Extended Aromatase Inhibitor Use Post-Tamoxifen Reduces Breast Cancer Recurrence

Judith Groch
VIENNA, Austria, Dec. 12 -- The aromatase inhibitor anastrozole (Arimidex) reduced the risk of breast cancer recurrence for postmenopausal women who took it for three years after five years of tamoxifen, a randomized trial found.
Action Points --->
Explain to patients who ask that this study found that after five years of tamoxifen, further treatment with an aromatase inhibitor may lower the risk of a recurrence but with the possibility of adverse drug-related events.
But overall survival was not affected even though the anastrozole arm had a 38% reduction in recurrence, Raimund Jakesz, M.D., of Vienna Medical University, and colleagues reported in the Dec. 11 issue of the Journal of the National Cancer Institute.
Earlier, a large clinical trial had found that women given five years of the nonsteroidal aromatase inhibitor letrozole (Femara), following five years of tamoxifen, had a 42% reduction in the risk of recurrence compared with women given a placebo. However, that trial was halted early at a median follow-up of 30 months, leaving the longer-term safety and efficacy data unknown.
So, to study the efficacy and tolerability of anastrozole given for three years following five years of tamoxifen, the researchers undertook the Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 6a.
The trial (ABCSG 6a) was an extension of the earlier ABCSG 6 trial, in which patients received five years of tamoxifen, with or without the aromatase inhibitor aminoglutethimide (Cytadren) given at the same time, for the first two years of therapy.
The ABCSG 6a trial included 856 patients (mean age 68.1) who had been given five years of tamoxifen and were disease-free at the end of the ABCSG 6 trial. They were randomized by computer to three years of anastrozole (1 mg daily) or no treatment, beginning within six weeks of completing tamoxifen.
At a median follow-up of 62.3 months, 387 women who received anastrozole for three years had a statistically significant 38% reduced risk of recurrence (locoregional recurrence, contralateral breast cancer, or distant metastasis) compared with 469 women who received no further treatment (HR: 0.62, 95% CI: 0.40 to 0.96, P=0.031).
The recurrence rate was 11.8% for patients with no further treatment at 10 years after surgery, compared with 7.1% for those treated with anastrozole.
However, overall survival rates -- 11.7% for the no-further- treatment patients and 10.3% for the anastrozole arm -- were not statistically different (P=0.57), the researchers reported.
Anastrozole was well tolerated, and no unexpected adverse events occurred, the researchers reported. Overall, 13 serious adverse events occurred, seven in the anastrozole arm and six among those given no further treatment. Of these events, only one in the anastrozole arm (fracture) was considered to be related to study treatment, the researchers said.
A potential study limitation, the investigators wrote, is that pre-randomization is not standard practice but was used to randomly assign all eligible patients in the ABCSG Trial 6 (those still in the trial and disease-free) to an arm in 6a. This was done to ensure that there would not be a gap in treatment between completion of five years of primary adjuvant therapy and the start of the extended study.
It is also possible, they said, that prior exposure to the aromatase inhibitor aminoglutethimide in trial 6 may have, to some extent, reduced the efficacy of subsequent therapy with a second aromatase inhibitor (anastrozole) in this study.
These data, Dr. Jakesz and colleagues wrote, are in accord with the results of the larger letrozole trial and indicate that extended adjuvant therapy with anastrozole is a valid therapeutic option for patients after five years of adjuvant tamoxifen.
However, the results raise the question of the optimal duration of adjuvant endocrine treatment with aromatase inhibitors. "We may now be in a position to investigate the possibility of tailoring the duration of adjuvant treatment to the requirements of individual patients or disease types, they wrote.
In an accompanying editorial asking "how much is enough?" Tatiana M. Prowell, M.D., and Vered Stearns, M.D., of Johns Hopkins wrote, "Is there a duration of adjuvant endocrine therapy with sequential tamoxifen and an aromatase inhibitor beyond which efficacy, in addition to safety, is compromised, as may be the case with tamoxifen monotherapy, and, if so, what is it?" Results from completed and ongoing studies should answer some of these questions, they said.
Meanwhile, they wrote, decisions regarding the most appropriate adjuvant regimen should consider a patient's individual risk of, and her concerns regarding, a recurrence of breast cancer and serious adverse events, such as fractures or thromboembolic events.
Ongoing studies of tissue specimens obtained from women enrolled in large randomized trials may provide valuable information regarding tumor and host characteristics predictive of the efficacy and toxic effects of aromatase inhibitors.
These results, they wrote, "should not only help to identify women who can safely forgo adjuvant therapy as well as those who are best treated with short-term or long-term adjuvant hormone therapy but also provide a rationale for the selection of the most appropriate drug or drugs to incorporate."
The anastrozole study was funded by AstraZeneca. Dr. Jakesz and co-author Ernst Kubista, M.D., are conducting research sponsored by AstraZeneca. Dr. Jakesz is a member of the speakers bureau for AstraZeneca. Dr. Stearns, an editorialist, has received investigator-initiated research funding from Pfizer and Novartis, the maker of letrozole.
Primary source: Journal of the National Cancer InstituteSource reference:Jakesz R, et al "Extended adjuvant therapy with anastrozole among postmenopausal breast cancer patients: results from the randomized Austrian Breast and Colorectal Cancer Study Group trial 6a" J Natl Cancer Inst 2007; 99: 1845-1853. Additional source: Journal of the National Cancer InstituteSource reference: Prowell TM, Stearns V, "Extended adjuvant therapy for breast cancer -- how much is enough?" J Natl Cancer Inst 2007; 99: 1825-1827.