Purpose: Since we have previously shown that the efflux rate of technetium 99m (Tc-99m) sestamibi, a transport substrate of P-glycoprotein (Pgp), is directly correlated with Pgp levels in untreated breast carcinoma, we tested whether tumor clearance of Tc-99m-sestamibi may be predictive of therapeutic response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Patients and Methods: Thirty-nine patients with stage ill disease, median tumor diameter 5.8 cm (range, 3 to 10)were enrolled onto this prospective clinical trial and underwent Tc-99m-sestamibi scan before neoadjuvant chemotherapy. Patients were injected intravenously (IV) with 740 MBq of Tc-99m-sestamibi; a 15-minute dynamic study was performed, and static planar images were obtained at 0.5, 1, 2, and 4 hours. The time to half clearance of Tc-99m-sestamibi was calculated in each patient from decoy corrected time-activity curves using a monoexponential fitting. Patients were treated with epirubicin 150 mg/m(2) IV every 2 weeks for three courses and then underwent surgery within 3 weeks from the completion of chemotherapy. Residual tumor vias assessed by pathologic examination of mastectomy specimens. Results: Seventeen of 39 patients showed a rapid tumor clearance of Tc-99m-sestamibi (time to half clearance [t(1/2)] less than or equal to 204 minutes) and 15 of these 17 (88%) showed a highly cellular macroscopic residual tumor at histology that indicated lack of tumor response to neoadjuvant chemotherapy. In contrast, only eight of 22 (36%) with prolonged retention of Tc-99m-sestamibi (t(1/2) > 204 minutes) showed residual macroscopic tumor at histology (Fisher's exact test, P < .01). Conclusion: A rapid tumor clearance of Tc-99m-sestamibi may predict lack of tumor response to neoadjuvant chemotherapy with drugs affected by the multidrug-resistant phenotype in patients with locally advanced breast carcinoma. (C) 1998 by American Society of Clinical Oncology.