Advances in Therapy

Therapeutic Efficacy of a Coriolus versicolor-Based Vaginal Gel in Women with Cervical Uterine High-Risk HPV Infection: A Retrospective Observational Study

A Coriolus versicolor-based vaginal gel is available for treating women with cervical uterine high-risk human papillomavirus (HPV) infection through re-epithelizing and re-balancing microbiota actions. A longitudinal retrospective observational study was performed to evaluate efficacy and safety of the gel. Women treated with Coriolus versicolor-based vaginal gel were compared with women not treated with the gel. Both groups were monitored for HPV infection by an HPV DNA test, Pap smear (cytology) and colposcopy at baseline and after 6 months. Overall, 183 high-risk HPV positive women were enrolled (97 treated and 86 controls). After 6 months, the HPV DNA test became negative in 67.0% versus 37.2% of treated and controls, respectively (p < 0.0001). Furthermore, 76.1% versus 40.8% registered a colposcopy improvement (p = 0.0005) and 60.4% versus 40.8% showed a remission (p = 0.05), for treated versus controls, respectively. Regarding to cytology, 78.5% of treated versus 37.7% of controls registered an improvement, while 70.8% of treated versus 34.8% of controls had a remission (p < 0.0001 for both variables). At multivariate analyses adjusted for age, smoking habit, and use of estroprogestinic pill, compared to controls, women treated with the gel showed a significantly higher likelihood to experience the clearence of HPV DNA (OR 4.81; 95% 2.43-9.53), and remission at colposcopy (OR 2.30; 95% 1.00-5.31), and cytology (OR 5.13; 95% 2.40-10.96) at 6 months. No adverse event was reported during the follow-up. The use of a Coriolus versicolor-based vaginal gel in high-risk HPV patients is safe and effective based on all examined tests.

Fertility Outcomes After Laparoscopic Cystectomy in Infertile Patients with Stage III–IV Endometriosis: a Cohort with 6–10 years of Follow-up

Ovarian endometriosis is the most common type of endometriosis (EM), affecting more than 40% of women with EM. Currently, surgical intervention is still controversial in infertile patients with ovarian endometriosis, especially in those with stage III-IV EM. Very few studies have been done to analyze long-term pregnancy results in patients with endometrioma more than 5 years after surgery. Therefore, the aim of this study was to explore the pregnancy outcomes and the related factors in patients with endometrioma and stage III-IV endometriosis during a long-term follow-up postoperatively. We collected 347 patients with ovarian endometriosis, which included 59 infertile patients with stage III-IV endometriosis who had a minimum of 5 years of postoperative follow-up after undergoing laparoscopic excision of ovarian endometriomas performed by a single doctor at the Peking Union Medical College Hospital from January 2009 to April 2013. A total of 59 infertile patients were recruited. The mean age was 31.8 ± 3.6 years. The mean size of the endometriomas was 6.8 ± 3.3 cm. Before surgery, dysmenorrhea was present in 88.1% (52/59) of the cases, while chronic pelvic pain was reported in nine cases (15.3%). A total of 20.3% (12/59) of cases were concurrent with leiomyoma, 52.5% (31/59) with deep infiltrating endometriosis (DIE), and 39.0% (23/59) with adenomyosis. During laparoscopy, 21 cases were diagnosed as stage III (35.6%) and 38 as stage IV (64.4%) EM according to the revised American Fertility Society (AFS) classification. After laparoscopic cystectomy, 38 (64.4%) patients became successfully pregnant by the 5th year. All the patients were divided into two groups according to the postoperative pregnancy outcomes. In univariate analysis, the higher mean age and concurrent diagnosis of adenomyosis were seen to be related to poor postoperative pregnancy outcomes (p < 0.05). In multivariate analysis, however, the mean age, chronic pelvic pain (CPP), and adenomyosis were independent risk factors of pregnancy outcomes between the two groups (p < 0.05). With a minimum follow-up of 6 years, 23.7% (14/59) of recurrence was observed in the entire study cohort. Infertile patients with endometrioma and stage III-IV EM may have lower pregnancy rates after laparoscopic cystectomy if they are older and present with CPP and adenomyosis. Our data showed a lower rate of recurrence but a higher rate of pregnancy after surgery.

Human Epididymis Protein 4 and Lewis y Enhance Chemotherapeutic Resistance in Epithelial Ovarian Cancer Through the p38 MAPK Pathway

Ovarian cancer has a high mortality rate due to difficulties in early detection and chemotherapy resistance. Human epididymal protein 4 (HE4) has been adopted as a novel serum biomarker for early ovarian cancer diagnosis, and the presence of Lewis y antigen modifications on HE4 in ovarian cancer cell lines has been detected in previous studies. The aim of this study was to analyze the expression of HE4 and Lewis y antigen in human ovarian cancer in order to find a correlation between them, as well as with the clinical pathological parameters of patients with ovarian cancer. Immunohistochemistry was used to detect the respective expression of these compounds in two patient groups (chemotherapy-resistant and chemotherapy-sensitive) containing a total of 95 patients. Then, a bioinformatic approach was adopted and online large sample databases (TCGA, CCLE, and GTEx; Metascape, Cytoscape) were used to explore the potential mechanisms of action of these compounds. The results of this study demonstrate that high HE4 and Lewis y expression could be used as markers for chemotherapy resistance and poor prognosis in patients with ovarian cancer. These two expression events were widely correlated in various cancer tissues and are thought to act by activating the p38 mitogen-activated protein kinases (MAPK) pathway and inducing Vascular Endothelial Growth Factor A (VEGFA), Prostaglandin-Endoperoxide Synthase 2 (PTGS2), Early Growth Response 1 (EGR1), and Hypoxia-Inducible Factor 1-Alpha (HIFI1A), thereby promoting malignant biological behavior and resistance in ovarian cancer. These findings not only reveal the possible mechanism by which HE4 and Lewis y antigen affect ovarian cancer but also identify a four-gene signature that could be very useful in ovarian cancer detection and/or the development of new targeted therapies.

Nomograms for Predicting Overall Survival and Cancer-Specific Survival of Young Patients with Epithelial Ovarian Cancer: Analysis Based on SEER Program

Currently, there is no clinical prediction model for young patients (≤ 45 years old) with epithelial ovarian cancer (EOC) based on large samples of clinical data. The purpose of this study was to construct nomograms using data extracted from the Surveillance, Epidemiology, and End Results (SEER) Program to predict the overall survival (OS) and cancer-specific survival (CSS) of patients and to further guide the choice of clinical treatment options. Data from a total of 6376 young patients with EOC collected from 1998 to 2016 were selected from the SEER database. These patients were randomly divided (7:3) into a training cohort (n = 4465) and a validation cohort (n = 1911). Cox and least absolute shrinkage and selection operator (LASSO) analyses were used to select the prognostic factors affecting OS and CSS, and the nomograms of OS and CSS were established. The performance of the nomogram models was assessed by C-index, area under the curve (AUC), calibration curves, and decision curve analysis (DCA). Sample were chosen from patients who underwent surgery in Shengjing Hospital to set external validation. Kaplan-Meier curves were plotted to compare survival outcomes between subgroups. Nomograms showed good predictive power and clinical practicality. The internal and external validation indicated better performance of the nomograms than the American Joint Committee on Cancer (AJCC) staging system and tumor grade system. Significant differences were observed in the survival curves of different risk subgroups. We constructed predictive nomograms to evaluate the OS and CSS of young patients with EOC. The nomograms will provide an individualized evaluation of OS and CSS for suitable treatment of young patients with EOC.

The High Expression of RRM2 Can Predict the Malignant Transformation of Endometriosis

A large number of epidemiological studies have revealed that women with endometriosis (EMS) have a higher risk of developing endometriosis-associated ovarian cancer (EAOC). At present, there are few studies on predicting the malignant transformation of ovarian endometriosis (OE). The purpose of this study is to identify and verify the molecules that may be able to predict the malignant transformation of OE. The gene expression profiles of ovarian cancer and OE were downloaded from Gene Expression Omnibus (GEO), and a common hub gene ribonucleotide reductase M2 (RRM2) was identified. A total of 44 patients with EAOC and 44 with OE were enrolled in this study. Immunohistochemistry (IHC) and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to detect the expression of RRM2, while the relationship between RRM2 and Ki-67 was analyzed by IHC co-localization. Bioinformatics analysis showed that the expression of RRM2 was low in EMS and high in ovarian cancer. RRM2 was obviously positively expressed in eutopic endometrium (EU), ectopic endometrium (EC), and cancer tissues of EAOC patients. The IHC signal and mRNA levels of RRM2 were higher in the EC of EAOC patients compared with OE patients (P < 0.01). In addition, there was a correlation between the expression of RRM2 and Ki-67 in EC of EAOC patients (P < 0.01). The upregulated expression of RRM2 in the EC of OE patients may indicate malignant transformation. High expression of RRM2 promotes abnormal proliferation of histiocytes. RRM2 can be used as a potential marker of malignant transformation of OE.

Biomarker Testing Journey Among Patients with Advanced Solid Tumors and Treatment Patterns by Homologous Recombination Repair Status: A Clinico-Genomic Database Study

Defects in the homologous recombination repair (HRR) pathway can include mutations in BRCA1 and BRCA2 (BRCAm) and other HRR genes (HRRm). These mutations are associated with a homologous recombination deficiency (HRD) phenotype. We evaluated testing journey and treatment patterns by BRCAm, HRRm, and HRD status in a real-world dataset. Deidentified data for patients who had undergone comprehensive genomic profiling using FoundationOne Among 9457 patients included in the overall population with evaluable biomarker status, 7856 (83.1%) received ≥ 1 systemic therapy. Among the 7856 patients who received systemic therapy, 2324 (30.0%) underwent testing before first-line therapy, 4114 (52.4%) were tested after receiving first-line therapy and before receiving subsequent therapy (if any), 970 (12.3%) were tested after second-line therapy and before receiving subsequent therapy (if any), and 447 (5.7%) patients underwent testing after receiving third-line therapy. A higher proportion of patients with BRCAm, HRRm, or HRD-positive status were treated with poly(ADP-ribose) polymerase (PARP) inhibitors across all lines of therapy. There was no evidence of a meaningful difference in the proportion of patients who received other treatment (including chemotherapy and immunotherapy) by BRCAm, HRRm, or HRD status. The majority of patients from this real-world dataset underwent FoundationOne

Fertility-Sparing Treatment for Atypical Endometrial Hyperplasia and Endometrial Cancer: A Cochrane Systematic Review Protocol

Endometrial cancer is the fifth most common cancer in women and atypical endometrial hyperplasia is a precancerous lesion. Obesity is an important risk factor for endometrioid endometrial adenocarcinoma and endometrial hyperplasia. Progesterone is recommended as first-line treatment in endometrial cancer or atypical endometrial hyperplasia in women who wish to preserve fertility, but optimal treatment schedules have not been defined. Metformin or bariatric surgery may also be useful in these women. The effectiveness and safety of fertility-preserving treatments being used for women with atypical endometrial hyperplasia and stage IA grade 1 endometrial cancer is unclear. Therefore, the systematic review aims to determine this point. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trial registers, conference proceedings, abstracts, cooperative trial groups and reference lists. We will include randomised controlled trials (RCTs) that compare fertility-preserving therapy including orally administered progesterone versus a levonorgestrel-releasing intrauterine system (IUS), metformin, other pharmacological interventions or bariatric surgery, and any of these interventions with womb-removing surgery. Quasi-randomised trials, non-randomised trials and cohort studies will be included. Two review authors will independently assess study eligibility and risk of bias and extract data. The primary outcomes are complete pathologic response and live birth rate. Secondary outcomes include overall survival, progression-free survival, pregnancy rate, need for hysterectomy, adverse events, psychological symptoms and quality of life. This review aims to clarify the effectiveness and risks of fertility-preserving treatments, including complete pathologic response rate, live birth rates, need for surgical treatment, adverse events, psychological symptoms and quality of life. The broad scope of the review includes the use of progesterone, metformin to reverse insulin resistance, and bariatric surgery or operative hysteroscopy. The results may help to determine the optimal fertility-sparing treatment in endometrial cancer and atypical endometrial hyperplasia. Prospero 2019 number CRD42019145991.

Cost-Effectiveness Analysis of HRD Testing for Previously Treated Patients with Advanced Ovarian Cancer in Italy

Ovarian cancer (OC) is the eighth most common cancer among women, and homologous recombination deficiency (HRD) is present in approximately 50% of these patients. For this group, poly(ADP-ribose) polymerase (PARP) inhibitors are more likely to be effective. The aim of the study was to investigate the cost-effectiveness of HRD testing versus BRCA testing (which identifies mutations present only in 25% of patients) in Italy to optimize the treatment management, possibly with PARP inhibitors. A cost-effectiveness partition survival model was developed to estimate the expected costs and outcomes (life years, LYs; quality-adjusted life years, QALYs) with lifetime horizon of HRD testing versus BRCA testing alone in women with high-grade serous or endometrioid advanced ovarian cancer. The option to perform the tests in sequence, that is, the BRCA test followed by the HRD test, in patients with BRCA-negative test was also considered, and the model accounted for the National Healthcare Service (NHS) perspective in Italy. The treatments represented the best available options according to the initial test results and according to PARP inhibitors available in Italy. A 3% discount rate was applied. Both deterministic and probabilistic sensitivity analyses were performed to test the robustness of the model results. HRD testing was shown to be a cost-effective strategy compared to BRCA testing (incremental cost-utility ratio 22,610€/QALY) and a cost-saving strategy compared to the sequence of tests. The probabilistic sensitivity analysis showed that the HRD test is cost-effective compared to BRCA testing in 98.5% of model simulations considering a willingness-to-pay threshold of 50,000€/QALY. The identification of genetic anomalies in patients with advanced OC is a costly process. Regardless, HRD upfront testing compared to BRCA testing had a cost-effective profile, allowing the efficient use of healthcare resources and better life expectancy and quality of life for patients.

Mesothelin Expression in Patients with High-Grade Serous Ovarian Cancer Does Not Predict Clinical Outcome But Correlates with CD11c+ Expression in Tumor

Mesothelin (MSLN) is overexpressed in several tumors including ovarian cancer and is the target of current trials. There is limited and conflicting data on MSLN prognostic impact in ovarian cancer. We performed a retrospective study on patients with high-grade serous ovarian cancer, analyzing MSLN expression by immunohistochemistry and examining the correlation of its expression to overall and progression-free survival. Correlations of expression of MSLN, CD8, and macrophage markers in different tumor compartments were also investigated. Positive MSLN expression was detected in 55.1% of primary tumors and 51.5% of the metastases. MSLN expression was not correlated with survival. We observed a significant positive correlation (r = 0.34, p = 0.01) between MSLN expression in the metastatic site and CD11c expression in total tumor area and perivascular area in the primary tumor. Our results show that MSLN expression does not correlate with clinical outcome. The impact of the correlation between MSLN and CD11c

Malignant Transformation and Associated Biomarkers of Ovarian Endometriosis: A Narrative Review

This review focuses on pathogenesis of endometriosis, its possible biomarkers and role in endometriosis-associated ovarian cancer. We analyzed various databases to obtain new insights, theories, and biomarkers associated with endometriosis. There are several theories of endometriosis development and biomarker changes including atypical forms. A number of studies have attempted to establish specific, reliable biomarkers to help diagnose endometriosis and endometriosis-associated diseases on the basis of different pathogenetic pathways. Nevertheless, despite intensive research extending even to the molecular level, the origin, natural history, malignant transformation, and laboratory management of endometriosis and related diseases are not yet clearly defined. Therefore, early laboratory diagnoses of endometriosis, its atypical form, and endometriosis-associated ovarian tumors are important problems that require further study in the context of advanced therapeutic strategies to provide maximal health benefits to patients.

Recurrent Ovarian Cancer with BRCAness Phenotype: A Treatment Challenge

Ovarian cancer is a leading cause of death among women with gynecologic malignancies. The relapse rate is high after platinum-based therapy, with the effectiveness of subsequent treatment lines decreasing over time. Recent data suggest the benefit of maintenance therapy with niraparib in platinum-sensitive recurrent disease. We report a case series of five women with advanced ovarian cancer and BRCAness phenotype who responded favorably, and in some cases with long-term response, to maintenance therapy with niraparib. Toxicities were as expected and generally manageable. Two patients developed grade 2/3 hematological toxicity, which resolved with treatment suspension and subsequent dose reductions, and one patient reported a rare skin toxicity while responding to full-dose niraparib treatment, which was controlled with photoprotection and sunscreen. This case series highlights the role of PARP1/2 inhibitors as a new standard of care as maintenance therapy for recurrent platinum-sensitive high-grade ovarian cancer, irrespective of BRCA status.

Health Care Resource Utilization and Costs Associated with Disease Progression in Ovarian Cancer

Ovarian cancer (OC) is one of the leading causes of cancer mortality among women in the United States. With the approval of first-line maintenance therapies, patients with OC experienced prolonged first-line progression-free survival. While the literature addresses some costs associated with OC, further research is needed on the costs of progression that are potentially deferred or prevented by early maintenance. The objective of this study was to capture the health care resource utilization and costs of patients with advanced OC who never received poly(ADP ribose) polymerase (PARP) inhibitor maintenance. We conducted a descriptive retrospective analysis of treatment patterns and the consequences of progression through several lines of therapy (LOTs) in patients with OC, using claims from commercial and Medicare Advantage health plan members in the United States from the Optum Research Database between January 1, 2010, and April 30, 2019. Patients were required to have an index OC diagnosis (≥ 2 non-diagnostic claims). We examined up to 4 LOTs and the time between treatments. A total of 5498 women met the eligibility criteria. As the number of LOTs increased, the median duration of each line decreased from 137 days in LOT1 to 94 days in LOT4, and the time between lines also decreased from 245 to 0 days. Ambulatory care visits were a major driver of health care resource utilization, with a median of about 6 monthly visits during active treatment. The mean total monthly health care costs for patients with at least 2 LOTs were US$8588 (SD: $8533) before LOT2 and increased to $15,358 (SD: $21,460) during or after LOT2. Prolonging progression-free survival after first-line treatment in patients with OC may provide the opportunity to delay or prevent later treatment, the financial toxicity felt by patients, and the economic burden to the health care system associated with progression.

Validation of an Administrative Claims-based Line of Therapy Algorithm for Women with Ovarian Cancer Using Medical Chart Review

New maintenance therapies to treat advanced ovarian cancer have added complexity to identifying lines of therapy (LOTs) for real-world evidence (RWE) studies. This study evaluated the performance of a claims-based algorithm that identifies LOTs among patients with ovarian cancer using medical chart review validation. The algorithm was developed previously utilizing the Optum Research Database (ORD), a US database that contains administrative claims data. To validate the algorithm, LOT results generated using claims data vs chart data were compared at the patient level by calculating the percent agreement between total number of active and maintenance LOTs, type of therapy (neoadjuvant vs adjuvant classification), and type of regimen (individual drugs). Patients with a diagnosis of ovarian cancer who initiated chemotherapy between December 1, 2014, and September 15, 2017, were included in the study. We report descriptive statistics, the percentage correspondence between medical records and claims data, and kappa statistics to measure the magnitude of agreement. A total of 294 patients were included in the analysis; 164 received only chemotherapy and no maintenance, 77 received bevacizumab, and 53 patients received poly (ADP-ribose) polymerase inhibitors (PARPi). Mean age was 64.9 years, and 47.3% had stage III cancer. The algorithm demonstrated substantial agreement between claims and medical records for total number of lines of active and maintenance therapy (weighted kappa 0.65 and 0.62 p < 0.0001). There was moderate-to-substantial agreement for neoadjuvant and adjuvant therapy (kappa 0.56 and 0.62 p < 0.0001). The algorithm performed best at identifying early treatment with a regimen match of 82% and 88% agreement for first-line active and first-line maintenance, respectively. We validated an administrative claims-based algorithm that demonstrates strong concordance with medical records for identifying LOT among patients with ovarian cancer. The algorithm can be applied in future studies to analyze treatment patterns and outcomes.