A new study from Mehta and others shows the combination of anastrozole and fulvestrant — which interfere with estrogen signaling by distinct mechanisms — increases progression-free and overall survival as compared with anastrozole alone or anastrozole followed by fulvestrant in women with HR-positive breast cancer.
Endocrine therapy plays a central role in the treatment of hormone-receptor (HR)-positive metastatic breast cancer. Selective aromatase inhibitors, such as anastrozole, letrozole, and exemestane, lower the estrogen level and are used as first-line endocrine treatments of HR-positive metastatic disease, owing to their superiority over tamoxifen.
• What is the mechanism of action of fulvestrant?
Fulvestrant (Faslodex, AstraZeneca) is an analogue of estradiol that down-regulates the estrogen receptor by disrupting estrogen-receptor dimerization and accelerating degradation of the unstable fulvestrant-estrogen-receptor complex. This effect leads to reduced cross-talk between the estrogen receptor and estrogen-independent growth factor signaling, thus delaying resistance to hormone therapy.
• What were the primary results of this study?
This trial tested the hypothesis that the combination of anastrozole and fulvestrant would delay the development of progressive disease in postmenopausal women with HR-positive metastatic breast cancer. Progression-free survival was significantly longer with the combination therapy than with anastrozole alone. The median progression-free survival was 13.5 months (95% confidence interval [CI], 12.1 to 15.1) in the group that received anastrozole alone and 15.0 months (95% CI, 13.2 to 18.4) in the group that received the combination therapy.
Morning Report Questions
Q: How did prior tamoxifen therapy effect results in the subgroup analysis?
A: Among the 414 women (59.7%) who had not received prior tamoxifen therapy, the median progression-free survival was 12.6 months in group 1 (anastrozole alone) and 17.0 months in group 2 (fulvestrant in combination with anastrozole) (hazard ratio for progression or death with combination therapy, 0.74; 95% CI, 0.59 to 0.92; P=0.006 with the use of the log-rank test). Among women who had received prior tamoxifen therapy, the estimated median progression-free survival was 14.1 months and 13.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.69 to 1.15; P=0.37 with the use of the log-rank test). The interaction between treatment and status with respect to prior tamoxifen therapy was not significant (P=0.22).
Q: What were the most common toxic effects observed during the study?
A: In general, the toxic effects were mild and did not differ significantly between the two groups. The most common grade 3 toxic effects were musculoskeletal pain (2.8%), influenza-like symptoms (2.4%), gastrointestinal disturbances (1.5%), and hematologic effects (1.5%). Toxic effects of grade 4 or higher were observed in four patients who received anastrozole alone (1.2%) and in five patients who received combination therapy (1.4%) (P=1.00). The four observed grade 4 toxic effects among patients who received anastrozole alone were thrombosis or embolism, joint pain, thrombocytopenia, and dyspnea. Two patients receiving the combination therapy had grade 4 toxic effects (thrombosis or embolism in one patient and neutropenia or lymphopenia in one patient).