IMPORTANCEPrior studies have shown that only a small proportion of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) experience benefit from programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given as monotherapy.There are data suggesting that activity may be greater with combination strategies. OBJECTIVE To compare the efficacy of eribulin plus pembrolizumab vs eribulin alone in patients with HR-positive, ERBB2 (formerly HER2)-negative MBC.DESIGN, SETTING, AND PARTICIPANTS Multicenter phase 2 randomized clinical trial of patients with HR-positive, ERBB2-negative MBC who had received 2 or more lines of hormonal therapy and 0 to 2 lines of chemotherapy.INTERVENTIONS Patients were randomized 1:1 to eribulin, 1.4 mg/m 2 intravenously, on days 1 and 8 plus pembrolizumab, 200 mg/m 2 intravenously, on day 1 of a 21-day cycle or eribulin alone. At time of progression, patients in the eribulin monotherapy arm could cross over and receive pembrolizumab monotherapy. MAIN OUTCOMES AND MEASURESThe primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and genomic alterations.RESULTS Eighty-eight patients started protocol therapy; the median (range) age was 57 (30-76) years, median (range) number of prior lines of chemotherapy was 1 (0-2), and median (range) number of prior lines of hormonal therapy was 2 (0-5). Median follow-up was 10.5 (95% CI, 0.4-22.8) months. Median PFS and ORR were not different between the 2 groups (PFS, 4.1 vs 4.2 months; hazard ratio, 0.80; 95% CI, 0.50-1.26; P = .33; ORR, 27% vs 34%, respectively; P = .49). Fourteen patients started crossover treatment with pembrolizumab; 1 patient experienced stable disease. All-cause adverse events occurred in all patients (grade Ն3, 65%) including 2 treatment-related deaths in the combination group, both from immune-related colitis in the setting of sepsis, attributed to both drugs. The PD-L1 22C3 assay was performed on archival tumor samples in 65 patients: 24 (37%) had PD-L1-positive tumors. Analysis indicated that PD-L1 status, TILs, TMB, and genomic alterations were not associated with PFS. CONCLUSIONS AND RELEVANCEIn this randomized clinical trial of patients with HR-positive, ERBB2-negative MBC, the addition of pembrolizumab to eribulin did not improve PFS, ORR, or OS compared with eribulin alone in either the intention-to-treat or PD-L1-positive populations. Further efforts to explore the benefits of adding checkpoint inhibition to chemotherapy among less heavily pretreated patients are needed.

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Gastrin is a known growth/differentiation factor for the gastric mucosa. Its effects are likely mediated by the induction of heparin-binding epidermal-like growth factor (HB-EGF), a member of the EGF family of growth factors that is expressed by gastric parietal cells. In this study, we investigated the regulation of the HB-EGF promoter by gastrin in a human gastric cancer cell line. Serial human HB-EGF promoter-luciferase reporter deletion constructs and heterologous promoter constructs were transfected into AGS-E cells and stimulated with gastrin (10(-7) M) with or without various signal transduction inhibitors. EMSA were also performed. Gastrin stimulation resulted in a fivefold increase in HB-EGF-luciferase activity. The cis-acting element mediating gastrin responsiveness was mapped to the -69 to -58 region of the HB-EGF promoter. Gastrin stimulation was PKC dependent and at least partially mediated by activation of the EGF receptor.

Screening mammography is more accurate in older women than in younger women, suggesting that it may be of value in assessing women in all age groups. These data do not address the impact of mammography screening on mortality or breast cancer outcomes.