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Drug development is paramount to improve outcomes in patients with gynecologic cancers. A randomized clinical trial should measure whether a clinically relevant improvement is detected with the new intervention compared with the standard of care, using reproductible and appropriate endpoints. Clinically meaningful improvements in overall survival and/or quality of life (QoL) are the gold standards to measure benefit of new therapeutic strategies. Alternative endpoints, such as progression-free survival, provide an earlier measure of the effect of the new therapeutic drug, and are not confounded by the effect of subsequent lines of therapy. Yet, its surrogacy with improved overall survival or QoL is unclear in gynecologic malignancies. Of relevance to studies assessing maintenance strategies are other time-to-event endpoints, such as progression-free survival two and time to second subsequent treatment, which provide valuable information on the disease control in the longer term. Translational and biomarker studies are increasingly being incorporated into gynecologic oncology clinical trials, as they may allow understanding of the biology of the disease, resistance mechanisms, and enable a better selection of patients who might benefit from the new therapeutic strategy. Globally, the endpoint selection of a clinical trial will differ according to the type of study, population, disease setting, and type of therapeutic strategy. This review provides an overview of primary and secondary endpoint selection of relevance for gynecologic oncology clinical trials.

A double-blind, randomized, placebo-controlled, phase 2 trial assessed gemcitabine in combination with the wee1 inhibitor adavosertib or placebo in platinum resistant or refractory high grade serous ovarian cancer (HGSOC), demonstrating improved progression free and overall survival favouring the adavosertib/gemcitabine arm. An exploratory objective of the study included the PRO-CTCAE assessment, to capture self-reporting of frequency, severity and/or interference of symptomatic adverse events (syAEs).PRO-CTCAE items at baseline, days 1 and 15 of each cycle and off treatment, were completed in two centres, with the objective of characterizing syAEs in the first three months of therapy. The maximum post-baseline score proportion for each syAE was tabulated per patient. The 12-week area under the curve (AUC12w) as a measure of syAE over-time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs.Sixty-one patients were approached for PRO-CTCAE surveys and 55 were evaluable. Among patients with HGSOC, 28 received gemcitabine/adavosertib (arm A) and 19 gemcitabine/placebo (arm B). Survey completion rates were high. The proportion of participants with positive (≥1) PRO-CTCAE scores was higher for difficulty swallowing with gemcitabine/adavosertib (arm A 35.7% vs arm B 5.3%, p = 0.02). The high score (≥3) syAEs showed more frequent diarrhea with gemcitabine/adavosertib (arm A 25% vs arm B 0%, p = 0.03). The proportions of worsening syAEs over time were higher in patients receiving gemcitabine/adavosertib for difficulty swallowing (arm A 35.7% vs arm B 5.3%; p = 0.03) and fatigue severity (arm A 71.43% vs arm B 42.1%; p = 0.04).The longitudinal assessment of patient self-reported tolerability showed greater difficulty swallowing and fatigue severity in patients receiving gemcitabine/adavosertib, compared to gemcitabine/placebo. PRO-CTCAE provides complementary and objective assessment of drug tolerability from a patient's perspective.

Supplementary Tables 1 and 2 show respectively the fold change of lysosomal function and size in treated sensitive/resistant cells obtained by mixed effect modelling. Supplementary Table 3 shows patients enrolled per dose-level (DL) and dose limiting toxicities (DLTs). Supplementary Tables 4 and 5 show the summary of all and treatment related adverse effects.

List of cell lines- Lentiviral constructs, lentivirus generation and infection- Apoptosis Assay- FILIPIN staining- Lysosomal assay and immunofluorescence

CRISPR screen OVCAR5. Results of the Itra sensitizing CRISPR screen on the OVCAR5 cell line using drugZ algorithm.

Supplementary Figure 1: Itra dose response in ovarian cancer cell lines. - Supplementary Figure 2: Analysis on ovarian cancer cell lines used in the Itra-sensitizing CRISPR screen (OVCAR5 and TOV1946). - Supplementary Figure 3: c18orf8 and VPS54 Knockout effects on the TOV1946 cell line. - Supplementary Figure 4: Itra+CQ dose responses. - Supplementary Figure 5: 5/10 uM CQ response and apoptosis assay results. - Supplementary Figure 6: Itra+CQ dose response in c18orf8 and VPS54 knockout cells and calculation of synergy scores. - Supplementary Figure 7: Intratumoural Itra/CQ detection and Ki-67 analysis in patient samples.

CRISPR screen TOV1946. Results of the Itra sensitizing CRISPR screen on the TOV1946 cell line using drugZ algorithm.

Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes; similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro, itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation.Significance:The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer.

Purpose:PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.Patients and Methods:The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib–olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.Results:Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.Conclusions:This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib–olaparib varied according to the PARPi resistance mechanism.

Supplementary figures S1-S5

Platinum is the backbone of systemic treatment in ovarian cancer and development of platinum resistance is associated with poor survival. Here, we perform a comprehensive review of the literature regarding resistance mechanisms and advances in therapy for platinum resistant ovarian cancer, with a focus on high-grade serous carcinoma. Platinum resistance can be intrinsic or acquired. Resistance mechanisms are complex and diverse. Intracellular mechanisms include restoration of homologous recombination repair, reduced intracellular accumulation of platinum, blocked cellular replication and inhibition of apoptosis. These act in concert with immunosuppressive, angiogenic and stromal changes in the tumour microenvironment to drive treatment resistance. Current molecular stratification lacks prognostic and predictive validity, limited in part by the extreme genomic complexity of high-grade serous ovarian cancer. Clinical trials represent an important option for patients as standard of care treatment options have limited efficacy. The most promising trials appear to focus on rational combinations of chemotherapy, immunotherapy, anti-angiogenics, PARP inhibitors, targeted therapy and/or antibody-drug conjugates. Resistance mechanisms are multifactorial with capacity to evolve over time, making clinical detection challenging. It is increasingly apparent that clinical trials must incorporate correlative studies to elucidate predictive biomarkers. They must also adopt endpoints that can appropriately measure benefit for palliative treatments. Future research must aim to deepen our understanding of the biology of this disease, and deliver meaningful benefit in terms of improved quality of life and overall survival for women with platinum resistant ovarian cancer.

Obesity is associated with a higher risk of several types of cancer, grouped as obesity-related cancers (ORC). Vitamin D deficiency is more prevalent in obese subjects, and it has been suggested to play a role in the association between obesity and cancer risk. The aim of the study was to analyze the association between vitamin D intake and the subsequent risk of ORC in a prospective Spanish cohort of university graduates. The SUN Project, initiated in 1999, is a prospective dynamic multipurpose cohort. Participants answered a 556-item lifestyle baseline questionnaire that included a validated food-frequency questionnaire. We performed Cox regression models to estimate the hazard ratios (HRs) of ORC according to quartiles of energy-adjusted vitamin D intake (diet and supplements). We included 18,017 participants (mean age = 38 years, SD = 12 years), with a median follow-up of 12 years. Among 206,783 person-years of follow-up, we identified 225 cases of ORC. We found no significant associations between vitamin D intake and ORC risk after adjusting for potential confounders: HRQ2vsQ1 = 1.19 (95% CI 0.81–1.75), HRQ3vsQ1 = 1.20 (95% CI 0.81–1.78), and HRQ4vsQ1 = 1.02 (95% CI 0.69–1.51). Dietary and supplemented vitamin D do not seem to be associated with ORC prevention in the middle-aged Spanish population.

Introduction Since the approval a decade ago of everolimus in combination with endocrine therapy (ET), the treatment landscape of metastatic breast cancer (mBC) has changed dramatically. Endocrine monotherapy after progression to CDK4/6 inhibitors has shown a limited progression-free survival (PFS) below 3 months. Evidence of the efficacy of everolimus plus ET after CDK4/6 inhibitors is scarce. Methods We performed a retrospective observational study of patients with mBC treated with everolimus between September 2011 and April 2022 in 4 Spanish hospitals. Clinical and demographic data were collected from medical records. Our main objective was to estimate the median progression-free survival (mPFS) for everolimus + ET in patients previously treated with a CDK4/6 inhibitor. We also collected the adverse events (AE) related to everolimus. Quantitative variables were summarized with medians (range), and qualitative variables with proportions. We used the Kaplan-Meier method for survival estimates. Results We identified a total of 297 mBC patients treated with everolimus plus ET. The median follow-up time was 20 months (interquartile range: 1 – 97 months). In this cohort, the median age at diagnosis was 49 years (26 – 84 years). At the moment of starting everolimus, the median number of previous lines of treatment was 2 (0 – 12), 22% of patients were ‘de novo’ metastatic, 67% presented visceral involvement, 40% had received previous chemotherapy for advanced disease, and 51% (n=152) had received a previous CDK4/6 inhibitor. The ET combined with everolimus was exemestane (77%), fulvestrant (18%), and tamoxifen (5%). 45% of patients were alive at data cut-off. In patients previously treated with a CDK4/6 inhibitor, the estimated median PFS (mPFS) was 5.9 months (95%CI: 5.0 – 7.8 months). In patients without visceral involvement (n=52), mPFS was 7.2 months (95%CI: 5.5 – 11.0 months), and 5.6 months (95%CI: 3.9 – 7.8 months) in the presence of visceral metastasis (n=100). In patients without previous chemotherapy in the metastatic setting (n=109), mPFS was 7.2 months (95%CI: 5.9 – 8.4 months), and 4.6 months (95%CI: 3.1 – 5.7 months) for patients who had received previous chemotherapy (n=43). For patients without a previous CDK4/6 inhibitor (n=145), the median PFS was 8.3 months (95%CI: 6.4 – 10.3 months). Everolimus starting doses were 10 mg (83%), 5 mg (15%), and 7.5 mg (2%). Dexamethasone mouthwash was used by 44% of patients. The most frequent AE were mucositis (51%; 3% grade 3), anemia (41%; 3% grade 3), hyperglycemia (34%; 2% grade 3), rash (28%; 2% grade 3), neumonitis (21%; 2% grade 3), and diarrhea (17%; 1% grade 3). There were no grade 4-5 adverse events. Dose reduction was made in 35% of patients, and in 16% of patients the treatment was discontinued due to toxicity. Conclusions In our cohort, the use of everolimus plus ET in mBC patients previously treated with a CDK4/6 inhibitor showed a clinically significant benefit in terms of PFS, especially in patients without visceral metastasis, and no previous chemotherapy for advanced disease. In this real-world study, the toxicity profile of everolimus was manageable. Citation Format: Rodrigo Sánchez-Bayona, Manuel Alva, Alfonso López de sa, Yolanda Jerez Gilarranz, Ana Sánchez de torre, Pablo Tolosa, Alicia de luna, Sara López-Tarruella, Laura Lema, Fernando Moreno, Isabel Echavarria, Ainhoa Madariaga, Javier Benítez, Blanca Herrero, Macarena Rey, Justo Ortega, Salvador Gámez, Andrea Modrego, Rocío Martín Lozano, Luis Figuero-Pérez, Roberto Jiménez, Marta González Sevilla, Irene González, Marianela Bringas Beranek, María de toro, Tatiana Massarrah, María del Monte-Millán, Marina Pinardo, Luis Manso, Coralia Bueno-Muiño, José Ángel García-Sáenz, Miguel Martín, Eva Ciruelos. A real-world evidence study of everolimus plus endocrine therapy beyond CDK4/6 inhibitors for HR+/HER2- advanced breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-01-04.

Public Health Emergencies of International Concern, such as the coronavirus disease 2019 pandemic, have a devastating impact on an individual and societal level, and there is an urgent need to learn, understand and bridge the therapeutic gap at a time of extreme stress on the patient, health care systems and staff. Well-designed, controlled clinical trials play a crucial role in the discovery of novel diagnostic and management strategies; however, these catastrophic circumstances pose unique challenges in initiating research studies at institutional, national, and international levels, highlighting the importance of a coordinated, collaborative approach. This review discusses key elements necessary to consider for developing clinical trials within a Public Health Emergency setting.

Objective We sought to evaluate the role of intrinsic chromosomal aberrations in determining favorable outcome to weekly paclitaxel (WP) in patients with epithelial ovarian cancer (EOC). Methods We evaluated the common genomic aberrations of two patients with EOC and exceptional WP response in the GENIUS study ( NCT03740503 ). We then searched for potential markers of unusual outcomes to WP in a validation cohort. We performed shallow whole genome sequencing (sWGS) in the tumor tissue of women with EOC considered as short-responders (SR; progression with ≤3 cycles) and long-responders (LR; response at ≥8 cycles) to WP monotherapy. Results We identified two women with exceptional response to WP, lasting over four years, who shared chromosome 8 gain as a common genomic aberration. In order to validate our findings, we reviewed 188 patients with EOC treated with WP and selected 61 women (39 SR, 22 LR) with unusual responses. By sWGS, there was no differential alterations in the copy number changes in chromosome 8, or in genes related to angiogenesis, tubulin superfamily, cell-cycle, apoptosis and paclitaxel metabolism or transportation pathways. Amongst the LR group, we identified six exceptionally long responders (ExLR), with responses lasting over a year. In an exploratory analysis, there was increased amplification of angiogenesis (VEGFB, MMP9), tubulin superfamily (TSC2) and apoptosis related genes (BCL2L1, BAD) in ExLR compared to SR. We identified one patient with a complete response to WP for over 7 years. Molecular profiling identified unique amplifications in interleukin related genes (CXCR1, CXCR2, IL1A, IL1B), not detected in other patients. Conclusion Intrinsic tumor pathways may impact outcome with weekly paclitaxel monotherapy and further investigations are required.

Purpose:PARP inhibitors (PARPi) are standard-of-care therapy for high-grade serous ovarian cancer (HGSOC). We investigated combining cediranib (antiangiogenic) with olaparib (PARPi) at emergence of PARPi resistance.Patients and Methods:The proof-of-concept EVOLVE study (NCT02681237) assessed cediranib–olaparib combination therapy after progression on a PARPi. Women with HGSOC and radiographic evidence of disease progression were enrolled into one of three cohorts: platinum sensitive after PARPi; platinum resistant after PARPi; or progression on standard chemotherapy after progression on PARPi (exploratory cohort). Patients received olaparib tablets 300 mg twice daily with cediranib 20 mg once daily until progression or unacceptable toxicity. The coprimary endpoints were objective response rate (RECIST v1.1) and progression-free survival (PFS) at 16 weeks. Archival tissue (PARPi-naïve) and baseline biopsy (post-PARPi) samples were mandatory. Genomic mechanisms of resistance were assessed by whole-exome and RNA sequencing.Results:Among 34 heavily pretreated patients, objective responses were observed in 0 of 11 (0%) platinum-sensitive patients, 2 of 10 (20%) platinum-resistant patients, and 1 of 13 (8%) in the exploratory cohort. Sixteen-week PFS rates were 55%, 50%, and 39%, respectively. The most common grade 3 toxicities were diarrhea (12%) and anemia (9%). Acquired genomic alterations at PARPi progression were reversion mutations in BRCA1, BRCA2, or RAD51B (19%); CCNE1 amplification (16%); ABCB1 upregulation (15%); and SLFN11 downregulation (7%). Patients with reversion mutations in homologous recombination genes and/or ABCB1 upregulation had poor outcomes.Conclusions:This is currently the largest post-PARPi study identifying genomic mechanisms of resistance to PARPis. In this setting, the activity of cediranib–olaparib varied according to the PARPi resistance mechanism.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment landscape in front-line and recurrent high-grade serous ovarian cancer. Maintenance strategies with PARPi have been assessed in randomized phase III trials in ovarian cancer; switch maintenance in the case of olaparib, niraparib, and rucaparib; and concurrent followed by continuation maintenance with veliparib. These studies have shown progression-free survival advantage with PARPi maintenance, with no major adverse changes in the quality of life; however, overall survival data remain immature to date. PARPi have also been incorporated in clinical practice as a single-agent treatment strategy in high-grade serous ovarian cancer, mainly in women who harbor alterations in the BRCA1/2 genes or have alterations in the homologous recombination deficiency (HRD) pathway. Contemporary studies are looking into potentially synergistic combination strategies with anti-angiogenics and immune checkpoint inhibitors, among others. The expansion of PARPi treatment has not been limited to ovarian cancer; talazoparib is licensed in patients with HER2-negative breast cancer with germline BRCA mutations (BRCAm), and front-line olaparib maintenance in patients with pancreatic cancer with germline BRCAm. Numerous studies assessing PARPi either in monotherapy or in combination with other agents are ongoing in multiple tumors, including prostate, endometrial, brain, and gastric cancers. Many patients are being treated with PARPi, some for prolonged periods of time. As a result, a thorough knowledge of the potential short- and long-term adverse events and their management is warranted to improve patient safety, treatment efficacy, and towards maintaining an appropriate dose intensity.

Drug repurposing is an attractive option for oncology drug development. Itraconazole is an antifungal ergosterol synthesis inhibitor that has pleiotropic actions including cholesterol antagonism, inhibition of Hedgehog and mTOR pathways. We tested a panel of 28 epithelial ovarian cancer (EOC) cell lines with itraconazole to define its spectrum of activity. To identify synthetic lethality in combination with itraconazole, a whole-genome drop-out genome-scale clustered regularly interspaced short palindromic repeats sensitivity screen in two cell lines (TOV1946 and OVCAR5) was performed. On this basis, we conducted a phase I dose-escalation study assessing the combination of itraconazole and hydroxychloroquine in patients with platinum refractory EOC (NCT03081702). We identified a wide spectrum of sensitivity to itraconazole across the EOC cell lines. Pathway analysis showed significant involvement of lysosomal compartments, the trans-golgi network and late endosomes/lysosomes; similar pathways are phenocopied by the autophagy inhibitor, chloroquine. We then demonstrated that the combination of itraconazole and chloroquine displayed Bliss defined synergy in EOC cancer cell lines. Furthermore, there was an association of cytotoxic synergy with the ability to induce functional lysosome dysfunction, by chloroquine. Within the clinical trial, 11 patients received at least one cycle of itraconazole and hydroxychloroquine. Treatment was safe and feasible with the recommended phase II dose of 300 and 600 mg twice daily, respectively. No objective responses were detected. Pharmacodynamic measurements on serial biopsies demonstrated limited pharmacodynamic impact. In vitro, itraconazole and chloroquine have synergistic activity and exert a potent antitumor effect by affecting lysosomal function. The drug combination had no clinical antitumor activity in dose escalation. Significance: The combination of the antifungal drug itraconazole with antimalarial drug hydroxychloroquine leads to a cytotoxic lysosomal dysfunction, supporting the rational for further research on lysosomal targeting in ovarian cancer.

Background. Axillary surgical management in patients with node-positive breast cancer at the time of diagnosis converted to negative nodes through neoadjuvant chemotherapy (NAC) remains unclear. Removal of more than two sentinel nodes (SLNs) in these patients may decrease the false negative rate (FNR) of sentinel lymph node biopsies (SLNBs). We aim to analyse the detection rate (DR) and the FNR of SLNB assessment according to the number of SLNs removed. Methods. A retrospective study was performed from October 2012 to December 2018. Patients with invasive breast cancer who had a clinically node-positive disease at diagnosis and with a complete axillary response after neoadjuvant chemotherapy were selected. Patients included underwent SLNB and axillary lymph node dissection (ALND) after NAC. The SLN was considered positive if any residual disease was detected. Descriptive statistics were used to describe the clinicopathologic features and the results of SLNB and ALND. The DR of SLNB was defined as the number of patients with successful identification of SLN. Presence of residual disease in ALND and negative SLN was considered false negative. Results. A total of 368 patients with invasive breast cancer who underwent surgery after complete NAC were studied. Of them, 85 patients met the eligibility criteria and were enrolled in the study. The mean age at diagnosis was 50.8 years. Systematic lymphadenectomy was performed in all patients, with an average of 10 lymph nodes removed. The DR of SLNB was 92.9%, and the FNR was 19.1. The median number of SLNs removed was 3, and at least, three SLNs were obtained in 42 patients (53.2%). When at least three sentinel nodes were removed, the FNR decreased to 8.7%. Conclusions. In this cohort, the SLN assessment was associated with an adequate DR and a high FNR. Removing three or more SLNs decreased the FNR from 19.1% to 8.7%. Complementary approaches may be considered for axillary lymph node staging after neoadjuvant chemotherapy. The study was approved by our institution’s ethics committee (Instituto de Investigacion Sanitaria Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain) (https://clinicaltrials.gov/ct2/show/NCEI:20/0048).

Purpose To provide evidence-based recommendations on the management of malignant bowel obstruction (MBO) for patients with advanced cancer. Methods The Multinational Association for Supportive Care in Cancer (MASCC) MBO study group conducted a systematic review of databases (inception to March 2021) to identify studies about patients with advanced cancer and MBO that reported on the following outcomes: symptom management, bowel obstruction resolution, prognosis, overall survival, and quality of life. The review was restricted to studies published in English, but no restrictions were placed on publication year, country, and study type. As per the MASCC Guidelines Policy, the findings were synthesized to determine the levels of evidence to support each MBO intervention and, ultimately, the graded recommendations and suggestions. Results The systematic review identified 17,656 published studies and 397 selected for the guidelines. The MASCC study group developed a total of 25 evidence-based suggestions and recommendations about the management of MBO-related nausea and vomiting, bowel movements, pain, inflammation, bowel decompression, and nutrition. Expert consensus-based guidance about advanced care planning and psychosocial support is also provided. Conclusion This MASCC Guideline provides comprehensive, evidence-based recommendations about MBO management for patients with advanced cancer.

ObjectivesIn response to the COVID-19 pandemic there have been significant developments in research, its conduct and the supporting ethical framework. While many protocols have been delayed, halted or modified, other research efforts have been accelerated, generating controversy. The goal of this paper is to determine the rates of references surrounding the ethical oversight of research as reported in current COVID-19-related research publications.DesignScoping review.SettingPopulation-based observational or interventional studies from December 2019 to May 2020 with sample size of two or more. Studies were searched through electronic databases including Medline, EMBASE, and Cochrane CENTRAL Register of Controlled Trials.ParticipantsEligibility criteria included participants within published studies who tested positive for COVID-19.Main outcomes and measuresData were extracted and charting methods included taking note of references to ethical frameworks, institutional review board (IRB), ethics committee (EC) or research ethics board (REB) involvement, consent processes, and other variables.Results11 556 articles were screened, with 656 included in the final analysis. References to ethics were present in 530 (80.8%) studies, with 491 (74.8%) involving IRB/ECs/REBs and 126 (19.2%) not referencing ethics. Consent processes were outlined in 201 (30.6%) studies, with 198 (30.2%) reporting that they obtained consent waivers, however, 257 (39.2%) did not mention consent at all. Differences (pConclusionsThe majority of published articles pertaining to COVID-19 research made mention of ethical considerations, however, national and regional variations in research ethics review requirements introduce heterogeneity between studies and raise important questions about the conduct of scientific research during global public emergencies.Trial registration numberOpen Science Framework: https://osfio/z67wb.

PURPOSE: Treatment for patients with recurrent endometrioid endometrial cancer (EEC) are limited as paclitaxel is the only second line chemotherapy with a response rate >13%. Targeting PIK3/mTOR in combination with hormonal therapy has shown promise. The addition of metformin may enhance this response. We conducted a phase II study evaluating everolimus, letrozole, and metformin in advanced/recurrent ECC. EXPERIMENTAL DESIGN: A Simon two-stage design was employed. Women with ≤2 prior chemotherapy regimens for recurrence were eligible. Pre-treatment biopsy was required, followed by everolimus 10mg PO, letrozole 2.5mg PO, and metformin 500mg PO BID on a 4 week cycle. The primary endpoint was clinical benefit (CB), defined as complete response (CR), partial response (PR), or stable disease (SD) confirmed at 16 weeks. Patients were treated until progression or toxicity. RESULTS: Sixty-two patients were enrolled. Median age was 62 years (40 – 77) with 401 cycles completed, median of 6 cycles (1 – 31). Fifty-four patients were evaluable for response with a CB rate of 50% (27/54). Best overall response (OR) was PR 28% (15/54) and SD 22% (12/54). Thirteen patients received > 12 cycles. Median follow-up was 17.9 months (2 – 47). Median PFS was 5.7 (95% CI 3.0 to 8.1) and OS was 19.6 months (95% CI 14.2 to 26.3). Positive progesterone receptor expression was associated with CB (89.5% versus 27.3%, p=0.001). CONCLUSIONS: Everolimus, letrozole and metformin resulted in 50% CB and 28% OR in women with recurrent EC. Progesterone receptor positive tumors may have better response; validation studies are needed.

Epithelial ovarian cancer has a very high rate of relapse after primary therapy; historically approximately 70% of patients with a complete clinical response to surgery and adjuvant chemotherapy will relapse and die of the disease. Although this number has slowly improved, cure rates remain less than 50%. As such, maintenance therapy with the aim of preventing or delaying disease relapse and the goal of improving overall survival has been the subject of intense study. Numerous earlier studies with agents ranging from radioactive phosphorus to extended frontline therapy or to monthly taxol administration demonstrated encouraging improvements in progression-free survival (PFS) only to find, disappointingly, no benefit in overall survival. In addition, the PFS advantage of maintenance therapy was associated with disconcerting side effects such that maintenance therapy was not adapted as standard of care. Studies with bevacizumab and PARP inhibitors have demonstrated a PFS advantage with a manageable side-effect profile. However, an overall survival advantage remains unclear, and the use of these approaches thus remains controversial. Furthermore, in recurrent disease, the length of chemotherapy and benefits of extended chemotherapy is unclear. Thus, additional trials assessing maintenance strategies in ovarian and other gynecologic malignancies are needed.

5579 Background: Adavosertib (AZD-1775) is a potent small molecule inhibitor of Wee-1, currently in clinical development. In a double-blind, placebo-controlled, phase 2 trial (NCT02151292), adavosertib and gemcitabine significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with recurrent platinum-resistant or platinum-refractory high grade serous ovarian cancer (HGSOV) compared to gemcitabine alone. We investigated whether plasma and intra-tumoral adavosertib concentrations correlated with survival in these patients. Methods: Adavosertib was administered orally on Days 1, 2, 8, 9, 15 and 16 at 175 mg per day, and gemcitabine was administered on Days 1, 8 and 15 at 1000 mg/m2 every 28 days. Serial blood samples were collected on Day 1 of cycle 1 after adavosertib administration. Tumor biopsies were taken 1-2 weeks after initiation of study treatments. Plasma and tumor adavosertib concentrations were determined using validated HPLC-MS/MS. Patients were divided into groups with plasma or tumor adavosertib concentrations above or below the biologically active concentration (BAC) of 125 ng/ml (Leijen et al, J Clin Onco 2016). Survival was described using the Kaplan-Meier method. Results: Among 61 HGSOV patients who received adavosertib, plasma samples were available in 47, and tumor samples were available in 31 patients. Among 25 non-HGSOV patients (exploratory cohort), plasma and tumor samples were available in 21 and 17 patients respectively. The mean maximum adavosertib concentration (Cmax) was 355.3 ± 120.9 ng/ml and 358.6 ± 117.9 ng/ml respectively. Cmax was above BAC in all patients. The mean tumor adavosertib concentration was 609.2 ± 1129.2 ng/ml (range: 0.47 – 5501 ng/ml) for HGSOV patients, and 964.2 ± 1611.2 ng/ml (range: 0.22 – 6116 ng/ml) for non-HGSOV patients. There was no correlation between Cmax and tumor adavosertib concentrations. In HGSOV, the median PFS was 5.8 months for patients with tumor concentrations above BAC, and 3.5 months for those with tumor concentrations below BAC (Hazard ratio (HR): 0.46, 95% confidence interval: 0.19 – 1.14, p = 0.06). No difference in PFS was seen in non-HGSOV patients according to tumor adavosertib concentration. Tumor adavosertib concentration did not correlate with OS. Conclusions: Although Cmax was above BAC in all patients, there was a high variability in tumor adavosertib concentrations. In HGSOV, higher tumor adavosertib concentration was associated with a trend towards improved PFS, but not OS. Our results indicate that the current adavosertib dosing regimen may not produce the desired concentrations in tumors for some patients, and further optimization may be needed.

Background Despite the growing integration of mandatory biopsies for correlative endpoints within oncology clinical trials, there are sparse data on patient-reported outcomes, perceptions, and preferences. Objective This study aimed to prospectively assess the impact of research biopsies on the quality of life in patients with gynecologic cancer, evaluate patient-reported outcomes, and determine factors associated with patients’ willingness to undergo sequential biopsies. Study Design We conducted a prospective study in patients with gynecologic malignancies undergoing research biopsies between 2015 and 2019 at Princess Margaret Cancer Centre ( ClinicalTrials.gov Identifier: NCT02334761 ). Here, we report the results of the paper-based surveys performed before and 1 week after biopsy. Although the questionnaires each assessed the impact of anxiety using a modified version of the Hospital Anxiety and Depression Scale, the postbiopsy questionnaire specifically assessed the likelihood of future biopsies, postbiopsy symptoms, complications, and perceptions. Results A total of 129 patients were enrolled, of which 91 (70.5%) completed at least 1 questionnaire. These patients had either ovarian (89%; 81 of 91) or endometrial cancer (11%; 10 of 91). Of all biopsies taken, 75% were from the abdomen or pelvis (67 of 89). There was 1 clinician-reported complication, a perihepatic hematoma (1%). Pain during the biopsy and physical discomfort were experienced by 60.3% (41 of 68) and 61.8% (42 of 68), respectively. Embarrassment and loss of dignity were experienced by 13.2% (9 of 68) and 11.8% (8 of 68), respectively. Although the mean Hospital Anxiety and Depression Scale score was in the normal range before and after biopsy, there was a significant decline in the total score after the biopsy (prebiopsy, 5.3 [standard deviation, 4.7] vs postbiopsy, 3.7 [standard deviation, 4.5]; P=.005); 84% of subjects (58 of 69) stated that they would definitely or likely consent to another biopsy. There was no impact on patients’ willingness for future biopsies based on Eastern Cooperative Oncology Group status, biopsy site, age, number of cores, and pain during the biopsy; however, subjects who reported feeling physically uncomfortable (odds ratio, 0.14; P=.005), embarrassed (odds ratio, 0.03; P=.004) or experienced loss of dignity (odds ratio, 0.05; P=.01) during the biopsy and those who experienced flu-like symptoms (odds ratio, 0.2; P=.018) or felt feverish (odds ratio, 0.2; P=.035) 1 week after biopsy, were less likely to undergo a sequential biopsy. Similarly, those with higher Hospital Anxiety and Depression Scale scores before biopsy (odds ratio, 0.83; P=.008) and after biopsy (odds ratio, 0.8; P=.003) were less likely to consent for another biopsy. Conclusion Research biopsies were generally well accepted. Most patients (83%) were willing to undergo serial biopsies if necessary. Addressing the potentially modifiable psychosocial aspects of the procedure may improve the experience with research biopsies for patients with gynecologic cancers.

ObjectiveMucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer with scarce literature guiding its management. We aimed to investigate the optimal surgical management of clinical stage I mucinous ovarian carcinoma by examining the prognostic significance of lymphadenectomy and intra-operative rupture on patient survival.MethodsWe conducted a retrospective cohort study of all pathology-reviewed invasive mucinous ovarian carcinomas diagnosed between 1999 and 2019 at two tertiary care cancer centers. Baseline demographics, surgical management details, and outcomes were collected. Five-year overall survival, recurrence-free survival, and the association of lymphadenectomy and intra-operative rupture on survival were examined.ResultsOf 170 women with mucinous ovarian carcinoma, 149 (88%) had clinical stage I disease. Forty-eight (32%; n=149) patients had a pelvic and/or para-aortic lymphadenectomy, but only 1 patient with grade 2 disease was upstaged due to positive pelvic lymph nodes. Intra-operative tumor rupture was documented in 52 cases (35%). On multivariable analysis, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between intra-operative rupture with overall survival (HR 2.2 (0.6–8.0); p=0.3) or recurrence-free survival (HR 1.3 (0.5–3.3); p=0.6), or lymphadenectomy with overall survival (HR 0.9 (0.3–2.8); p=0.9) or recurrence-free survival (HR 1.2 (0.5–3.0); p=0.7). Advanced stage was the only factor that was significantly associated with survival.ConclusionsIn clinical stage I mucinous ovarian carcinoma, systematic lymphadenectomy has low utility, as very few patients are upstaged and recurrence typically occurs in the peritoneum. Furthermore, intra-operative rupture does not appear to independently confer a worse survival, and therefore these women may not benefit from adjuvant treatment based on rupture alone.

Objectives: The aim of this study was to assess the impact of research biopsies on quality of life of patients (pts) with gynecologic malignancies, and determine which factors are associated with the pts willingness to undergo future biopsies. Methods: We conducted a prospective study on pts with gynecologic malignancies undergoing research biopsies between 2015 and 2020 at a tertiary Canadian cancer centre. Eligible pts were ≥18 years old and had an ECOG status of ≤2. Pts completed the questionnaires prior to the biopsy (Q1) and 1 week after the biopsy (Q2). Q1 collected general information, perceived risks and the modified Hospital Anxiety and Depression Scale (HADS; range 0-21, normal Results: 129 pts were enrolled, 88 were evaluable and completed Q1/Q2. The site of biopsy was abdomen/pelvis 78%, liver 16%, other 6%. Pts had predominantly recurrent disease (99%), 91% had ovarian and 9% endometrial cancer. Median age was 61.5 years (32-80). Ethnicity was White in 79%, Asian 15%, and others in 6% of pts. 92% of pts were involved in interventional clinical trials. Mean time from biopsy request to biopsy was 10.4 days (standard deviation [sd] 13.9). The mean HADS score was within normal ranges in Q1 and Q2, with a significant decline in the total score after the biopsy (Q1 5.3 [sd 4.7] and Q2 3.7 [sd 4.5]; p=0.005). Figure 1 describes the pts reported post-biopsy symptoms and perceptions in Q2. At Q2, 83% of pts reported that they would definitely or likely consent for another research biopsy. We then correlated each of the factors with pts willingness to undergo future research biopsies. There was no significant difference according to ECOG status (p=0.74), site of biopsy (p=0.99), age (p=0.56). None of the post-biopsy reported symptoms showed a significant impact in pts willingness to undergo future biopsies, including feverish feeling (OR:0.33, p=0.12), nausea/vomiting (OR:0.51, p=0.3), pain in biopsy area (OR:0.4, p=0.19), flu-like symptoms (OR:0.3, p=0.06). In terms of biopsy related perceptions, we did not detect a significant correlation with pain during procedure (OR:0.3 p=0.23). Whereas, pts with higher HADS scores in Q2 (OR:0.83, p=0.005), those who felt physically uncomfortable (OR:0.1, p=0.02), felt embarrassed (OR:0.03, p=0.005), or felt loss of dignity during the biopsy (OR:0.05, p=0.015) were less likely to consent for future research biopsies. Download : Download high-res image (244KB) Download : Download full-size image Conclusions: Research biopsies were generally well accepted in pts that underwent a biopsy, and 83% of pts reported willingness to undergo subsequent research biopsies. The mean HADS level was within normal ranges before the biopsy and decreased significantly post-procedure. Higher HADS scores, embarrassment, loss of dignity and physical discomfort during the procedure significantly influenced the likelihood of obtaining serial biopsies. A better understanding of the impact of research biopsies in pts is vital to improve their experience.

Objectives: Mucinous ovarian carcinoma (MOC) is the most common histology in young women eligible for fertility-sparing surgery. The aim of the study was to evaluate the safety and reproductive outcomes after fertility-sparing surgery in invasive mucinous ovarian carcinomas. Methods: A retrospective review was performed of all MOCs diagnosed between 1999 and 2019 at two tertiary care cancer centers. Pathology was reviewed to rule out cases with metastasis from gastrointestinal tract primary. The demographics and survival outcomes were compared between women who underwent fertility-sparing surgery and those who underwent radical surgery (at least hysterectomy, bilateral salpingo-oophorectomy±staging). Five-year overall survival (OS) and recurrence free survival (RFS) were calculated from Kaplan-Meier curves and comparisons made using log-rank test. Cox proportional hazard models were constructed to evaluate the effect of fertility sparing surgery on survival. Results: Of 149 women with apparent stage I disease upon presentation, 43 (29%) underwent fertility-sparing surgery in the form of unilateral salpingo-oophorectomy±omentectomy and lymphadenectomy. Compared to women who underwent radical surgery, these women were younger (30 years vs 55 years; p Conclusions: Fertility-sparing surgery in apparent stage I MOC is not associated with worse survival outcomes; however, it is important that candidates are carefully selected based on pathologic factors. In those with aggressive histologic components, radical surgery should be considered.

A 47-year-old woman was referred to Princess Margaret Cancer Centre, Toronto, Canada, in November 2016, with abdominal pain, distension, and weight loss. Baseline serum Ca125 was 1615 U/mL, and prior cytological analysis of ascitic fluid in October 2016 confirmed a diagnosis of high grade serous

Platinum chemotherapy remains the cornerstone of treatment for epithelial ovarian cancer (OC) and Poly (ADP-ribose) polymerase inhibitors (PARPi) now have an established role as maintenance therapy. The mechanisms of action of these agents is, in many ways, complementary, and crucially reliant on the intracellular DNA Damage Repair (DDR) response. Here, we review mechanisms of primary and acquired resistance to treatment with platinum and PARPi, examining the interplay between both classes of agents. A key resistance mechanism appears to be the restoration of the Homologous Recombination (HR) repair pathway, through BRCA reversion mutations and epigenetic upregulation of BRCA1. Alterations in non-homologous end-joint (NHEJ) repair, replication fork protection, upregulation of cellular drug efflux pumps, reduction in PARP1 activity and alterations to the tumour microenvironment have also been described. These resistance mechanisms reveal molecular vulnerabilities, which may be targeted to re-sensitise OC to platinum or PARPi treatment. Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation. Translational studies to elucidate mechanisms of treatment resistance should be incorporated into future clinical trials, as understanding these biologic mechanisms is crucial to developing new and effective therapeutic approaches in advanced OC.

Cervical cancer is the most common gynecologic malignancy worldwide.[1][1] The recommendation of adjuvant treatment following radical hysterectomy in early stage cervical cancer is usually tailored according to International Federation of Gynecology andObstetrics (FIGO) stage and risk factors.[1][1

Poly ADP-ribose polymerase (PARP) inhibitors have transformed the treatment landscape of high-grade ovarian cancer.[1][1] The presence of homologous recombination deficiencies and particularly alterations in the BRCA genes are well described biomarkers of response.[2][2] Until the American Society

High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination (HR) and transcriptional regulation. BRCA mutation confers distinct characteristics, including an increased response to DNA-damaging agents, such us platinum chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, several mechanisms of resistance to these agents have been described, including increased HR capacity through reverse BRCA mutations, non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps. Current treatments of ovarian cancer including surgery, chemotherapy, targeted treatment and maintenance strategies, as well as resistance mechanisms will be reviewed, focusing on future trends with respect to BRCA mutation carriers.

5541 Background: A 4 month improvement in OS was demonstrated when Wee1 inhibitor adavosertib (Ad) and gemcitabine (G; arm A) was compared to G and placebo (P; arm B) in a phase 2 trial in recurrent ovarian cancer (NCT02151292). The patient reported outcome version of the CTCAE (PRO-CTCAE) was used to capture self-report of the frequency, severity and/or interference (scored 0-4; higher scores indicating worse symptomatic adverse events [syAEs]). Methods: Ad/P was given orally on D1-2, D8-9, D15-16 with G D1, D8, D15 in a 28-day cycle. English speaking pts in 2 centres completed PRO-CTCAE items electronically in clinic at baseline, D1 and D15 of each cycle and off treatment. An exploratory objective was to characterize syAEs in the first 3 months of therapy. We calculated 12-week area under the curve (AUC12w) as a measure of syAE over time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs and compared arms A and B using an independent samples t-test. We assessed proportion of scores 3-4 at 6 time-points and compared them using Fisher’s Exact Test at each survey. Results: 51 pts were enrolled and completed ≥1 survey, 47 were evaluable for primary outcome (arm A: 28, B: 19). ECOG status was ≤1 in 44/47 pts. Median number of cycles of therapy were 5 (1-16) in arm A, and 2 (1-16) in B. Survey completion rates were high (arm A 93%, B 95%). Mean AUC12w fatigue severity (A 152 [standard error 9] vs B 112 [10]; p = 0.005) and interference (A 144 [11] vs 98 [15]; p = 0.018), diarrhea frequency (A 70 [12] vs B 33 [9]; p = 0.014), mucositis (A 23 [6] vs B 6 [3]; p = 0.012) and difficulty swallowing severity (A 10 [3] vs B 2 [2]; p = 0.023) were higher in arm A (any grade). There were no statistically significant between-arm differences in abdominal pain, bloating, nausea, vomiting and anxiety. The iAUC12w was significantly higher in arm A vs B for difficulty swallowing severity (A 10.1 [3] vs B -2.7 [4.7]; p = 0.02), mucositis severity (A 19.9 [6.6] vs B -3.1 [6.9]; p = 0.02) and fatigue severity (A 35.2 [8.2] vs B -3.1 [9.8]; p = 0.005). Proportions with high scores (3-4) were only significantly higher at C1D15 for fatigue severity in arm A (A 55% vs B 19%, p = 0.044). No significant differences were seen in other 3-4 scores per survey time. Conclusions: This is the first study evaluating pts self-reported toxicity with adavosertib in a randomized setting, allowing pts self-evaluation of toxicity in the context of improved PFS and OS. Greater fatigue, diarrhea, mucositis and difficulty swallowing were experienced by pts receiving adavosertib and gemcitabine, but score 3-4 reached significance on C1D15 fatigue only. No significant differences were detected in syAE profile for nausea, vomiting, abdominal pain, bloating and anxiety. This approach allows objective assessment of pts perception of toxicity with complex therapy. Clinical trial information: NCT02151292.

5574 Background: Treatment options in recurrent endometrial carcinoma (EC) are limited. Endometrioid EC shows alterations in PTEN, a possible biomarker of response to PARP inhibitors (PARPi). Similarly, homologous recombination deficiency (HRd), a biomarker of response to PARPi in ovarian cancer, is associated with serous EC harbouring TP53 mutations. Preclinical EC models have shown synergy between combining a PARPi and immune checkpoint inhibitor (ICI). Methods: A pilot multi-centre, non-randomized, phase II trial enrolled patients (pts) with recurrent serous or endometrioid EC in two consecutive cohorts (NCT03016338). In the first cohort (C1) pts received niraparib 200 or 300 mg qd, based on baseline body weight and platelet count, in 4 week (w) cycles. In the second cohort (C2) niraparib was given with dostarlimab 500 mg q 3 w for 4 cycles, followed by 1000 mg q 6 w thereafter. There was no limit on prior lines of therapy. Prior ICI was not allowed in C2. Primary endpoint was clinical benefit rate (CBR; complete, partial response or stable disease ≥16w). Secondary endpoints included toxicity assessment and ORR. CT scans were performed q 8 w. Potential biomarkers were assessed in archival tissue by IHC (PTEN, p53, MMR, PDL-1 [threshold 1%]) and a NGS panel (including TP53, PTEN, POLE and other HRd genes). Tumour mutational burden-high (TMBh) was defined as top 20% mutation load. Results: In C1, 25 pts were enrolled (23 evaluable for response). Median age was 69 years old, 64% had serous EC, 72% were platinum resistant (PlatR) and median prior therapies was 2 (range 1-4). Median number of cycles was 3. The CBR was 20% (95% CI: 9-39) and median clinical benefit (CB) duration was 5.3 (1.8-7.2) months. The ORR was 1/23 (4%; 0-20). Related grade (g) ≥3 AEs ≥10% were anemia (24%), fatigue (16%) and thrombocytopenia (16%). In C2, 22 pts were enrolled (all evaluable) and two continue on-treatment. Median age was 64 years old, 46% had serous EC, 68% were PlatR and median prior therapies was 2 (1-6). Three pts had MMR deficient (MMRd) tumors (14%) and one pt a POLE mutation (5%). Median number of cycles was 3. The CBR was 31.8% (16-53) and median CB duration was 6.8 months (3.7-9.5). The ORR was 3/22 (14%; 3-35), out of the three responders one had MMRd and one a POLE mutation. Related g≥3 AEs ≥10% were anemia (27%) and neutropenia (14%). No significant correlation was detected between CB and IHC markers (PTEN, p53, MMR, PDL-1), or NGS ( PTEN, TP53, HRd TMBh) in C1 and C2. Conclusions: Niraparib as single agent for treatment in a PlatR enriched recurrent EC population showed modest activity with clinical benefit rate at 16w of 20%. The combination of niraparib and dostarlimab showed a clinical benefit rate at 16w of 31.8% in a predominantly PlatR recurrent EC. PTEN loss by IHC or NGS, and alterations in HRd genes did not correlate with clinical benefit. Clinical trial information: NCT03016338.

Solitary fibrous tumors (SFTs) are a rare type of soft tissue sarcoma of unpredictable clinical behavior. Some clinicopathologic characteristics have also been related to patient outcome. This study is a retrospective review of 30 patients. We analyzed the clinical course and pathological factors to predict recurrence. The mean age was 55.9 years. Forty-five percent were located in the thoracic region. The mean tumor size was 10 cm (max24). Thirty-three percent had a relapse and 20 % have died. Median time to relapse was 7.18 (1–13) years. Median overall survival (OS) was 15.5 years (0–32). On histopathologic analysis, 6 % percent had >4 mitoses, 23 % had necroses, and 36 % had atypia/pleomorphism. Forty-three percent had tumor size >10 cm. Forty-six percent had at least one characteristic of malignancy. None of this data could predict clinical behavior by itself. SFT can be an aggressive disease and relapses can occur several years from diagnosis. We did not find any clinicopathologic factors that could predict the tumor behavior accurately. Nevertheless, it should be consider that we included different tumor locations and the sample size is small.

Many drugs can produce enterocolitis and they should always be included in the differential diagnosis of this clinical picture. Entities such as antibiotic-associated colitis and neutropenic colitis have been known for some time and recently a new type of drug-induced colitis has emerged due to monoclonal antibodies. Ipimumab is a humanized monoclonal antibody against the CTLA4 molecule that is involved in the maturation and regulation of T lymphocyte activation. This drug causes immune activation and has an immune-mediated antitumor effect with excellent results in tumours such as melanoma. However, several immune-related adverse effects may occur in different organs. The most frequently involved site is the gastrointestinal tract, with adverse effects ranging from mild diarrhoea to colitis with systemic involvement, intestinal perforation, and even death. Although no similarities have been found in the pathogenesis with inflammatory bowel disease, treatments have been used in correlation with its autoimmunological profile: anti-TNF alpha corticosteroids have shown clinical efficacy in moderate to severe disease. However the use of anti-TNF treatment has not been defined and the safety profile is unknown. The inclusion of these new therapies in the treatment of several tumours requires familiarity with these entities and their management should be approached as a new challenge for the gastroenterologist. For that reason, we conducted a review of ipilimumab-induced colitis, evaluating essential features of its symptoms, diagnosis and treatment.

6062 Background: Malignant Bowel Obstruction (MBO) is one of the most common and devastating complications in women with gynecological cancer (GC). There is currently no consensus guideline to improve patient (pt) care in this setting. MAMBO (NCT03260647) is an ongoing prospective study evaluating the clinical implementation of a novel management algorithm for multidisciplinary management of MBO in GC pts. We report preliminary patient outcomes. Methods: All GC pts at Princess Margaret Cancer Centre with a confirmed diagnosis of or are at risk of MBO are eligible for enrollment. Participants follow a low fiber diet titrated by severity of symptom and their monthly weight and albumin levels are recorded, along with standardized patient-reported outcome measures (PROMs) at different time points. For pts who develop MBO, inpatient and ambulatory management algorithms are applied using a multidisciplinary and interprofessional care model consisting of nurses, surgeons, oncologists, radiologists, nutritionists, total parenteral nutrition team, social work, and palliative care. Decisions regarding most optimal management strategies are made by this team with regular MAMBO rounds. A retrospective analysis of pts hospitalized with MBO between 2012 and 2017 was performed in order to have a historical comparison for outcome and survival analysis using Kaplan Meier methods. Results: Since August 2017, 70 pts have been enrolled in MAMBO. Most had high-grade serous ovarian carcinoma (75%), of whom 68% are platinum-resistant. So far, 36 (51%) developed MBO, 6 of whom had multiple sequential episodes. Mean number of days in hospital with MBO was 10 days (median 7, range 0-45), compared to 18 days (median 9, range 0-134) for historical control (p = 0.009). There was no significant loss in weight 6 months from MBO diagnosis but a significant reduction in albumin level by 2.75 g/L after 3 months (p = 0.005). PROMs suggest fatigue and general lack of wellbeing were the symptoms with highest distress. Most patients (78%) received chemotherapy following MBO and most received weekly paclitaxel (36%). Median time from first MBO to death was 219 days (95% CI: 101-not reached) for all-comers in MAMBO and 174 days (95% CI: 98-363) for MBO requiring hospitalization, compared to 108 days (95% CI: 79-160) for historical controls (p = 0.007 and p = 0.062, respectively). Conclusions: Patient care and outcomes from MBO seem to be improved in GC pts enrolled in MAMBO compared to historical controls. Clinical trial information: NCT03260647.

6049 Background: Autophagy is a mechanism of resistance to platinum chemotherapy. Itraconazole (Itr), an antifungal agent, can alter cholesterol-trafficking, leading to accumulation of cholesterol in endosomes/lysosomes and resulting in cancer cell death. Itr is also involved in regulation of angiogenesis, mTOR and Hedgehog pathways. In preclinical studies the Itr effect can be enhanced by combining it with the autophagy inhibitor hydroxychloroquine (H). Drug repurposing studies with Itr have shown a signal of activity in prostate, lung and basal cell carcinoma. Methods: A rolling-6 phase I design was used to enroll patients (pts) with platinum-resistant/refractory EOC. Pts received Itr 300mg twice daily (BID) with H as per dose escalation schedule (range 200mg BID- 600mg BID), continuously in a 28-day cycle. Primary objective was establishment of MTD; secondary objective was objective response rate, progression free survival (PFS). Pre- and on-treatment biopsies were mandatory to evaluate exploratory objectives assessing effect on apoptosis/proliferation, angiogenesis, cholesterol metabolism and mechanism of cytotoxicity. RNAseq and IHC was performed in the sequential biopsies. Results: 11 pts were enrolled, 9 evaluable for efficacy. Histology was high 91% and low-grade serous 9%. Median lines of prior therapy was 7. RP2D was Itr 300mg BID and H 600mg BID. 1 DLT was seen in dose-level 2 was grade 3 hypertension. Other grade ≥3 related toxicity were grade 3 hypokalemia and grade 4 QTc prolongation (1 pt, dose-level 3). No objective responses were observed and 1 pt had stable disease. Median PFS was 1.6 months (1-1.7). Pre- and on-treatment biopsy was available for 10 pts. Increase in autophagy related protein, LC3, P62 and lysosomal marker, LAMP1, expression by IHC was identified in 3 pts. RNAseq revealed no differences between pre and on treatment samples in cholesterol homeostasis, angiogenesis, lysosomal-autophagy, PI3K-mTOR pathways. Conclusions: The combination of Itr and H was feasible but did not show antitumour activity in this heavily pre-treated platinum resistant EOC population. Increase of IHC expression in autophagy related proteins was detected in 30% of pts but did not correlate with patient benefit. Clinical trial information: NCT03081702. [Table: see text]