Amenorrhea During Treatment Helps Breast Cancer Prognosis

SAN ANTONIO, Dec. 18 -- Premature ovarian failure during breast cancer treatment may mean a better relapse free survival, according to Austrian researchers.

Treatment-induced amenorrhea reduced relapse risk by about 44% for women under age 40, reported Michael Gnant, M.D., of the Medical University of Vienna at the San Antonio Breast Cancer Symposium here.

The results suggest a greater role for ovarian suppression in this population, he said.

"For premenopausal patients with endocrine-responsive disease who do not experience treatment-induced amenorrhea during chemotherapy, additional ovarian suppression may be advisable," Dr. Gnant said.

The study included 1,099 initially premenopausal women with estrogen or progestin receptor-positive stage I or II breast cancer. After surgery, they were randomized to ovarian ablation with 3.6 mg of Zoladex (goserelin) every 28 days for three years and 20 mg of tamoxifen daily for five years, or to six cycles of 600 mg/m² of Cytoxan (cyclophosphamide), 40 mg/m² of methotrexate, and 600 mg/m² Adrucil (fluorouracil) intravenously on days one and eight.

The patients (mean age 45.3) typically had a good prognosis at baseline (50% node negative, about 30% HER2/neu positive). Amenorrhea, defined as no menstrual periods from treatment month three to six or beyond, occurred among 76.7% of patients overall (100% of the ovarian ablation group and 53.1% of the chemotherapy group).

At the 11-year follow up, 19.1% overall had died and 28.4% relapsed. Ten-year relapse free survival was 82.7%, 15-year relapse free survival was 71.8%, 10-year overall survival was 84.1%, and 15-year overall survival was 80.9%.

The researchers reported that while those who had amenorrhea had a significant 10% higher relapse free survival at 10 years, the effect decreased to borderline significance at 11 years (P=0.02). The overall survival showed a similar trend with a 3.5% difference maintained to 10 years then lost (P=0.26).

Menstruation cessation improved the likelihood of relapse-free survival significantly (hazard ratio 0.579, 95% confidence interval 0.403 to 0.832, P=0.0031), but not overall survival (HR 0.821, 95% CI 0.593 to 1.136, P=0.2342).

Among the subset of patients in the chemotherapy group, amenorrhea likewise significantly improved relapse free survival (HR 0.560, 95% CI 0.349 to 0.899, P=0.0163) but not overall survival (HR 0.785, 95% CI 0.530 to 1.164, P=0.2286).

The significance of these findings may have diminished as women became menopausal during the long follow-up, commented Eric Winer, M.D., of the Dana-Farber Cancer Institute in Boston, who was not involved in the study.

The findings supported this speculation, as the benefit for amenorrhea appeared to be entirely accounted for by the youngest women. For the chemotherapy group, the researchers reported:

• Among women age 40 or younger, there was a trend to improved relapse free survival with amenorrhea (P=0.0965),
• Among women ages 41 to 50, there was no association between menstruation and relapse free survival (P=0.7585), and
• Among women older than 50, the same lack of significant association was seen (P=0.3368).

The results were unaffected by hormone receptor status, but women with HER2/neu-negative tumors appeared to get more benefit that those with HER2/neu overexpressing tumors (recurrence free survival P=0.013 versus P=0.31 between groups for HER2/neu negative and positive, respectively).

Although Dr. Gnant said the data has not yet been examined for duration of amenorrhea, a significant proportion of the women did not resume menses. Other studies have found women in their 30s may have about a 50% chance of resuming menses after chemotherapy if they have treatment-induced amenorrhea while women in their 40s may have only a 20% chance.

However, he said that he would suggest considering only temporary ovarian suppression if women continue to have their period during chemotherapy.

"We are not talking about inducing unnatural menopause in a 30-year-old woman," he said.