BALTIMORE—In a study of 1,504 premenopausal women with node-positive, receptor-positive breast cancer, the combination of tamoxifen(Drug information on tamoxifen) (Nolvadex), goserelin(Drug information on goserelin) (Zoladex), and CAF chemotherapy reduced the relative risk of breast cancer recurrence by 26%, compared with CAF alone.
Adding just goserelin (an LHRH analogue) to standard CAF (cyclophosphamide, doxorubicin(Drug information on doxorubicin), fluorouracil(Drug information on fluorouracil)) produced “only borderline improvement” in disease-free survival and then mostly for women under age 40, said Nancy Davidson, MD, professor of oncology, Johns Hopkins University.
In a presentation at the 35th annual meeting of the American Society of Clinical Oncology (Atlanta), Dr. Davidson reported results of Trial E5188 (INT-0101) for the Eastern Cooperative Oncology Group (ECOG), which conducted the study with the Southwest Oncology Group (SWOG) and the Cancer and Leukemia Group B (CALGB). The phase III study had three treatment arms: six cycles of CAF alone, CAF plus 5 years of goserelin for ovarian ablation, and CAF plus goserelin and 5 years of tamoxifen.
For CAF plus goserelin, the hazard ratio for recurrence was 0.85 (a 15% relative reduction), which was of borderline significance using one-sided testing. Adding tamoxifen to CAF and goserelin produced a hazard ratio for recurrence of 0.74 (26% relative reduction), which was significant at P < .01.
Five-year disease-free survival was increased significantly with the addition of tamoxifen: 67% for CAF alone, 70% for CAF plus goserelin, and 77% for CAF plus both endocrine agents. All three treatment groups had an overall 5-year survival rate of approximately 85%, Dr. Davidson said.
“The question arose of whether the addition of hormone therapy might benefit certain subsets of premenopausal women,” Dr. Davidson said. As a consequence, the researchers analyzed subgroups based on age and estrogen levels after therapy.
They reasoned that the benefit of ovarian ablation with goserelin would more likely be seen in younger women, who are more likely to remain premenopausal after chemotherapy.
Five-year disease-free survival for the approximately 500 study participants who were younger than age 40 at time of entry was significantly increased with goserelin: 54% with CAF, 65% with CAF plus goserelin, and 72% with CAF plus both hormonal therapies. For those 40 years of age or older, there was no difference in 5-year disease-free survival with the addition of goserelin, but the addition of tamoxifen to CAF plus goserelin improved disease-free survival to 79%.
“Together these results suggest that adding goserelin to CAF is helpful for women under age 40 but not for older premenopausal women,” Dr. Davidson said. “In contrast, in this analysis, the benefit of tamoxifen was more striking in women over the age of 40.”
The researchers also looked at the relationship between serial estrogen levels as an indicator of ovarian function and effect of therapy. At the end of CAF therapy, about 40% of women under age 40 had postmenopausal estrogen levels, but the addition of goserelin with or without tamoxifen led to sustained postmenopausal estrogen levels in more than 70% of patients. For women over age 40, more than 70% had postmenopausal estrogen levels after CAF, and the addition of either hormone therapy had no effect.
The investigators then looked at the approximately 1,000 women who had serum drawn for estrogen levels within 1 month of completing CAF. For women who had premenopausal estrogen levels after CAF, the addition of goserelin reduced the relative risk of disease recurrence by 36% (0.64 hazard ratio), which was borderline statistically significant. In contrast, in the women with postmenopausal estrogen levels after CAF, the addition of goserelin showed no benefit.
Thus, Dr. Davidson said, “the clinical benefit of adding goserelin to CAF was limited to those women whose estrogen level was still in the premenopausal range after CAF.”
The same analysis for adding tam-oxifen showed no effect on the hazard ratio for recurrence among women with premenopausal estrogen levels after CAF, compared with a significant relative reduction in risk of 50% in the women with postmenopausal estrogen levels after CAF.
Dr. Davidson reported that rates of unexpected toxicities, severe weight gain, and endometrial cancer were similar in all three groups. Goserelin patients did have more hot flashes, however.
