Learning Objectives After completing this course, the reader will be able to: Identify which advanced breast cancer patients in the three subsets studied (with nonvisceral metastases, with visceral metastases without liver involvement, and with liver metastases) responded most favorably to first‐line therapy. Describe the limitations of first‐line treatment in the three subsets of patients with advanced breast cancer. Explain how KPS assessment correlates with overall survival in patients with advanced breast cancer with different sites of metastatic lesions. Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com Purpose. The letrozole study 025 is a large (n = 907), international, double‐blind, randomized, phase III trial in postmenopausal women with advanced breast cancer. This subanalysis compares the efficacies of letrozole and tamoxifen as first‐line therapy in postmenopausual women with advanced breast cancer according to site of metastatic lesions and Karnofsky Performance Status (KPS). Materials and Methods. Nine hundred seven patients with advanced breast cancer were randomly assigned to once‐daily oral letrozole (2.5 mg; Femara®; Novartis Pharma AG; Basel, Switzerland) or tamoxifen (20 mg; Tamofen®; Leiras OY; Turku, Finland). Time to progression (TTP) was estimated using the Kaplan‐Meier product‐limit method. Treatments were compared by Cox proportional hazards regression models. Results. Letrozole treatment significantly prolonged TTP in all subsets of patients: those with nonvisceral metastases, those with visceral metastases without liver involvement, and those with liver metastases. The reduction in risk of progression ranged from 25%, for patients with nonvisceral metastases, to 36%, for patients with liver metastases. The distributions of baseline KPS scores for both treatment groups were similar (57% had KPS scores ≥90). Time to worsening of 20 points or more in KPS score was significantly longer with letrozole than with tamoxifen, but modest numbers of patients experienced such deterioration (letrozole, 20%, tamoxifen, 22%, in patients without visceral metastases; 23%–24% in patients with liver metastases; and letrozole, 14%, tamoxifen, 30%, in patients with visceral metastases without liver involvement). Conclusion. These data demonstrate the consistent superiority of letrozole over tamoxifen and support the use of letrozole as a new standard of endocrine therapy in postmenopausal women with advanced breast cancer.