Extracellular Vesicles and Ovarian Cancer

Extracellular vesicles (EVs) are a varied group of cell-derived, microscopic, fluid-filled pouches released from cells into neighboring microenvironments that are quickly gaining recognition as a potentially powerful tool against epithelial ovarian cancer (EOC). Recent studies show that not only do EVs play an integral part in the development of cancer through intercellular communication, cell survival, and immune modulation but also may assist with early diagnosis and improved treatments. EOC currently has few effective screening options for early detection of this disease; and, therefore, it is detected at an advanced stage where it is more likely to recur, develop chemoresistance, and ultimately become fatal. Newer research has evaluated EVs as biomarkers for early screening and diagnosis and as novel targets for treatment of EOC. Moreover, EVs are possible targets for novel immunomodulatory therapies to directly target cancer cells or make cancer cells more susceptible to other treatment modalities. Therefore, EVs present an exciting, promising approach which may improve clinical outcome for EOC patients

The Effects of Natural Epigenetic Therapies in 3D Ovarian Cancer and Patient-Derived Tumor Explants: New Avenues in Regulating the Cancer Secretome.

High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes

The Effects of Natural Epigenetic Therapies in 3D Ovarian Cancer and Patient-Derived Tumor Explants: New Avenues in Regulating the Cancer Secretome

High mortality rates in ovarian cancer have been linked to recurrence, metastasis, and chemoresistant disease, which are known to involve not only genetic changes but also epigenetic aberrations. In ovarian cancer, adipose-derived stem cells from the omentum (O-ASCs) play a crucial role in supporting the tumor and its tumorigenic microenvironment, further propagating epigenetic abnormalities and dissemination of the disease. Epigallocatechin gallate (EGCG), a DNA methyltransferase inhibitor derived from green tea, and Indole-3-carbinol (I3C), a histone deacetylase inhibitor from cruciferous vegetables, carry promising effects in reprograming aberrant epigenetic modifications in cancer. Therefore, we demonstrate the action of these diet-derived compounds in suppressing the growth of 3D ovarian cancer spheroids or organoids as well as post-treatment cancer recovery through proliferation, migration, invasion, and colony formation assays when compared to the synthetic epigenetic compound Panobinostat with or without standard chemotherapy. Finally, given the regulatory role of the secretome in growth, metastasis, chemoresistance, and relapse of disease, we demonstrate that natural epigenetic compounds can regulate the secretion of protumorigenic growth factors, cytokines, extracellular matrix components, and immunoregulatory markers in human ovarian cancer specimens. While further studies are needed, our results suggest that these treatments could be considered in the future as adjuncts to standard chemotherapy, improving efficiency and patient outcomes

Disease Extent at Secondary Cytoreductive Surgery is Predictive of Progression-free and Overall Survival in Advanced Stage Ovarian Cancer: an NRG Oncology/Gynecologic Oncology Group study

Purpose GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule >1 cm in greatest diameter) following primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). Methods Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3 cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N= 40 (19.9%), no gross disease/microscopically positive N= 8 (4.0%), and gross disease N=153 (76.1%). Results The median PFS for patients with no gross disease/microscopically negative was 16.1 months, no gross disease/microscopically positive was 13.5 months and for gross disease was 11.7 months, p=0.002. The median OS for patients with no gross disease/microscopically negative was 51.5 months, no gross disease/microscopically positive was 42.6 months and for gross disease was 34.9 months, p=0.018. Conclusion Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS

Outcomes of the “BRCA Quality Improvement Dissemination Program”: An Initiative to Improve Patient Receipt of Cancer Genetics Services at Five Health Systems

OBJECTIVE: A quality improvement initiative (QII) was conducted with five community-based health systems\u27 oncology care centers (sites A-E). The QII aimed to increase referrals, genetic counseling (GC), and germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC). METHODS: QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher\u27s exact test, and logistic regression. RESULTS: For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes. CONCLUSION: A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Pleural metastases exhibiting high-grade endometrial stromal sarcoma with both rearrangement of the YWHAE gene and BCORL1 alteration

Endometrial stromal sarcoma (ESS) is a rare malignant neoplasm of endometrial stroma. High-grade ESS (HGESS) is aggressive and commonly relapses after surgical and neoadjuvant therapy. The abdomen and pelvis are common sites of metastasis, however, distant metastases to the liver, lung, vertebrae, and brain have been reported. We encountered a 49-year-old female who presented with shortness of breath and was subsequently found to have a left pleural effusion and multiple pleural masses. Hysterectomy and bilateral salpingo-oophorectomy performed three years ago revealed an intramural 7 cm uterine mass with a serpiginous growth pattern and lymphovascular invasion. The tumor cells, plump to spindled in morphology, were positive for cyclin D1, focally positive for CD10, and negative for desmin, AE1/AE3, and CAM5.2. FISH studies showed rearrangement of the YWHAE gene (17p13.3) and molecular assay revealed BCORL1 alteration C1065 (3195C > A). The findings supported the diagnosis of HGESS for which the patient underwent post-operative chemotherapy. Biopsy of the current pleural lesion revealed a nonspecific malignant spindle cell neoplasm with a nonspecific immunohistochemical phenotype. However, FISH studies further revealed rearrangement of the YWHAE gene (17p13.3). The findings support the diagnosis of metastatic HGESS. HGESS, a rare tumor with a nonspecific immunostain profile, can metastasize to unusual body sites including the pleura, as in our case. To our knowledge, this is the first case of HGESS with both the YWHAE gene rearrangement and  BCORL1 alteration presenting in the setting of pleural effusion and pleural metastases. Tumor cells displaying spindle cell morphology, a nonspecific finding, raise broad differential diagnoses, including HGESS, an important consideration to keep in mind for women with or without a history of uterine neoplasm

A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study

OBJECTIVES: Docetaxel is an inhibitor of microtubule depolymerization and has demonstrated activity in paclitaxel-resistant breast cancer and gynecologic cancer. The Gynecologic Oncology Group (GOG) conducted a study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma to determine its activity, and nature and degree of toxicity, in this cohort of patients. METHODS: Patients with platinum- and paclitaxel-resistant ovarian or peritoneal carcinoma, defined as progression while on or within 6 months of therapy, were eligible if they had measurable disease and had not received more than one chemotherapy regimen. Docetaxel at a dose of 100 mg/m(2) was administered iv over 1 h every 21 days. A prophylactic regimen of oral dexamethasone 8 mg bid was begun 24 h before docetaxel administration and continued for 48 h thereafter. Hepatic function was strictly monitored. RESULTS: Sixty patients were entered and treated with a total of 256 courses, with all 60 evaluable for toxicity and 58 evaluable for response. Responses were observed in 22.4% of patients, with 5.2% achieving complete response and 17.2% achieving partial response (95% CI, 12.5-35.3%). The median duration of response was 2.5 months. The likelihood of observing a response did not appear to be related to the length of the prior paclitaxel-free interval or duration of prior paclitaxel infusions. The principal adverse effect of grade 4 neutropenia occurred in 75% of patients. There was one treatment-related death. Dose reductions were required in 36% of patients. CONCLUSIONS: Docetaxel is active in paclitaxel-resistant ovarian and peritoneal cancer but, in view of significant hematologic toxicity, further study is warranted to ascertain its optimal dose and schedule

Epigenetic Therapy Augments Classic Chemotherapy in Suppressing the Growth of 3D High-Grade Serous Ovarian Cancer Spheroids over an Extended Period of Time

Recurrent high-grade serous ovarian cancer (HGSC) is clinically very challenging and prematurely shortens patients&rsquo; lives. Recurrent ovarian cancer is characterized by high tumor heterogeneity; therefore, it is susceptible to epigenetic therapy in classic 2D tissue culture and rodent models. Unfortunately, this success has not translated well into clinical trials. Utilizing a 3D spheroid model over a period of weeks, we were able to compare the efficacy of classic chemotherapy and epigenetic therapy on recurrent ovarian cancer cells. Unexpectedly, in our model, a single dose of paclitaxel alone caused the exponential growth of recurrent high-grade serous epithelial ovarian cancer over a period of weeks. In contrast, this effect is not only opposite under treatment with panobinostat, but panobinostat reverses the repopulation of cancer cells following paclitaxel treatment. In our model, we also demonstrate differences in the drug-treatment sensitivity of classic chemotherapy and epigenetic therapy. Moreover, 3D-derived ovarian cancer cells demonstrate induced proliferation, migration, invasion, cancer colony formation and chemoresistance properties after just a single exposure to classic chemotherapy. To the best of our knowledge, this is the first evidence demonstrating a critical contrast between short and prolonged post-treatment outcomes following classic chemotherapy and epigenetic therapy in recurrent high-grade serous ovarian cancer in 3D culture