable analysis, when adjusted for biopsy Gleason score, age, PSA, ECOG PS and time from initial diagnosis to blood draw, high plasma IL-8 at the optimal cutpoint remained significant (HR=2.07; p=0.0002).Conclusions and Interpretation: In mCRPC patients, high plasma IL-8 and PD-L1 levels were associated with reduced OS (separately and combined). Circulating IL-8 and PD-L1 should be evaluated as biomarkers for selection of patients for immune checkpoint inhibitor and anti-IL-8 therapy.Funding Statement: None.Declaration of Interests: Kim Leitzel: travel funding for SABCS 2018, ASCO 2019: Protein SimpleDr. Joseph Drabick: Outside work: Sanofi (not related to manuscript).Howard Spiegel: Full-time employee of Protein Simple.Ethics Approval Statement: The institutional review boards of the Dana‐Farber Cancer Institute (DFCI) and Penn State Hershey Medical Center approved this study. All patients provided written informed consent to allow analysis of clinical data for research purposes through participation in a serum banking protocol and had data collected in the DFCI Prostate Cancer Clinical Research Information System.

Abstract Background: B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor family and has two ligands, B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). These ligands activate cell proliferation and inhibit apoptosis of normal and malignant B-cells including in multiple myeloma (MM) cell lines. Berenson et al have recently reported that circulating BCMA levels are elevated in B-cell malignancies and can be used to monitor disease and predict PFS and OS for patients with MM, Waldenstroms's macroglobulinemia and chronic lymphocytic leukemia (CLL). On the other hand, recent studies have shown that serum BCMA levels are very low among patients with MM in complete remission with low antibody levels and those with primary immune deficiencies specifically those with combined variable immune deficiency and X-linked agammaglobulinemia. Studies of the potential role of serum BCMA for patients with solid tumors has not been evaluated to date. Methods: The pretreatment serum from 139 patients with hormone receptor-positive metastatic breast cancer who were enrolled in a phase 3 randomized clinical trial of second-line hormone therapy was evaluated using an ELISA for BCMA. The BCMA ELISA was from R&D Systems (Minneapolis, MN). Serum BCMA was correlated with TTP using categorical serum BCMA cutpoints. Results: Pretreatment serum BCMA levels had a median of 55.61 ng/ml, an interquartile range of 34.20 and 78.79 ng/ml, and full range from 3.99 to 1193.26 ng/ml. In univariate analysis for TTP, reduced serum BCMA correlated with shorter TTP at the following dichotomous cutpoints: 15 ng/ml [HR=2.60, p=0.064, n=6 (4.3%) of patients below cutpoint]; 20 ng/ml [HR=2.88, p=0.005, n=10 (7.2%) of patients below cutpoint]; 25 ng/ml [HR=2.16, p=0.023, n=13 (9.4%) of patients below cutpoint]; and 30 ng/ml [HR=1.77, p=0.016, n=27 (19.4%) of patients below the cutpoint]. Conclusions: In a phase 3 randomized clinical trial of second-line hormone therapy among patients with hormone receptor-positive metastatic breast cancer, reduced pretreatment serum BCMA was associated with shorter TTP. This may be due to the association of reduced serum BCMA with immune deficiency; and, thus, lead to shorter TTP among patients with metastatic breast cancer. Evaluation of serum BCMA as a new biomarker to predict outcomes for breast cancer and other solid tumor patients deserves further study. Citation Format: Ali SM, Leitzel K, Li M, Udd K, Wang J, Sanchez E, Chen H, Berenson J, Lipton A. Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-10.

Background: B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor family and has two ligands, B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). These ligands activate cell proliferation and inhibit apoptosis of normal and malignant B-cells including in multiple myeloma (MM) cell lines. Berenson et al have recently reported that circulating BCMA levels are elevated in B-cell malignancies and can be used to monitor disease and predict PFS and OS for patients with MM, Waldenstroms9s macroglobulinemia and chronic lymphocytic leukemia (CLL). On the other hand, recent studies have shown that serum BCMA levels are very low among patients with MM in complete remission with low antibody levels and those with primary immune deficiencies specifically those with combined variable immune deficiency and X-linked agammaglobulinemia. Studies of the potential role of serum BCMA for patients with solid tumors has not been evaluated to date. Methods: The pretreatment serum from 139 patients with hormone receptor-positive metastatic breast cancer who were enrolled in a phase 3 randomized clinical trial of second-line hormone therapy was evaluated using an ELISA for BCMA. The BCMA ELISA was from RD 20 ng/ml [HR=2.88, p=0.005, n=10 (7.2%) of patients below cutpoint]; 25 ng/ml [HR=2.16, p=0.023, n=13 (9.4%) of patients below cutpoint]; and 30 ng/ml [HR=1.77, p=0.016, n=27 (19.4%) of patients below the cutpoint]. Conclusions: In a phase 3 randomized clinical trial of second-line hormone therapy among patients with hormone receptor-positive metastatic breast cancer, reduced pretreatment serum BCMA was associated with shorter TTP. This may be due to the association of reduced serum BCMA with immune deficiency; and, thus, lead to shorter TTP among patients with metastatic breast cancer. Evaluation of serum BCMA as a new biomarker to predict outcomes for breast cancer and other solid tumor patients deserves further study. Citation Format: Ali SM, Leitzel K, Li M, Udd K, Wang J, Sanchez E, Chen H, Berenson J, Lipton A. Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2 nd -line hormone therapy trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-10.

Abstract Background: Intravenous (IV) bisphosphonates (BP) are currently used to treat bone metastases and prevent skeletal-related events (SRE) in patients with advanced breast cancer. In a phase 3 study, denosumab, a fully human monoclonal antibody against RANKL, was shown to be superior to zoledronic acid (ZA) in delaying or preventing SREs in patients with breast cancer and bone metastases. This prespecified analysis compares ZA and denosumab for the incidence of acute-phase reactions (flu-like syndrome including pyrexia, chills, flushing, bone pain, arthralgias, and myalgias) during the first 3 days after initial treatment in that study. Methods: Eligible patients were randomized in a double-blind, double-dummy fashion to receive IV ZA 4 mg (adjusted for creatinine clearance as specified by the Zometa label) or subcutaneous denosumab 120 mg every 4 weeks. Most patients (99%) were women; mean (SD) age was 57 (12) years, and baseline characteristics were balanced between groups. Safety analyses were conducted in patients who received ≥1 dose of denosumab (N=1020) or ZA (N=1013). Patient records were searched for adverse events (AEs) and serious AEs that occurred during the first 3 days after the first administration of study drug, using 37 prespecified MedDRA 12.0 preferred terms potentially indicating acute-phase reactions. Per study protocol, AEs were considered serious if they were fatal, life-threatening, required or prolonged in-patient hospitalization, resulted in a persistent or significant disability, or were considered to present a significant medical hazard. Results: AEs associated with acute-phase reactions in the first 3 days after treatment occurred in fewer patients in the denosumab group (10.4%) than in the ZA group (27.3%; P<0.0001), and no events were attributed to denosumab. The most common acute-phase reaction AEs included pyrexia (0.9% denosumab, 11.5% ZA), fatigue (2.4% denosumab, 4.0% ZA), bone pain (1.3% denosumab, 3.6% ZA), chills (0.3% denosumab, 3.6% ZA), and arthralgia (1.5% denosumab, 3.2% ZA). No patients (0%) in the denosumab group and 10 patients (1%) in the ZA group reported serious AEs associated with acute-phase reactions during the first 3 days. These events included pyrexia (n=7); bone pain (n=2); and asthenia, back pain, chest pain, chills, headache, and malaise (n=1 each). For 6 of the 10 patients, events of pyrexia, chest pain, chills, and bone pain were resolved within 4 days. Three patients with serious acute-phase reaction AEs discontinued ZA treatment after the first dose. Conclusion: Patients treated with denosumab experienced no serious AEs of acute-phase reaction and significantly fewer overall AEs of acute-phase reaction than patients receiving ZA. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-09.

667 Background: One of the first steps in metastasis is the ability of primary breast cancer cells to detach and invade the circulation. The presence of ≥5 circulating tumor cells (CTCs) in 7.5 mL blood from metastatic breast cancer patients predicts shorter progression-free and overall survival (M Christofanilli et al NEJM 351:781–791, 2004). The purpose of our study was to determine if CTCs were present in the blood of patients who had recently completed adjuvant chemotherapy. Methods: Blood was obtained from 33 breast cancer patients within 12 months after completing adjuvant chemotherapy. No patient had evidence of metastatic cancer on imaging. CTCs were immunomagnetically separated and fluorescently stained with the CellSearch Kit. Cells were classified using the CellSpotter Analyzer as CTCs if they stained positive for DAPI (nuclear dye), and cytokeratin 8, 18 and/or 19, and if they stained negative for the leukocyte-specific antibody CD45. Results: In a control group of 145 healthy females, 8 (5.5%) had 1 CTC/7.5 mL blood. In 199 patients with benign disease, 14 (7.0%) had 1 CTC/7.5 mL, and only 1 (0.5%) had 3 CTCs/7.5 mL detected in their blood. Of the 33 total patients in this study, 3 patients (9.1%) had ≥1 CTC/7.5 mL detected in their blood samples (one patient had 1 CTC in one 7.5 mL tube, and another patient had 2 CTCs in one 7.5 mL tube. The second 7.5 mL tube from both of these patients had no CTCs. The third patient had 1 CTC in three of the four 7.5 mL tubes tested). In the other 30 patients, no CTCs were detected (0/4 tubes in 16 patients; 0/2 tubes in 14 patients). In summary, CTCs were detected in 3/33 (9.1%) adjuvant breast cancer patients, 8/145 (5.5%) healthy controls, and 15/199 (7.5%) benign disease patients. There were no significant differences in the proportion of CTCs between these groups (p≥0.30, Fisher’s exact test). Of 6 patients with 3+ IHC for HER-2/neu in the primary tumor, 2 (33%) had CTCs in their blood. Conclusions: No significant difference in the proportion of CTCs detected was observed between breast cancer patients who recently completed adjuvant chemotherapy and the control groups. Patient accrual and follow-up in this study continues to determine if the presence of elevated CTCs is associated with early recurrence of the disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Immunicon