Guidelines for goals of care discussions in patients with gynecologic cancer.

This article represents a distillation of literature to provide guidance for goals of care discussions with patients who have gynecologic malignancies. As clinicians who provide surgical care, chemotherapy, and targeted therapeutics, gynecologic oncology clinicians are uniquely positioned to form longitudinal relationships with patients that can enable patient-centered decision making. In this review, we describe optimal timing, components, and best practices for goals of care discussions in gynecologic oncology.

Association of Genomic Instability Score, Tumor Mutational Burden, and Tumor-Infiltrating Lymphocytes as Biomarkers in Uterine Serous Carcinoma.

Background: Uterine serous carcinomas represent 10% of uterine carcinomas but account for nearly 40% of deaths from the disease. Improved molecular characterization of these tumors is instrumental in guiding targeted treatment and improving outcomes. This study assessed the genomic instability score (GIS), tumor mutational burden (TMB), and tumor-infiltrating lymphocytes (TILs) in patients with USC. Methods: A retrospective cohort study evaluated patients with USC following staging surgery. The GIS and TMB were determined from archived specimens. We evaluated the tumoral expression of CD3, CD4, CD8, FOXP3, and CD68 using immunohistochemistry. T-tests were used to assess associations of TILs with the GIS. Results: We evaluated 53 patients with USC. The median GIS was 31 (range: 0−52) and a higher GIS was not associated with progression-free (PFS) or overall survival (OS). The median TMB was 1.35 mt/Mb; patients with TMB > 1.35 mt/Mb had improved PFS and OS (p = 0.005; p = 0.002, respectively). Tumors with increased CD3+ and CD4+ immune cells had a higher mean GIS (p = 0.013, p = 0.002). Conclusions: TMB > 1.35 mt/Mb was associated with improved survival in USC patients, whereas the GIS was not. Lower TMB thresholds may provide prognostic value for less immunogenic tumors such as USC. In this limited cohort, we observed that increased TIL populations were correlated with a higher GIS.

Cost-effectiveness of management strategies for patients with recurrent ovarian cancer and inoperable malignant bowel obstruction.

OBJECTIVES: Patients with recurrent platinum-resistant ovarian cancer often present with inoperable malignant bowel obstruction (MBO) from a large burden of abdominal disease. Interventions such as total parenteral nutrition (TPN) and chemotherapy may be used in this setting. We aim to describe the relative cost-effectiveness of these interventions to inform clinical decision making. METHODS: Four strategies for management of platinum-resistant recurrent ovarian cancer with inoperable MBO were compared from a societal perspective using a Monte Carlo simulation: (1) hospice, (2) TPN, (3) chemotherapy, and (4) TPN + chemotherapy. Survival, hospitalization rates, end-of-life (EOL) setting, and MBO-related utilities were obtained from literature review: hospice (survival 38 days, 6% hospitalization), chemotherapy (42 days, 29%), TPN (55 days, 25%), TPN + chemotherapy (74 days, 47%). Outcomes were the average cost per strategy and incremental cost-effectiveness ratios (ICERs) in US dollars per quality-adjusted life year (QALY) gained. RESULTS: In the base case scenario, TPN + chemotherapy was the most costly strategy (mean; 95% CI) ($49,741; $49,329-$50,162) and provided the highest QALYs (0.089; 0.089-0.090). The lowest cost strategy was hospice ($14,591; $14,527-$14,654). The TPN alone and chemotherapy alone strategies were dominated by a combination of hospice and TPN + chemotherapy. The ICER of TPN + chemotherapy was $918,538/QALY compared to hospice. With a societal willingness to pay threshold of $150,000/QALY, hospice was the strategy of choice in 71.6% of cases, chemotherapy alone in 28.4%, and TPN-containing strategies in 0%. CONCLUSIONS: TPN with or without chemotherapy is not cost-effective in management of inoperable malignant bowel obstruction and platinum-resistant ovarian cancer.

Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer.

Despite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes in patients with ovarian cancer. Progress in this regard has been hindered by the lack of relevant syngeneic ovarian cancer models to study tumor immunity and evaluate immunotherapies. To address this problem, we developed a luciferase labeled murine model of high-grade serous ovarian cancer, STOSE.M1 luc. We defined its growth characteristics, immune cell repertoire, and response to anti PD-L1 immunotherapy. As with human ovarian cancer, we demonstrated that this model is poorly sensitive to immune checkpoint modulators. By developing the STOSE.M1 luc model, it will be possible to probe the mechanisms underlying resistance to immunotherapies and evaluate new therapeutic approaches to treat ovarian cancer.

Novel Therapies in Gynecologic Cancer.

During the past decade, considerable strides have been made in the understanding and treatment of gynecologic cancers. The advent of PARP inhibitors, antiangiogenic therapies, immunotherapy combinations, and targeted agents have altered the standard of care in ovarian, endometrial, and cervical cancers. However, continued advancement in the treatment of gynecologic cancers is critical. Fortunately, exciting work defining new therapeutic targets and novel treatment strategies is on the horizon. Here, we discuss emerging treatments for gynecologic cancers, including endometrial, cervical, ovarian, and rare gynecologic cancers. We highlight research that has deepened our understanding of the unique biology and molecular underpinnings of these cancers and is being translated into powerful new treatment approaches. We particularly highlight the advent of immunotherapy in endometrial cancer; radiosensitizers in cervical, vaginal, and vulvar cancers; targeted therapies in ovarian cancer; and molecularly driven approaches to treat rare gynecologic cancers. Continued basic, translational, and clinical research holds the promise to change the landscape of gynecologic cancer and improve the lives of all women impacted by these diseases.

Primary treatment of advanced ovarian cancer: how does the 'real world' practice?

Aims: This study evaluated primary treatment modalities in advanced ovarian cancer according to sociodemographic characteristics and characterized chemotherapy regimens used. Methods: This was a retrospective study of newly diagnosed advanced ovarian, tubal or peritoneal cancer patients at two hospitals from 2011 to 2016. Results: Of 175 women, 41% received neoadjuvant chemotherapy and 59% received primary cytoreductive surgery. Within the neoadjuvant chemotherapy group, 23% did not have a surgical consultation prior to initiating treatment. Women receiving neoadjuvant chemotherapy lived closer to an academic center and more frequently received carboplatin/paclitaxel every 3 weeks. Cytoreductive surgery patients more frequently received intraperitoneal chemotherapy. Conclusion: The authors identified disparities in age, insurance, distance from treatment center and chemotherapy choice in the primary treatment for ovarian cancer.

Lay abstract Aims: This study evaluated surgery versus chemotherapy in stage III or IV ovarian cancer and whether differences exist between different groups of patients. Methods: This study looked at newly diagnosed stage III/IV ovarian, tubal or peritoneal cancer patients at two hospitals from 2011 to 2016. Results: Of 175 women, 41% received neoadjuvant chemotherapy and 59% received primary cytoreductive surgery. Within the neoadjuvant chemotherapy group, 23% did not see a gynecologic oncologist prior to initiating treatment. Women receiving neoadjuvant chemotherapy lived closer to an academic center and more frequently received carboplatin/paclitaxel every 3 weeks. Cytoreductive surgery patients more frequently received intraperitoneal chemotherapy. Conclusion: The authors identified differences in age, insurance, distance from treatment center and chemotherapy choice in the treatment for ovarian cancer.

PET-detected asymptomatic recurrence is associated with improved survival in recurrent cervical cancer.

PURPOSE: We aimed to examine utilization patterns of positron emission tomography scans (PET or PET/CT) beyond 6 months after cervical cancer treatment. We investigated survival outcomes of asymptomatic patients with PET-detected recurrence. METHODS: We performed a retrospective review of 283 patients with stage IA-IVA cervical cancer treated with primary chemoradiation. The 107 patients (37.8%) with recurrence were categorized as "asymptomatic PET-detected recurrence" (n = 23) or "standard detection" (n = 84) and we compared clinical characteristics and outcomes using multivariate logistic regression analysis. RESULTS: Late post-treatment PET (≥ 6 months after treatment) was performed in 35.3% (n = 100). Indications for late post-treatment PET included restaging in setting of known recurrence (23.6%), follow up of prior ambiguous imaging findings (9.7%), and new symptoms or exam findings (6.7%). However, late post-treatment PET was most commonly performed outside of current imaging guidelines, in asymptomatic patients without suspicion for recurrence (60.0%), presumably for surveillance. The median time to recurrence was 12.1 months (IQR 7.3-26.6). 23 patients (21.5%) had recurrence detected late post-treatment PET while asymptomatic (n = 23/107). Patients with asymptomatic PET-detected recurrence had improved survival by 26.3 months compared to the standard detection cohort (50.3 vs 24.0 months, p = 0.0015). On multivariate analysis, predictors of survival after recurrence were presence of distant metastases at diagnosis (p = 0.010) and asymptomatic PET-detected recurrence (p = 0.039). CONCLUSIONS: PET imaging in asymptomatic patients beyond 6 months after treatment may have clinical benefit and warrants further study. Detection of recurrence by PET in asymptomatic patients ≥ 6 months after chemoradiation was associated with prolonged survival by more than   2 years.

An integrated molecular profile of endometrioid ovarian cancer.

OBJECTIVE: Endometrioid ovarian carcinoma (EOVC) is an uncommon subtype of epithelial ovarian carcinoma and its molecular characteristics have been incompletely described. Prior sequencing investigations have been limited to targeted gene panels. We performed whole-exome sequencing to build an unbiased genetic profile of molecular alterations in endometrioid ovarian tumors with a goal to better understand this disease in the context of epithelial ovarian cancer and endometrioid uterine cancers. METHODS: Whole-exome sequencing was performed on EOVC samples (n = 26) and matched normals (n = 15). Gene mutations, mutational signatures and copy number variations (CNVs) informed a multi-dimensional regression classifier allowing for comparison to endometrial carcinoma (UCEC) and high grade serous ovarian carcinoma (HGSC). RESULTS: EOVC has a distinct and heterogeneous genomic profile. Identified significantly mutated genes in EOVC (PTEN, CTNNB1, PIK3CA, KMT2D, KMT2B, PIK3R1, ARID1A and TP53) occurred at similar frequencies in UCEC. Hypermutation, resulting from both mismatch repair deficiency (MMRd) and POLE mutation, was observed in EOVC at a frequency similar to UCEC. Like UCEC, a subset of EOVC cases closely resembled HGSC, harboring TP53 mutations, homologous recombination deficiency (HRd) mutation signatures and widespread CNVs. A machine-learning classifier confirmed the heterogeneous composition of EOVC. Potential therapeutic targets were identified in 62% of EOVC cases. We validated our findings in an orthogonal clinical sequencing registry of EOVC cases. CONCLUSIONS: We identified that EOVC are a molecularly heterogeneous group of epithelial ovarian cancers with distinct mutational signatures. In an age of precision oncology, there is a pressing need to understand the unique molecular drivers in uncommon histologic subtypes to facilitate genomically driven oncologic treatments.

Fertility treatment is associated with multiple meningiomas and younger age at diagnosis.

PURPOSE: Meningiomas are more common in females and 70-80% express the progesterone receptor, raising the possibility that high-dose exogenous estrogen/progesterone exposure, such as occurs during fertility treatments, may increase the risk of developing a meningioma. The goal of this study was to report the incidence of prior fertility treatment in a consecutive series of female meningioma patients. METHODS: A retrospective review (2015-2018) was performed of female patients with meningioma, and those with prior fertility treatment were compared to those without fertility treatment using standard statistical methods. RESULTS: Of 206 female patients with meningioma, 26 (12.6%) had a history of fertility treatments. Patients underwent various forms of assisted reproductive technology including: in vitro fertilization (50.0%), clomiphene with or without intrauterine insemination (34.6%), and unspecified (19.2%). Median follow up was 1.8 years. Tumors were WHO grade I (78.6%) or grade II (21.4%). Patients who underwent fertility treatments presented at significantly younger mean age compared to those who had not (51.8 vs. 57.3 years, p = 0.0135, 2-tailed T-test), and on multivariate analysis were more likely to have multiple meningiomas (OR 4.97, 95% CI 1.4-18.1, p = 0.0154) and convexity/falx meningiomas (OR 4.45, 95% CI 1.7-11.5, p = 0.0021). CONCLUSIONS: Patients in this cohort with a history of fertility treatment were more likely to present at a younger age and have multiple and convexity/falx meningiomas, emphasizing the importance of taking estrogen/progesterone exposure history when evaluating patients with meningioma. Future clinical studies at other centers in larger populations and laboratory investigations are needed to determine the role of fertility treatment in meningioma development.

Mutant p53 regulates LPA signaling through lysophosphatidic acid phosphatase type 6.

Emerging evidence has indicated that high-grade serous ovarian cancer (HGSOC) originates in the fallopian tube, where the earliest known genetic lesion is the mutation of TP53. In addition to such genetic changes, HGSOC is characterized by altered metabolism, including the production of oncogenic lipids such as lysophosphatidic acid (LPA). To understand the crosstalk between TP53 mutations and LPA signaling, we utilized primary fallopian tube epithelial cells (FTEC) engineered to overexpress mutant p53. We found that gain-of-function (GOF) p53 mutations downregulated the LPA-degrading enzyme lysophosphatidic acid phosphatase type 6 (ACP6), leading to upregulation of focal adhesion signaling in an LPA-dependent manner. Although highly expressed in normal fallopian tube epithelium, ACP6 expression was significantly reduced in ovarian cancer tumors and early in situ lesions. Downregulation of ACP6 in ovarian cancer cells was necessary and sufficient to support HGSOC proliferation, adhesion, migration, and invasion. Using mouse models of metastasis, we established that attenuation of ACP6 expression was associated with increased tumor burden. Conversely, overexpression of ACP6 suppressed invasive behavior. These data identify an involvement of oncogenic p53 mutations in LPA signaling and HGSOC progression through regulation of ACP6 expression.

Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity.

The pattern of ovarian cancer metastasis is markedly different from that of most other epithelial tumors, because it rarely spreads hematogenously. Instead, ovarian cancer cells exfoliated from the primary tumor are carried by peritoneal fluid to metastatic sites within the peritoneal cavity. These sites, most notably the abdominal peritoneum and omentum, are organs covered by a mesothelium-lined surface. To investigate the processes of ovarian cancer dissemination, we assembled a complex three-dimensional culture system that reconstructs the lining of the peritoneal cavity in vitro. Primary human fibroblasts and mesothelial cells were isolated from human omentum. The fibroblasts were then mixed with extracellular matrix and covered with a layer of the primary human mesothelial cells to mimic the peritoneal and omental surfaces encountered by metastasizing ovarian cancer cells. The resulting organotypic model is, as shown, used to examine the early steps of ovarian cancer dissemination, including cancer cell adhesion, invasion, and proliferation. This model has been used in a number of studies to investigate the role of the microenvironment (cellular and acellular) in early ovarian cancer dissemination. It has also been successfully adapted to high throughput screening and used to identify and test inhibitors of ovarian cancer metastasis.