No abstract

Progestin resistance is a major obstacle to treating early stage, well-differentiated endometrial cancer as well as recurrent endometrial cancer. The mechanism behind the suboptimal response to progestin is not well understood. The PTEN tumor suppressor gene is frequently mutated in type I endometrial cancers and this mutation results in hyperactivation of the PI3K/AKT pathway. We hypothesized that increased activation of AKT promotes an inadequate response to progestins in endometrial cancer cells. Ishikawa cells stably transfected with progesterone receptor B (PRB23 cells) were treated with the AKT inhibitor, MK-2206, which effectively decreased levels of p(Ser473)-AKT in a dose-dependent (10 nM to 1 uM) and time-dependent manner (0.5 h to 24 h). MK-2206 inhibited levels of p(Thr308)-AKT and a downstream target, p(Thr246)-PRAS40, but did not change levels of p(Thr202/Tyr204)ERK or p(Thr13/Tyr185)SAPK/JNK, demonstrating specificity of MK-2206 for AKT. Additionally, MK-2206 treatment of PRB23 cells resulted in a significant increase in levels of progesterone receptor B (PRB) protein. Microarray analysis of PRB23 cells identified PDK4 as the most highly upregulated gene among 70 upregulated genes in response to R5020. Inhibition of AKT further upregulated progestin-mediated expression of PDK4 but did not affect another progestin-responsive gene, SGK1. Treatment of PRB23 cells with R5020 and MK-2206 independently decreased viability of cells while the combination of R5020 and MK-2206 caused the greatest decrease in cell viability. Furthermore, mice with xenografted tumors treated with MK-2206 alone or with progesterone alone exhibited modest reductions in their tumor volume. The largest decrease in tumor size was observed in the mice treated with both MK-2206 and progesterone; these tumors exhibited the least proliferation (Ki67) and the most apoptosis (cleaved caspase-3) of all the treatment groups. In summary, inhibition of AKT stabilizes the Progesterone Receptor B and augments progesterone response in endometrial cancer cells that have hyperactivated AKT.

A 12.5% risk for VTE merits consideration of prophylaxis during chemotherapy in this cohort. A randomized, controlled trial is needed to clarify whether the benefits of long-term prophylaxis outweigh the risks and costs of such therapy.

Background Immune checkpoint inhibitors (ICIs) have modest activity in ovarian cancer (OC). To augment their activity, we used priming with the hypomethylating agent guadecitabine in a phase II study. Methods Eligible patients had platinum-resistant OC, normal organ function, measurable disease, and received up to 5 prior regimens. The treatment included guadecitabine (30 mg/m 2 ) on days 1–4, and pembrolizumab (200 mg i.v.) on day 5, every 21 days. The primary endpoint was the response rate. Tumor biopsies, plasma, and PBMCs were obtained at baseline and after treatment. Results Among 35 evaluable patients, 3 patients had partial responses (8.6%), and 8 (22.9%) patients had stable disease, resulting in a clinical benefit rate of 31.4% (95% CI: 16.9%–49.3%). The median duration of clinical benefit was 6.8 months. Long-interspersed element 1 (LINE1) was hypomethylated in post-treatment PBMCs, and methylomic and transcriptomic analyses showed activation of antitumor immunity in post-treatment biopsies. High-dimensional immune profiling of PBMCs showed a higher frequency of naive and/or central memory CD4 + T cells and of classical monocytes in patients with a durable clinical benefit or response (CBR). A higher baseline density of CD8 + T cells and CD20 + B cells and the presence of tertiary lymphoid structures in tumors were associated with a durable CBR. Conclusion Epigenetic priming using a hypomethylating agent with an ICI was feasible and resulted in a durable clinical benefit associated with immune responses in selected patients with recurrent OC. Trial registration ClinicalTrials.gov NCT02901899. Funding US Army Medical Research and Material Command/Congressionally Directed Medical Research Programs (USAMRMC/CDMRP) grant W81XWH-17-0141; the Diana Princess of Wales Endowed Professorship and LCCTRAC funds from the Robert H. Lurie Comprehensive Cancer Center; Walter S. and Lucienne Driskill Immunotherapy Research funds; Astex Pharmaceuticals; Merck & Co.; National Cancer Institute (NCI), NIH grants CCSG P30 CA060553, CCSG P30 CA060553, and CA060553.

The use of either a 2-0 welded-loop unidirectional barbed suture or a 2-0 monofilament absorbable suture to close the vaginal cuff is safe and well tolerated.

No abstract

6025 Background: Platinum resistant ovarian cancer (PROC) remains a disease of high need. Immune checkpoint inhibitors (ICI) have modest activity. We hypothesized that priming with a hypomethylating agent (HMA) guadecitabine (G) will improve the anti-tumor activity of ICI in PROC by enhancing tumor cell recognition by CD8+ T cells. Methods: This open-label phase II study used a Simon’s two-stage design. Eligible patients (pts) had recurrent PROC; ECOG PS of 0-1; normal end organ function; and measurable disease. Up to 5 prior cytotoxic regimens were allowed. Treatment consisted of G 30mg/m2 sq D1-4 and pembrolizumab (P) 200mg iv D5. Each cycle was 21 days. The primary endpoint was response rate (RR). Secondary endpoints were progression-free survival (PFS), clinical benefit rate (CBR), and toxicity assessment. Translational endpoints were LINE1 methylation in PBMCs, global tumor methylation, and immune endpoints. Tumor biopsies were obtained at baseline and after 2 cycles. If 2 patients experienced clinical benefit in stage I [n = 16], enrollment proceeded to stage II. The null hypothesis was rejected for ≥ 6 responses in 35 evaluable patients. Results: 48 pts were enrolled, 43 were treated, and 33 were evaluable for response. Histology was serous (35), endometrioid (2), clear cell (3) and other (3). Median age was 63 (range 40-88) and median number of prior regimens was 4 [range 1-8]. Two PRs were recorded in the first stage, allowing second stage of enrollment. Overall, there were 2 PRs (RR = 6.6%) and 16 pts had stable disease (SD) [48%]. The clinical benefit rate (PR + SD > 3 months) was 27%. One patient continued treatment for > 2 yrs. Grade 3-4 related toxicities were neutropenia [20], lymphopenia, (9), anemia (2), neutropenic fever (1), rash (1), and others (8). There were 13 grade 3-4 SAEs and 4 grade 5 SAEs, assessed as being unrelated to treatment. LINE1 was hypomethylated in PBMCs D5 vs. D1 (n = 21, p = 0.001). Epic arrays measured global tumor methylation, with 39579 CpG sites (0.05%) being differentially methylated (C2D5 vs. C1D1, n = 11, paired t-test; p < 0.01). Main pathways affected included endosomal transport, K+ transport, cathecolamine secretion, etc. PDL1 staining in archival tissue showed tumor staining > 0 in 16 of 35 and tumor/stroma interface staining > 0 in 20 of 35 specimens. Antigen-specific cytotoxic T cell activity was increased in CD8+ cells from ascites (C2D5 vs. C1D1). Conclusions: G+P has modest anti-tumor activity in patients with PROC, but some patients experienced prolonged disease stabilization. Biomarkers of response are being investigated. Clinical trial information: NCT02901899.

High-grade endometrial cancer often presents with occult metastatic disease and this presentation pattern can be considered a contraindication to minimally invasive surgery. We sought to compare the surgical and oncologic outcomes of patients with high-grade endometrial cancer who underwent surgical management/staging via the robotic approach versus the traditional open approach. A retrospective analysis was performed of patients with high-grade endometrial cancer who were treated at a single institution from January 2008 through December 2011. High-grade endometrial histology was defined as FIGO grade 2 or 3 endometrioid, serous, clear cell or uterine carcinosarcoma. Pre-operatively, all patients had clinical stage I disease based on a combination of physical examination and imaging studies. Baseline patient demographics, operative results, complications and oncologic outcomes were analyzed. Eighty consecutive patients were included. Forty-seven patients underwent surgical management using the robotic approach and 33 patients underwent a traditional operation via laparotomy. The groups were well matched in terms of age, body mass index, medical co-morbidities, stage and histology. The average hospital stay for patients who underwent open surgery was significantly longer than for those who underwent a robotic approach [5.6 versus 1.4 days (p = 0.0001)]. Of the patients who underwent robotic surgery, 7/47 (15 %) experienced an operative complication versus 18/33 (55 %) in the open surgery cohort (p = 0.002). The average number of pelvic lymph nodes retrieved in each cohort was 12. The average number of para-aortic lymph nodes retrieved in each group was 4. On final pathologic analysis, 20 patients in the robotic surgery arm were found to have disease that had spread beyond the uterus (43 %), compared to 14 in the traditional surgery group (42 %). There were 11/47 (23 %) recurrences in the robotic surgery group during the study period, compared to 8/33 (24 %) in the laparotomy group. There were no significant differences in progression-free or overall survival between the two cohorts. Robotic surgery is safer than laparotomy for patients with high-grade endometrial cancer. The oncologic outcomes appear similar. Minimizing morbidity in this patient population is important since many are elderly and will require adjuvant therapy.