Endocrine maneuvers have considerable use in the management of advanced breast cancer, and progestins are hormonal agents with considerable antitumor activity. Sequential studies suggest a steep dose-response relationship for medroxyprogesterone. Megestrol acetate, (Megace, Bristol-Myers Oncology Division, Evansville, IN) an easily used progestin, has activity in advanced breast cancer, but dose response for this agent has not clearly been shown. This study was initiated to evaluate the tolerability and toxicity of escalating doses of megestrol acetate. Forty patients with advanced breast cancer who were not eligible for treatment with other conventional hormones or chemotherapy were entered into the study. All patients had disease progression on previous treatments, and all with visceral disease had disease progression while on one or more chemotherapy regimens. Using specially formulated 160-mg tablets (Bristol-Myers Oncology Division), three patients were entered at each of three dose levels: 480,800, and 1,280 mg/d. Thirty-one patients were entered at 1,600 mg/d. There were 39 postmenopausal women and one man; the median age was 58 years; the median performance status was 80%. Among 31 patients with measurable disease, there were six complete responses (CRs) and five partial responses (PRs); 11 of the 31 had stable disease. Fourteen patients had received previous megestrol acetate with disease progression on treatment: Six had had primary treatment failure. One of these 14 achieved CR, three achieved PR, and eight acheived stable disease on the high-dose regimens. Toxicities were mild (grade 0 to 1) and included mild BP elevation, weight gain, increased appetite, hyperglycemia, edema, dyspnea, congestive heart failure, and other mild problems.(ABSTRACT TRUNCATED AT 250 WORDS)