NCCN VERSION 2 2015

NCCN Guidelines Version 2.2015 Breast Cancer

NCCN Guidelines Index Breast Cancer Table of Contents Discussion

hormone receptor-negative with disease localized to the bone or soft tissue only or with asymptomatic visceral disease, irrespective of HER2 tumor status. For postmenopausal women who are antiestrogen naive or who are more than 1 year from previous antiestrogen therapy, the options include either an aromatase inhibitor, selective ER modulator, or an ER down-regulator. According to some studies, aromatase inhibitors appear to have superior outcome compared with tamoxifen, although the differences are modest. 433-436 A Cochrane review has also suggested a survival benefit favoring the aromatase inhibitors over other endocrine therapies, although the advantage is small. 437 A randomized phase III trial comparing tamoxifen and exemestane as first-line endocrine therapy for postmenopausal women with metastatic breast cancer showed no significant differences in progression-free survival (PFS) or OS between the two arms. 435 A randomized phase II study compared anastrozole versus fulvestrant in over 200 patients with advanced breast cancer. 438,439 In the initial analysis, fulvestrant was as effective as anastrozole in terms of overall response (36.0% vs. 35.5%; odds ratio, 1.02; 95% CI, 0.56 –1.87; P = .947) in evaluable patients (n= 89 for fulvestrant and n=93 for anastrozole). 438 The updated follow-up results showed an improved time to progression with fulvestrant compared to anastrazole (median time to progression was 23.4 months for fulvestrant vs. 13.1 months for anastrozole; HR, 0.63; 95% CI, 0.39– 1.00; P =.0496). 439 This study used a higher 500 mg loading dose every 2 weeks for 3 doses and then 500 mg monthly. 438 Fulvestrant appears to be at least as effective as anastrozole in patients whose disease progressed on previous tamoxifen, 440,441 and a reanalysis of these studies suggests a longer duration of response favoring fulvestrant. 442 A phase II study of fulvestrant in postmenopausal women with advanced breast cancer and disease progression following aromatase inhibitor

therapy documented a partial response rate of 14.3% with an additional 20.8% of patients achieving stable disease for at least 6 months. 443 The clinical benefit rates of exemestane and fulvestrant observed in a phase III trial of postmenopausal women with hormone receptor-positive advanced breast cancer who experienced disease progression on prior nonsteroidal aromatase inhibitor therapy were comparable (32.2% vs. 31.5%; P = .853). 444 In that study, fulvestrant was administered as a 500 mg loading dose followed by doses of 250 mg on day 14, day 28, and then monthly. A separate phase III randomized study in postmenopausal women with metastatic ER-positive breast cancer compared fulvestrant 500 mg every 2 weeks for 3 doses followed by 500 mg monthly versus fulvestrant 250 mg monthly. The PFS was superior with the fulvestrant 500 mg regimen (HR 0.80; 95% CI, 0.68– 0.94; P = .006), 445 indicating an increased duration of response with the higher dose of fulvestrant. The final analyses demonstrated an increase in median OS (4.1 months) and reduced risk of death (19%) with a dose of 500 mg compared with 250 mg. Median OS was 26.4 vs. 22.3 months (HR: 0.81; 95% CI: 0.69-0.96; P = .016). 446 Combination endocrine therapy in postmenopausal women with hormone receptor-positive, previously untreated metastatic breast cancer has been reported from two studies comparing single-agent anastrozole versus anastrozole plus fulvestrant. In one study (FACT), combination endocrine therapy was not superior to single-agent anastrozole (time to progression HR 0.99; 95% CI, 0.81–1.20; P = .91). 447 In the second study (S0226), PFS (HR 0.80; 95% CI, 0.68–0.94; stratified log-rank P = .007) and OS (HR 0.81; 95% CI, 0.65–1.00; stratified P = .049) were superior with combination anastrozole plus fulvestrant. 448 An unplanned subset analysis in this trial suggested that patients without prior adjuvant tamoxifen experienced

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