Developed over a century ago, endocrine therapy remains the most effective and the most clearly targeted form of systemic therapy for breast cancer. Endocrine treatments work best in women whose tumors are positive for estrogen receptors (ER) and/or progesterone receptors (PR). As we search for newer targeted therapies that will shrink cancers effectively with few undesired side effects and carry out complex statistical analyses to identify predictive factors, we should keep in mind the first targeted cancer therapy—ovarian ablation for breast cancer—and the first predictive factor for treatment of any cancer—the estrogen receptor.
Adjuvant treatment for premenopausal women is an important current focus in the setting of breast cancer. In Canada, 20% of newly diagnosed breast cancer cases occur in patients under 50 years of age, 4% are in women under 40, and 1% to 2% are in those under 35. Of these, about half will have ER- and/or PR-positive disease.
Ovarian Ablation as Adjuvant Endocrine Therapy
or many years, adjuvant ovarian ablation was believed to be helpful in premenopausal women with breast cancer, but randomized trials were not done. A few small randomized trials were carried out in the 1960s and 1970s, but prior to the first Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Overview (aka the Oxford Overview) in 1984, it was generally thought that these trials showed no benefit for ovarian ablation. This strategy therefore came to be considered an outmoded breast cancer therapy. When the meta-analytic techniques used in the EBCTCG Overview were applied to these small trials, however, it became apparent that ovarian ablation was effective.
Ovarian Ablation as Primary Adjuvant Systemic Therapy
The meta-analytic techniques used in the EBCTCG Overview have shown that ovarian ablation is associated with a relatively large positive effect on both disease-free survival (DFS) and overall survival (OS) in premenopausal women. In women with or without involved axillary lymph nodes,[4-6] the effects of ovarian ablation were significantly positive in the subgroup of trials in which women were randomized to receive ovarian ablation alone vs no systemic therapy. However, studies of ovarian ablation plus chemotherapy vs the same chemotherapy alone showed only a slight trend toward a positive effect.[4-6] The lack of a large and obvious benefit in women who also received chemotherapy may relate to the ovarian suppressive effect secondary to chemotherapy, which occurs in many premenopausal women. This effect may be less applicable in very young women, but the data—even in the EBCTCG Overview—are too scant to be sure.
The most recent EBCTCG Overview, carried out in September 2005–2006, included updated information on 12,000 women under age 50 in 16 trials of ovarian ablation/suppression vs no treatment of this sort. There were more women and more breast cancer deaths in trials of ovarian ablation in the presence of chemotherapy (more than 3,300 recurrences and more than 2,800 deaths) than in trials of ovarian ablation in the absence of chemotherapy (about 1,000 recurrences and 900 breast cancer deaths) (personal communication, R. Peto, 2006).
This updated analysis showed a clear difference between the trials of ovarian ablation vs no treatment in the absence of chemotherapy—in which a large and highly significant positive effect persisted with regard to DFS (52.2% vs 40.8% at 15 years [difference = 11.5%; standard error (SE) = 2.6])—and the trials of ovarian ablation plus chemotherapy vs the same chemotherapy, which showed no significant difference with regard to DFS (54.7% vs 55.3% [difference = 0.6%; SE = 2.9]). Breast cancer deaths were also reduced by about 5% after 10 years and by about 11% after 20 years in trials of ovarian ablation/suppression in the absence of chemotherapy, but by only 2% to 3% after 10 years in the presence of chemotherapy. Twenty-year data are not available for trials of ovarian ablation/suppression in the presence of chemotherapy.
The development of the luteinizing hormone-releasing hormone (LHRH) analogs has increased interest in the use of ovarian ablation in premenopausal women. In one fairly large phase III trial, an LHRH analog was shown to be as effective as surgical ovarian ablation in the treatment of metastatic breast cancer. In addition, a meta-analysis of four small studies comparing tamoxifen plus an LHRH analog to an LHRH analog alone have suggested that the combination is superior in terms of disease progression and overall survival in the metastatic setting. It has been suggested that this observation might extend into the adjuvant setting, where the combination of an LHRH analog and tamoxifen could prove superior to either alone.
Various LHRH analogs—in particular, the drug goserelin (Zoladex)—have now been tested in large trials of adjuvant therapy. The study designs are of two types: (1) those comparing goserelin, tamoxifen, or goserelin plus tamoxifen to chemotherapy in the premenopausal setting, and (2) those that add either goserelin, tamoxifen, or goserelin plus tamoxifen to chemotherapy in the same group of women.
In the most recent EBCTCG Overview (September 2006), five trials of the LHRH agonist goserelin vs no goserelin in 5,700 women were identified. As in 2000, data from only three of these trials in 4,200 women were available. These trials are included with those of ovarian ablation in the EBCTCG synopsis above. In the Eastern Cooperative Oncology Group (ECOG) E5188 trial, all patients received CAF chemotherapy (cyclophosphamide, doxorubicin [Adriamyin], fluorouracil [5-FU]). In the Zoladex In Premenopausal Patients (ZIPP) trial, 1,173 of 2,710 women received chemotherapy prior to randomization to goserelin and/or tamoxifen. In the French Fdration Nationale des Centres de Lutte contre le Cancer (FNCLCC) trial, all 16,212 women received chemotherapy before being randomized to goserelin or control.
he ZIPP trial has been independently reported and now fully published. Its design was that of a large 2×2 factorial study in which premenopausal women with early-stage disease were randomized, after primary surgery, to (1) tamoxifen for 2 years, (2) goserelin (26 monthly subcutaneous injections), (3) tamoxifen plus goserelin, or (4) no endocrine therapy. Some patients electively received tamoxifen or did not and were randomized to only the goserelin option. The study protocol also permitted the use of elective adjuvant chemotherapy. A total of 2,631 women (56% node-negative) were studied. ER status was available in 1,577 (60%).
At a median follow-up of 4.3 years, fewer recurrences were observed among patients who were randomized to receive goserelin than among those randomized to not receive goserelin—261 (20%) vs 330 (24.9%); hazard ratio (HR) = 0.77; 95% confidence interval (CI) = 0.66–0.90; P = .001. This effect was most pronounced among women who were known to have ER-positive disease. The benefit of goserelin appeared to be somewhat less pronounced among those who received concurrent adjuvant tamoxifen or adjuvant chemotherapy, but the differences compared to patients who did not receive concurrent treatments were not statistically significant. The investigators also noted a trend toward fewer deaths among women allocated to receive goserelin—140 (10.7%) vs 165 (12.4%); HR = 0.84; 95% CI = 0.67–1.05; P =.12.
Thus, in this study, medical castration with goserelin for 2 years in premenopausal patients with ER-positive disease produced a statistically significant benefit in terms of DFS, and a trend toward improvement in OS, irrespective of concurrent adjuvant tamoxifen or chemotherapy.
The study from the ECOG, conducted by Davidson and colleagues, also examined the role of goserelin with or without tamoxifen in premenopausal women. In this study, 1,503 eligible premenopausal node positive women who all received CAF chemotherapy were randomized to either goserelin alone (CAFZ) or goserelin plus tamoxifen (CAFZT) for 5 years. The use of CAFZT in comparison to CAFZ was associated with significantly better DFS (P < .01) and time to recurrence (TTR) (P < .01) but not a significant difference in OS (P =.23). The addition of goserelin alone to CMF (cyclophosphamide, methotrexate, 5-FU) showed only a trend toward improved DFS (P =.15), TTR (P =.17), and OS (P =.14).
A preliminary hypothesis-generating analysis presented by Dr. Davidson, however, suggested that the addition of goserelin had a greater effect in younger women and/or in women who did not become postmenopausal as a result of chemotherapy, whereas the addition of tamoxifen seemed more effective in older women and/or in women who became menopausal as a result of their chemotherapy. This hypothesis remains to be further explored and substantiated in other prospective randomized trials.
A more complete and updated meta-analysis published in The Lancet in May 2007 obtained data from 11,906 premenopausal women with early breast cancer randomized in 16 trials. In this meta-analysis, LHRH agonists, when used as the only systemic adjuvant treatment, did not significantly reduce recurrence (28.4% relative reduction [RR]; 95% CI consistent with a 50.5% reduction to a 3.5% increase; P =.08) or death after recurrence (17.8% RR; 95% CI = 52.8% reduction to 42.9% increase, P = .49) in hormone receptor–positive cancers. The addition of LHRH agonists to tamoxifen, chemotherapy, or both reduced recurrence by 12.7% (95% CI = 2.4% RR to 21.9% RR, P =.02), and death after recurrence by 15.1% (95% CI = 1.8% RR to 26.7% RR, P =.03). LHRH agonists were ineffective in hormone receptor–negative tumors.
In this 2007 meta-analysis the results of the EBCTCG’s previous meta-analysis were both supported and refined. The number of patients included in trials of LHRH agonists was substantially larger than that available in the previous published Overview. The results broadly supported those of previous analyses but also showed new and important details. It is of particular interest that in this 2007 meta-analysis, the LHRH agonists benefit women younger than 40 after chemotherapy but not older premenopausal women.
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