Mixing Adjuvant Therapies Prolongs Early Breast Cancer Survival

SUTTON, England, April 4 -- Halting ovarian function by suppression or ablation offers little further benefit for most women already getting adjuvant tamoxifen with or without chemotherapy for early breast cancer, researchers here found.

The three adjuvant treatments had previously been shown to improve early breast cancer survival as monotherapies, but little long-term data had been available for combinations, said Judith Bliss, M.Sc., of the Institute of Cancer Research here, and colleagues.

So they conducted two large studies of combination adjuvant therapy for early breast cancer among women receiving five years of tamoxifen therapy. Both trials were started in the early 1990s before estrogen receptor status was routinely tested, Dr. Bliss and colleagues wrote in the April 4 Journal of the National Cancer Institute.

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.

Among those who received ovarian ablation or suppression according to randomization (11% refused), 68.8% had menopause induced by radiation, 22.8% had surgical ablation, and 8.4% took a luteinizing hormone-releasing hormone agonist every 28 days for at least two years.

The hormone agonists used were 3.6 mg of goserelin (Zoladex) and 3.75 mg of leuprorelin acetate (Lupron). Neither is FDA approved for the treatment of early breast cancer.

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).

"We cannot rule out the possibility that a subgroup of premenopausal patients with ER-positive tumors who did not receive chemotherapy or who did not become amenorrheic with chemotherapy, benefited from the addition of ovarian ablation or suppression," the researchers wrote.

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).

While "there is no evidence for the emergence of such effects in the Adjuvant Breast Cancer Ovarian Ablation or Suppression Trial," Dr. Bliss and colleagues noted, "it is possible that benefits of ovarian ablation or suppression will emerge after further follow-up data have accrued."

In the second trial they reported, the Adjuvant Breast Cancer Chemotherapy Trial, 1,991 women ages 26 to 81 were randomized to tamoxifen alone or with chemotherapy.

In most cases, chemotherapy consisted of cyclophosphamide (Cytoxan), methotrexate, and 5-fluorouracil (87%) or anthracycline-based regimens (11%), such as doxorubicin (Adriamycin) and cyclophosphamide.

Radiotherapy was allowed, and 244 of 619 premenopausal women had elective ovarian ablation or suppression at their physician's discretion.

Over the median 6.4 years of follow-up, the findings were (tamoxifen with versus without chemotherapy):

• Combination adjuvant therapy tended to improve relapse-free survival adjusted for nodal status, retrospectively determined ER status, and age (298 versus 332 events, HR 0.86, 95% CI 0.73 to 1.01; P=0.06).
• Five-year relapse-free survival was 72.0% versus 69.6% (absolute difference 2.4%, 95% CI -1.8% to 6.6%).
• Overall survival was significantly improved with the addition of chemotherapy (243 versus 282 all-cause mortality events, adjusted HR 0.83, 95% CI 0.70 to 0.99, P=0.03).

Because the benefit for overall survival emerged only at five years (78.7% versus 77.3%, absolute difference 1.4%, 95% CI -2.4% to 5.3%), "it is likely that the true impact of the addition of chemotherapy on overall survival benefit is only just emerging," Dr. Bliss and colleagues wrote. Newer chemotherapy regimens may also add to the benefit, they said.

These findings confirmed the synergistic effect of chemotherapy and tamoxifen reported by the Early Breast Cancer Trialists' Collaborative Group in The Lancet in 2005.

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 hazard ratios showed that premenopausal women received less benefit from the combination of all three adjuvant treatments (0.94, 95% CI 0.57 to 1.55) than from tamoxifen plus chemotherapy in the absence of ovarian ablation or suppression (0.76, 95% CI 0.51 to 1.14).

The findings reaffirmed the role of chemotherapy in the tamoxifen era with no surprises, but left questions about ovarian suppression unanswered for the subset of young, premenopausal patients with estrogen responsive tumors, according to an editorial by Kathleen I. Pritchard, M.D., of the Toronto Sunnybrook Regional Cancer Center.

"These subset results may relate partly to the fact that chemotherapy in those without deliberate ovarian ablation or suppression produced ovarian ablation or suppression in many cases," Dr. Pritchard wrote.

The study supported this, in that vasomotor symptoms were twice as severe with chemotherapy among premenopausal women overall as without it, the researchers added.

Dr. Pritchard said based on the results, "further investigation of ovarian ablation or suppression added to tamoxifen or to chemotherapy is worthwhile, particularly in young premenopausal women who do not become amenorrheic following chemotherapy."

"The real question, however, is whether the subset of women with high hormone responsivity and low or intermediate risk of recurrence could be effectively treated with endocrine therapy alone," she continued.