Citations 2
Comparison of 99mTc-Sestamibi Molecular Breast Imaging and Breast MRI in Patients With Invasive Breast Cancer Receiving Neoadjuvant Chemotherapy
Hunt, Katie N. , Conners, Amy Lynn , O’Connor, Michael K. , Weinshilboum, Richard, Wang, Liewei , Carter, Jodi M. , McLaughlin, Sarah A. , Aspitia, Alvaro Moreno, Gray, Richard J. , Northfelt, Don W., O'Connor, Michael K, Suman, Vera, Kalari, Krishna, Carter, Jodi, Northfelt, Don, Goetz, Matthew P. , Suman, Vera J. , Kalari, Krishna R. , Boughey, Judy C. , Carter, Jodi
American Journal of Roentgenology | June 5, 2019 | Volume: 213 | Issue: 4 | Pages: 932-943
First-in-Human Phase I Study of the Tamoxifen Metabolite Z-Endoxifen in Women With Endocrine-Refractory Metastatic Breast Cancer
Northfelt, Don W., Mahr, Michael A. , Ralya, Andrew T., Kuffel, Mary J., Buhrow, Sarah A. , Safgren, Stephanie L. , McGovern, Renee M., Black, John L. , Dockter, Travis , Haddad, Tufia C. , Erlichman, Charles , Adjei, Alex A. , Visscher, Dan W., Kipp, Benjamin R. , Liu, Minetta C. , Hawse, John R. , Doroshow, James H. , Collins, Jerry M. , Streicher, Howard , Ames, Matthew M. , Élez, Elena , Reid, Joel M. , Kuffel, Mary, Black, John, Haddad, Tufia, Visscher, Dan, Chalmers, Zachary R, Frampton, Garrett, Ingle, James N. , Safgren, Stephanie L , Goetz, Matthew P. , Suman, Vera J. , Chalmers, Zachary Rockow , Frampton, Garrett M. , Elez, Elena
Journal of Clinical Oncology | August 30, 2017 | Volume: 35 | Issue: 30 | Pages: 3391-3400
Purpose Endoxifen is a tamoxifen metabolite with potent antiestrogenic activity. Patients and Methods We performed a phase I study of oral Z-endoxifen to determine its toxicities, maximum tolerated dose (MTD), pharmacokinetics, and clinical activity. Eligibility included endocrine-refractory, estrogen receptor–positive metastatic breast cancer. An accelerated titration schedule was applied until moderate or dose-limiting toxicity occurred, followed by a 3+3 design and expansion at 40, 80, and 100 mg per day. Tumor DNA from serum (circulating cell free [cf); all patients] and biopsies [160 mg/day and expansion]) was sequenced. Results Of 41 enrolled patients, 38 were evaluable for MTD determination. Prior endocrine regimens during which progression occurred included aromatase inhibitor (n = 36), fulvestrant (n = 21), and tamoxifen (n = 15). Patients received endoxifen once daily at seven dose levels (20 to 160 mg). Dose escalation ceased at 160 mg per day given lack of MTD and endoxifen concentrations > 1,900 ng/mL. Endoxifen clearance was unaffected by CYP2D6 genotype. One patient (60 mg) had cycle 1 dose-limiting toxicity (pulmonary embolus). Overall clinical benefit rate (stable > 6 months [n = 7] or partial response by RECIST criteria [n = 3]) was 26.3% (95% CI, 13.4% to 43.1%) including prior tamoxifen progression (n = 3). cfDNA mutations were observed in 13 patients ( PIK3CA [n = 8], ESR1 [n = 5], TP53 [n = 4], and AKT [n = 1]) with shorter progression-free survival ( v those without cfDNA mutations; median, 61 v 132 days; log-rank P = .046). Clinical benefit was observed in those with ESR1 amplification (tumor; 80 mg/day) and ESR1 mutation (cfDNA; 160 mg/day). Comparing tumor biopsies and cfDNA, some mutations ( PIK3CA, TP53, and AKT) were undetected by cfDNA, whereas cfDNA mutations ( ESR1, TP53, and AKT) were undetected by biopsy. Conclusion In endocrine-refractory metastatic breast cancer, Z-endoxifen provides substantial drug exposure unaffected by CYP2D6 metabolism, acceptable toxicity, and promising antitumor activity.