Real-world outcomes associated with use of front-line bevacizumab in ovarian cancer.

BACKGROUND: In the pivotal ICON7 study, addition of bevacizumab to front-line treatment of ovarian cancer (OC) significantly improved overall survival (OS) (p = 0.03) in a high-risk subgroup of patients with suboptimally debulked/unresectable stage III or IV disease, leading to approval in Ontario, Canada in March 2016. Here we describe utilization of bevacizumab for front-line, high-risk OC and determine outcomes in routine clinical practice. METHODS: Provincial administrative databases were utilized to identify all patients treated with front-line bevacizumab following its approval. Median OS (mOS) was determined using the Kaplan-Meier method. Factors associated with OS were identified using a Cox proportional hazard model. A comparative effectiveness analysis was performed to determine mOS pre- (2006-2016) and post- (2016-2019) approval. RESULTS: From March 2016 to October 2019, 282 patients received bevacizumab. Mean age was 64 years old, and 58% had stage IV disease. Median survival was 29 months and was longer in stage III (37 months) compared to stage IV disease (28 months). In a comparative effectiveness analysis of patients with stage IV serous OC, post-approval uptake of bevacizumab was low (23%). Median OS was similar pre (26 months) and post (27 months) approval (HR 0.92, 0.75-1.12, p = 0.383). CONCLUSIONS: Survival in real-world patients treated with front-line bevacizumab is shorter than in pivotal clinical trials. Survival in stage IV serous patients has not significantly improved post public reimbursement of bevacizumab. This analysis was limited by poor uptake, however mOS was similar in patients who did and did not receive bevacizumab.

Effect of PARP Inhibitor Combined with Bevacizumab on Platinum-Resistant Recurrent Ovarian Epithelial Carcinoma.

Objective: This study was aimed at investigating the efficacy of PARP inhibitor combined with bevacizumab in the treatment of platinum-resistant recurrent ovarian epithelial carcinoma. Methods: A total of 84 patients with platinum-resistant recurrent ovarian epithelial carcinoma treated in our hospital from May 2017 to June 2018 were selected as the research objects. The patients were divided into observation group (n = 42) and control group (n = 42) according to random number table method. The observation group was treated with olaparib combined with bevacizumab, while the control group was treated with albumin-bound paclitaxel combined with bevacizumab, and the clinical efficacy of the two groups was observed. The levels of serum carbohydrate antigen 125 (CA125), carbohydrate antigen 199 (CA199), and epididymal protein 4 (HE4) were determined. The levels of miRNA124, mirNA-21, and miRNA-203 in the two groups were detected. The incidence of adverse reactions was compared between the two groups. The quality of life of the two groups was assessed using FACT-G scale. The drug safety of the two groups was observed. All patients were followed up for 3 years, and the survival time of the two groups was recorded. The Kaplan-Meier method was used to analyze the survival of the two groups. Results: The overall response rate (ORR) (69.05%) and disease control rate (DCR) (88.10%) of the observation group were higher than those of the control group (40.48% and 66.67%), and the differences were statistically significant (both P < 0.05). After treatment, the levels of serum CA125, CA199, HE4, miRNA124, miRNA-21, and miRNA-203 and the improvement degree of quality of life score in the observation group were greater than those in the control group, with statistical significances (all P < 0.05).The 1-year, 2-year, and 3-year survival rates of the observation group (97.62%, 88.10%, and 80.95%) were higher than those of the control group (71.43%, 57.14%, and 47.62%), with statistical significances (all P > 0.05). Conclusion: PARP inhibitor combined with bevacizumab had good effect in the treatment of platinum-resistant recurrent ovarian epithelial carcinoma and can effectively improve the survival time and quality of life of patients.

Safety Profile of Niraparib as Maintenance Therapy for Ovarian Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Patients with epithelial ovarian cancer (EOC), treated with niraparib maintenance, present with haematological and gastrointestinal toxicities. Limited data exist on niraparib safety assessment. OBJECTIVE: To evaluate niraparib safety profile, as maintenance therapy, in women with platinum-sensitive EOC. METHODS: PubMed and Cochrane searches were carried out up to April 2021 for randomised controlled trials (RCTs) evaluating niraparib versus placebo in EOC patients with a response to platinum-based chemotherapy. Regarding the meta-analysis, for dichotomous data, the pooled risk ratio (RR) was calculated. RESULTS: A total of 1539 patients from three RCTs revealed that niraparib-treated patients are associated with a significantly higher risk of any grade of nausea (RR, 2.15; 95% CI, 1.86 to 2.48), fatigue (RR, 1.26; 95% CI, 1.05 to 1.52, p < 0.00001), anemia (RR, 6.86; 95% CI, 2.54 to 18.52, p = 0.0001), thrombocytopenia (RR, 7.02; 95% CI, 1.68 to 29.38, p < 0.00001), vomiting (RR, 2.51; 95% CI, 1.50 to 4.19, p = 0.0005), neutropenia (RR, 2.96; 95% CI, 1.13 to 7.73, p < 0.00001), headache (RR, 2.08; 95% CI, 1.57 to 2.74, p < 0.00001), constipation (RR, 2.10; 95% CI, 1.72 to 2.57, p < 0.00001) and insomnia (RR, 2.48; 95% CI, 1.52 to 2.89, p = 0.0003) when compared with placebo. For grade 3 or 4 adverse effects, significantly higher risk was only noted for fatigue (RR,6.25; 95% CI, 1.70 to 23.05, p = 0.006), anemia (RR, 16.23; 95% CI, 4.86 to 54.17, p < 0.00001), thrombocytopenia (RR, 35.12; 95% CI, 12.23 to 100.82, p < 0.00001) and neutropenia episodes (RR, 6.35; 95% CI, 2.08 to 19.39, p = 0.001) for those taking niraparib. Notably, incidents of adverse effects and discontinuation rates were substantially lower among patients treated with an individualised niraparib dose than those treated with the standard one. Efficacy was not reduced, and no treatment-related deaths occurred during the included trials. CONCLUSION: Niraparib is considered an effective and well-tolerated choice, with an improved safety profile, for the maintenance treatment of EOC patients.

Statin therapy and association with ovarian cancer risk in the New England Case Control (NEC) study.

Statins are widely used to lower blood cholesterol and reduce risk for cardiovascular diseases, but attention has recently focused on a role in cancer prevention or therapy. Here we present data from a large case-control study addressing whether statin use can lower the risk for epithelial ovarian cancer (EOC). Between 1992 and 2008, data including medications used for at least 6 months were collected from 2,040 cases with EOC and 2,100 frequency-matched controls without the disease who participated in the New England Case Control study. We used unconditional logistic regression controlling for matching factors and potential confounders to examine the association between statin use and the risk for EOC. Overall, women who used statins had 32% lower risk of ovarian cancer compared to non-users (Odds ratio (OR) 0.68, 95% Confidence Interval (CI): 0.54-0.85), adjusting for the matching factors and other covariates. The reduced risk was most apparent in women taking a lipophilic statin who began use after age 49, and who had used them 2-4.9 years. Statin use was associated with lower risks for both serous and non-serous histologic subtypes with the strongest effect seen for mucinous and mixed epithelial subtypes. The association became apparent about a decade after the introduction of statins and did not appear to be confounded by indications for use of statins or medications used concomitantly. In this case-control study, statins were found to lower the risk for both serous and non-serous EOC and especially mucinous EOC.

The role of metformin and statins in the incidence of epithelial ovarian cancer in type 2 diabetes: a cohort and nested case-control study.

OBJECTIVE: To obtain evidence of the effects of metformin and statins on the incidence of ovarian cancer in women with type 2 diabetes (T2D). DESIGN: A retrospective cohort study and nested case-control study. SETTING: The data were obtained from a diabetes database (FinDM) combining information from several nationwide registers. POPULATION: A cohort of 137 643 women over 40 years old and diagnosed with T2D during 1996-2011 in Finland. METHODS: In full cohort analysis Poisson regression was used to estimate the hazard ratios (HR) in relation to ever use of metformin, insulin other oral anti-diabetic medication or statins. In the nested case-control analysis 20 controls were matched to each case of ovarian cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different medications. The estimates were adjusted for age and duration of T2D. MAIN OUTCOME MEASURE: Incidence of ovarian cancer. RESULTS: In all, 303 women were diagnosed with ovarian cancer during the follow up. Compared with other forms of oral anti-diabetic medication, metformin (HR 1.02, 95% CI: 0.72-1.45) was not found to be associated with the incidence of ovarian cancer. Neither was there evidence for statins to affect the incidence (HR 0.99, 95% CI: 0.78-1.25). In nested case-control analysis the results were essentially similar. CONCLUSIONS: No evidence of an association between the use of metformin or statins and the incidence of ovarian cancer in women with T2D was found. TWEETABLE ABSTRACT: No evidence found for metformin or statins reducing the incidence of ovarian cancer.

17ß-Estradiol sensitizes ovarian surface epithelium to transformation by suppressing Disabled-2 expression.

Estrogen replacement therapy increases the risk of human ovarian cancer and exogenous estradiol accelerates the onset of ovarian cancer in mouse models. This study uses primary cultures of mouse ovarian surface epithelium (OSE) to demonstrate that one possible mechanism by which estrogen accelerates the initiation of ovarian cancer is by up-regulation of microRNA-378 via the ESR1 pathway to result in the down-regulation of a tumour suppressor called Disabled-2 (Dab2). Estrogen suppression of Dab2 was reproducible in vivo and across many cell types including mouse oviductal epithelium and primary cultures of human ovarian cancer cells. Suppression of Dab2 resulted in increased proliferation, loss of contact inhibition, morphological dysplasia, and resistance to oncogene-induced senescence - all factors that can sensitize OSE to transformation. Given that DAB2 is highly expressed in healthy human OSE and is absent in the majority of ovarian tumours, this study has taken the first steps to provide a mechanistic explanation for how estrogen therapy may play a role in the initiation of ovarian cancer.