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Anastrozole and fulvestrant combination extended survival in patients with metastatic breast cancer
The combination of anastrozole and fulvestrant extended median survival of women with hormone-receptor–positive metastatic breast cancer when compared with standard therapy of either anastrozole alone or sequential anastrozole and fulvestrant, according to study results.
In prior studies, anastrozole (Arimidex, AstraZeneca) exhibited the ability to suppress estrogen production, while fulvestrant (Faslodex, AstraZeneca) demonstrated high efficacy in a low-estrogen environment. In addition, the combination of fulvestrant and an aromatase inhibitor — compared with either agent alone — delayed the development of resistance by down-regulating several signaling molecules involved in the development of resistance.
To determine whether the combination of anastrozole and fulvestrant would be superior to anastrozole alone as first-line therapy for metastatic breast cancer, Rita Mehta, MD, and colleagues from the UC Irvine Medical Center conducted a phase 3 randomized trial of 694 postmenopausal women with previously untreated metastatic disease from June 1, 2004, to July 1, 2009.
During the study, patients were randomly assigned to receive either 1 mg of anastrozole orally once daily in combination with injections of fulvestrant — given in sequential dosing on the first day, every 2 weeks, and then once every 28 days after the first month — or 1 mg of anastrozole orally once daily, with possible crossover to fulvestrant alone following disease progression.
Median PFS was 15 months for patients who received the anastrozole and fulvestrant combination vs. 13.5 months for patients who received anastrozole alone, according to study results. The combination was observed to be generally more effective than anastrozole alone in all subgroups, with no significant interactions.
In addition, median OS was longer among patients assigned to the combination therapy (47.7 months vs. 41.3 months), despite the fact that 41% of the patients in the anastrozole group crossed over to fulvestrant after progression.
“The improvement in overall survival that was observed in our study has not been seen in other trials of first-line hormonal therapy for HR-positive metastatic breast cancer,” the researchers wrote. “Specifically, in the trials comparing aromatase-inhibitor therapy with tamoxifen therapy, the benefit from aromatase inhibitors with respect to progression-free survival failed to translate into a benefit with respect to overall survival, a finding that was attributed to the crossover of some patients in the tamoxifen group to an aromatase inhibitor.”
Three deaths that were possibly associated with treatment occurred in the combination group. 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 included thrombosis or embolism, joint pain, thrombocytopenia and dyspnea. Two patients in the combination group experienced grade 4-toxic effects. One experienced thrombosis or embolism, and the other experienced neutropenia or lymphopenia.
“The results of our study suggest that trials of adjuvant therapy should be performed in which the combination of an aromatase inhibitor and high-dose fulvestrant is compared with an aromatase inhibitor alone or high-dose fulvestrant alone in patients with estrogen-receptor–positive tumors for whom chemotherapy is not necessary,” the researchers concluded.
Disclosure: The researchers report consulting relationships with Genomic Health Inc., Enzon, Eisai, Roche, Genentech, Novartis, Bristol-Myers Oncology and Abraxis, as well as grants from NCI.
Perspective
Back to TopThis trial, SWOG 0226, showed a benefit from combining fulvestrant (Faslodex, AstraZeneca) with an aromatase inhibitor, anastrozole, in terms of both PFS and OS as first-line therapy for recurrent/advanced hormone receptor-positive breast cancer. This was in distinct contrast to the earlier published FACT trial, which also compared anastrozole with or without fulvestrant as first-line therapy, and showed no difference in outcome.
What were the main differences between these trials and how are we to apply these results in standard practice? The FACT trial was slightly smaller, but the main difference was that a much higher percentage of patients had received prior hormonal therapy in the combination arm (70% vs. 37% in the SWOG trial). A subanalysis of the SWOG trial did not show a significant improvement in PFS in patients who received adjuvant tamoxifen. Also, in the SWOG trial, a much higher percent of patients (39% overall) presented with advanced disease at their initial presentation of breast cancer. That is higher than typically seen, suggesting that many patients may have been enrolled from underserved populations. In the FACT trial, all enrolled patients had recurred after early-stage breast cancer.
The FACT trial also included local recurrence-only disease, a group that has a lower rate of progression, as well as patients who recurred while on adjuvant endocrine therapy (27% in the combination group). Both trials used the 250-mg monthly maintenance dose of fulvestrant, which in the metastatic setting has been shown to be inferior to the now-approved dose of 500 mg.
For all these reasons, we cannot consider combination therapy to be a new standard for first-line hormonal therapy. However, in postmenopausal (or ovary-suppressed) patients who are presenting with metastatic disease or have not received prior hormonal therapy, this option certainly deserves further study. We are starting to understand biological differences that drive resistance to hormonal therapy, and future trials must include correlative studies that address this issue — ideally using biopsies of recurrent tumor.
Perspective
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The hormonal therapy of metastatic breast cancer does have efficacy. However, with median survivals from metastatic breast cancer in the 2- to 4-year range, there clearly is a need for improvement. Combining non–cross-resistant hormonal strategies is one attempt to improve outcomes in hormone-sensitive metastatic breast cancer. In this study, anastrozole — an aromatase inhibitor — was combined with fulvestrant (Faslodex, AstraZeneca), an ER down regulator. Despite use of a lower dose of fulvestrant (250 mg intramuscularly every month instead of the slightly more effective and widely used 500 mg intramuscularly every month), the combination was more effective than anastrozole alone. It is interesting that there is at least one negative trial of this combination, and there needs to be some effort to try to resolve the contrasting trial results. Nonetheless, this regimen appears to be an advance in the treatment of hormone-sensitive metastatic breast cancer and likely will gain acceptance in the coming months.
Perspective
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In a simplistic way of thinking, combining an aromatase inhibitor plus a pure estrogen receptor antagonist makes sense for treating hormone receptor- positive breast cancer: The aromatase inhibitor marked reduces the levels of circulating estrogen, and the fulvestrant helps to block any residual estrogen that might be left over.
The results of the SWOG 0226 study of maximal estrogen suppression with combination fulvestrant (Faslodex, AstraZeneca) plus anastrozole therapy vs. anastrozole alone for the first-line treatment of metastatic breast cancer appears impressive due to improvements in both PFS and OS benefits for the combination arm (the latter outcome having been challenging to demonstrate in metastatic breast cancer trials to date). But how do we explain these outcomes in light of the previously reported negative FACT trial, in which the same combination of anastrozole plus fulvestrant was not superior to anastrozole alone?
SWOG 0226 and FACT enrolled slightly different populations, which might explain the mixed results: About 60% of the participants were naive to prior endocrine therapy in the SWOG study, whereas 33% of participants in the FACT trial had not received prior endocrine therapy. Confounding OS outcomes in the SWOG study is the fact that only 41% of subjects in the aromatase inhibitor alone arm crossed over to receive fulvestrant (crossover in the FACT trial was not reported). I would be curious to see whether OS is improved in a study in which patients receive upfront combination vs. sequential endocrine therapies, especially since one of the guiding principles for treating metastatic breast cancer to date has been that there is little data suggesting that any particular sequence or combinations of agents to treat metastatic breast cancer results in superior survival; as a result, quality of life and a patient’s individual clinical situation are considered most important.