Retrospective Analysis of Bevacizumab in Combination with Fotemustine in Chinese Patients with Recurrent Glioblastoma Multiforme

The aim of this study was to assess the activity and safety of bevacizumab (BEV) and fotemustine (FTM) for the treatment of recurrent glioblastoma multiforme (GBM) patients and explore the potential prognostic parameters on survival. This study retrospectively analyzed all patients with GBM who were treated with at least one cycle of BEV and FTM from July 2010 to October 2012. A total of 176 patients with recurrent GBM were enrolled. The response rate and disease control rate were 46.6% and 90.9%, respectively. A 6-month PFS rate of 33.3% (95% CI: 26.5%–40.3%) and a median PFS of 5.0 (95% CI: 2.4–7.5) months were observed. The median OS was 8.0 (95% CI: 6.7–9.2) months. Multivariate analysis showed that risk factors with a significant influence on the PFS of all patients were Karnofsky Performance Status (KPS) (≥70 versus <70, HR=0.53, 95% CI: 0.39–0.73, and P=0.01) and MGMT status (methylated versus unmethylated, HR=0.69, 95% CI: 0.52–0.97, and P=0.04). The most common treatment-related adverse events were fatigue, proteinuria, hypophonia, hypertension, thrombocytopenia, anemia, and neutropenia. In conclusion, combination of BEV with FTM is well tolerated and may derive some clinical benefits in recurrent GBM patients. Higher KPS and MGMT promoter hypermethylation were suggested to be associated with prolonged survival

Progesterone Receptor Attenuates STAT1-Mediated IFN Signaling in Breast Cancer.

Why some tumors remain indolent and others progress to clinical relevance remains a major unanswered question in cancer biology. IFN signaling in nascent tumors, mediated by STAT1, is a critical step through which the surveilling immune system can recognize and destroy developing tumors. In this study, we have identified an interaction between the progesterone receptor (PR) and STAT1 in breast cancer cells. This interaction inhibited efficient IFN-induced STAT1 phosphorylation, as we observed a decrease in phospho-STAT1 in response to IFN treatment in PR-positive breast cancer cell lines. This phenotype was further potentiated in the presence of PR ligand. In human breast cancer samples, PR-positive tumors exhibited lower levels of phospho-STAT1 as compared with their PR-negative counterparts, indicating that this phenotype translates to human tumors. Breast cancer cells lacking PR exhibited higher levels of IFN-stimulated gene (ISG) RNA, the transcriptional end point of IFN activation, indicating that unliganded PR alone could decrease transcription of ISGs. Moreover, the absence of PR led to increased recruitment of STAT1, STAT2, and IRF9 (key transcription factors necessary for ISG transcription) to ISG promoters. These data indicate that PR, both in the presence and absence of ligand, attenuates IFN-induced STAT1 signaling, culminating in significantly abrogated activation of genes transcribed in response to IFNs. PR-positive tumors may use downregulation of STAT1-mediated IFN signaling to escape immune surveillance, leading to the development of clinically relevant tumors. Selective immune evasion of PR-positive tumors may be one explanation as to why over 65% of breast cancers are PR positive at the time of diagnosis.This work was supported by the National Cancer Institute (NCI) R00CA166643 (to C.R.H.), Department of Defense Breast Cancer Research Program W81XWH-16-1-0320 (to C.R.H.), Susan G. Komen Foundation CCR16376147 (to C.R.H.), V Foundation V2015-025 (to C.R.H.), National Institutes of Health R01GM114142 (to V.X.J.), U54CA217297 (to V.X.J.), and 1S10OD021805-01 (to Z.L.), the Owens Foundation (to V.X.J.), and NCI Cancer Center Support Grant P30 CA168524 (to C.R.H.)