Optimizing disease progression assessment using blinded central independent review and comparing it with investigator assessment in the PRIMA/ENGOT-ov26/GOG-3012 trial: challenges and solutions.

OBJECTIVE: Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy. METHODS: PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention. RESULTS: There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups. CONCLUSION: PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.

Outcomes after targeted treatment based on somatic tumor genetic testing for women with gynecologic cancers.

OBJECTIVE: Molecular tumor profiling and next-generation sequencing are being increasingly utilized, but there are limited data on the therapeutic implications and potential benefits of targeted treatments. We aim to characterize gynecologic oncology patients referred for somatic tumor genetic mutation testing and assess survival outcomes, efficacy, and toxicities of those receiving targeted therapy. METHODS: We conducted a retrospective chart review of gynecologic oncology patients referred for somatic tumor testing by next generation sequencing between 1/1/2012-8/23/2019. The primary objective was to compare overall and progression free survival between those treated with targeted therapy (group 1) versus traditional treatment (group 2). RESULTS: Most patients (70%) had additional treatment options available based on actionable mutations. The median number of somatic mutations identified was 5 (range 0-53). Patients in group 1 had more actionable somatic mutations (median 2 versus 0, p < 0.001). There was no difference in OS (median 64 versus 76 months, p = 0.97) or PFS (median 2 versus 8 months, p = 0.05) between the groups. While fewer patients in group 1 experienced neuropathy (0 versus 5, p = 0.02), grade I/II thrombocytopenia (7 versus 13, p = 0.03), grade III/IV thrombocytopenia (0 versus 4, p = 0.02), and grade III/IV neutropenia (1 versus 9, p = 0.002), all other non-hematologic toxicities were similar in the two groups. CONCLUSIONS: Most gynecologic cancer patients have actionable mutations and may benefit from a personalized targeted therapy treatment plan. Next generation sequencing can be used to identify clinically actionable mutations in gynecologic cancers and guide the selection of treatments, thereby expanding treatment options without worsening survival or toxicity.

Malignant bowel obstruction due to uterine or ovarian cancer: Are there differences in outcome?

OBJECTIVES: To describe and compare treatments and outcomes of patients with malignant bowel obstructions (MBO) due to uterine or ovarian cancer. METHODS: Retrospective chart review from two institutions of women admitted 1/1/2005-12/31/2016 with a MBO from recurrent/progressive uterine or ovarian cancer. Data collected includes patient characteristics, cancer-directed treatments before and after MBO, MBO management strategies, and survival after MBO. RESULTS: Women with MBO from uterine cancer (n = 46) and ovarian cancer (n = 130) underwent similar inpatient interventions such as inpatient chemotherapy and surgery. Median overall survival (OS) after admission for MBO for all patients was 105 days and was shorter for uterine cancer patients (57 vs 131 days, p = 0.0013). Uterine and ovarian cancer patients who had surgery had similar survival (182 vs 210 days, p = 0.6), as did those discharged on hospice from their first admission for MBO (26 vs 38 days, p = 0.1). Uterine and ovarian cancer patients had similar rates of post-discharge chemotherapy (37% vs 50%, p = 0.12), but uterine cancer patients who had chemotherapy still had shorter survival (151 vs 225 days, p = 0.03). CONCLUSIONS: MBO has a relatively poor prognosis. Ovarian and uterine cancer patients whose interventions included surgery or hospice had similar outcomes. Among patients managed medically without hospice, uterine cancer patients experienced worse survival, even when candidates for subsequent chemotherapy. Patient counseling regarding goals of care at this difficult juncture can be informed by these findings and will be enhanced by patient-reported and qualitative data on the patient experience with MBO.

Clinical outcomes in ovarian cancer patients receiving three versus more cycles of chemotherapy after neoadjuvant treatment and interval cytoreductive surgery.

OBJECTIVES: To compare clinical outcomes for stage IIIC and IV ovarian cancer patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery followed by up to three versus more cycles of post-operative chemotherapy. METHODS: We conducted a multi-institution retrospective cohort study of patients treated from January 2005 to February 2016 with neoadjuvant platinum-based therapy followed by interval surgery and post-operative chemotherapy. The following were exclusion criteria: more than four cycles of neoadjuvant chemotherapy, bevacizumab with neoadjuvant chemotherapy, non-platinum therapy, prior chemotherapy, and elevated CA125 values after three post-operative chemotherapy cycles. Progression-free and overall survival and toxicity profiles were compared between groups receiving up to three cycles versus more that three cycles post-operatively. RESULTS: A total of 100 patients met inclusion criteria: 41 received up to three cycles and 59 received more than three cycles. The groups were similar in terms of age, body mass index, performance status, tumor histology, optimal cytoreduction rates, and median number of neoadjuvant chemotherapy cycles. Median progression-free survival was 14 vs 16.6 months in those receiving up to three cycles versus more than three cycles, respectively (HR 0.99, 95% CI 0.58 to 1.68, p=0.97). Similarly, median overall survival was not different at 47.1 vs 69.4 months, respectively (HR 1.96, 95% CI 0.87 to 4.42, p=0.10). There were no differences in grade 2 or higher chemotherapy-related toxicities. CONCLUSIONS: Extending post-operative chemotherapy beyond three cycles in patients receiving neoadjuvant chemotherapy and interval cytoreductive surgery with normalization of CA125 levels was not associated with improved survival or greater toxicity. Future study in a larger cohort is warranted to define optimal length of cytotoxic treatment.

Bilateral salpingectomy with delayed oophorectomy for ovarian cancer risk reduction: A pilot study in women with BRCA1/2 mutations.

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) reduces ovarian cancer risk in BRCA1/2 mutation carriers, but the adverse effects of the associated early-onset surgical menopause are problematic. Despite suggestive evidence, no data demonstrate whether bilateral salpingectomy alone lowers the risk of developing ovarian cancer in BRCA mutation carriers. We conducted a pilot study of bilateral salpingectomy with delayed oophorectomy (BS/DO) in BRCA mutation carriers to determine the safety and acceptability of the procedure. METHODS: In this prospective, multicenter, non-randomized pilot study, pre-menopausal BRCA1/2 mutation carriers aged 30 to 47 years chose screening, RRSO, or BS/DO. For those undergoing BS/DO, the delayed oophorectomy was recommended at age 40 years for BRCA1 and age 45 years for BRCA2 patients. We compared surgical and psychosocial outcomes between time points and between arms. RESULTS: Of the 43 patients enrolled, 19 (44%) chose BS/DO, 12 (28%) chose RRSO, and 12 (28%) chose screening. The cohort was 37% BRCA1 carriers and 63% BRCA2 carriers. One serous tubal intraepithelial carcinoma (STIC) was found in an RRSO patient, and no cases of occult ovarian cancers were found. There were no surgical complications. Twelve months after surgery, responses on the Cancer Worry Scale indicated decreased worry in the BS/DO (P < 0.0001) and RRSO (P = 0.01) arms, while responses on the State Anxiety Inventory indicated decreased anxiety in the BS/DO arm (P = 0.02) compared with preoperative responses. CONCLUSIONS: In this pilot study, BRCA mutation carriers who underwent bilateral salpingectomy had no intraoperative complications, were satisfied with their procedure choice, and had decreased cancer worry and anxiety after the procedure.

Is carboplatin-based chemotherapy as effective as cisplatin-based chemotherapy in the treatment of advanced-stage dysgerminoma in children, adolescents and young adults?

OBJECTIVE: Dysgerminoma is the most common malignant ovarian germ cell tumor (GCT) with peak incidence during adolescence and young adulthood. Current standard of care for patients with disease that has spread outside of the ovary (advanced-stage) utilizes platin-based chemotherapy regimens. The study objective was to compare clinical outcomes between platin-based (carboplatin versus cisplatin) strategies across all age groups (children < 11 years (y), adolescents = 11-25 y and young adult women > 25 y) for advanced-stage dysgerminoma. METHODS: The Malignant Germ Cell Tumor International Consortium (MaGIC) pooled data from six GCT trials (3 = pediatric, 3 = adult) conducted internationally by pediatric and gynecologic oncology clinical trial organizations (CTOs) between 1983 and 2009. Newly diagnosed patients, with advanced-stage (FIGO IC-IV) dysgerminoma, who received either carboplatin- or cisplatin-based chemotherapy were eligible for analysis. RESULTS: 126 eligible patients were identified; 56 patients (38 = pediatric, 18 = adult) received carboplatin-based and 70 patients (50 = pediatric, 20 = adult) received cisplatin-based chemotherapy. Mean age was 20 y (range = 6-46 y). The median follow-up was 10.3 y (range = 0.17-21.7 y). The five-year event-free survival (EFS5) and overall survival (OS5) was 0.94 (95%CI, 0.88-0.97) and 0.96 (95%CI, 0.91-0.99) respectively. Survival outcomes were comparable between carboplatin-(EFS5 = 0.96 (95%CI, 0.85-0.99), OS5 = 0.96 (95%CI, 0.85-0.99)) and cisplatin-(EFS5 = 0.93 (95%CI, 0.83-0.97), OS5 = 0.96 (95%CI, 0.87-0.99)) based regimens. Across three age groups, comparison of the EFS5 (<11 y = 0.1, 11-25 y = 0.91 (95%CI, 0.82-0.96), >25 y = 0.97 (95%CI, 0.81-0.99)) and OS5 (<11 y = 0.1, 11-25 y = 0.95 (95%CI, 0.87-0.99), >25 y = 0.97 (95%CI, 0.81-0.99)) did not demonstrate any statistically significant differences in outcomes. CONCLUSIONS: Patients diagnosed with dysgerminoma have an excellent OS, across all ages, even in the context of metastatic disease. Data from three large CTOs supports the investigation of carboplatin-based regimens in the frontline treatment of all patients with advanced-stage dysgerminoma to minimize treatment-related toxicities.

Surgical outcomes among elderly women with endometrial cancer treated by laparoscopic hysterectomy: a NRG/Gynecologic Oncology Group study.

OBJECTIVE: Tolerance of and complications caused by minimally invasive hysterectomy and staging in the older endometrial cancer population is largely unknown despite the fact that this is the most rapidly growing age group in the United States. The objective of this retrospective review was to compare operative morbidity by age in patients on the Gynecologic Oncology Group Laparoscopic Surgery or Standard Surgery in Treating Patients With Endometrial Cancer or Cancer of the Uterus (LAP2) trial. STUDY DESIGN: This is a retrospective analysis of patients from Gynecologic Oncology Group LAP2, a trial that included clinically early-stage uterine cancer patients randomized to laparotomy vs laparoscopy for surgical staging. Differences in the rates and types of intraoperative and perioperative complications were compared by age. Specifically complications between patients <60 vs ≥60 years old were compared caused by toxicity analysis showing a sharp increase in toxicity starting at age 60 years in the laparotomy group. RESULTS: LAP2 included 1477 patients ≥60 years old. As expected, with increasing age there was worsening performance status and disease characteristics including higher rates of serous histology, high-stage disease, and lymphovascular space invasion. There was no significant difference in lymph node dissection rate by age for the entire population or within the laparotomy or laparoscopy groups. Toxicity analysis showed a sharp increase in toxicity seen in patients ≥60 years old in the laparotomy group. Further analysis showed that when comparing laparotomy with laparoscopy in patients <60 years old vs ≥60 years old and controlling for race, body mass index, stage, grade, and performance status, patients <60 years old undergoing laparotomy had more hospital stays >2 days (odds ratio, 17.48; 95% confidence interval, 11.71-27.00, P < .001) compared with patients <60 years old undergoing laparoscopy. However, when comparing laparotomy with laparoscopy in patients ≥60 years old, in addition to hospital stay >2 days (odds ratio, 12.77; 95% confidence interval, 8.74-19.32, P < .001), there were higher rates of the following postoperative complications: antibiotic administration (odds ratio, 1.63; 95% confidence interval, 1.24-2.14, P < .001), ileus (odds ratio, 2.16; 95% confidence interval, 1.42-3.31, P <0.001), pneumonias (odds ratio, 2.36; 95% confidence interval, 1.01-5.66, P = .048), deep vein thromboses (odds ratio, 2.87; 95% confidence interval, 1.08-8.03, P = .035), and arrhythmias (odds ratio, 3.21; 95% confidence interval, 1.60-6.65, P = .001) in the laparotomy group. CONCLUSION: Laparoscopic staging for uterine cancer is associated with decreased morbidity in the immediate postoperative period in patients ≥60 years old. These results allow for more accurate preoperative counseling. A minimally invasive approach to uterine cancer staging may decrease morbidity that could affect long-term survival.

Ovarian Yolk Sac Tumors; Does Age Matter?

BACKGROUND: Whereas among pediatric oncologists, ovarian yolk sac tumor (O-YST) is considered a chemosensitive tumor, it is often cited as an adverse prognostic factor in adult women with ovarian germ cell tumors. METHODS: The Malignant Germ Cell International Consortium data set included 6 pediatric clinical trials (United States, United Kingdom, and France) and 2 adult gynecology clinical trials (United States). Any patient with an O-YST that was International Federation of Gynecology and Obstetrics stage IC or higher and treated with a platinum-based chemotherapy was eligible. Age was modeled as a continuous and a categorical variable (children, 0-10 years; adolescents, 11-17 years; and adults, ≥18 years). In addition, analyses to establish the optimal cut point for age were conducted. Tumors were coded as pure YST (YST +/- teratoma), mixed YST (YST + other malignant germ cell component), or putative YST ("mixed" germ cell tumor + alpha-fetoprotein >1000 ng/mL). Histology, stage (II/III vs IV), preoperative alpha-fetoprotein levels (<1000; 1000-10,000, or >10,000 ng/mL), and chemotherapeutic regimen (carboplatin vs cisplatin) were analyzed as covariates. RESULTS: Two hundred fifty-one patients (median age, 13 years; range, 0-38 years) were identified (78 children, 139 adolescents, and 34 adults). Histology was pure, mixed, and putative in 129, 56, and 66 cases, respectively. Twenty-six patients had stage IV disease, similarly distributed in the 3 age groups. Median follow-up was 5.8 years. The overall 5-year event-free survival and overall survival was 91% (95% confidence interval, 87%-94%) and 96% (92%-98%), respectively. Age did not affect risk of event or death, modeled either as a categorical or continuous variable. Analysis failed to identify an age cut point that affected risk. None of the other covariates investigated had a prognostic impact on event-free survival or overall survival. CONCLUSIONS: Ovarian yolk sac tumors have an excellent outcome across all age-groups. Age has no apparent impact on the probability of event or death, allowing pediatric and gynecologic oncologists to enroll patients onto joint pediatric and adult trials.

Venous Thromboembolism in Patients Receiving Extended Pharmacologic Prophylaxis After Robotic Surgery for Endometrial Cancer.

OBJECTIVE: This study aims to determine the rate of postoperative venous thromboembolism (VTE) in endometrial cancer patients undergoing robotic hysterectomy with or without extended pharmacologic VTE prophylaxis. METHODS/MATERIALS: A retrospective chart review of women undergoing robotic hysterectomy with or without other procedures for endometrial cancer from January 2010 to February 2015 was conducted at 2 institutions. Charts were manually abstracted, and rates of VTE within 30 and 60 days after surgery were determined. Patients were then stratified by those who did and did not receive extended VTE prophylaxis. RESULTS: A total of 403 patients were included, of which 367 patients (91%) received extended pharmacologic prophylaxis and 36 patients (9%) did not. Low molecular weight heparin prescriptions ranged from 7 to 30 days. Patients receiving extended prophylaxis (EP) were older (63 ± 11 vs 57 ± 12; P = 0.004), more frequently underwent lymphadenectomy (67% vs 34%; P < 0.001), and had higher-grade tumors compared with patients not receiving EP. Overall 30-day and 60-day VTE rates were 0.7% and 1.2%, respectively. There were no significant differences in 30-day and 60-day VTE rates among patients that did and did not receive EP, although a trend toward lower VTE rates in the EP group was observed (30-day rates 0.5% vs 2.8% respectively, P = 0.25; 60-day rates 0.8% vs 5.6%, P = 0.07). CONCLUSIONS: In this study, 30-day and 60-day VTE rates after minimally invasive surgery for endometrial cancer were low. Rates were also similar to those of previous reports in this setting in which the majority of patients did not receive extended VTE prophylaxis. Given the consistent finding that postoperative VTE in this population is rare regardless of prophylaxis use and the variability in practice patterns for VTE prophylaxis, the development of best practice guidelines for EP use specific to this setting is warranted.

Patterns and utility of routine surveillance in high grade endometrial cancer.

OBJECTIVE: To evaluate surveillance methods and their utility in detecting recurrence of disease in a high grade endometrial cancer population. METHODS: We performed a multi-institutional retrospective chart review of women diagnosed with high grade endometrial cancer between the years 2000 and 2011. Surveillance data was abstracted and analyzed. Surveillance method leading to detection of recurrence was identified and compared by stage of disease and site of recurrence. RESULTS: Two hundred and fifty-four patients met the criteria for inclusion. Vaginal cytology was performed in the majority of early stage patients, but was utilized less in advanced stage patients. CA-125 and CT imaging were used more frequently in advanced stage patients compared to early stage. Thirty-six percent of patients experienced a recurrence and the majority of initial recurrences (76%) had a distant component. Modalities that detected cancer recurrences were: symptoms (56%), physical exam (18%), surveillance CT (15%), CA-125 (10%), and vaginal cytology (1%). All local recurrences were detected by symptoms or physical exam findings. While the majority of loco-regional and distant recurrences (68%) were detected by symptoms or physical exam, 28% were detected by surveillance CT scan or CA 125. One loco-regional recurrence was identified by vaginal cytology but no recurrences with a distant component detected by this modality. CONCLUSIONS: Symptoms and physical examination identify the majority of high grade endometrial cancer recurrences, while vaginal cytology is the least likely surveillance modality to identify a recurrence. The role of CT and CA-125 surveillance outside of a clinical trial needs to be further reviewed.

Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.

BACKGROUND: Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. METHODS: In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. FINDINGS: Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). INTERPRETATION: Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. FUNDING: American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

Gynecologic Cancer InterGroup (GCIG) consensus review for squamous cell carcinoma of the ovary.

Squamous cell carcinoma of the ovary is a rare complication of mature cystic teratoma. The epidemiology, pathology, diagnosis, and management of this rare tumor are reviewed. Clinical characteristics, preoperative imaging, and tumor markers may help to predict malignancy preoperatively. Complete cytoreduction should be the aim of surgery. The prognosis for stage 1A disease is good, but for women with advanced or recurrent disease, it is very poor and has not improved in recent years. At present, there are insufficient data to provide clear guidance on the optimal management strategy for advanced disease, and there is a need to gain an understanding of the biology and to develop novel effective therapies. This will require coordinated international collaboration.

Real-World First-Line Maintenance Niraparib Monotherapy Use Following Chemotherapy Plus Bevacizumab: The SW1TCH Study.

INTRODUCTION: Clinical trials have demonstrated prolonged survival associated with niraparib first-line maintenance (1LM) therapy, compared with placebo, for patients with ovarian cancer (OC). However, data are limited on real-world 1LM niraparib monotherapy use, particularly as switch 1LM, following first-line (1L) combination chemotherapy plus bevacizumab. This real-world study aimed to describe patient demographics, clinical characteristics, and clinical outcomes of patients with OC receiving 1LM niraparib monotherapy following 1L combination chemotherapy plus bevacizumab. METHODS: This retrospective observational study used data from a US-based nationwide database of deidentified, electronic health record-derived data. Patients diagnosed with OC during the study period (1 January 2011-30 November 2022, inclusive) were eligible if they received 1L chemotherapy plus bevacizumab treatment followed by 1LM niraparib monotherapy, initiated between 1 January 2017 (inclusive) and 2 September 2022. Patients were followed from index date (initiation of niraparib 1LM) until the first occurrence of death, end of follow-up, or end of study. Clinical outcomes were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Kaplan-Meier curves were used to estimate TTD, TTNT, and 95% confidence intervals (CIs). RESULTS: Among 93 patients selected, median age at index was 67 years (interquartile range [IQR] 60-72 years). Most patients had BRCA wild-type/homologous recombination (HR)-proficient or BRCA wild-type/HR unknown disease (75.3%). In all, 18 (19.4%) patients had HR-deficient disease. Five (5.4%) patients had unknown test results for both BRCA and HR deficiency status. Median follow-up time was 16.3 months (IQR 8.7-25.4 months), and median time from end of 1L therapy to 1LM initiation was 35.0 days (IQR 25.0-53.9 days). Median TTD was 9.3 months (95% CI 6.1-11.3 months). Median TTNT was 12.9 months (95% CI 11.5-19.0 months). CONCLUSIONS: This real-world study provided insights into switch maintenance with 1LM niraparib monotherapy, which may be a viable treatment option for patients with advanced OC.

Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Insights into the field carcinogenesis of ovarian cancer based on the nanocytology of endocervical and endometrial epithelial cells.

Ovarian cancer ranks fifth in cancer fatalities among American women. Although curable at early stages with surgery, most women are diagnosed with symptoms of late-stage metastatic disease. Moreover, none of the current diagnostic techniques are clinically recommended for at-risk women as they preferentially target low-grade tumors (which do not affect longevity) and fail to capture early signatures of more lethal serous tumors which originate in the fimbrae region of the fallopian tubes. Hence, the early detection of ovarian cancer is challenging given the current strategy. Recently, our group has developed a novel optical imaging technique, partial wave spectroscopic (PWS) microscopy, that can quantify the nanoscale macromolecular density fluctuations within biological cells via a biomarker, disorder strength (Ld ). Using the concept of field carcinogenesis, we propose a method of detecting ovarian cancer by PWS assessment of endometrial and endocervical columnar cells. The study includes 26 patients (controls = 15, cancer = 11) for endometrium and 23 (controls = 13, cancer = 10) for endocervix. Our results highlight a significant increase in Ld (% fold-increase > 50%, p-value < 0.05) for columnar epithelial cells obtained from cancer patients compared to controls for both endocervix and endometrium. Overall, the quantification of field carcinogenic events in the endometrium and the novel observation of its extension to the cervix are unique findings in the understanding of ovarian field carcinogenesis. We further show independent validation of the presence of cervical field carcinogenesis with micro-RNA expression data.

Treatment Patterns and Outcomes Among Patients With Advanced or Recurrent Endometrial Cancer Initiating First-Line Therapy in the United States.

Background: Patients with advanced or recurrent endometrial cancer (EC) typically have limited treatment options and poor long-term survival outcomes following first-line therapy. Real-world treatment patterns and survival outcomes data are limited for patients in this setting. Objectives: The objective of this retrospective study was to describe real-world demographics, clinical characteristics, treatment patterns, and overall survival among patients in the United States with primary advanced or recurrent EC who initiated at least 1 line of therapy (LOT). Methods: Patients with a diagnosis of primary advanced or recurrent EC in a real-world database from January 1, 2013, to July 31, 2021, were included. The date for inclusion was the date of EC diagnosis documentation; patients were indexed for treatment patterns and outcomes at the start of the first LOT and at the start of each subsequent LOT they initiated. Data were stratified by subgroups of patients who had mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors. Results: A total of 1961 patients who received at least 1 LOT were included. Most patients in this cohort, and the dMMR/MSI-H subgroup, received a platinum combination as first-line treatment, with carboplatin-paclitaxel being the most common regimen. Only 53% of patients who received first-line treatment subsequently received second-line therapy. Of the patients who received at least 1 LOT, use of immunotherapy in the second-line setting was more common in the dMMR/MSI-H subgroup. Median overall survival ranged from 14.1 to 31.8 months across the 5 most frequently used first-line treatment regimens in the ≥1 LOT cohort and became shorter with each subsequent LOT. Discussion: The use of platinum-based chemotherapy for first-line treatment of advanced or recurrent EC predominates in the real-world setting, despite the poor long-term survival outcomes associated with most of these regimens. Conclusions: Patients with recurrent/advanced EC have a poor prognosis, highlighting the need for therapies with more durable benefits.

Real-world Outcomes Associated With Poly(ADP-ribose) Polymerase Inhibitor Monotherapy Maintenance in Patients With Primary Advanced Ovarian Cancer.

OBJECTIVE: This study used real-world population data to assess the trends of first-line (1L) poly(ADP-ribose) polymerase inhibitor (PARPi) maintenance treatment uptake and outcomes in patients with primary advanced ovarian cancer (AOC). METHODS: Patients diagnosed with AOC between January 1, 2017, and June 30, 2021, who completed 1L chemotherapy were selected from a real-world database. Descriptive analyses were performed to evaluate patient demographics, clinicopathological characteristics, and 1L treatment patterns. Time to next treatment or death was used as a proxy for real-world progression-free survival (rwPFS). Kaplan-Meier methods and Cox models were used for statistical analyses. RESULTS: Of 705 patients who completed 1L chemotherapy, 166 received PARPi monotherapy and 539 underwent active surveillance (AS). Median follow-up was 10.9 months for PARPi monotherapy and 20.6 months for AS. PARPi monotherapy use increased from 6% in 2017 to 53% in 2021. Overall, patients receiving PARPi monotherapy had longer rwPFS than those who underwent AS (not reached vs 9.53 mo) respectively. rwPFS was also longer in patients who received PARPi monotherapy compared with AS in patients with BRCA- mutated disease (not reached vs 11.4 mo), BRCA- wild-type disease (13.5 vs 9.1 mo), homologous recombination-deficient tumors (not reached vs 10.2 mo), and homologous recombination-proficient or unknown status tumors (13.5 vs 9.3 mo). CONCLUSIONS: Our real-world analysis suggested that 47% of patients with primary AOC did not receive PARPi maintenance in the year 2021. PARPi use was associated with significantly improved outcomes compared with AS.

Nonsteroidal antiinflammatory drugs and progestins synergistically enhance cell death in ovarian epithelial cells.

OBJECTIVE: There is growing evidence that progestins and nonsteroidal antiinflammatory drugs (NSAIDs) may prevent ovarian cancer. Because both induce apoptosis, we investigated the potential for synergistic impact of combined drug treatment on cell death. STUDY DESIGN: Using normal and malignant human ovarian epithelial cells and an NSAID-sensitive human colon cancer cell line, we evaluated the effects of progestins and NSAIDs alone and in combination on apoptosis. RESULTS: Both progestins and NSAIDs dose dependently inhibited cell growth (P < .0001). Doses of NSAIDs or progestins that independently reduced cell viability by less than 30% synergistically reduced cell viability by 70-95% when combined. Similarly, the NSAID/progestin combination conferred 4- to 18-fold (P < .05) increased apoptosis over either treatment alone. CONCLUSION: Our results suggest it may be possible to combine progestins and NSAIDs to achieve ovarian cancer prevention at lower doses of each than are required for single administration, thereby lessening the risk of side effects posed by these agents.