title: A phase II study of medroxyprogesterone acetate in patients with hormone receptor negative metastatic breast cancer: translational breast cancer research consortium trial 007.
abstract: Preclinical data suggest that medroxyprogesterone acetate (MPA) has both anti-metastatic and anti-angiogenic activity in the absence of hormone receptors (HR). This phase II trial assessed the activity of MPA alone or in combination with low-dose chemotherapy in patients with metastatic HR-negative breast cancer. Postmenopausal women with HR-negative disease were eligible if they had not received more than 3 chemotherapy regimens for metastatic disease. All patients were treated with MPA 1,000-1,500 mg/day orally; patients in cohort two also received low-dose oral cyclophosphamide and methotrexate (ldCM, 50 mg/day and 2.5 mg twice daily on Days 1 and 2 each week). Tissue and circulating biomarkers were assessed serially. The primary endpoint was clinical benefit response defined as objective response or stable disease >6 months. Thirty patients were enrolled (14 MPA monotherapy; 16 MPA + ldCM); median age was 55 (35-80); nearly all had visceral involvement. Despite dose escalation in 90 % of patients, only 17 (57 %) patients ever achieved MPA trough concentrations >50 ng/ml. One patient developed grade 4 renal failure in the setting of rapid disease progression and dehydration. There were no objective responses. One patient in each cohort (~7 %) had stable disease for > 6 months. Skin Nm23 expression increased after 4 weeks of MPA + ldCM, but there were no significant changes in TSP-1, PAI-1 antigen, or PAI-1 activity. MPA had limited activity and does not warrant further development in patients with HR-negative advanced breast cancer. Poor bioavailability limited exposure despite dose escalation.
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, RT 473, Indianapolis, IN, 46202, USA, kathmill@iupui.edu.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: Sandra K
authors.initials: SK
authors.lastname: Althouse
authors.forename: Lisle
authors.initials: L
authors.lastname: Nabell
authors.forename: Hope
authors.initials: H
authors.lastname: Rugo
authors.forename: Lisa
authors.initials: L
authors.lastname: Carey
authors.forename: Gretchen
authors.initials: G
authors.lastname: Kimmick
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Merino
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis
chemical_list: D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D017258:Medroxyprogesterone Acetate