Cost-Effectiveness of Unselected Multigene Germline and Somatic Genetic Testing for Epithelial Ovarian Cancer.

BACKGROUND: Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)-based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. METHODS: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. RESULTS: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of $175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45% to 46% or if overall survival with PARPi reaches a hazard ratio of 0.28. Unselected panel germline testing alone (without PARPi therapy) is cost-effective, with payer-perspective ICERs of £11,291/QALY or $68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year's testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. CONCLUSIONS: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone.

Evaluation of follow-up strategies for women with epithelial ovarian cancer following completion of primary treatment.

BACKGROUND: This is an update of a previous Cochrane Review, last updated in 2014. Ovarian cancer is the eighth most common cancer and seventh most common cause of death due to cancer in women worldwide. Traditionally, most women who have been treated for cancer undergo long-term follow-up in secondary care. However, it has been suggested that the use of routine review may not be effective in improving survival, or health-related quality of life (HRQOL), or relieving anxiety. In addition, traditional follow-up may not be cost-effective. OBJECTIVES: To compare the potential effects of different strategies of follow-up in women with epithelial ovarian cancer, following completion of primary treatment. SEARCH METHODS: For this update, we searched the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL 2022, Issue 11, MEDLINE, and Embase from August 2013 to November 2022. We also searched review articles and contacted experts in the field. SELECTION CRITERIA: All randomised controlled trials (RCTs) that evaluated follow-up strategies for women with epithelial ovarian cancer following completion of primary treatment. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. Two review authors independently selected potentially relevant trials, extracted data, and assessed risk of bias. They compared results, and resolved disagreements by discussion. We assessed the certainty of evidence, using the GRADE approach, for the outcomes of interest: overall survival (OS), health-related quality of life (HRQOL), psychological effects, and cost analysis. MAIN RESULTS: For this update, we included one new RCT, including 112 women with ovarian, fallopian tube, or peritoneal cancer, who had completed primary treatment by surgery, with or without chemotherapy. This study reported the effect of individualised, i.e. individually tailored, nurse-led follow-up versus conventional medical follow-up on HRQOL, psychological outcomes, and cost-analysis. Individualised follow-up improved HRQOL in one of the two scales, with a decrease in mean difference (MD) in the QLQ-C30 discomfort scale following 12 months of individualised treatment compared to 12 months of conventional treatment (MD -5.76 points, 95% confidence interval (CI) -10.92 to -0.60; 1 study, 112 participants; low-certainty evidence; minimal important difference 4 to 10 points). There may be little or no difference in the other HRQOL scale (QLQ-Ov28, MD -0.97 points, 95% CI -2.57 to 0.63; 1 study, 112 participants: low-certainty evidence); psychological outcome, measured with the hospital anxiety and depression scale (HADS; MD 0.10 point, 95% CI -0.81 to 1.02; 1 study, 112 participants: low-certainty evidence), or cost analysis (MD -GBP 695.00, 95% CI -1467.23 to 77.23; 1 study, 112 participants: moderate-certainty evidence). Our previous review included one RCT, with 529 women in a confirmed remission, with normal CA125 concentration and no radiological evidence of disease, after surgery and first-line chemotherapy for ovarian cancer. This study evaluated immediate treatment of ovarian cancer relapse following a rise of serum CA125 levels versus delaying treatment until symptoms developed for OS, and HRQOL. There was little or no difference in OS between the immediate and delayed arms after a median follow-up of 56.9 months (unadjusted hazard ratio (HR) 0.98, 95% CI 0.80 to 1.20; 1 study, 529 participants; moderate-certainty evidence). Time from randomisation to first deterioration in global health score or death was shorter in the immediate treatment group than in the delayed treatment group (HR 0.71, 95% CI 0.58 to 0.88). AUTHORS' CONCLUSIONS: Limited evidence from one trial suggests that routine surveillance with CA125 in asymptomatic women and treatment at CA125-defined relapse does not seem to offer survival advantage when compared to treatment at symptomatic relapse. However, this study pre-dates the use of PARPi maintenance treatment and the increased use of secondary cytoreductive surgery, so the results may be limited in their applicability to current practice. Limited evidence from one trial suggests that individualised nurse-led follow-up may improve HRQOL in women with ovarian cancer following completion of primary treatment. Large RCTs are needed to compare different types of follow-up, looking at survival, HRQOL, psychological effects, and cost as outcomes.

ICON 9-an international phase III randomized study to evaluate the efficacy of maintenance therapy with olaparib and cediranib or olaparib alone in patients with relapsed platinum-sensitive ovarian cancer following a response to platinum-based chemotherapy.

BACKGROUND: Two novel biological agents-cediranib targeting angiogenesis, and olaparib targeting DNA repair processes-have individually led to an improvement in ovarian cancer control. The aim of ICON9 is to investigate the combination of cediranib and olaparib maintenance in recurrent ovarian cancer following platinum-based therapy. PRIMARY OBJECTIVE: To assess the efficacy of maintenance treatment with olaparib in combination with cediranib compared with olaparib alone following a response to platinum-based chemotherapy in women with platinum-sensitive ovarian, fallopian tube or peritoneal cancer during first relapse. STUDY HYPOTHESIS: Maintenance therapy with cediranib and olaparib in combination is associated with improved patient outcomes compared with olaparib alone. TRIAL DESIGN: International phase III randomized controlled trial. Following a response to platinum-based chemotherapy patients are randomized 1:1 to either oral olaparib and cediranib (intervention arm) or oral olaparib alone (control arm). MAJOR INCLUSION CRITERIA: Patients with a known diagnosis of high grade serous or endometrioid carcinoma of the ovary, fallopian tube or peritoneum, progressing more than 6 months after first-line platinum-based chemotherapy, who have responded to second-line platinum-based chemotherapy. PRIMARY ENDPOINTS: Progression-free and overall survival. Co-primary endpoints to be assessed using a fixed-sequence gatekeeping approach: (1) progression-free survival, all patients; (2) progression-free survival, BRCA wild type; (3) overall survival, all patients; (4) overall survival, BRCA wild type. SAMPLE SIZE: 618 patients will be recruited. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is expected to be completed in 2024 with presentation of results in 2025. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03278717.

Phase 1 dose-finding and pharmacokinetic study of eribulin-liposomal formulation in patients with solid tumours.

BACKGROUND: This phase 1 study examined the safety, tolerability, pharmacokinetics and preliminary efficacy of eribulin-liposomal formulation (eribulin-LF) in patients with advanced solid tumours. METHODS: Eligible patients with ECOG PS 0-1 were treated with eribulin-LF either on day 1 every 21 days (Schedule 1), or on days 1 and 15 every 28 days (Schedule 2). Doses ranged from 1.0 to 3.5 mg/m2, with dose escalation in a 3 + 3 design. The dose-expansion phase evaluated eribulin-LF in select tumour types. PRIMARY OBJECTIVES: maximum tolerated dose (MTD) and the recommended dose/schedule of eribulin-LF. RESULTS: Totally, 58 patients were enroled (median age = 62 years). The MTD was 1.4 mg/m2 (Schedule 1) or 1.5 mg/m2 (Schedule 2), the latter dose selected for the dose-expansion phase. Dose-limiting toxicity (DLTs) in Schedule 1: hypophosphatemia and increased transaminase levels. DLTs in Schedule 2: stomatitis, increased alanine aminotransferase, neutropenia and febrile neutropenia. The pharmacokinetic profile of eribulin-LF showed a similar half-life to that of eribulin (~30 h), but with a 5-fold greater maximum serum concentration and a 40-fold greater area-under-the-curve. Eribulin-LF demonstrated clinical activity with approximately 10% of patients in both schedules achieving partial responses. CONCLUSIONS: Eribulin-LF was well tolerated with a favourable pharmacokinetic profile. Preliminary evidence of clinical activity in solid tumours was observed.

Prognostic Factors for Survival among Patients with Small Bowel Neuroendocrine Tumours Associated with Mesenteric Desmoplasia.

BACKGROUND: Small intestinal neuroendocrine tumours (SI NETs) represent 30-50% of small bowel neoplasms and are often associated with diverse fibrotic complications. Mesenteric fibrosis is a hallmark of SI NETs which may cause substantial morbidity and is considered an adverse feature. However, survival analyses in this group of patients are lacking. METHODS: The aim of this retrospective study was to determine the overall survival (OS) and factors affecting prognosis in a large cohort of 147 patients with SI NETs and radiological evidence of mesenteric desmoplasia from our centre. The severity of desmoplasia was graded radiologically and its effect on OS and long-term complications was assessed. The median follow-up period was 82 months. RESULTS: The median OS was 8.7 years (95% CI 6.8-9.9) with an overall 5-year survival of 71%. The univariate analysis demonstrated that an age >65 years, a liver tumour burden >50% of the hepatic parenchyma, carcinoid heart disease, chromogranin A levels >10 times the upper limit of normal, and urinary 5-hydroxyindoleacetic acid (5-HIAA) levels >5 times the upper limit of normal were poor prognosticators, while primary resection was associated with a longer OS. However, only an age >65 years and urinary 5-HIAA levels >10 times the upper limit of normal remained statistically significant after multivariate analysis. The severity of mesenteric desmoplasia did not seem to demonstrate a statistically significant relationship to OS or long-term outcomes. CONCLUSION: This study is the first comprehensive survival analysis of patients with SI NETs associated with mesenteric desmoplasia and has provided important and clinically relevant epidemiological data for this group of patients.

A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer.

OBJECTIVE: Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer. METHODS: In this open-label, phase 2 study (NCT01685255), patients were randomised 1:1 to epacadostat 600mg or tamoxifen 20mg twice daily for successive 28-day cycles and stratified by time since completion of first-line chemotherapy to first CA-125 elevation (3 to <12 or ≥12months). The primary endpoint was investigator-assessed progression-free survival (PFS; RECIST v1.1). Secondary endpoints included CA-125 response (Gynecologic Cancer InterGroup criteria), overall survival, safety, and tolerability. RESULTS: The study was terminated primarily due to slow accrual and lack of evidence of superiority. Median PFS was 3.75months for epacadostat (n=22) versus 5.56months for tamoxifen (n=20; HR, 1.34 [95% CI, 0.58-3.14]; P=0.54). Of evaluable patients, 1 (5.0%) epacadostat and 3 (15.8%) tamoxifen patients had confirmed CA-125 responses. The most common treatment-emergent adverse event was fatigue (epacadostat, 36.4%; tamoxifen, 40.0%). Immune-related adverse events, observed with epacadostat only, were primarily rash (18.2%) and pruritus (9.1%). Epacadostat pharmacokinetics/pharmacodynamics were consistent with its known mechanism of action. IDO1 expression was observed in 94% of archival tumour samples. CONCLUSIONS: This first report of immunotherapy evaluation in biochemical-only relapse ovarian cancer and of IDO1 inhibitor monotherapy in ovarian cancer found no significant difference in efficacy between epacadostat and tamoxifen. Epacadostat was generally well tolerated.

PARP inhibitors in ovarian cancer: Clinical evidence for informed treatment decisions.

Ovarian cancer is the fifth leading cause of female cancer deaths in the Western world. Significant progress has been made in the treatment of patients with ovarian cancer, however, the majority of patients experience disease recurrence and new therapies are being sought for such patients. Clinical investigation of poly(ADP-ribose) polymerase (PARP) inhibitors for ovarian cancer treatment has demonstrated promising activity in this disease. Here, we review the development of PARP inhibitors and their future role in the treatment of patients with ovarian cancer. Studies of olaparib, the first PARP inhibitor to be approved in Europe and the USA, in patients with recurrent ovarian cancer have demonstrated clinical efficacy with improvements in progression-free survival. In maintenance therapy of platinum-sensitive ovarian cancer there is supporting evidence of clinical benefit from exploratory endpoints that include time to first subsequent treatment and time to second subsequent treatment. Adverse events that should be monitored following treatment with PARP inhibitors include nausea, vomiting, fatigue and anaemia. Based on the evidence presented, patients who will receive the greatest benefit from PARP inhibition are those with platinum-sensitive relapsed ovarian cancer and a BRCA mutation.

Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study.

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51-62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51-71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.

IgG and IgE avidity characteristics of peanut allergic individuals.

The role of antibody avidity in allergy is poorly understood and there is no existing literature describing antibody avidity in food allergy. The main aim of this study was to investigate IgE and IgG avidity to a total peanut protein extract (TPPE) and purified Ara h 2 in a group of well-characterized peanut allergic individuals. Forty peanut allergic patients underwent a double-blind placebo-controlled low-dose peanut challenge, during which the severity of the patients' peanut allergy was scored. Serum peanut-specific IgE (psIgE) and IgG (psIgG) concentrations were measured for 37 individuals and the avidities of the same antibodies to a TPPE and purified Ara h 2 were determined using a thiocyanate ELISA method. Both IgE and IgG avidity to Ara h 2 showed weak positive correlations with challenge score [r = 0.459 (p = 0.012) and r = 0.486 (p = 0.003), respectively]. IgE avidity to TPPE showed a weak positive correlation with skin prick test results (SPT), r = 0.467 (p = 0.004) and there was an inverse relationship between the ratio of total IgE:psIgE and challenge score r = -0.561 (p < 0.001). No significant relationship was found between the ratios of IgE avidity:IgG avidity and challenge score or SPT. This is the first description of IgE and IgG avidity in peanut allergy, and it appears that the avidities of IgE and IgG antibodies to purified Ara h 2 are weakly related to the severity of peanut allergy (as measured by a challenge score).