Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer.

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

Health care services utilization in patients with ovarian cancer receiving PARP inhibitor maintenance treatment in a US community oncology setting.

OBJECTIVES: The objective of this study was to describe healthcare resource use (HCRU) in addition to treatment patterns and discontinuations, in patients with ovarian cancer (OC) initiating PARP inhibitor (PARPi) maintenance treatment in a US community oncology setting. METHODS: This was a retrospective study of patients with OC initiating PARPi monotherapy maintenance during 01/01/2017 to 06/30/2019 (followed until 12/31/2019). Patients aged ≥18 years at first diagnosis of OC with ≥2 visits within The US Oncology Network were included. Structured and chart review data as well as claims data were used to describe treatment patterns and HCRU. RESULTS: Of the 162 charts reviewed, the median age of patients was 66 years and 80% had stage III or IV disease at diagnosis. In the niraparib, rucaparib and olaparib groups, proportions of patients experiencing dose interruptions were 51%, 50%, and 28%, and discontinuations due to toxicity were 37%, 17% and 15%, respectively. Within the first 6 months, mean numbers of total claims were 43.5, 56.4, and 36.0 in the niraparib, rucaparib, and olaparib groups, and laboratory claims were 13.9, 19.4, and 15.6, respectively. Proportions of patients with hospitalizations (niraparib 40%, rucaparib 32%, olaparib 19%; p = 0.03), also differed as did emergency department visits (niraparib 37%, rucaparib 23%, olaparib 16%; p = 0.02). CONCLUSION: Despite patients initiating niraparib having higher rates of dose management events and toxicity-related discontinuations, outpatient and laboratory utilization were similar across all three PARPi. Adequate monitoring of these medications, with differing toxicities, should be emphasized to potentially decrease dose reductions and toxicities.

A systematic review of stage IVA cervical cancer treatment: Challenges in the management of an understudied group.

OBJECTIVE: Stage IVA patients comprise a small proportion of participants in cervical cancer trials, yet survival outcomes are disproportionately poor. We aim to perform a systematic review evaluating stage IVA cervical cancer. METHODS: This systematic review was completed via PRISMA 2020 guidelines using two databases. Inclusion criteria comprised Phase III trials (2004-2024) assessing stage IVA cervical cancer including patients by stage. Searches had MeSH terms: ((cervical cancer) AND (stage IVA) AND (locally advanced)). 761 were articles identified, including books, trials, reviews, and meta-analyses. Of the articles identified, 12 met inclusion criteria. RESULTS: A total of 133 (3.8% of study populations) stage IVA and 818 (40% of study populations) stage III-IVA cervical cancer patients were analyzed. Two studies (stage IVA n = 15; 3.1%) established cisplatin as chemoradiotherapy agent of choice, while one study (stage IVA n = 2; 1%) showed no benefit with cisplatin versus radiotherapy alone. Four studies (stage IVA n = 32; 3.6%; stages IIIB-IVA n = 220; 24%) found no benefit with adjuvant chemotherapy, with one analyzing stage IIIB-IVA patients (progression-free survival (PFS) hazard ratio (HR) = 0.84; 95% confidence interval (CI): 0.57-1.23). Three studies (stage IVA n = 71; 5%) found no benefit adding immunomodulator (stage IVA overall survival HR = 3.48; 95% CI: 0.52-23.29), hypoxic cell sensitizer, or immunotherapy (stage III-IVA PFS HR = 0.71; 95% CI: 0.49-1.03) to chemoradiotherapy. One study (stages III-IVA n = 598; 56%) found benefit adding immunotherapy to chemoradiotherapy (stage III-IVA PFS HR = 0.58; 95% CI: 0.42-0.8). One study (stage IVA n = 13; 3.5%) showed benefit with induction chemotherapy. CONCLUSION: Trials have not included substantial IVA patients to draw reasonable conclusions. Despite mixed results for immunotherapy, adjuvant chemotherapy, and induction chemotherapy, the exact benefit for stage IVA patients remains unknown. Future clinical trials should include a greater number of stage IVA cervical cancer patients and analyze them individually.

Health-related quality of life in patients with newly diagnosed advanced ovarian cancer treated with niraparib vs placebo: Results from the phase 3 randomized PRIMA/ENGOT-OV26/GOG-3012 trial.

OBJECTIVE: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.

The power of hope: Views of Ovarian Cancer patients on how maintenance therapy Affects their Lives (VOCAL).

Aim: To assess maintenance preference and trade-offs for patients with advanced epithelial ovarian cancer. Methods: Patients completed a time trade-off exercise ranking five maintenance approaches. Patients' preferred approach was compared with alternatives to determine the progression-free time they would trade off to remain on their preferred approach. Results: Of 152 patients (median age 53 years, 68% White), 56% chose one of four maintenance medications, mostly to feel proactive and 44% chose active surveillance. Compared with their preferred approach, patients were willing to trade a mean progression-free time before switching of 2.3 months for once-daily oral medications, 3.2 months for twice-daily oral medications, 5.5 months for intravenous infusions every 3 weeks (iv. q3), 6.1 months for active surveillance and 7.5 months for iv. q3 and twice-daily oral. Conclusion: Findings highlight the importance of patients' awareness of all maintenance approaches and involving them in the decision-making process.

What is the article about? The VOCAL study looked at maintenance approach preferences of patients with advanced epithelial ovarian cancer. Maintenance approach refers to the methods used after a patient has completed their initial chemotherapy to prevent disease progression for as long as possible. US patients completed an online survey, ranking five different maintenance approaches: No medication (active surveillance); Once-daily oral medication (e.g. pills); Twice-daily oral medication; Medication by intravenous infusion every 3 weeks; Medication by intravenous infusion every 3 weeks and oral twice-daily. Patients were asked to assume the same time to disease progression for all five approaches and the same side effects for the four approaches involving medications (2­5). Each patient then indicated how much time to disease progression they were willing to trade off to remain on their preferred approach before switching to an alternative. What were the results? Overall, 152 patients completed the survey (median age: 53 years, 68% White). Most patients preferred a medication approach (56%, n = 85) to active surveillance (44%, n = 67). Of the 85 patients who preferred medication, 66% (n = 56) reported this was to feel proactive in preventing their cancer returning. Once-daily oral medication was the most acceptable alternative to the patients' preferred maintenance approach, given they were willing to trade the least 'disease-free' time (2.3 months) before accepting a switch. What do the results mean? Individual patient preferences vary, and healthcare professionals should work with patients to determine which approach is most appropriate for them.

Latest advances in immuno-oncology for endometrial cancer: single-agent and combination regimens.

PURPOSE OF REVIEW: The scope of immuno-oncology in endometrial cancer has changed rapidly in the last several years, requiring up-to-date knowledge for those who treat these patients. RECENT FINDINGS: This article will focus on molecular profiling, recent trials, and FDA approvals of targeted immuno-oncology medications in endometrial cancer. These include immune checkpoint inhibitors alone or with combination treatment. SUMMARY: The publication of the TCGA has led to significant focus on molecular subgroupings into POLEm, MMRd, NSMP, and p53m groups. For those patients with MMRd vs. MMRp tumors, there are indications for single agent immune checkpoint inhibitors with dostarlimab or pembrolizumab. For those with MMRp tumors, the addition of lenvatinib to pembrolizumab has proven clinical benefit. The recent publication of the RUBY and NRG-GY018 trials have shown clinical benefit in both subgroups with addition of immune checkpoint inhibitor to platinum-based chemotherapy. Now there is approval for use of dostarlimab in frontline chemotherapy and maintenance for advanced stage or recurrent endometrial cancer. Several upcoming trials investigating molecular subgroups from the TCGA are eagerly anticipated.

The impact of varying levels of residual disease following cytoreductive surgery on survival outcomes in patients with ovarian cancer: a meta-analysis.

BACKGROUND: Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease. METHODS: Medline, Embase, and Cochrane databases (January 2011 - July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy. RESULTS: Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0-1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0-1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0-1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p < 0.05). Subgroup analyses showed an association between residual disease and disease progression/reduced survival irrespective of type of surgery, disease stage, or type of adjuvant chemotherapy. CONCLUSIONS: This meta-analysis provided an update on the impact of residual disease following primary or interval cytoreductive surgery, and demonstrated that residual disease was still highly predictive of progression-free survival and overall survival in adults with ovarian cancer despite changes in ovarian cancer therapy over the last decade. Higher numerical categories of residual disease were associated with reduced survival than lower categories.

Multi-omics data integration reveals metabolome as the top predictor of the cervicovaginal microenvironment.

Emerging evidence suggests that host-microbe interaction in the cervicovaginal microenvironment contributes to cervical carcinogenesis, yet dissecting these complex interactions is challenging. Herein, we performed an integrated analysis of multiple "omics" datasets to develop predictive models of the cervicovaginal microenvironment and identify characteristic features of vaginal microbiome, genital inflammation and disease status. Microbiomes, vaginal pH, immunoproteomes and metabolomes were measured in cervicovaginal specimens collected from a cohort (n = 72) of Arizonan women with or without cervical neoplasm. Multi-omics integration methods, including neural networks (mmvec) and Random Forest supervised learning, were utilized to explore potential interactions and develop predictive models. Our integrated analyses revealed that immune and cancer biomarker concentrations were reliably predicted by Random Forest regressors trained on microbial and metabolic features, suggesting close correspondence between the vaginal microbiome, metabolome, and genital inflammation involved in cervical carcinogenesis. Furthermore, we show that features of the microbiome and host microenvironment, including metabolites, microbial taxa, and immune biomarkers are predictive of genital inflammation status, but only weakly to moderately predictive of cervical neoplastic disease status. Different feature classes were important for prediction of different phenotypes. Lipids (e.g. sphingolipids and long-chain unsaturated fatty acids) were strong predictors of genital inflammation, whereas predictions of vaginal microbiota and vaginal pH relied mostly on alterations in amino acid metabolism. Finally, we identified key immune biomarkers associated with the vaginal microbiota composition and vaginal pH (MIF), as well as genital inflammation (IL-6, IL-10, MIP-1α).

Correlation between progression-free survival and overall survival in patients with ovarian cancer after cytoreductive surgery: a systematic literature review.

OBJECTIVES: This analysis aimed to better define the relationship between progression-free survival and overall survival in adult patients with ovarian cancer (including fallopian tube or primary peritoneal cancer) following primary cytoreductive surgery or interval cytoreductive surgery. METHODS: A systematic literature review was carried out across the Medline, Embase, and Cochrane Central databases on 7 July 2020 (date limits 1 January 2011 to 7 July 2020) to identify studies with the following eligibility criteria: clinical trials/observational studies including >200 patients with ovarian cancer aged ≥18 years, evaluating overall survival/progression-free survival following cytoreductive surgery by residual disease status in the United States, Europe, Japan, or China. Weighted linear regression models were used to assess any correlation between median progression-free survival and overall survival, and between logHR for progression-free survival and logHR for overall survival. Risk of bias was assessed for all included studies. RESULTS: Of the 50 studies reported, 43 were observational studies (41 retrospective and two prospective cohort studies), and seven were reporting for randomized clinical trials-of which four were retrospective data analyses. For analyses of the relationship between overall survival and progression-free survival, 21 studies were eligible. The weighted linear regression model showed a strong positive association between the two survival endpoints. Goodness-of-fit analysis measured the adjusted R2 as 0.84 (p<0.001); a positive association was also observed between logHRs for overall survival and progression-free survival in the included studies. CONCLUSIONS: Median progression-free survival was predictive of median overall survival. This correlation between progression-free survival and overall survival after primary treatment for ovarian cancer highlights the validity of progression-free survival as a primary endpoint. Observational studies contributed most data, with limited information on disease stage and histology.

Factors Associated with Inpatient Narcotic Medication Usage after Robotic-assisted Laparoscopy.

STUDY OBJECTIVE: Describe factors that contribute to an increased narcotic medication use after robotic-assisted laparoscopic (RAL) surgery. DESIGN: A retrospective cohort. SETTING: A teaching hospital. PATIENTS: All patients undergoing RAL surgery by gynecologist oncologists at St. Joseph's Hospital and Medical Center over a 3-year period. INTERVENTIONS: RAL by gynecologist oncologists. MEASUREMENTS AND MAIN RESULTS: Using retrospective chart review, patients who underwent RAL surgery from 2012 to 2015 in the division of gynecologic oncology were identified; 757 patients were eligible for inclusion in the study. Total narcotic use during the postoperative hospital stay was converted to oral morphine milligram equivalents (OME). Bivariate correlations of total OME narcotics to multiple variables were evaluated using Spearman's rho. The average age, body mass index, and length of stay were 53.76 years (17-92), 31.75 kg/m2 (17-56), and 1.56 days (range, 0-19), respectively. Increased OME correlated positively with body mass index (Spearman's rho = .077, p = .036), any intraoperative complication (Spearman's rho = .05, p = .886), any postoperative complication (Spearman's rho = .16, p <.0001), length of stay in days (Spearman's rho = .282, p <.0001), procedure time (Spearman's rho .023, p = .52), and total anesthesia time (Spearman's rho, .032). Total OME narcotics were correlated negatively with age of 65 years or older (Spearman's rho, -.144, p <.0001) and use of patient-controlled analgesia (Spearman's rho, -.185, p <.0001). CONCLUSION: Age younger than 65 years seems to be a predictor for increased requirement of total morphine equivalent medication after RAL surgery, whereas patient-controlled analgesia use had a negative association.

Impact of disease progression on health-related quality of life of advanced ovarian cancer patients - Pooled analysis from the PRIMA trial.

OBJECTIVE: Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS: The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS: This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS: Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL.

Implicit biases in healthcare: implications and future directions for gynecologic oncology.

Health disparities have been found among patients with gynecologic cancers, with the greatest differences arising among groups based on racial, ethnic, and socioeconomic factors. Although there may be multiple social barriers that can influence health disparities, another potential influence may stem from healthcare system factors that unconsciously perpetuate bias toward patients who are racially and socioeconomically disadvantaged. More recent research suggested that providers hold these implicit biases (automatic and unconscious attitudes) for stigmatized populations with cancer, with emerging evidence for patients with gynecologic cancer. These implicit biases may guide providers' communication and medical judgments, which, in turn, may influence the patient's satisfaction with and trust in the provider. This narrative review consolidated the current research on implicit bias in healthcare, with a specific emphasis on oncology professionals, and identified future areas of research for examining and changing implicit biases in the field of gynecologic oncology.

Gastrointestinal symptoms and diagnosis preceding ovarian cancer diagnosis: Effects on treatment allocation and potential diagnostic delay.

OBJECTIVE: To determine whether gastrointestinal (GI) disorder insurance claims in the year preceding a diagnosis of ovarian cancer (OC) lead to differing treatment allocations. The hypothesis is that GI disorders may be indicative of advanced OC. METHODS: This retrospective study identified patients with newly diagnosed OC from January 2015 to January 2019 in the IBM® MarketScan® US commercial insurance and Medicare databases. Analysis was limited to patients with primary or interval debulking surgery or chemotherapy, with or without GI claims in the year prior to diagnosis, with commercial or Medicare coverage for ≥12 months prior and ≥1 month after the index date. Patients were compared in terms of the odds of treatment with neoadjuvant chemotherapy (NCT) or primary debulking surgery (PDS) (logistic regression analysis). Median treatment-free interval in the subset of patients with antineoplastic treatment was compared (Kaplan-Meier analysis). RESULTS: Of the 6286 patients, 22% had a diagnosis of ≥1 GI disorder before their OC diagnosis. Of these patients, 39% were diagnosed with a GI disorder between 6 and 12 months before OC diagnosis and 61% were diagnosed <6 months prior. Women with a GI diagnosis were more likely to undergo NCT than PDS (odds ratio [OR], 1.37; P < 0.0001); this remained significant even when controlling for age, region, insurance plan type, and index year (OR, 1.24; P = 0.001). CONCLUSIONS: In this database, ≈25% of women with OC had a GI claim within the past year and were more likely treated with NCT, an indicator of more advanced disease with a worse prognosis. This suggests that OC should be considered in the differential diagnosis among women with GI complaints, which could alter treatment allocation.

Management of nausea and vomiting from poly(ADP-ribose) polymerase inhibitor therapy for advanced ovarian cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors have rapidly emerged as a new class of daily oral chemotherapeutic agents that have the potential to dramatically alter the way in which primary peritoneal, fallopian tube and ovarian cancers are treated. However, the management of nausea and vomiting, the most common toxicities incurred by these agents, remains poorly understood. The purpose of this review is to provide an overview of current guidelines, antiemetic agents and management steps for patients experiencing nausea and vomiting associated with the use of PARP inhibitors.

Real world experience of poly (ADP-ribose) polymerase inhibitor use in a community oncology practice.

OBJECTIVE: This study aims to describe the real-world experience, including the clinical and financial burden, associated with PARP inhibitors in a large community oncology practice. METHODS: Retrospective chart review identified patients prescribed olaparib, niraparib or rucaparib for maintenance therapy or treatment of recurrent ovarian, primary peritoneal or fallopian tube cancer across twelve gynecologic oncologists between December 2016 and November 2018. Demographic, financial and clinical data were extracted. One PARP cycle was defined as a single 28-day period. For patients treated with more than one PARPi, each course was described separately. RESULTS: A total of 47 patients and 506 PARP cycles were identified (122 olaparib, 24%; 89 rucaparib, 18%; 294 niraparib, 58%). Incidence of grade ≥ 3 adverse events were similar to previously reported. Toxicity resulted in dose interruption, reduction and discontinuation in 69%, 63% and 29% respectively. Dose interruptions were most frequent for niraparib but resulted in fewer discontinuations (p-value 0.01). Mean duration of use was 7.46 cycles (olaparib 10.52, rucaparib 4.68, niraparib 7.34). Average cost of PARPi therapy was $8018 per cycle. A total of 711 phone calls were documented (call rate 1.4 calls/cycle) with the highest call volume required for care coordination, lab results and toxicity management. CONCLUSIONS: Although the toxicity profile was similar to randomized clinical trials, this real-world experience demonstrated more dose modifications and discontinuations for toxicity management than previously reported. Furthermore, the clinical and financial burden of PARP inhibitors may be significant and future studies should assess the impact on patient outcomes.

Uterine Inflammatory Myofibroblastic Tumor Showing an Atypical ALK Signal Pattern by FISH and DES-ALK Fusion by RNA Sequencing: A Case Report.

Inflammatory myofibroblastic tumors (IMTs) are spindle cell neoplasms of intermediate (borderline) biologic potential with tendency for local recurrence but low risk of metastasis. They affect children more than adults. The most common sites of involvement are the lung, soft tissue, peritoneum, bladder, and less commonly the gynecologic tract. IMTs are characterized by spindle to epithelioid cells with myofibroblastic differentiation, some degree of smooth muscle differentiation, myxoid stroma and usually associated with brisk lymphoplasmacytic infiltrates. In about half of the cases, IMTs are associated with rearrangements of the anaplastic lymphoma kinase (ALK) gene located at chromosome 2p23. The ALK rearrangement can be detected by immunohistochemistry for ALK protein expression (mostly cytoplasmic with or without perinuclear accentuation) or by fluorescent in situ hybridization (FISH) using dual-color break-apart probes for which the typical pattern is seen as split 3' end (red) and 5' end (green) probe signals in addition to single normal, unsplit red-green signal pair (yellow). Herein we describe a case of uterine IMT initially misdiagnosed intraoperatively as leiomyoma which showed sparse lymphocytic infiltrates, positive ALK expression by immunohistochemistry, a predominantly atypical FISH signal pattern (1 yellow and 1 red signal only) and few typical signal patterns (1 yellow, 1 red, and 1 green signal) in a smaller population of tumor cells. The RNA sequencing showed a recently described DES-ALK fusion transcript in the tumor cells, suggesting an intrachromosomal inversion and deletion as the likely underlying mechanism for the atypical FISH pattern. Familiarity with the unusual morphology and atypical FISH pattern is crucial given that this tumor has an activating ALK rearrangement and may benefit from targeted tyrosine kinase inhibitors in the future.

The development and use of vascular targeted therapy in ovarian cancer.

Combination vascular-targeted therapies (VTTs) represent a promising approach for patients with platinum-resistant recurrent ovarian cancer (OC). VTTs include two mechanistically distinct classes of agents: anti-angiogenic agents (AAs) and vascular-disrupting agents (VDAs). AAs suppress growth of new tumor vasculature through inhibition of vascular endothelial growth factor (VEGF) and other pro-angiogenic molecules. Bevacizumab, a monoclonal antibody that binds to VEGF, has improved progression-free survival (PFS) when given with chemotherapy in patients with advanced OC. VDAs target the established tumor vascular network, inducing vessel occlusion, shutdown of circulation, and widespread necrosis within the tumor interior - a region often resistant to conventional chemotherapy and radiation. Tubulin-binding VDAs such as BNC105P, ombrabulin, and combretastatin A4-phosphate (CA4P) have been studied for the treatment of OC. These agents act by binding tubulin in the endothelial cells of tumor vessels, triggering cytoskeletal disruption, altering cellular shape, and destabilizing cell-cell junctions, which lead to increased vascular leakage and, ultimately, to disruption of blood flow. Fundamental differences between the vascular networks of tumors and those of normal tissues allow these agents to selectively reduce tumor circulation while having little effect on non-malignant tissues. Animal studies and clinical trials show enhanced efficacy when VDAs are combined with chemotherapy as well as AAs. The latter combination allows targeting of different aspects of the tumor vasculature, a strong rationale for combining these two drug classes into a single regimen. CA4P is the only VDA in active development for OC. In a phase II trial of patients with recurrent OC, CA4P added to bevacizumab improved PFS compared with bevacizumab alone. The phase II, placebo-controlled PAZOFOS trial (NCT02055690) is evaluating the effects of CA4P plus the anti-angiogenic agent pazopanib in recurrent OC. FOCUS, a phase II/III, placebo-controlled trial (NCT02641639), is currently evaluating CA4P plus bevacizumab and chemotherapy in platinum-resistant OC.

Hereditary predisposition to ovarian cancer, looking beyond BRCA1/BRCA2.

OBJECTIVE: Genetic predisposition to ovarian cancer is well documented. With the advent of next generation sequencing, hereditary panel testing provides an efficient method for evaluating multiple genes simultaneously. Therefore, we sought to investigate the contribution of 19 genes identified in the literature as increasing the risk of hereditary breast and ovarian cancer (HBOC) in a BRCA1 and BRCA2 negative population of patients with a personal history of breast and/or ovarian cancer by means of a hereditary cancer panel. METHODS: Subjects were referred for multi-gene panel testing between February 2012 and March 2014. Clinical data was ascertained from requisition forms. The incidence of pathogenic mutations (including likely pathogenic), and variant of unknown significance were then calculated for each gene and/or patient cohort. RESULTS: In this cohort of 911 subjects, panel testing identified 67 mutations. With 7.4% of subjects harboring a mutation on this multi-gene panel, the diagnostic yield was increased, compared to testing for BRCA1 and BRCA2 mutations alone. In the ovarian cancer probands, the most frequently mutated genes were BRIP1 (n=8; 1.72%) and MSH6 (n=6; 1.29%). In the breast cancer probands, mutations were most commonly observed in CHEK2 (n=9; 2.54%), ATM (n=3; 0.85%), and TP53 (n=3; 0.85%). CONCLUSIONS: Although further studies are needed to clarify the exact management of patients with a mutation in each gene, this study highlights information that can be captured with panel testing and provides support for incorporation of panel testing into clinical practice.

Neurotoxicity in ovarian cancer patients on Gynecologic Oncology Group (GOG) protocol 218: characteristics associated with toxicity and the effect of substitution with docetaxel: an NRG Oncology/Gynecologic Oncology Group study.

OBJECTIVES: To describe characteristics associated with neurotoxicity (NT) in advanced ovarian cancer patients treated on Gynecologic Oncology Group 218 and examine effect of substituting docetaxel for paclitaxel in these patients. METHODS: The development of NT was defined as Common Toxicity Criteria grade (G)≥1. The association between substitution with docetaxel and NT improvement was explored with generalized estimating equations adjusting for treatment cycle and NT grading at previous cycle. RESULTS: Of 1864 evaluable patients, 1329 (71%) developed G≥1 NT during the study. Nearly half appeared within the first two cycles of chemotherapy, with 31% experiencing G≥2. Older patients or those with worse quality of life (QoL) scores at baseline (p<0.05) were more likely to experience NT. One-hundred-six patients received docetaxel as substitute for paclitaxel. Of them, 47 patients started with docetaxel at cycle one due to reaction to paclitaxel (n=32), fear of NT (n=4), and other reasons (n=11), whereas 59 patients switched to docetaxel during cycle 2-6 due to NT (n=32), reaction to paclitaxel (n=19), and other reasons (n=8). Although the protocol instructed otherwise, the majority continued paclitaxel despite G≥2 NT symptoms. There was no evidence that substitution with docetaxel improved NT (Odds Ratio: 1.57; 95% CI 0.98-2.54; p>0.05). Of 59 patients who switched to docetaxel, only seven (12%) discontinued taxane prior to chemotherapy completion. A roughly equal chance of worsening NT was reported on paclitaxel (6%) as on docetaxel (5%). CONCLUSIONS: Age and worse QoL at baseline are associated with NT. Substitution of docetaxel did not improve NT symptoms.