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BACKGROUND Studies utilizing serial [99mTc]‐sestamibi (MIBI) scintimammography have reported accurate prediction of tumor response in patients with locally advanced breast carcinoma (LABC) undergoing neoadjuvant chemotherapy. The pathologic response of LABC to presurgical treatment regimens is a prognostic indicator of survival. The authors tested whether MIBI uptake posttherapy predicted survival. METHODS Sixty‐two patients with LABC underwent MIBI scintimammography just before chemotherapy and 2 months after treatment initiation. An additional MIBI scan was performed if treatment lasted > 3 months. The affected breast was imaged within 10 minutes after injection to reflect early uptake, which the authors have shown to be related to tumor blood flow. MIBI uptake was quantified using the lesion‐to‐normal breast (L:N) ratio. Most patients (93%) received weekly dose‐intensive doxorubicin‐based treatment. Disease‐free survival (DFS) and overall survival (OS) were compared with posttherapy primary MIBI uptake and with other established prognostic factors for neoadjuvantly treated LABC, namely, primary tumor pathologic response and posttherapy axillary lymph node status. RESULTS Patients with high uptake on the last observed MIBI scan (i.e., the L:N ratio was greater than the median value) had poorer DFS and OS (P < 0.01 and P = 0.01, respectively). Residual MIBI uptake retained independent prognostic significance in preliminary multivariate analysis that included other established prognostic markers. CONCLUSIONS High primary breast tumor MIBI uptake after neoadjuvant chemotherapy predicted poor survival, suggesting serial MIBI imaging may provide a useful quantitative surrogate end point for neoadjuvant chemotherapy trials. Given the association between MIBI uptake and tumor blood flow, this prognostic capability may be related to retained tumor vascularity after treatment. Cancer 2005. © 2005 American Cancer Society.