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

Original Contribution Parental Smoking and the Risk of Childhood Leukemia

Cigarette smoke has been linked to adult myeloid leukemia; however, the association between parental smoking and childhood leukemia remains unclear. Parental smoking and the risk of childhood leukemia were examined in the Northern California Childhood Leukemia Study, a case-control study, between 1995 and 2002. The present analysis included 327 acute childhood leukemia cases (281 acute lymphoblastic leukemia (ALL) and 46 acute myeloid leukemia (AML)) and 416 controls matched on age, sex, maternal race, and Hispanic ethnicity. Maternal smoking was not associated with an increased risk of either ALL or AML. Paternal preconception smoking was significantly associated with an increased risk of AML (odds ratio 3.84, 95 % confidence interval: 1.04, 14.17); an increased risk for ALL was suggestive for paternal preconception smoking (odds ratio 1.32, 95 % confidence interval: 0.86, 2.04). Greater risks of ALL were observed compared with the risk associated with paternal preconception smoking alone, when paternal preconception smoking was combined with maternal postnatal smoking (pinteraction 0.004) or postnatal passive smoking exposure (pinteraction 0.004). These results strongly suggest that exposure to paternal preconception smoking alone or in combination with postnatal passive smoking may be important in the risk of childhood leukemia. case-control studies; child; leukemia; smoking Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CI, confidence interval; OR, odds ratio

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