Results from an updated analysis of overall survival (OS) for patients with hormone receptor (HR)-positive metastatic breast cancer randomly assigned (1:1) to receive first-line anastrozole with or without fulvestrant in a large phase 3 clinical trial ( Identifier: NCT00075764) showed significantly improved OS for patients receiving combination therapy compared with anastrozole alone. The findings from this study were published online in the New England Journal of Medicine.1

Single-agent anastrozole, an aromatase inhibitor, is a standard-of-care approach for the frontline treatment women of with ER-positive metastatic breast cancer. In this study, the combination of standard-dose anastrozole with fulvestrant, a selective estrogen receptor down-regulator (at a loading dose of 500 mg on day 1, with 250 mg administered on days 14 and 28 and then 250 mg administered as maintenance therapy every 28 days for most patients), was compared with standard-dose anastrozole alone.1

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Of the 707 patients who underwent randomization and were stratified according to whether or not they had received prior adjuvant tamoxifen therapy, 694 patients were available for this analysis. Median follow-up was 7 years for patients without disease progression.

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Median OS was 49.8 months for patients in the combination arm and 42.0 months for those receiving anastrozole alone (hazard ratio [HR], 0.82; 95% CI, 0.69-0.98; P =.03). Of note, approximately 45% of the patients receiving anastrozole alone crossed over to receive anastrozole/fulvestrant combination therapy at disease progression in the absence of visceral crisis.

Interestingly, a subgroup analysis of only those women who had not received prior tamoxifen therapy showed a more marked OS difference between the 2 treatment groups in favor of the combination regimen (52.2 months vs 40.3 months; HR, 0.73; 95% CI, 0.58-0.92). Conversely, no OS difference was observed between the 2 study arms in the subgroup of patients who had received prior treatment with tamoxifen (48.2 months [combination therapy] vs 43.5 months; HR, 0.97; 95% CI, 0.74-1.27).

With respect to long-term treatment toxicity, grade 3 adverse events occurred in 15% and 13% of patients receiving combination and single-agent therapy, respectively (P =.47).  No new grade 4 or grade 5 adverse events beyond those previously reported occurred in the combination therapy arm, (ie, grade 5 pulmonary emboli in 2 patients; grade 5 cerebrovascular ischemic event in 1 patient; and grade 4 pulmonary emboli, and grade 4 neutropenia or lymphopenia, each in 1 patient).  

In the single-agent anastrozole arm, a new grade 4 adverse event (ie, thromboembolism) was reported in 1 patient, in addition to the 4 previously reported grade 4 adverse events (thrombosis/embolism, arthralgia, thrombocytopenia, and dyspnea, each occurring in 1 patient).

“These results are very exciting,” said Rita Mehta, MD, a member SWOG’s breast cancer research committee, a clinical professor at the University of California Irvine, and the medical director of the Breast Center at Chao Family Comprehensive Cancer Center. She also noted that this OS benefit is particularly interesting in light of the fact that patients treated with combination therapy received fulvestrant doses that were lower than what is considered typical.2


  1. Mehta RS, Barlow WE, Albain KS, et al. Overall survival with fulvestrant plus anastrozole in metastatic breast cancer. New Engl J Med. 2019;380:1226-1234.
  2. SWOG Cancer Research Network. Fulvestrant plus anastrozole extends lives of women with advanced HR+ breast cancer.