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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. ispartof: GYNECOLOGIC ONCOLOGY vol:166 issue:3 pages:494-502 ispartof: location:United States status: published

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.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).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 diagnosed6 months prior. Women with a GI diagnosis were more likely to undergo NCT than PDS (odds ratio [OR], 1.37; P0.0001); this remained significant even when controlling for age, region, insurance plan type, and index year (OR, 1.24; P = 0.001).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.

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.

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.

Introduction/Background* Clinical trials consistently demonstrate the detrimental impact of progressive disease (PD) on patients’ health-related quality of life (HRQoL). Progression-free survival (PFS) is an established regulatory endpoint. However, PFS is often excluded as an efficacy endpoint on the basis that — PFS is not patient relevant — in early benefit assessment by select EU health technology agencies. The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) Phase 3 trial showed niraparib significantly prolongs median PFS vs placebo in patients with AOC responsive to 1L platinum (Pt)-based chemotherapy, (CT), regardless of biomarker status. This post-hoc analysis of PRIMA is the first study to examine the relationship between HRQoL and PD in a broad frontline AOC maintenance treatment setting. Methodology In PRIMA, patients with AOC responsive to 1L Pt CT were randomised 2:1 to once-daily, maintenance niraparib or placebo. Impact of PD on patient HRQoL, irrespective of treatment, was evaluated within the pooled ITT population by comparing HRQoL at the last on-treatment (pre-progression) visit with HRQoL at end of treatment (EOT), +4 weeks, +8w, +12w, and +24w. Assessments included FOSI, EORTC QLQ-C30, EQ-5D-VAS, and EORTC QLQ-OV28 abdominal/GI symptom scale. ANCOVA was applied with treatment as a fixed effect and HRQoL at last on-treatment visit as a continuous covariate. Mixed models for repeated measurements (MMRM) evaluated cumulative HRQoL changes. Result(s)* Significant reductions in HRQoL from pre- to post-progression were observed across all measures. Compared with pre-progression, FOSI scores (Least-squares mean [95% CI]) were lower at EOT+4w (-2.2 [-2.8, -1.6]) and EOT+24w (-1.7 [-2.3, -1.1]); each p Conclusion* These findings demonstrate HRQoL is negatively impacted by PD in AOC. Preservation of HRQoL, an important therapy goal in the maintenance setting particularly for asymptomatic patients, can be achieved with PFS prolongation. PFS is of significant relevance and clinically important for AOC patients.

Introduction/Background* Although most patients with ovarian cancer (OC) respond to first-line (1L) treatment, ≈70% experience recurrence within 3 years. Limited evidence exists on the interaction of prognostic factors and the risk of progressive disease (PD). This study assessed whether the number of risk factors (RFs) impacted time to PD in patients treated with maintenance therapy (MT) or active surveillance (AS) after completing 1L therapy. Methodology This retrospective cohort study included patients diagnosed with OC between January 1, 2011, and February 28, 2021, from the Flatiron Health electronic health record-derived de-identified US database. Patients ≥18 years old, with stage III/IV disease, who received 1L platinum-based therapy, had ECOG performance score of 0/1, and had ≥12 weeks of follow-up after 1L treatment were included. Patients were classified into 2 risk categories: moderate risk (stage III disease, no visual residual disease, primary debulking surgery, and BRCA mutant) or high risk (presence of ≥1 of the following: stage IV disease, visible residual disease, interval debulking surgery/no surgery, or BRCA wild type/unknown status). High-risk patients were further grouped by total number of RFs. Patients were followed from index date (ID), defined as end of 1L treatment. The target trial emulation method was used to account for potential selection and immortal time biases. Patients were classified as having received MT if MT was started within 120 days of ID. Result(s)* Of the 1251 patients with advanced OC evaluated, 26% (n=323) initiated 1L MT and 74% (n=928) did not. Of patients who received MT, 5% (n=16) were moderate risk and 95% (n=307) were high risk. Only 4% (n=34) of AS patients were moderate risk and 96% (n=894) were high risk. Time to next treatment (TTNT) decreased with more RFs (table 1). Notably, among patients in the high-risk category, median TTNT was longer in patients who received 1L MT than in those who received AS (table 1). Conclusion* The number of RFs impacted the risk of PD, irrespective of the type of treatment the patient received after completion of 1L treatment. For high-risk patients, greater TTNT prolongation was associated with 1L MT but not AS.

Introduction/Background* This systematic literature review evaluated the relationship between progression-free survival (PFS) and overall survival (OS) in adult patients with ovarian cancer following primary debulking or interval debulking surgery. Methodology MEDLINE®, Embase® and Cochrane Central were searched between 1 January 2011 and 7 July 2020 to identify eligible clinical trials or observational studies conducted in the target population. Gray literature, bibliographies and conference proceedings were also searched. Weighted linear regression analysis was used to evaluate the correlation between PFS and OS in patients with ovarian cancer by residual disease (RD) status. Result(s)* Forty-seven observational studies and three randomized controlled trials were eligible for inclusion, with sample size ranging between 203 and 8,652 patients. There was a strong positive association between PFS and OS, irrespective of RD status (median OS = 4.49 + [2.27 x median PFS]; adjusted R2 = 0.84). Similarly, there was a strong positive association between the log hazard ratios (logHR) for PFS and OS (logHR OS = 0.03 + [1.01 x logHR PFS]); adjusted R2 = 0.86) across RD categories. Conclusion* Among patients with ovarian cancer who had received frontline treatment (primary debulking or interval debulking surgery), there is a positive correlation between PFS and OS. This meta-analysis expands on the growing body of evidence showing that ovarian cancer treatments effective in delaying disease progression can meaningfully extend OS.

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.

Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between locally secreted cancer biomarkers and features of the local CVM to better understand the complex interplay between host, virus and vaginal microbiota (VMB). We enrolled women with ICC, high- and low-grade squamous intraepithelial lesions, as well as, HPV-positive and healthy HPV-negative controls. A broad range of cancer biomarkers was present in the local CVM and specifically elevated in ICC patients. The majority of cancer biomarkers were positively correlated to other biomarkers and linked to genital inflammation. Several cancer biomarkers were also negatively correlated to Lactobacillus abundance and positively correlated with abnormal vaginal pH. Finally, a hierarchical clustering analysis of cancer biomarkers and immune mediators revealed three patient clusters, which varied in levels of cancer biomarkers, genital inflammation, vaginal pH and VMB composition. Specific cancer biomarkers discriminated patients with features of the CVM, such as high genital inflammation, elevated vaginal pH and dysbiotic non-Lactobacillus-dominant VMB, that have been associated with HPV persistence, dysplasia and progression to ICC.

Objective Implicit prejudice and stereotyping may exist in health care providers automatically without their awareness. These biases can correlate with outcomes that are consequential for the patient. This study examined gynecologic oncology care providers' implicit prejudice and stereotyping toward cervical cancer. Methods Members of professional gynecologic oncology organizations were asked to complete two Implicit Association Tests to determine if they implicitly associate cervical cancer with feelings of anger (prejudice) and beliefs about culpability for the disease (stereotypes), compared to ovarian cancer. Linear models and Student t-tests examined average levels of implicit bias and moderators of the implicit bias effects. Results One-hundred seventy-six (132 female, 43 male, 1 nonresponse; X ¯ age = 39.18 years, SDage = 10.58 years) providers were recruited and the final sample included 151 participants (93 physicians and 58 nurses, X ¯ age = 38.93, SDage = 10.59). Gynecologic oncology providers showed significant levels of implicit prejudice, X ¯ = 0.17, SD = 0.47, 95% CI: (0.10, 0.25), toward cervical cancer patients. They also showed significant levels of implicit stereotyping of cervical cancer patients, X ¯ = 0.15, SD = 0.42, 95% CI: (0.08, 0.21). Whereas physicians did not demonstrate significant levels of implicit bias, nurses demonstrated greater levels of implicit prejudice and implicit stereotyping. Providers without cultural competency/implicit bias training demonstrated greater bias than those who had completed such training (p Conclusions This study provides the first evidence that gynecologic oncology providers hold implicit biases related to cervical cancer. Interventions may be designed to target specific groups in gynecologic oncology to improve interactions with patients.

BACKGROUND: Endometriosis is complex, but identifying the novel biomarkers, inflammatory molecules, and genetic links holds the key to the enhanced detection, prediction and treatment of both endometriosis and endometriosis related malignant neoplasia. Here we review the literature relating to the specific molecular mechanism(s) mediating tumorigenesis arising within endometriosis. METHODS: Guidance (e.g. Cochrane) and published studies were identified. The Published studies were identified through PubMed using the systematic review methods filter, and the authors’ topic knowledge. These data were reviewed to identify key and relevant articles to create a comprehensive review article to explore the molecular fingerprint associated with in endometriosis-driven tumorigenesis. RESULTS: An important focus is the link between C3aR1, PGR, ER1, SOX-17 and other relevant gene expression profiles and endometriosis-driven tumorigenesis. Further studies should also focus on the combined use of CA-125 with HE-4, and the role for OVA1/MIA as clinically relevant diagnostic biomarkers in the prediction of endometriosis-driven tumorigenesis. CONCLUSIONS: Elucidating endometriosis’ molecular fingerprint is to understand the molecular mechanisms that drive the endometriosis-associated malignant phenotype. A better understanding of the predictive roles of these genes and the value of the biomarker proteins will allow for the derivation of unique molecular treatment algorithms to better serve our patients.

Introduction/Background Although most patients with ovarian cancer (OC) respond to first line (1L) treatment, 70% of women experience disease progression (PD) within 3 years. Identifying prognostic factors that impact survival is crucial to identify patients who may benefit from new treatment regimens such as maintenance therapies. The objective of this study was to assess the association between visible residual disease (VRD) following interval (IDS) or primary debulking surgery (PDS) and other clinical factors, and the risk of PD or death in patients with advanced OC in a real-world setting. Methodology This retrospective cohort study included patients diagnosed with invasive ovarian cancer between January 1, 2011 and February 29, 2020, from the Flatiron Health electronic health record-derived de-identified US database (most OC patients (87%) originate from community oncology practices). Inclusion/exclusion criteria are shown in table 1. The index date (ID) was defined as the last date of 1L treatment. Multivariate Cox regression models were used to identify demographic and clinical factors associated with time to next treatment (TTNT,a proxy for PD), defined as time from ID to start date of second line treatment, death, or last confirmed structured activity. Overall survival (OS) was defined as time from ID to death or last confirmed structured activity. Kaplan Meier analysis was used to assess median TTNT and OS. Results A total of 1,920 advanced OC patients with a median (25th, 75th percentile) age of 67.0 (58.0, 75.0) years were included. Most patients were white (74%) and originated from a community oncology practice (88%). While 67% of patients had evidence of a BRCA biomarker test, only 5% had evidence of a homologous recombination deficient (HRD) test. Results are shown in table 2. Statistically significant predictors of OS were VRD, age, BRCA status, Eastern Cooperative Oncology Group (ECOG) score, extent of debulking, histology, stage of disease, and therapy modality. Statistically significant predictors of TTNT included: VRD, BRCA status, extent of debulking, histology, practice type, race, stage of disease, and therapy modality. Conclusion VRD was a key predictor of TTNT and mortality in patients with advanced OC. Among biomarkers, BRCA status was a key predictor of OC outcomes; HRD could not be assessed due to lack of data. A key strength of this study is that it presents outcomes from community practices primarily, whereas most retrospective studies contain a higher proportion of academic practices. Disclosures Dr. Chase reports speakers’ bureau fees from GSK. Dr. Gonzalez-Martin reports personal fees and non-financial support from AstraZeneca; Grant and personal fees from GSK, Clovis Oncology, Roche Holding AG, Merck & Co., Inc., Genmab, INMUNOGEN, Pharma Mar, S.A., and Oncoinvent AS. Drs. Kalilani, Perhanidis, Sansbury, Woodward and Gupta are employees of GlaxoSmithKline.

Background Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor that is approved for use in heavily pretreated pts and as maintenance treatment of pts with newly diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy (CT). Here we report PROs in pts receiving niraparib and placebo (PBO) in the PRIMA/ENGOT-OV26/GOG-3012 trial. Methods This double-blind, PBO-controlled, phase 3 study randomised 733 pts with newly diagnosed advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete or partial response (CR or PR) to first-line (1L) platinum-based CT. Pts received niraparib or PBO once daily for 36 months or until disease progression. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review. PROs, a secondary endpoint, were collected every 8 weeks for 56 weeks, then every 12 weeks thereafter while treatment was ongoing. Once a pt discontinued treatment, PRO evaluations were performed at the time of treatment discontinuation and then at 4, 8, 12, and 24 weeks (±1 week for each time point) after the end of treatment, regardless of the status of subsequent treatment. The validated PRO instruments utilised were FOSI, EQ-5D-5L, EORTC-QLQ-C30, and EORTC-QLQ-OV28. Results Compliance rates were high for all of the PRO instruments used in the study. PRO analysis of the EORTC-QLQ-C30 and EORTC-QLQ-OV28 did not indicate a difference in health-related quality of life scores of pts treated with niraparib vs placebo. Mean scores between niraparib and placebo arms were similar at each time point. Overall, the health utility index showed a slight improvement trend in pts who received niraparib vs placebo. Conclusion Consistent with PRO results in the NOVA study, pts receiving niraparib in the PRIMA trial did not experience a decrease in quality of life compared with those receiving placebo. Disclosures Sponsor: GlaxoSmithKline, Waltham, MA, USA NCT number: NCT02655016 Encore statement: This data is presented on behalf of the original authors with their permission. Presented at the European Society for Medical Oncology (ESMO) Annual Meeting, September 19–21, 2020, Virtual. Dr. Maenpaa reports Honoraria from Tesaro, AstraZeneca, Clovis, Roche, MSD and OrionPharma Dr. Pothuri reports grants, personal fees and non-financial support from GSK; Advisory Board fees from AstraZeneca and Clovis Oncology. Dr. Chase reports speakers’ bureau fees from GSK. Dr. Gonzalez-Martin reports personal fees and non-financial support from AstraZeneca; Grant and personal fees from GSK, Clovis Oncology, Roche Holding AG, Merck & Co., Inc., Genmab, INMUNOGEN, Pharma Mar, S.A., and Oncoinvent AS. Dr. Monk reports consulting and advisory role at Merck, GSK, Roche/Genentech, AstraZeneca, Advaxiz, Cerulean Pharma, Amgen, Immunogen, NuCana BioMed, Clovis Oncology, Pfizer, Mateon Therapeutics, Precision Oncology, Perthera, Abbvie, Myriad Pharmaceuticals, Incyte, VBL Therapeutics, Takeda, Samumed, Oncomed, OncoSec, ChemoID, Geistlich Pharma, Eisai and Chemocare; Speakers’ bureau at Roche/Genentech, AstraZeneca, Janssen, Clovis Oncology and GSK; Honoraria from Merck, GSK, Roche/Genentech, AstraZeneca, Advaxis, Immunogen, NuCana BioMed, Clovis Oncology, Pfizer, Mateon Therapeutics, Precision Oncology, Pethera, Abbvie, Myriad Pharmaceuticals, Incyte, Janssen, Amgen, Genmab, Samumed, Takeda, VBL Therapeutics, Puma Biotechnology, Immunomedics, Conjupro Biotherapeutics, Agenus, OncoQuest, ChemoID, Geistlich Pharma, Eisai and Chemocare; and Research funding from Novartis, Amgen, Genentech, Lilly, Janssen, Array BioPharma, GSK, Morphotek, Pfizer, Advaxis, AstraZeneca, Immunogen, Regeneron, and Nucana. Drs. Han, Bender, and Follana have nothing to disclose. Drs. Bacque and Li are employees of GlaxoSmithKline.

Introduction Niraparib is a poly(ADP-ribose) polymerase inhibitor approved for treatment in heavily pretreated patients and maintenance of patients with newly diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. Here we report safety and patient-reported outcomes (PROs) in the overall population and subgroups from PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016). Methods This double-blind, placebo-controlled, phase 3 study randomized 733 patients. Patients received a 300-mg QD fixed starting dose (FSD) of niraparib or placebo for 36 months or until progression/toxicity. A protocol amendment introduced an individualized starting dose (ISD): 200 mg in patients with body weight Results In the overall population, the most common grade ≥3 treatment-emergent adverse events (TEAEs) were hematologic (table 1). In patients receiving ISD, these TEAEs decreased. No treatment-related deaths occurred. PRO analysis showed no difference in niraparib-treated patients versus placebo in the overall population or in the homologous recombination deficient, homologous recombination proficient, FSD, and ISD subgroups. Conclusions ISD incorporation improved the safety profile of niraparib without compromising efficacy. Niraparib was well tolerated, with similar PRO scores across the treatment period. Hematologic toxicities were manageable through implementation of dose interruptions and reductions. Funding GlaxoSmithKline NCT: NCT02655016

Emerging evidence suggests that a complex interplay between human papillomavirus (HPV), microbiota, and the cervicovaginal microenvironment contribute to HPV persistence and carcinogenesis. Integration of multiple omics datasets is predicted to provide unique insight into HPV infection and cervical cancer progression. Cervicovaginal specimens were collected from a cohort (n=100) of Arizonan women with cervical cancer, cervical dysplasia, as well as HPV-positive and HPV-negative controls. Microbiome, immunoproteome and metabolome analyses were performed using 16S rRNA gene sequencing, multiplex cytometric bead arrays, and liquid chromatography-mass spectrometry, respectively. 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 bioinformatic analyses revealed that cancer biomarker concentrations were reliably predicted by Random Forest regressors trained on microbiome and metabolome 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 cancer state. 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 and TNFα), as well as genital inflammation (IL-6, IL-10, leptin and VEGF). Integration of multiple different microbiome “omics” data types resulted in modest increases in classifier performance over classifiers trained on the best performing individual omics data type. However, since the most predictive features cannot be known a priori, a multi-omics approach can still yield insights that might not be possible with a single data type. Additionally, integrating multiple omics datasets provided insight into different features of the cervicovaginal microenvironment and host response. Multi-omics is therefore likely to remain essential for realizing the advances promised by microbiome research.

Emerging evidence suggests that the vaginal microbiota play a role in HPV persistence and cervical neoplasia development and progression. Here we examine a broad range of immune checkpoint proteins in the cervicovaginal microenvironment across cervical carcinogenesis and explore relationships among these key immunoregulatory proteins, the microbiota composition, and genital inflammation. First, we demonstrate that immune checkpoint molecules can be measured in cervicovaginal lavages. Secondly, we identify CD40, CD27, and TIM-3 to specifically discriminate cervical cancer from other groups and CD40, CD28, and TLR2 to positively correlate to genital inflammation. Finally, PD-L1 and LAG-3 levels negatively, whereas TLR2 positively correlate to health-associated Lactobacillus dominance. Overall, our study identifies immune checkpoint signatures associated with cervical neoplasm and illuminates the multifaceted microbiota-host immunity network in the local microenvironment. This study provides a foundation for future mechanistic studies and highlights the utility of cervicovaginal lavage profiling for predicting and monitoring response to cancer therapy.

IntroductionTo describe patient-reported outcomes and toxicities at time of treatment discontinuation secondary to progression or toxicities in advanced/recurrent cervical cancer patients receiving chemotherapy with bevacizumab.MethodsSummarize toxicity, grade, and health-related quality of life within 1 month of treatment discontinuation for women receiving chemotherapy with bevacizumab in GOG240.ResultsOf the 227 patients who received chemotherapy with bevacizumab, 148 discontinued study protocol treatment (90 for disease progression and 58 for toxicity). The median survival time from treatment discontinuation to death was 7.9 months (95% CI 5.0 to 9.0) for those who progressed versus 12.1 months (95% CI 8.9 to 23.2) for those who discontinued therapy due to toxicities. The most common grade 3 or higher toxicities included hematologic, gastrointestinal, and pain. Some 57% (84/148) of patients completed quality of life assessment within 1 month of treatment discontinuation. Those patients who discontinued treatment due to progression had a mean decline in the FACT-Cx TOI of 3.2 points versus 2.2 in patients who discontinued therapy due to toxicity. This was a 9.9 point greater decline in the FACT-Cx TOI scores than those who discontinued treatment due to progression (95% CI 2.8 to 17.0, p=0.007). The decline in quality of life was due to worsening physical and functional well-being. Those who discontinued treatment due to toxicities had worse neurotoxicity and pain.DiscussionPatients who discontinued chemotherapy with bevacizumab for toxicity experienced longer post-protocol survival but significantly greater declination in quality of life than those with progression. Future trial design should include supportive care interventions that optimize physiologic function and performance status for salvage therapies.

Background Vaginal dysbiosis has emerged as a key risk factor in HPV acquisition, persistence, and potentially cervical carcinogenesis. However, the biological mechanisms driving persistence and carcinogenesis have not been elucidated. Hence, our objective was to perform metabolic profiling of the cervicovaginal microenvironment to identify interactions between virus, host and microbes in the context of genital inflammation, dysplasia, and cancer. Methods In a multicenter study, metabolic profiles of 78 premenopausal, non-pregnant women with low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL), invasive cervical cancer (ICC), or healthy controls (HPV-positive and -negative Ctrl) were analyzed using gas chromatography-mass spectrometry. Metabolome and vaginal microbiome datasets were integrated using state-of-the-art bioinformatic tools (PICRUSt, AMON, and MIMOSA). Hierarchical clustering analysis (HCA) and principal component analysis (PCA) were employed to reveal the influence of genital inflammation, patient groups, and microbiota on metabolic profiles. Receiver Operating Characteristics (ROC) analysis was used to discriminate metabolites for each patient group. Statistical differences were tested using ANOVA or Mann-Whitney U test. Results Metabolomes of ICC patients (n=468 metabolites) formed a distinct cluster on PCA and HCA plots, due to enrichment of membrane lipids. Amino acid and nucleotide metabolites were depleted in HPV-positive Ctrl, LSIL and HSIL groups (P 0.9, P 0.7). Anti-inflammatory nucleotides, adenosine and cytosine positively correlated with Lactobacillus abundance (Spearman’s rho>0.5) and negatively correlated with genital inflammation (Spearman’s rho Conclusion The complex virus-host-microbe interplay within the cervicovaginal microenvironment lead to unique metabolic fingerprints that could be exploited for future development of diagnostics, preventatives or treatments to positively impact women’s health outcomes. Disclosure No significant relationships.

Background Dysbiotic vaginal microbiota have been implicated as contributors to persistent HPV-mediated cervical carcinogenesis and genital inflammation with mechanisms unknown. Given that cancer is a metabolic disease, metabolic profiling of the cervicovaginal microenvironment has the potential to reveal the functional interplay between the host and microbes in HPV persistence and progression to cancer. Methods Our study design included HPV-negative/positive controls, women with low-grade and high-grade cervical dysplasia, or cervical cancer (n = 78). Metabolic fingerprints were profiled using liquid chromatography-mass spectrometry. Vaginal microbiota and genital inflammation were analysed using 16S rRNA gene sequencing and immunoassays, respectively. We used an integrative bioinformatic pipeline to reveal host and microbe contributions to the metabolome and to comprehensively assess the link between HPV, microbiota, inflammation and cervical disease. Findings Metabolic analysis yielded 475 metabolites with known identities. Unique metabolic fingerprints discriminated patient groups from healthy controls. Three-hydroxybutyrate, eicosenoate, and oleate/vaccenate discriminated (with excellent capacity) between cancer patients versus the healthy participants. Sphingolipids, plasmalogens, and linoleate positively correlated with genital inflammation. Non-Lactobacillus dominant communities, particularly in high-grade dysplasia, perturbed amino acid and nucleotide metabolisms. Adenosine and cytosine correlated positively with Lactobacillus abundance and negatively with genital inflammation. Glycochenodeoxycholate and carnitine metabolisms connected non-Lactobacillus dominance to genital inflammation. Interpretation Cervicovaginal metabolic profiles were driven by cancer followed by genital inflammation, HPV infection, and vaginal microbiota. This study provides evidence for metabolite-driven complex host-microbe interactions as hallmarks of cervical cancer with future translational potential. Fund Flinn Foundation (#1974), Banner Foundation Obstetrics/Gynecology, and NIH NCI (P30-CA023074).

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.

Introduction: In 2008, we published on the application of supportive care to ovarian cancer patients which involves caring for a patient’s symptoms during and/or after treatment with an objective of providing these women with an improved quality of life (QoL). This complex, multi-dimensional field involves all body systems and collaboration among multiple medical specialties.Areas Covered: In this updated review, we have incorporated new data investigating QoL and supportive care in ovarian cancer, maintaining our format of analyzing the data by separating it into two categories: tumor-related and treatment-related morbidities. The main themes within these categories include nausea and vomiting, abdominal pain, anxiety and depression, fatigue and anemia, small bowel obstruction, sexual dysfunction, and peripheral neuropathy, to name a few.Expert Commentary: While all of these components are challenging to manage, the oncologist must act as a facilitator who either addresses these needs or send the...

Olaparib is a poly(ADP-ribose) polymerase inhibitor that received accelerated approval from the US Food and Drug Administration as monotherapy for patients with germline BRCA mutations and ovarian cancer treated with three or more prior lines of chemotherapy. This article summarizes the mechanism of poly(ADP-ribose) polymerase inhibition, therapeutic profile and uses of olaparib, and current and ongoing literature pertaining to olaparib in advanced ovarian cancer.

Persistent human papillomavirus (HPV) infection is the vital factor driving cervical carcinogenesis; however, other features of the local cervicovaginal microenvironment (CVM) may play a critical role in development of precancerous cervical dysplasia and progression to invasive cervical carcinoma (ICC). Here we investigated relationships between immunoproteomic and metabolic profiles and features of the cervicovaginal microenvironment, such as HPV status, vaginal microbiota (VMB), vaginal pH and genital inflammation, to better understand the complex interplay between host, virus and bacteria. In this multicenter study we enrolled 78 women with ICC, high- and low-grade squamous intraepithelial lesions, as well as HPV-positive and healthy HPV-negative controls. Vaginal swabs and cervicovaginal lavages (CVL) were collected for HPV genotyping, microbiome, metabolome and immunoproteome analyses. The VMB compositions were determined using 16S rRNA gene sequencing. Cervicovaginal metabolic fingerprints were profiled using liquid chromatography-mass spectrometry. Levels of immune mediators and other proteins in CVL samples were evaluated using multiplex cytometric bead arrays. Abnormal vaginal pH and dysbiotic non-Lactobacillus-dominated VMB were associated with Hispanic ethnicity and severity of cervical neoplasm. We also identified microbial signatures (e.g. Sneathia spp.) to be enriched in ICC and all precancerous groups. Notably, Sneathia abundance was also increased in patients with abnormal pH and those of Hispanic origin. Analyses of 62 protein targets in CVL samples revealed elevated levels of pro-inflammatory cytokines and chemokines, growth and angiogenic factors, apoptosis-related, immune checkpoint and other proteins in ICC patients. Levels of many of these proteins depended on the VMB structure and genital inflammation. These proteomic signatures positively correlated with dysbiotic non-Lactobacillus-dominated VMB and abnormal vaginal pH, both features associated with Hispanic ethnicity. Furthermore, metabolomic analysis also revealed that VMB, together with genital inflammation, are the major drivers of metabolic profiles in the local CVM. Finally, using hierarchical clustering analyses, we identified groups of patients who significantly varied in the levels of cancer-related proteins, genital inflammation, vaginal pH and VMB composition regardless of disease severity. These microenvironmental factors may impact the HPV persistence/progression and consequently increase the risk of cervical cancer. Our study demonstrated that the racial/ethnic differences in the VMB compositions may contribute to cervical cancer disparity in Hispanic women. In the future we are planning to expand our investigation of the VMB in Native American women, which will further illuminate the relationship between race/ethnicity, the VMB, and HPV. Citation Format: Pawel Laniewski, Zehra Esra Ilhan, Nicholas A. Bokulich, Haiyan Cui, Denise J. Roe, Dana M. Chase, J. Gregory Caporaso, Melissa M. Herbst-Kralovetz. Integrative multi-omics approach reveals complex interplay between HPV, host and microbiome during cervical carcinogenesis in Hispanic and non-Hispanic women [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A094.

While high-risk human papillomavirus (HPV) infection is a well-established risk factor for cervical cancer, there are likely other factors within the local microenvironment that contribute to cervical carcinogenesis. Here we investigated relationships between HPV, vaginal pH, vaginal microbiota (VMB) composition, level of genital immune mediators and severity of cervical neoplasm. We enrolled women with low- and high-grade cervical dysplasia (LGD, HGD), invasive cervical carcinoma (ICC), and healthy controls. HPV16, HPV45, HPV58, and HPV31 were the most prevalent in our cohort with HPV16 and HPV31 genotypes more prevalent in Hispanics. Vaginal pH was associated with ethnicity and severity of cervical neoplasm. Lactobacillus dominance decreased with the severity of cervical neoplasm, which correlated with elevated vaginal pH. Hispanic ethnicity was also associated with decreased Lactobacillus dominance. Furthermore, Sneathia was enriched in all precancerous groups, ICC, abnormal pH and Hispanic origin. Patients with ICC, but not LGD and HGD, exhibited increased genital inflammatory scores and elevated specific immune mediators. Notably, IL-36γ was significantly associated with ICC. Our study revealed local, host immune and microbial signatures associated with cervical carcinogenesis and provides an initial step to understanding the complex interplay between mucosal inflammation, HPV persistence and the VMB.