Background Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy. Methods We performed a randomized phase II trial of intravenous temsirolimus 25 mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20 mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma. Results There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT)and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded. Conclusions Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy. These findings will have implications for future trial design.

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The primary gynecologic cancers include cancers of the endometrium, ovary, and cervix. Worldwide, cervical cancer is the most common gynecologic cancer, whereas endometrial cancer is the most common in the US. Ovarian cancer is the fifth most deadly cancer in women, with 5-year survival rates for advanced disease at only 27%. As such, there is an urgent need for reliable screening tools and novel targeted therapeutic regimens for these malignancies. The EGFR/HER family of receptors has been associated with the development and progression of many solid tumors. Despite clear roles for these receptors in other cancers, the expression of HER family members in gynecologic cancers and their relationship with disease stage, grade, and response to treatment remain controversial. In this review, we describe the existing evidence for the use of HER family members as diagnostic and prognostic indicators as well as their potential as therapeutic targets in gynecologic cancers.

The epigenome offers an additional facet of cancer that can help categorize patients into those at risk of disease, recurrence, or treatment failure. We conducted a retrospective, nested, case-control study of advanced and recurrent high-grade serous ovarian cancer (HGSOC) patients in which we assessed epigenome-wide association using Illumina methylationEPIC arrays to characterize DNA methylation status and RNAseq to evaluate gene expression. Comparing HGSOC tumors with normal fallopian tube tissues we observe global hypomethylation but with skewing towards hypermethylation when interrogating gene promoters. In total, 5,852 gene interrogating probes revealed significantly different methylation. Within HGSOC, 57 probes highlighting 17 genes displayed significant differential DNA methylation between primary and recurrent disease. Between optimal vs suboptimal surgical outcomes 99 probes displayed significantly different methylation but only 29 genes showed an inverse correlation between methylation status and gene expression. Overall, differentially methylated genes point to several pathways including RAS as well as hippo signaling in normal vs primary HGSOC; valine, leucine, and isoleucine degradation and endocytosis in primary vs recurrent HGSOC; and pathways containing immune driver genes in optimal vs suboptimal surgical outcomes. Thus, differential DNA methylation identified numerous genes that could serve as potential biomarkers and/or therapeutic targets in HGSOC.

Progesterone, acting through its receptor, PR (progesterone receptor), is the natural inhibitor of uterine endometrial carcinogenesis by inducing differentiation. PR is downregulated in more advanced cases of endometrial cancer, thereby limiting the effectiveness of hormonal therapy. Our objective was to understand and reverse the mechanisms underlying loss of PR expression in order to improve therapeutic outcomes. Using endometrial cancer cell lines and data from The Cancer Genome Atlas, our findings demonstrate that PR expression is downregulated at four distinct levels. In well-differentiated cancers, ligand-induced receptor activation and downregulation are intact. miRNAs mediate fine tuning of PR levels. As differentiation is lost, PR silencing is primarily at the epigenetic level. Initially, recruitment of the polycomb repressor complex 2 to the PR promoter suppresses transcription. Subsequently, DNA methylation prevents PR expression. Appropriate epigenetic modulators reverse these mechanisms. These data provide a rationale for combining epigenetic modulators with progestins as a therapeutic strategy for endometrial cancer.Significance: Traditional hormonal therapy for women with endometrial cancer can be molecularly enhanced by combining progestins with epigenetic modulators, thereby increasing progesterone receptor expression and significantly improving treatment efficacy.