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Anti-estrogen drug combination confers durable survival benefit in breast cancer subset
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The addition of fulvestrant to anastrozole as first-line therapy improved long-term survival in postmenopausal women with hormone receptor-positive metastatic breast cancer, according to results of a randomized study published in The New England Journal of Medicine.
Researchers observed the survival benefit despite about 45% of women assigned only anastrozole crossing over to receive fulvestrant after disease progression. The benefit of the combination appeared particularly notable among women without previous exposure to adjuvant endocrine therapy.
“Estrogen drives the tumor growth via estrogen receptors on tumor cells, [and] anastrozole works by reducing the amount of estrogen available to the tumor,” Rita S. Mehta, MD, clinical professor at University of California, Irvine, and medical director of the breast center at Chao Family Comprehensive Cancer Center, told HemOnc Today. “However, [the] tumor becomes resistant to lower estrogen by eventually growing in response to even the lower levels of estrogen via estrogen receptor, likely through a mutation in the estrogen receptor or via alternative growth signaling pathways. Moreover, there is cross talk between these growth signaling pathways. So, our hypothesis was that fulvestrant not only blocks the estrogen receptor but also degrades the estrogen receptor, [which] should delay the development of resistance to anastrozole.”
Mehta and colleagues previously reported that the combination of fulvestrant, a selective estrogen-receptor down regulator, and anastrozole, an aromatase inhibitor, increased PFS and OS in postmenopausal women with hormone receptor-positive metastatic breast cancer compared with anastrozole alone.
The current study reported the final outcomes of 694 women randomly assigned to receive fulvestrant plus anastrozole (n = 349) or anastrozole alone (n = 345).
Median follow-up was 7 years among women who did not experience disease progression, with a maximum of 12 years.
Overall, 247 women in the combination-therapy group (71%) and 261 women in the anastrozole-only group (76%) died.
Results showed women assigned the combination had significantly longer OS than women assigned anastrozole alone (49.8 months vs. 42 months; HR = 0.82; 95% CI, 0.69-0.98) and significantly longer PFS (15 months vs. 13.5 months; HR = 0.81; 95% CI, 0.69-0.94).
Among women who had no prior tamoxifen use (n = 414), median OS was longer with the combination vs. anastrozole alone (52.2 months vs. 40.3 months; HR = 0.73; 95% CI, 0.58-0.92), as was median PFS (16.7 months vs. 12.7 months; HR = 0.73; 95% CI, 0.6-0.89).
Among women who had received tamoxifen previously (n = 280), researchers observed similar results in the combination vs. anastrozole-only groups in median OS (48.2 months vs. 43.5 months; HR = 0.97; 95% CI, 0.74-1.27) and median PFS (13.9 months vs. 13.6 months; HR = 0.93; 95% CI, 0.73-1.19).
Both groups had similar incidence of grade 3 to grade 5 adverse events, which included pulmonary emboli, neutropenia, lymphopenia, thromboembolism, thrombosis, embolism, arthralgia, thrombocytopenia and dyspnea.
“This is a practice-changing study, given patients had improvement in median OS and 5-year OS,” Mehta told HemOnc Today. “The study results were particularly compelling in the endocrine therapy-naive population and in patients with long time from diagnosis to relapse. This improvement was seen despite no additional grade 4 to grade 5 toxicity in the combination arm and absence of statistically significant grade 3 adverse events in the combination vs. anastrozole-alone arm, despite the longer time on combination.” – by John DeRosier
For more information:
Rita S. Mehta, MD, can be reached at Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, 101 The City Drive, Bldg. 23, Orange, CA 92868; email: rsmehta@uci.edu.
Disclosures: AstraZeneca provided the study drugs. NCI and NIH funded this study. Mehta reports research funding from AstraZeneca, NCI, NIH, Novartis, OBI Pharma and Pfizer. Please see the study for all other authors’ relevant financial disclosures.
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