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Item Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole(Elsevier, 2015-07) Ingle, James N.; Kalari, K. R.; Buzdar, Aman U.; Robson, Mark E.; Goetz, Matthew P.; Desta, Zeruesenay; Barman, Poulami; Dudenkov, Tanda T.; Northfelt, Donald W.; Perez, Edith A.; Flockhart, David A.; Williard, Clark V.; Wang, Liewei; Weinshilboum, Richard M.; Department of Medicine, IU School of MedicinePURPOSE: We determined hormone concentrations (estradiol [E2], estrone [E1], estrone conjugates [E1-C], androstenedione [A], testosterone [T]) before and on anastrozole therapy where we also determined plasma concentrations of anastrozole and its metabolites. EXPERIMENTAL: Postmenopausal women who were to receive adjuvant anastrozole for resected early breast cancer were studied. Pretreatment, blood samples were obtained for the acquisition of DNA and for plasma hormone measurements (E2, E1, E1-C, A, and T). A second blood draw was obtained at least 4 weeks after starting anastrozole for hormone, anastrozole and metabolite measurements. For hormone assays, a validated bioanalytical method using gas chromatography negative ionization tandem mass spectrometry was used. Anastrozole and metabolite assays involved extraction of plasma followed by LC/MS/MS assays. RESULTS: 649 patients were evaluable. Pretreatment and during anastrozole, there was large inter-individual variability in E2, E1, and E1-C as well as anastrozole and anastrozole metabolite concentrations. E2 and E1 concentrations were below the lower limits of quantitation in 79% and 70%, respectively, of patients on anastrozole therapy, but those with reliable concentrations had a broad range (0.627-234.0 pg/mL, 1.562-183.2 pg/mL, respectively). Considering E2, 8.9% had the same or higher concentration relative to baseline while on anastrozole, documented by the presence of drug. CONCLUSIONS: We demonstrated large inter-individual variability in anastrozole and anastrozole metabolite concentrations as well as E1, E2, E1-C, A, and T concentrations before and while on anastrozole. These findings suggest that the standard 1mg daily dose of anastrozole is not optimal for a substantial proportion of women with breast cancer.Item Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer(American Association for Cancer Research, 2022) Sweeney, Christopher J.; Percent, Ivor J.; Babu, Sunil; Cultrera, Jennifer L.; Mehlhaff, Bryan A.; Goodman, Oscar B.; Morris, David S.; Schnadig, Ian D.; Albany, Costantine; Shore, Neal D.; Sieber, Paul R.; Guba, Susan C.; Zhang, Wei; Wacheck, Volker; Donoho, Gregory P.; Szpurka, Anna M.; Callies, Sophie; Lin, Boris Kin; Bendell, Johanna C.; Medicine, School of MedicinePurpose: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. Patients and methods: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. Results: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). Conclusions: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.