Epithelial ovarian cancer: Evolution of management in the era of precision medicine.

Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.

Survival with Cemiplimab in Recurrent Cervical Cancer.

BACKGROUND: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. METHODS: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. RESULTS: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P<0.001). The overall survival benefit was consistent in both histologic subgroups (squamous-cell carcinoma and adenocarcinoma [including adenosquamous carcinoma]). Progression-free survival was also longer in the cemiplimab group than in the chemotherapy group in the overall population (hazard ratio for disease progression or death, 0.75; 95% CI, 0.63 to 0.89; two-sided P<0.001). In the overall population, an objective response occurred in 16.4% (95% CI, 12.5 to 21.1) of the patients in the cemiplimab group, as compared with 6.3% (95% CI, 3.8 to 9.6) in the chemotherapy group. An objective response occurred in 18% (95% CI, 11 to 28) of the cemiplimab-treated patients with PD-L1 expression greater than or equal to 1% and in 11% (95% CI, 4 to 25) of those with PD-L1 expression of less than 1%. Overall, grade 3 or higher adverse events occurred in 45.0% of the patients who received cemiplimab and in 53.4% of those who received chemotherapy. CONCLUSIONS: Survival was significantly longer with cemiplimab than with single-agent chemotherapy among patients with recurrent cervical cancer after first-line platinum-containing chemotherapy. (Funded by Regeneron Pharmaceuticals and Sanofi; EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 ClinicalTrials.gov number, NCT03257267.).

Correlating the KELIM (CA125 elimination rate constant K) score and the chemo-response score as predictors of chemosensitivity in patients with advanced ovarian carcinoma.

BACKGROUND: The objective of this study is to assess the correlation between the pre-operative CA125 Elimination rate constant K(KELIM) score and the intraoperative chemo-response score (CRS) in patients with advanced high grade serous ovarian cancer(HGSC) treated with neoadjuvant chemotherapy(NACT). METHODS: This is a retrospective cohort study of patients with Stage III-IV HGSC treated with NACT from March 2010 to December 2019 at Princess Margaret Cancer Center, Toronto, Canada. KELIM scores were calculated based on the tool devised by You et al. available online. CRS was assessed using an established 3-tier scoring system. An association analysis was performed to determine if the KELIM score assessed during NACT can predict CRS score at the time of interval cytoreductive surgery(ICS). RESULTS: 172 patients were included in this analysis. Patients with CRS 1-2 had a lower median Platinum Free Interval(PFI) (9.24 vs 13.64 months, p = 0.005), lower median progression free survival(PFS) (14.99 vs 20.29 months, p = 0.003) and lower 5-year overall survival(OS) (63.8% vs 69.7%, p = 0.54) compared to patients with CRS3. Among patients with CRS 1-2(n = 115), 68.7% had KELIM <1, while 56.2% of patients with CRS3 had KELIM ≥1(56.2%), p = 0.0017, suggesting a correlation between the KELIM and CRS scores. Furthermore, patients with KELIM ≥1 and CRS3 had significantly higher PFS compared to other groups(median PFS 28.27 months vs 17.66 months for KELIM ≥1/CRS 1/2; 17.13 months for KELIM <1/CRS 3; and 14.53 months for KELIM <1/CRS 1-2, p = 0.003). CONCLUSION: The biochemical KELIM score correlated with the surgical pathologic CRS score and may predict pathological response to chemotherapy. This information can be utilized to tailor and personalize treatment in patients with advanced ovarian malignancy.

High grade adverse event reporting and enrolment in gynecologic oncology clinical trials.

OBJECTIVE: The primary objective is to assess factors associated with treatment related high grade (CTCAE grade ≥ 3) adverse event (AE) reporting among participants in gynecologic oncology clinical trials. METHODS: All AEs recorded in the Princess Margaret Clinical Trial adverse event database between 01/2016 and 12/2018 were evaluated. Gynecologic oncology clinical trials assessing systemic therapy were included. Inferential statistics on risk factors of related grade ≥ 3 adverse event reporting and GEE logistic models with Odds Ratios (OR) were performed. Multivariable analysis adjusting for age, clinical trial phase, sponsor, and therapy type. RESULTS: The gynecology cancer clinical trials accrued 317 unique patients (359 nested on trials) in 42 systemic therapy trials. In the period, 17,175 related AEs were reported in the gynecological cancer trials, 7.4% were grade ≥ 3. On multivariable analysis, no odds differences of grade ≥ 3 related AEs were detected according to study phase. Patients in immunotherapy clinical trials had lower odds of related grade ≥ 3 AEs than patients on targeted or other therapy (adjusted OR [aOR] 0.43; 95% CI 0.24-0.75). There was greater odds of related grade ≥ 3 AEs in clinical trials assessing combination vs single therapeutics (aOR 2.26, 95% CI 1.34-3.80). Patients aged ≥65 (aOR 1.77; 95% CI 1.08-2.89) had greater odds of related grade ≥ 3 AEs than patients aged 50 to 65 years. When compared to other disease sites, the odds of having a grade  ≥ 3 related AE reported in gynecology clinical trials was no different. CONCLUSIONS: In this cohort, factors influencing the odds of related grade ≥ 3 AE reporting in gynecologic trials included type of therapy and age. The study phase did not correlate with odds of high-grade AE reporting.

HER2-low and Overexpression in Mucinous Ovarian Cancer: Analysis of ASCO/CAP and ToGA Immunohistochemical Scoring.

Mucinous ovarian carcinoma is an uncommon malignancy characterized by resistance to chemotherapy and poor survival in the metastatic setting. HER2 amplification is a frequent late event in carcinogenesis, yet the incidence of HER2-low in mucinous ovarian carcinoma is unknown. Further, the optimal method for determining overexpression in these tumors is not established. We sought to assess the ASCO/CAP and ToGA trial scoring methods for HER2 IHC with correlation to FISH, p53, and mismatch repair protein status and to determine the incidence of HER2-low in mucinous ovarian carcinoma. A total of 29 tumors from 23 patients were included. Immunohistochemistry for HER2, p53, MLH1, PMS2, MSH2, and MSH6 was performed. Scoring was performed according to the ASCO/CAP and ToGA trial criteria. HER2 FISH was performed and scored according to the ASCO/CAP criteria. The proportion of HER2-low, defined as 1+ or 2+ staining with negative FISH, was determined. Using ASCO/CAP, 26% demonstrated 3+ while 35% demonstrated 2+ staining. Using ToGA, 30% demonstrated 3+ while 57% demonstrated 2+ staining. By FISH, 26% were positive for HER2 amplification. Both systems captured all FISH-positive cases; the use of ASCO/CAP resulted in fewer equivocal and false-positive cases. Among HER2-negative cases, 88% were HER2-low. Aberrant p53 expression was detected in 55% of cases; mismatch repair deficiency was not identified in any cases. ASCO/CAP guidelines are accurate and resource-effective in determining HER2 overexpression in mucinous ovarian carcinoma. HER2-low is common in these tumors; further studies to determine the role of HER2-targeted therapy including antibody-drug conjugates are indicated.

Electronic malignant bowel obstruction symptom monitoring smartphone application for patients with gynecologic cancers.

OBJECTIVES: Implementation of an interprofessional program at Princess Margaret Cancer Centre, including nurse-led proactive calls to support patients with gynecologic cancers with malignant bowel obstruction, demonstrated improved outcomes compared with historical controls. The aim of the study was to convert the proactive calls into an electronic monitoring program to assess it's feasibility and scalability in patients with gynecologic cancers with or at risk of malignant bowel obstruction. METHODS: 'My Bowels on Track' smartphone application included weekly/biweekly electronic patient-reported outcomes (PROs), educational materials, and a secure messaging system. Based on PRO answers, an alerting system flagged patients with symptoms or uncompleted PROs. Nurses tracked and called patients on receiving clinical or compliance alerts. The primary objective was to assess adherence (≥70% PRO completion per patient considered an adherent patient) in the first 2 months on the program. A secondary objective was to assess the positive predictive value (PPV) of the alerts to trigger recommendations. RESULTS: Forty patients were enrolled between August 2021 and September 2022. Median age was 64.5 years (range 29-79 years). Primary diagnosis was ovarian (75%), endometrial (17.5%), or cervical (7.5%) cancer, and 92.5% of patients were receiving systemic therapy. Median duration on the program was 55 days (range 8-121 days). The 2-month adherence was 65% (95% CI 50% to 80%) and the overall adherence was 60% (95% CI 43% to 75%). Sixty-five symptom-related alerts (75% severe, 25% moderate) were reported in 60% (24/40) of patients. There were 59 recommendations triggered by the alerts. The PPV of the alerts to trigger actions was 72% (95% CI 58% to 82%). CONCLUSIONS: This pilot electronic malignant bowel obstruction monitoring program with real-time PRO assessment was feasible, and 65% of participants were adherent during the first 2 months on the program. The PRO response-based alerting system flagged concerning symptoms in 60% of participants, with a PPV of 72% to trigger nurse-led actions and/or management recommendations. TRIAL REGISTRATION NUMBER: NCT03260647.

Computational modeling of ovarian cancer dynamics suggests optimal strategies for therapy and screening.

High-grade serous tubo-ovarian carcinoma (HGSC) is a major cause of cancer-related death. Treatment is not uniform, with some patients undergoing primary debulking surgery followed by chemotherapy (PDS) and others being treated directly with chemotherapy and only having surgery after three to four cycles (NACT). Which strategy is optimal remains controversial. We developed a mathematical framework that simulates hierarchical or stochastic models of tumor initiation and reproduces the clinical course of HGSC. After estimating parameter values, we infer that most patients harbor chemoresistant HGSC cells at diagnosis and that, if the tumor burden is not too large and complete debulking can be achieved, PDS is superior to NACT due to better depletion of resistant cells. We further predict that earlier diagnosis of primary HGSC, followed by complete debulking, could improve survival, but its benefit in relapsed patients is likely to be limited. These predictions are supported by primary clinical data from multiple cohorts. Our results have clear implications for these key issues in HGSC management.

Molecular, cellular and systemic aspects of epithelial ovarian cancer and its tumor microenvironment.

Ovarian cancer encompasses a heterogeneous group of malignancies that involve the ovaries, fallopian tubes and the peritoneal cavity. Despite major advances made within the field of cancer, the majority of patients with ovarian cancer are still being diagnosed at an advanced stage of the disease due to lack of effective screening tools. The overall survival of these patients has, therefore, not substantially improved over the past decades. Most patients undergo debulking surgery and treatment with chemotherapy, but often micrometastases remain and acquire resistance to the therapy, eventually leading to disease recurrence. Here, we summarize the current knowledge in epithelial ovarian cancer development and metastatic progression. For the most common subtypes, we focus further on the properties and functions of the immunosuppressive tumor microenvironment, including the extracellular matrix. Current and future treatment modalities are discussed and finally we provide an overview of the different experimental models used to develop novel therapies.

Safety of fertility sparing management in invasive mucinous ovarian carcinoma.

BACKGROUND: The aim of the study was to evaluate the safety of fertility-sparing surgery in invasive mucinous ovarian carcinomas (MOC). METHODS: Retrospective review was performed of MOCs diagnosed between 1999 and 2019 at two tertiary cancer centers. Pathology was reviewed to rule out metastasis from gastrointestinal tract. 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). Cox proportional hazard models were constructed to evaluate the effect of fertility sparing surgery on survival. RESULTS: Of 134 with stage I disease, 42 (31%) underwent fertility-sparing surgery with unilateral salpingo-oophorectomy. Compared to women who underwent radical surgery, these women were younger with low grade, early-stage disease. Two patients (5%) in the fertility-sparing cohort experienced a recurrence and 1 of these 2 patients died due to disease progression. There was no difference in either OS or RFS between those that underwent fertility-sparing surgery and radical surgery. In a multivariable analysis adjusting for age and use of adjuvant chemotherapy, fertility-sparing surgery was not significantly associated with OS (HR 0.18; 95% CI 0.01-2.78) or RFS (HR 0.19; 95% CI 0.03-1.45). There were 4 patients (9%) with documented full-term delivery with median interval to conception of 11 months. CONCLUSIONS: Fertility-sparing surgery in stage I MOC is not associated with worse outcomes compared to radical surgery and is reasonable to offer to those with early stage disease who wish to retain fertility.

Symptom screening with Targeted Early Palliative care (STEP) versus usual care for patients with advanced cancer: a mixed methods study.

PURPOSE: Although early palliative care is recommended, resource limitations prevent its routine implementation. We report on the preliminary findings of a mixed methods study involving a randomized controlled trial (RCT) of Symptom screening with Targeted Early Palliative care (STEP) and qualitative interviews. METHODS: Adults with advanced solid tumors and an oncologist-estimated prognosis of 6-36 months were randomized to STEP or symptom screening alone. STEP involved symptom screening at each outpatient oncology visit; moderate to severe scores triggered an email to a palliative care nurse, who offered referral to in-person outpatient palliative care. Patient-reported outcomes of quality of life (FACT-G7; primary outcome), depression (PHQ-9), symptom control (ESAS-r-CS), and satisfaction with care (FAMCARE P-16) were measured at baseline and 2, 4, and 6 months. Semi-structured interviews were conducted with a subset of participants. RESULTS: From Aug/2019 to Mar/2020 (trial halted due to COVID-19 pandemic), 69 participants were randomized to STEP (n = 33) or usual care (n = 36). At 6 months, 45% of STEP arm patients and 17% of screening alone participants had received palliative care (p = 0.009). Nonsignificant differences for all outcomes favored STEP: difference in change scores for FACT-G7 = 1.67 (95% CI: -1.43, 4.77); ESAS-r-CS = -5.51 (-14.29, 3.27); FAMCARE P-16 = 4.10 (-0.31, 8.51); PHQ-9 = -2.41 (-5.02, 0.20). Sixteen patients completed qualitative interviews, describing symptom screening as helpful to initiate communication; triggered referral as initially jarring but ultimately beneficial; and referral to palliative care as timely. CONCLUSION: Despite lack of power for this halted trial, preliminary results favored STEP and qualitative results demonstrated acceptability. Findings will inform an RCT of combined in-person and virtual STEP.

Overcoming PARP inhibitor resistance in ovarian cancer.

Ovarian cancer (OC) is one of the most lethal tumors in women, mostly diagnosed at advanced stages. Standard of care is based on surgery and platinum-based chemotherapy which provides high rates of response, although most patients will relapse. Poly(ADP-ribose) polymerase inhibitors (PARPi) have recently been incorporated in the treatment strategy for high-grade OC, particularly for those with defects in DNA repair pathways (homologous repair deficiency (HRd)). However, some tumor cells may not respond and some others will develop mechanisms of resistance to adapt. The most known mechanism of PARPi resistance is the reversion of HRd to homologous repair proficiency driven by epigenetic and genetic changes. Ongoing research is exploring different agents that are trying to re-sensitize tumor cells,overcome or bypass resistance to PARPi. Current investigations are focused on agents that target replication stress and DNA repair pathways, improve drug delivery, and target other cross-talk pathways. A crucial challenge in practice will be to identify and select patients for the appropriate therapy or combination strategies. However, efforts are needed to decrease overlapping toxicity and define the correct schedule timing of dosing to maximize the therapeutic index.

Gestational trophoblastic neoplasia: does centralization of care impact clinical management?

OBJECTIVE: International societies advocate for gestational trophoblastic neoplasia referral to designated expert centers. This study assessed the impact of centralization of trophoblastic care on clinical outcomes. METHODS: A centralized program was implemented in 2018 at two affiliated academic hospitals, Princess Margaret Cancer Center and Mount Sinai Hospital. A retrospective analysis of patients treated between 2000 and 2022 was performed and the clinical outcomes were compared before (2000-2017) and after (2018-2022) centralization. Statistical analyses were performed with significance set as p<0.05. RESULTS: A total of 94 patients with trophoblastic neoplasia were included: 60 pre-centralization and 34 post-centralization, 79.8% low-risk and 18.1% high-risk. Centralization led to significant improvement for: (1) accurate score documentation (from 37.9% to 89.3%,); (2) contraception counseling (from 67.2% to 96.7%); (3) median time from diagnosis to chemotherapy (from 9 days to 1 day); and (4) incomplete follow-up (from 20.7% to 3.3%) (all p<0.05). First-line chemotherapy for low-risk neoplasia was dactinomycin in 47.9% and 87.0% pre- and post-centralization, respectively (p=0.005). The median number of chemotherapy cycles decreased from seven to four (p=0.01), and the median number of consolidation cycles increased from two to three (p<0.001). Serum human chorionic gonadotropin (hCG) levels of 10 000-100 000 IU/L were significantly associated with longer time to hCG normalization and higher risk of resistance to first-line chemotherapy compared with hCG levels <1000 IU/L. CONCLUSION: Centralization of trophoblastic neoplasia care leads to greater guideline compliance, faster chemotherapy initiation, fewer chemotherapy cycles with optimized consolidation, and enhanced surveillance completion. This supports the establishment of trophoblastic neoplasia expert centers.

Impact of lymphadenectomy and intra-operative tumor rupture on survival in early-stage mucinous ovarian cancers.

OBJECTIVE: Mucinous 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. METHODS: We 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. RESULTS: Of 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. CONCLUSIONS: In 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.

A phase I study of the Wee1 kinase inhibitor adavosertib (AZD1775) in combination with chemoradiation in cervical, upper vaginal, and uterine cancers.

OBJECTIVE: Wee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers. METHODS: A multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45-50 Gy in 1.8-2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m2 and adavosertib 100 mg/m2 on days 1, 3 and 5 of each week during chemoradiation. The primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy. RESULTS: Ten patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level -1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free. CONCLUSION: The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.

Clinical parameters affecting survival outcomes in patients with low-grade serous ovarian carcinoma: an international multicentre analysis.

BACKGROUND: Women with low-grade ovarian serous carcinoma (LGSC) benefit from surgical treatment; however, the role of chemotherapy is controversial. We examined an international database through the Ovarian Cancer Association Consortium to identify factors that affect survival in LGSC. METHODS: We performed a retrospective cohort analysis of patients with LGSC who had had primary surgery and had overall survival data available. We performed univariate and multivariate analyses of progression-free survival and overall survival, and generated Kaplan-Meier survival curves. RESULTS: Of the 707 patients with LGSC, 680 (96.2%) had available overall survival data. The patients' median age overall was 54 years. Of the 659 patients with International Federation of Obstetrics and Gynecology stage data, 156 (23.7%) had stage I disease, 64 (9.7%) had stage II, 395 (59.9%) had stage III, and 44 (6.7%) had stage IV. Of the 377 patients with surgical data, 200 (53.0%) had no visible residual disease. Of the 361 patients with chemotherapy data, 330 (91.4%) received first-line platinum-based chemotherapy. The median follow-up duration was 5.0 years. The median progression-free survival and overall survival were 43.2 months and 110.4 months, respectively. Multivariate analysis indicated a statistically significant impact of stage and residual disease on progression-free survival and overall survival. Platinum-based chemotherapy was not associated with a survival advantage. CONCLUSION: This multicentre analysis indicates that complete surgical cytoreduction to no visible residual disease has the most impact on improved survival in LGSC. This finding could immediately inform and change practice.

Management of Malignant Bowel Obstruction: An Innovative Proactive Outpatient Nurse-Led Model of Care for Patients With Advanced Gynecologic Cancer.

BACKGROUND: Malignant bowel obstruction (MBO) in patients with advanced gynecologic cancer (GyCa) can negatively impact clinical outcomes and quality of life. Oncology nurses can support these patients with adequate tools/processes. PROBLEM: Patients with GyCa with/at risk of MBO endure frequent emergency or hospital admissions, impacting patient care. APPROACH: Optimizing oncology nurses' role to improve care for patients with GyCa with/at risk of MBO, the gynecology oncology interprofessional team collaborated to develop a proactive outpatient nurse-led MBO model of care (MOC). OUTCOMES: The MBO MOC involves a risk-based algorithm engaging interdisciplinary care, utilizing standardized tools, risk-based assessment, management, and education for patients and nurses. The MOC has improved patient-reported confidence level of bowel self-management and decreased hospitalization. Following education, nurses demonstrated increased knowledge in MBO management. CONCLUSIONS: An outpatient nurse-led MBO MOC can improve patient care and may be extended to other cancer centers, fostering collaboration and best practice.

New approaches for targeting platinum-resistant ovarian cancer.

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.

Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer. METHODS: In this double-blind, randomised, placebo-controlled, phase 2 trial, women with measurable recurrent platinum-resistant or platinum-refractory high-grade serous ovarian cancer were recruited from 11 academic centres in the USA and Canada. Women were eligible if they were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, a life expectancy of more than 3 months, and normal organ and marrow function. Women with ovarian cancer of non-high-grade serous histology were eligible for enrolment in a non-randomised exploratory cohort. Eligible participants with high-grade serous ovarian cancer were randomly assigned (2:1), using block randomisation (block size of three and six) and no stratification, to receive intravenous gemcitabine (1000 mg/m2 on days 1, 8, and 15) with either oral adavosertib (175 mg) or identical placebo once daily on days 1, 2, 8, 9, 15, and 16, in 28-day cycles until disease progression or unacceptable toxicity. Patients and the team caring for each patient were masked to treatment assignment. The primary endpoint was progression-free survival. The safety and efficacy analysis population comprised all patients who received at least one dose of treatment. The trial is registered with ClinicalTrials.gov, NCT02151292, and is closed to accrual. FINDINGS: Between Sept 22, 2014, and May 30, 2018, 124 women were enrolled, of whom 99 had high-grade serous ovarian cancer and were randomly assigned to adavosertib plus gemcitabine (65 [66%]) or placebo plus gemcitabine (34 [34%]). 25 women with non-high-grade serous ovarian cancer were enrolled in the exploratory cohort. After randomisation, five patients with high-grade serous ovarian cancer were found to be ineligible (four in the experimental group and one in the control group) and did not receive treatment. Median age for all treated patients (n=119) was 62 years (IQR 54-67). Progression-free survival was longer with adavosertib plus gemcitabine (median 4·6 months [95% CI 3·6-6·4] with adavosertib plus gemcitabine vs 3·0 months [1·8-3·8] with placebo plus gemcitabine; hazard ratio 0·55 [95% CI 0·35-0·90]; log-rank p=0·015). The most frequent grade 3 or worse adverse events were haematological (neutropenia in 38 [62%] of 61 participants in the adavosertib plus gemcitabine group vs ten [30%] of 33 in the placebo plus gemcitabine group; thrombocytopenia in 19 [31%] of 61 in the adavosertib plus gemcitabine group vs two [6%] of 33 in the placebo plus gemcitabine group). There were no treatment-related deaths; two patients (one in each group in the high-grade serous ovarian cancer cohort) died while on study medication (from sepsis in the experimental group and from disease progression in the control group). INTERPRETATION: The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. This therapeutic approach might be applicable to other tumour types with high replication stress; larger confirmatory studies are required. FUNDING: US National Cancer Institute Cancer Therapy Evaluation Program, Ontario Institute for Cancer Research, US Department of Defense, Princess Margaret Cancer Foundation, and AstraZeneca.

Validation of the KELIM score as a predictor of response to neoadjuvant treatment in patients with advanced high grade serous ovarian cancer.

OBJECTIVE: The objective of this study is to externally validate the KELIM (rate of elimination of CA-125 elimation) score in patients with high grade serous ovarian cancer(HGSC)undergoing NACT and determine its relation to outcome of cytoreduction, platinum sensitivity, progression free(PFS) and overall survival(OS). METHODS: This is a retrospective cohort study of patients with Stage III-IV HGSC diagnosed between January 1, 2010 and December 31, 2019 and treated with NACT. KELIM score was calculated using at least 3 CA-125 values within the first 100 days of chemotherapy. Demographic parameters were collected and Kaplan Meier survival analyses were performed for PFS and OS. This study was approved by local ethics board. RESULTS: 217 patients met inclusion criteria. Median follow-up was 28.93 months(range 2.86-135.06). There was no significant difference in stage, functional status, cytoreductive outcome or BRCA status(germline or somatic) between patients with a KELIM ≥ 1 and <1. Patients with a KELIM<1 had a lower median PFS (13.58 vs 19.69, p < 0.001), median platinum free interval(PFI) (7.66 vs 13.64, p < 0.001) and 5-year OS (57% vs 72%, p = 0.0140) compared to patients with KELIM≥1 . After adjusting for stage, treatment delays, bevacizumab or poly adenosine diphosphate-ribose polymerase(parp)-inhibitor use, and BRCA status, patients with KELIM<1 had a high risk of disease progression(HR = 1.57 (95% CI 1.08-2.28) and death(HR = 1.99 (95% CI 1.01-3.95) compared to KELIM≥1. BRCA status was independently associated to an increase on KELIM score (OR = 1.917, 95% CI 1.046-3.512, p = 0.035). CONCLUSION: Patients with advanced HGSC undergoing NACT with a KELIM <1 were more likely to have platinum-resistant disease, worse PFS and worse OS when compared to patients with KELIM≥1. The KELIM score can be a helpful tool to predict chemo-response and aid in treatment decision making.

Patient self-reporting of tolerability using PRO-CTCAE in a randomized double-blind, placebo-controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in patients with platinum resistant or refractory epithelial ovarian carcinoma.

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.