Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status

INTRODUCTION: To evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse. METHODS: The medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR. RESULTS: The incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007–0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51–101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97–12.84; P = 0.001) were independent predictive factors for CNS relapse. CONCLUSION: CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs

Lactational coumestrol exposure increases ovarian apoptosis in adult rats

This study is the first to examine the increased apoptosis in the adult rat ovary after lactational exposure to coumestrol (COU), a potent phytoestrogen. Lactating dams were gavaged at doses of 0.01, 0.1, 1, and 10 mg/kg COU during the lactation period and the reproductive effects of female pups were investigated in young adults. Rats were sacrificed at postnatal days (PND) 81–84. Ovarian weights were reduced significantly at 0.1 and 1.0 mg/kg COU. The reduction in the ovarian weight occurred in parallel with an increase in the apoptosis at PND 135–140. A marked dose-dependent increase in the expressions of active caspase-3 and -7 was observed in ovarian granulosa cells. Immunostaining for active caspase-3 and the TUNEL staining of apoptotic cells were also increased in ovaries exposed to COU in a dose-dependent manner. These results suggest new sights into the effect of lactational exposure to COU on the female reproductive health

1020O A phase I, first-in-human, open-label, dose escalation study of MGD019, an investigational bispecific PD-1 x CTLA-4 DART® molecule in patients with advanced solid tumours

Background MGD019 is a bispecific, Fc-bearing (IgG4) DART molecule that blocks PD-1 and CTLA-4, with increased activity on dual PD-1/CTLA-4-expressing cells. MGD019 enhances in vitro T-cell responses to levels achieved by a combination of nivolumab and ipilimumab replicas. MGD019 was well tolerated in cynomolgus monkeys, with biological evidence of CTLA-4 antagonism but a safety profile similar to PD-1 blockade alone. MGD019 may offer risk/benefit improvements vs PD-1 plus CTLA-4 combinations. Methods This study characterizes safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and preliminary antitumor activity of MGD019 in patients (pts) with advanced solid tumors. Dose Escalation enrolled pts in a 3+3+3 design up to 10 mg/kg. Cohort Expansion will further characterize safety and antitumor activity per RECIST v1.1 in pts treated at the MTD/MAD. Results At data-cutoff, 33 pts (39% checkpoint-experienced, 3 median prior lines of therapy) were treated in Dose Escalation from 0.03 to 10 mg/kg. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 26/33 (78.8%) pts, most commonly fatigue (24%), nausea, arthralgia, pruritus, and rash (18% each). The rate of Grade ≥ 3 TRAEs was 24.2%. Immune-related SAEs included enteritis, enterocolitis, pneumonitis, and myocarditis (n=1 each). Half-life was 12 days; full on-target binding to circulating T cells sustained through trough was observed at doses ≥ 3.0 mg every 3 weeks. Among 25 response-evaluable pts, 4 objective responses were observed (microsatellite stable colorectal cancer, metastatic thymoma [both confirmed PRs], anti-PD-L1-refractory serous fallopian tube carcinoma [unconfirmed PR with \u3e50% reduction of CA-125], and prostatic adenocarcinoma [confirmed CR with resolution of PSA]); 9 pts had stable disease. Dose-dependent ICOS upregulation on circulating CD4+ T cells was evident, consistent with CTLA-4 engagement. Potential correlative biomarkers are being investigated. Conclusions MGD019 has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Clinical trial identification NCT03761017