Peroxisome proliferator-activated receptor-alpha gene, obesity, and breast cancer incidence and survival: a LIBCSP ancillary study

Peroxisome proliferator-activated receptor-alpha (PPARA) has been shown to increase fatty acid oxidation and decrease cytokine levels, and has been implicated in insulin production. Genetic variants of PPARA have been associated with cardiovascular disease, obesity and type II diabetes mellitus. Although no research to date has investigated the possible link between PPARA and breast cancer incidence and survival, the function of this gene suggests that it could play a role in breast cancer development and prognosis. Six PPARA polymorphisms were evaluated in association with incident breast cancer (n=1073 cases, n=1112 controls) and survival (n=1073 cases) in the Long Island Breast Cancer Study Project, a population-based case-control study. The National Death Index was used to determine vital status through December 31, 2002. The case-control study analyses used unconditional logistic and multilevel regression, and haplotype-based analyses while the survival analyses employed Kaplan-Meier curves, Cox regression and haplotype-based analyses for all-cause and breast cancer-specific mortality (n = 132 (12.3%) and 88 (8.2%), respectively). The odds of breast cancer were doubled among women with PPARA polymorphism rs4253760 (OR=1.97 for rare vs. common homozygote alleles; 95% CI: 1.14, 3.43). This association remained constant with the inclusion of all interrogated polymorphisms studied in hierarchical models. rs4253760 was also associated with over a two-fold increase in all-cause mortality at time of disease diagnosis with inclusion of a continuous time interaction (HR=2.25 for rare vs. common homozyote alleles; 95% CI: 1.00, 5.08). This beta coefficient for this time interaction is negative, implying that survival is improving over time, so that the HR is equal to 0.69 (95% CI: 0.36, 1.29) following five years of follow-up. Thus, caution is necessary when interpreting the results for this polymorphism. Haplotype analyses did not reveal any differences between cases and controls or survival. Our results are the first to evaluate the relationship between PPARA and breast cancer incidence and survival and suggest that replication in an independent cohort is warranted

Real-World Outcomes Following First-Line Treatment in Patients with Advanced Ovarian Cancer with Multiple Risk Factors for Disease Progression who Received Maintenance Therapy or Active Surveillance

IntroductionWe evaluated real-world outcomes in patients with advanced ovarian cancer (AOC) based on their cumulative risk profile and maintenance therapy (MT) status following first-line (1L) treatment.MethodsThis retrospective observational study of a nationwide electronic health record-derived de-identified database included adult patients diagnosed with stage III/IV OC from January 1, 2011 to February 28, 2021, who received 1L therapy and had ≥ 12 weeks of follow-up after the index date (end of 1L therapy). Patients were grouped according to whether they received MT or active surveillance (AS) following 1L treatment and by the cumulative number of risk factors (RF) present (stage IV disease; no surgery/treated with neoadjuvant therapy and interval debulking surgery; had postoperative visible residual disease; and had BRCA wild-type disease/unknown BRCA status). Time to next treatment (TTNT) and overall survival (OS) were assessed with a cloning and inverse probability of censoring (IPC)-weighted Kaplan-Meier method.ResultsAmong 1920 patients, 22.2% received MT and 77.8% received AS. Median IPC-weighted TTNT and OS were 13.3 months (95% CI 11.7-15.8) and 39.1 months (95% CI 32.5-48.6) in the MT cohort, respectively, and 8.6 months (95% CI 8.0-9.5) and 38.4 months (95% CI 36.4-41.0) in the AS cohort, respectively. Almost all patients had ≥ 1 RF (MT 95.3%; AS 96.7%). Median IPC-weighted TTNT was shorter among patients with more RF in both cohorts (MT: 1 RF, 19.3 months, 95% CI 13.5-37.8; 2 RF, 17.2 months, 95% CI 12.8-20.2; 3 RF, 11.0 months, 95% CI 8.2-13.8; 4 RF, 7.0 months, 95% CI 6.2-8.8; AS: 1 RF, 17.7 months, 95% CI 13.5-22.3; 2 RF, 10.2 months, 95% CI 9.1-11.5; 3 RF, 6.5 months, 95% CI 5.8-7.4; 4 RF, 4.1 months, 95% CI 3.5-4.5).ConclusionRegardless of RF number, MT was associated with longer TTNT in real-world patients with AOC

Safety of cetirizine in pregnancy

Managing symptoms of allergic rhinitis (AR) and urticaria in pregnant women is important to reduce complications and negative outcomes. The objective of this study was to provide information on the pregnancy outcomes of women exposed to the antihistamine cetirizine (CTZ). The UCB Pharma Patient Safety Database was searched for pregnancies up to 28 February 2015. Maternal CTZ exposure reports were extracted, and pregnancy outcomes were examined, including exposure, comorbidities and infant events. 228 of 522 pregnancies with maternal CTZ exposure had available outcomes; 49 were prospective. The majority (83.7%) resulted in live births; four spontaneous miscarriages, three induced abortions and one stillbirth were reported. Most pregnancies were exposed during the first trimester. Two congenital malformations were reported. The results suggest that CTZ exposure is not associated with adverse pregnancy outcomes above the background rates. While reassuring, the strengths and limitations of a safety database study need to be considered.Impact statement What is already known on this subject? AR and urticaria can substantially affect pregnant women, and adequately managing their symptoms is important to reduce maternal and foetal complications. Antihistamines are efficacious, however, there is still a lack of data regarding use during pregnancy. Although current evidence indicates that antihistamines are well-tolerated during pregnancy, data regarding foetal safety are inconclusive. What do the results of this study add? Our study suggests that CTZ exposure during pregnancy is not linked to an increase in adverse outcomes. CTZ exposure mainly happened during the first trimester only, when most organogenesis takes place. Most of the maternally exposed, prospective pregnancies resulted in live births (83.7%). Congenital malformations occurred in 2/41 live births from the CTZ-exposed pregnancies. What are the implications of these findings for clinical practice and/or further research? Our study presents a detailed data analysis from a large number of CTZ-exposed pregnancies, and its results are in line with those from previous reports. While the limitations of a safety database study need to be considered, the results shown here are reassuring. Further prospectively reported pregnancies are required, before definite conclusions on the risks of CTZ exposure during pregnancy can be drawn

Sequential treatment with afatinib and osimertinib in patients with EGFR mutation-positive non-small-cell lung cancer : an observational study

Aim: To assess outcomes in patients with EGFR mutation-positive (Del19, L858R) non-small-cell lung cancer receiving sequential afatinib and osimertinib in a real-world clinical setting. Materials & methods: In this retrospective, observational, multicenter study, patients (n = 204) had T790M-positive disease following first-line afatinib and started osimertinib treatment [>/=]10 months prior to data entry. Primary outcome was time on treatment. Results: Overall median time on treatment was 27.6 months (90% CI: 25.9-31.3), 30.3 months (90% CI: 27.6-44.5) in Del19-positive patients and 46.7 months (90% CI: 26.8-not reached) in Asians. The 2-year overall survival was 78.9%. Conclusion: In real-world clinical practice, sequential afatinib and osimertinib facilitates prolonged, chemotherapy-free treatment in patients with T790M acquired resistance, and is a potentially attractive strategy, especially for Del19-positive tumors

Pregnancy Outcomes in Subjects Exposed to Certolizumab Pegol.

OBJECTIVE To provide information on pregnancy outcomes in women receiving certolizumab pegol (CZP). METHODS The UCB Pharma safety database was searched for pregnancies through to September 1, 2014. Reports for maternal and paternal CZP exposure were included and outcomes examined, and data on CZP exposure, pregnancy, comorbidities, and infant events were extracted by 2 independent reviewers. Concomitant medications and disease activity were reviewed for clinical trial patients. RESULTS Of 625 reported pregnancies, 372 (59.5%) had known outcomes. Paternal exposure pregnancies (n = 33) reported 27 live births, 4 miscarriages, 1 induced abortion, and 1 stillbirth. Maternal exposure pregnancies (n = 339) reported 254 live births, 52 miscarriages, 32 induced abortions, and 1 stillbirth. Almost all reported pregnancies had exposure to CZP in the first trimester, when organogenesis takes place, and a third of them continued the drug into the second and/or third trimesters. The most frequent indications for maternal CZP use were Crohn disease (192/339) and rheumatic diseases (118/339). Twelve cases of congenital malformation and a single neonatal death were reported. CONCLUSION Analysis of pregnancy outcomes after exposure to CZP supports previous reports, suggesting a lack of harmful effect of maternal CZP exposure on pregnancy outcomes. However, additional data from a larger number of outcomes after exposure and studies including an unexposed comparison group are required to fully evaluate CZP safety and tolerability in pregnancy

Unmet Medical Needs in the Treatment and Management of Generalized Pustular Psoriasis Flares: Evidence from a Survey of Corrona Registry Dermatologists

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening systemic and chronic autoinflammatory disease characterized by sterile, neutrophilic pustules. The standard of care for GPP varies by region, with limited information and experience of flares and their treatment. Our aim was to establish current unmet needs in GPP by better understanding the natural history of GPP, examining how dermatologists diagnose GPP and GPP flares, and establishing the range and adequacy of GPP treatment options currently prescribed by dermatologists. METHODS: Eligible dermatologists (N = 29) completed a 28-question structured survey, covering ten themes, ranging from GPP diagnostic criteria to GPP symptoms and treatment. RESULTS: All dermatologists stated that pustules were necessary to diagnose a GPP flare. The most frequently reported triggering factors for GPP were steroid withdrawal (64%), infection (58%), and stress (50%). Most dermatologists indicated that available treatment options for GPP flares were adequate most (79%) or all (14%) of the time. Despite this reported adequacy, 38% of dermatologists reported that it was at least somewhat common for a flare to require hospitalization. Furthermore, 72% of dermatologists indicated that treatments were too slow to control flares, and 66% indicated that treatments did not adequately prevent new flares at least sometimes . CONCLUSION: This survey suggests that there are key features of GPP flares, and could initiate discussion around forming consensus guidelines for diagnosis and management. While the results suggest that moderately effective therapies may exist, the need for GPP-specific treatments remains

Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.

Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted