Cancer Treatment Today

In premenopausal women with early stage (stage I and II) breast cancer, the standard adjuvant treatment remains tamoxifen. Outside of a clinical trial, some doctors will add ovarian suppression to tamoxifen, and there is some evidence to support this approach. The evidence to support ovarian suppression is strongest in women who have not also received chemotherapy.

There are two international clinical trials that are comparing ovarian suppression plus an aromatase inhibitor with ovarian suppression plus tamoxifen or tamoxifen alone. These randomized phase III trial studies ovarian suppression with either tamoxifen or exemestane to see how well they work compared to tamoxifen alone in treating premenopausal women who have undergone surgery for hormone-responsive breast cancer.

In the Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial, 2,144 premenopausal and perimenopausal women were randomized to tamoxifen alone or with the addition of ovarian ablation or suppression. They could also be given elective chemotherapy at their physician’s discretion.
The hormone agonists used were 3.6 mg of goserelin (Zoladex) and 3.75 mg of leuprorelin acetate (Lupron). After an average 5.9 years of follow-up, the findings were (tamoxifen with ovarian ablation or suppression versus tamoxifen without ovarian ablation or suppression):

Those who had ovarian ablation or suppression were no less likely to relapse than those who did not (hazard ratio 0.95, 95% confidence interval 0.81 to 1.12, P=0.56).
Five-year relapse-free survival was similar between groups (73.7% versus 72.8%, absolute difference 0.9%, 95% CI -3.1% to 4.9%).
All-cause mortality was likewise similar between groups (HR 0.94, 95% CI 0.78 to 1.13, P=0.44).
Five-year survival was similar as well (82.6% versus 80.3%, absolute difference of 2.3%, 95% CI -1.2% to 5.9%). The findings were unchanged by adjusting for prognostic factors, including age, nodal status, and estrogen receptor status, or use of chemotherapy (overall survival P=0.50, relapse-free survival P=0.56).

As expected, ovarian ablation or suppression was more effective for the 39% of women whose tumors were retrospectively determined to be ER-positive. But even this group ovarian ablation or suppression did not have a significant benefit (HR 0.84, 95% CI 0.59 to 1.20).

There was a signal for benefit, though, in the small group of 56 women younger than 40 who did not receive chemotherapy. This “group considered biologically to have the most to gain from ovarian ablation or suppression” had a 0.55 hazard ratio for overall survival (95% CI 0.17 to 1.85).
The overall findings fit relatively well with those of the large meta-analyses of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). As reported in The Lancet in 2005, ovarian ablation or suppression showed only a 3% absolute benefit for mortality after 15 years, though this was statistically significant (P=0.004).

In the second trial , the Adjuvant Breast Cancer Chemotherapy Trial, 1,991 women ages 26 to 81 were randomized to tamoxifen alone or with chemotherapy. Adjusting for ovarian suppression use had little effect on the Adjuvant Breast Cancer Chemotherapy Trial findings. Again, however, there was a suggestion that ovarian suppression may not be best in the setting of chemotherapy for premenopausal women.

The most recent study is from the February 2009 issue of the New England Journal. After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. IN CONCLUSION, OVARIAN SUPRESSION WITH TAMOXIFEN OR ARIMIDEX ADDED APPEARS TO BE SUPPORTED BY RANDOMIZED SATA.

Lupron alone is not as well studied. Most studies added Lupron or Zoladex to oral hormonal antagonists. NCCN BINV-J recomemnds tamoxifen With or without ovarian supression or ablation.

nccn.org, breast cancer, 2019

Pistelli M, Mora AD, Ballatore Z, Berardi R. Aromatase inhibitors in premenopausal women with breast cancer: the state of the art and future prospects. Curr Oncol. 2018;25(2):e168-e175.

Bliss JM, et al “Polychemotherapy for Early Breast Cancer: Results From the International Adjuvant Breast Cancer Chemotherapy Randomized Trial” J Natl Cancer Inst 2007;99: 506-515.

Gnant, Michael, Mlineritsch, Brigitte, Schippinger, Walter, Luschin-Ebengreuth, Gero, Postlberger, Sabine, Menzel, Christian, Jakesz, Raimund, Seifert, Michael, Hubalek, Michael, Bjelic-Radisic, Vesna, Samonigg, Hellmut, Tausch, Christoph, Eidtmann, Holger, Steger, Gunther, Kwasny, Werner, Dubsky, Peter, Fridrik, Michael, Fitzal, Florian, Stierer, Michael, Rucklinger, Ernst, Greil, Richard, the ABCSG-12 Trial Investigators, Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer N Engl J Med 2009 360: 679-691