Cancer Treatment Today

There are two international clinical trials that compared ovarian suppression plus an aromatase inhibitor with ovarian suppression plus tamoxifen or tamoxifen alone. These randomized phase III trial study 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 Zoladex In Pre-menopausal Patients (ZIPP) study was designed to determine whether addition of goserelin (‘Zoladex’) and/or tamoxifen to adjuvant therapy (radiotherapy and/or chemotherapy), provided benefit to pre- or peri-menopausal women with operable, early breast cancer. A combined analysis of four randomised trials using a core protocol was performed. Patients (n=2710) were randomised into a 2×2 factorial trial based on goserelin and tamoxifen (n=1800) or randomised to receive goserelin or not (n=910; some received elective tamoxifen) for 2 years. The analysis presented here compares women who did (n=1354) or did not (n=1356) receive goserelin. After a median follow-up of 5.5 years, goserelin provided a significant benefit for event-free survival (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.69, 0.92; P=0.002) and overall survival (HR 0.81; 95% CI 0.67, 0.99; P=0.038). Goserelin was well tolerated. These data show that the addition of goserelin to standard adjuvant therapy is more effective than standard therapy alone in pre-menopausal women with early breast cancer.The addition of zoledronic acid to adjuvant endocrinetherapy improves disease-free survival in premenopausal patientswith estrogen-responsive early breast cancer.

In conclusion, ovarian ablation accompanied by tamoxifen is still being investigated versus an ovarian ablaton alone as an adjunct to or instead of chemotherapy. However, Zoladex alone was approved in Canada in April 2008.The addition of zoledronic acid to adjuvant endocrinetherapy improves disease-free survival in premenopausal patientswith estrogen-responsive early breast cancer. The use of Lupron or Zoladex alone after optimal chemotherapy is expressed by NCCN in this language: “Chemotherapy and endocrine therapy used a adjuvant should be given sequentially with endocrine therapy following chemotherapy. Early evidence shoes similar benefits form LHRH agonists as from ovarian ablation. However, the absolute benefit from chemotherapy may be small. The decision to add chemotherapy to endocrine therapy should be individualized…”.

Adjuvant hormonal therapy or chmotherpay are currently recommended for premenupousal patients with breast cancer. In addition, However, NCCN also lists an option of adjuvant chemotherapy followed by hormonal therapy on p. BINV-6.

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015 Jul 23.

O.C. Freedman, MD,* G.G. Fletcher, MSc,† S. Gandhi, MSc MD,‡ M. Mates, MD,§ S.F. Dent, MD,‖ M.E. Trudeau, MD,* and A. Eisen, MD*Adjuvant endocrine therapy for early breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline
Curr Oncol. 2015 Mar; 22(Suppl 1): S95–S113.

Kaufmann M, Jonat W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, Schumacher M & Sauerbrei W 2003 Survival analyses from the ZEBRA study. Goserelin (Zoladex) versus CMF in premenopausal women with node-positive breast cancer. European Journal of Cancer 39 1711–1717.

Kellie L Jones and Aman U Buzdar A review of adjuvant hormonal therapy in breast cancer Endocrine-Related Cancer 11 (3) 391-406