Questions: (1) In female patients with locally advanced breast cancer (labc) and good response to neoadjuvant chemotherapy (nact), including endocrine therapy, what is the role of breast-conserving surgery (bcs) compared with mastectomy? (2) In female patients with labc, a. is radiotherapy (rt) indicated for those who have undergone mastectomy? b. does locoregional rt, compared with breast or chest wall rt alone, result in a higher survival rate and lower recurrence rates? c. is rt indicated for those achieving a pathologic complete response (pcr) to nact? (3) In female patients with labc who receive nact, is the most appropriate axillary staging procedure sentinel lymph node biopsy (slnb) or axillary dissection? Is slnb indicated before nact rather than at the time of surgery? (4) How should female patients with labc that does not respond to initial nact be treated? Methods: This guideline was developed by Cancer Care Ontario’s Program in Evidence-Based Care (pebc) and the Breast Cancer Disease Site Group (dsg). A systematic review was prepared based on literature searches conducted using the medline and embase databases for the period 1996 to December 11, 2013. Guidelines were located from that search and from the Web sites of major guideline organizations. The working group drafted recommendations based on the systemic review. The systematic review and recommendations were then circulated to the Breast Cancer dsg and the pebc Report Approval Panel for internal review; the revised document underwent external review. The full three-part evidence series can be found on the Cancer Care Ontario Web site. Recommendations: a. For most patients with labc, modified radical mastectomy should be considered the standard of care. For some patients with noninflammatory labc, bcs can be considered on a case-by-case basis when the surgeon deems that the disease can be fully resected and the patient expresses a strong preference for breast preservation. b. For patients with labc, rt after mastectomy is recommended. c. It is recommended that, after bcs or mastectomy, patients with labc receive locoregional rt encompassing the breast or chest wall and local node-bearing areas. d. It is recommended that postoperative rt remain the standard of care for patients with labc who achieve pcr to nact. e. It is recommended that axillary dissection remain the standard of care for axillary staging in labc, with the judicious use of slnb in patients who are advised of the limitations of the current data. f. Although slnb either before or after nact is technically feasible, the data are insufficient to make any recommendation about the optimal timing of slnb with respect to nact. Limited data suggest higher sentinel lymph node identification rates and lower false negative identification rates when slnb is conducted before nact; however, those data must be balanced against the requirement for two operations if slnb is not performed at the time of resection of the main tumour. g. It is recommended that patients receiving neoadjuvant anthracycline–taxane-based therapy (or other sequential regimens) whose tumours do not respond to the initial agent or agents, or who experience disease progression, be expedited to the next agent or agents of the regimen. h. For patients who, in the opinion of the treating physician, fail to respond or progress on firstline nact, several therapeutic options can be considered, including second-line chemotherapy, hormonal therapy (if appropriate), rt, or immediate surgery (if technically feasible). Treatment should be individualized through discussion at a multidisciplinary case conference, considering tumour characteristics, patient factors and preferences, and risk of adverse effects. i. It is recommended that prospective randomized clinical trials be designed for patients with labc who fail to respond to nact so that more definitive treatment recommendations can be developed.