Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
von Stephanie B. Helber ; Gabriele Procaccini ; Elizabeth F. Belshe ; Alex Santillán-Sarmiento ; Ulisse Cardini ; Stefanie Bröhl ; Michael Schmid ; Hauke Reuter ; Mirta Teichberg
von Martin Metzenmacher ; Hans-Georg Kopp ; Frank Griesinger ; Niels Reinmuth ; Martin Sebastian ; Monika Serke ; Cornelius Florian Waller ; Michael Thomas ; Jochen Eggert ; Gerald Schmid-Bindert ; Mathias Hoiczyk ; Daniel Christian Christoph ; Martin Kimmich ; Burkhard Deuß ; Stephanie Seifert ; Swantje Held ; Martin Schuler ; Thomas Herold ; Frank Breitenbuecher ; Wilfried Ernst Erich Eberhardt
Background:Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor?chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule.Methods:Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500?mg/m2 and cisplatin 75?mg/m2 on day 1 (arm A), or pemetrexed 500?mg/m2 (day 1) and cisplatin 40?mg/m2 (day 1?+?8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life.Results:We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1?6) and five (1?6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34?1.62), p?=?0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9?months); [HR?=?1.07; (0.68?1.68), p?=?0.78]. Median progression-free survival was 7.0?months in A and 6.2?months in B [HR?=?1.63; (1.17?2.38); p?=?0.01]. Adverse events of CTCAE grade??3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B.Conclusion:Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone.Trial Registration:European Clinical Trials Database (EudraCT) number 2011-001963-37.
Therapeutic advances in medical oncology Thousand Oaks, Calif. : Sage, 2009 13(2021) vom: Jan., Artikel-ID 1758835921996506, Seite 1-16 Online-Ressource
