New Standards for Hormonal Treatment of Breast Cancer

HAMBURG, Germany —Recent clinical trials presented at the 25th Congress of the European Society of Medical Oncology (ESMO) suggest that new standards for the hormonal treatment of breast cancer may be emerging.

Adjuvant Goserelin vs CMF

In the Zoladex Early Breast Cancer Research Association (ZEBRA) study, the luteinizing hormone-releasing hormone (LHRH) agonist goserelin (Zoladex) emerged as a serious alternative to adjuvant chemotherapy for pre- and peri-menopausal women with node-positive, estrogen-receptor (ER)-positive breast cancer.

The chief advantage of goserelin monotherapy is that it matches the efficacy of the CMF chemotherapy regimen (cyclophosphamide, methotrexate, 5-fluorouracil) without causing nausea, vomiting, and alopecia, said Moise Namer, MD, of Antoine Lacassagne Center, Nice, France.

Between 1990 and 1996, ZEBRA trialists at 102 centers in 15 countries randomized more than 1,600 women who had undergone surgery for breast cancer to receive either goserelin or the CMF regimen.

Dr. Namer pointed out that study participants were stratified according to ER status and age. Three quarters of the women in both treatment arms were ER positive, and roughly three quarters had between one and three positive lymph nodes.

After a median follow-up period of 6 years, Dr. Namer said, disease-free survival among ER-positive patients was equivalent in those treated with goserelin and in those assigned to cytotoxic chemotherapy.

In contrast, CMF was significantly more effective than hormonal treatment in ER-negative women. “Measurement of ER status is vital for treatment decisions,” he stressed.

The overall survival results mirrored the disease-free survival outcome, although the data lack maturity, Dr. Namer said.

Reversible Amenorrhea

“In the goserelin arm, amenorrhea was achieved in almost 100% of patients, but, most importantly, menses returned after cessation of treatment,” Dr. Namer said. With CMF, however, amenorrhea proved to be irreversible.

Not surprisingly, CMF produced a significantly higher incidence of nausea and vomiting (56% vs 5% with goserelin) and alopecia (43% vs 3% with goserelin).

The most prominent side effects of goserelin were those typical of estrogen suppression, with vaginal dryness developing in 24% of women (vs 14% with CMF) and hot flashes occurring in 72% (vs 42% with CMF).

Neoadjuvant Letrozole vs Tamoxifen

In the largest endocrine comparative trial performed to date in the neoadjuvant setting, the aromatase inhibitor letrozole (Femara) proved superior to tamoxifen (Nolvadex) in reducing tumor size and facilitating breast-conserving surgery.

“If there is an indication for preoperative endocrine therapy in postmenopausal breast cancer patients, letrozole should be used rather than tamoxifen,” said Wolfgang Eiermann, MD, of the Red Cross Women’s Clinic, Munich, Ger-many.

The Letrozole Neoadjuvant Breast Cancer Study group, encompassing 55 centers in 16 countries, randomly assigned more than 300 ER-positive and/or progestogen-receptor (PR)-positive postmenopausal women with early breast cancer (T2-4, N0-2, M0) to 4 months of therapy with letrozole 2.5 mg once daily or tamoxifen 20 mg once daily. All patients were ineligible for breast-conserving therapy at the time of enrollment.

The results revealed a striking benefit with letrozole treatment, irrespective of whether objective response was assessed clinically (55% vs 36% with tamoxifen, P < .001); by ultrasound (35% vs 25% with tamoxifen, P = .042); or by mammography (34% vs 17% with tamoxifen, P < .001).

Baseline tumor size, number of positive nodes, and age had no influence on the response to letrozole, Dr. Eiermann said.

Mastectomy could be avoided in 45% of letrozole-treated patients, but in only 35% of those assigned to tamoxifen (P = .022). Eligibility for breast-conserving surgery increased most markedly in women whose tumors were initially larger than 5 cm in size, Dr. Eiermann noted.

Letrozole vs Tamoxifen in Advanced Disease

Letrozole also proved superior to tamoxifen as first-line hormonal treatment for postmenopausal women with locally advanced or metastatic breast cancer, reported Henning Mouridsen, MD, of Rigshospitalet, Copenhagen, on behalf of the Letrozole P025 Breast Cancer Study Group.

In this double-blind trial, more than 900 women were randomized to therapy with letrozole 2.5 mg once daily or tamoxifen 20 mg once daily until progression occurred, at which point patients suitable for another endocrine therapy were crossed over to the alternative treatment. Approximately two thirds of participants were ER and/or PR positive, while receptor status was unknown in the remainder.

Patients were ineligible for inclusion if they had recurrence while receiving adjuvant tamoxifen or within 12 months of completing such therapy; prior endocrine therapy or more than one prior course of chemotherapy for metastatic disease; or CNS metastases or major lung or liver involvement.

Letrozole significantly prolonged the median time to progression to 9.4 months, compared with 6.0 months with tamoxifen. “These data correspond to a hazard ratio of 0.7, which means that the chance of progression was 30% lower for patients on letrozole than for patients on tamoxifen,” Dr. Mouridsen said. “The difference was highly significant, P = .0001,” he added.

The median time to failure was likewise significantly longer with letrozole than with tamoxifen (9.1 vs 5.7 months, P = .0001).

The benefit in favor of letrozole held for all patient subgroups, independent of receptor status, dominant site of disease, or prior adjuvant endocrine therapy.

Objective Response

“An objective response was observed in 30% of patients randomized to letro-zole, as against 20% of those on tamoxi-fen,” Dr. Mouridsen reported. “This gives an odds ratio of 1.7 and a P value of .0006, indicating that the chance of response was 70% higher for patients randomized to letrozole, compared to tamoxifen.”

Similarly, 49% of letrozole-treated patients showed clinical benefit, compared with 38% of those treated with tamoxifen.

Here again, the superior response rate with letrozole was evident across the board, in all patient subgroups, he said. The durations of response and clinical benefit were similar with both endocrine treatments, however.

Letrozole was as well tolerated as tamoxifen. The frequencies of such side effects as hot flushes, nausea, and hair thinning were similar in both treatment arms, although there was a nonsignificant trend toward a lower incidence of thromboembolic events with letrozole.

“On the basis of these data, letrozole should now be considered as first-line therapy for advanced breast cancer,” Dr. Mouridsen said.

Anastrozole vs Tamoxifen in Advanced Disease

Additional support for the value of aromatase inhibitors in the first-line treatment of advanced breast cancer came from two large randomized trials, one North American and the other European, that compared anastrozole (Arimidex) 1 mg/d with tamoxifen 20 mg/d in more than 1,000 postmenopausal women.

In the North American trial, anas-trozole significantly delayed the time to progression by 44%, compared with tamoxifen, reported Aman Buzdar, MD, of M.D. Anderson Cancer Center. The median time to progression was 11.1 months among patients receiving the aromatase inhibitor vs 5.6 months in the tamoxifen group (P = .005).

After a median follow-up interval of 18 months, clinical benefit was apparent in 59% of anastrozole-treated patients vs 46% of those receiving tamoxifen (P = .0098).

The benefit of anastrozole was not replicated in the European study, however. Dr. Buzdar attributed this discrepancy to the fact that 89% of participants in the American trial were known to be ER or PR positive, compared with 45% of their European counterparts.

Indeed, analysis of time to progression only in those European enrollees who were receptor positive pointed to a benefit in favor of anastrozole. Pooled data from the 700 receptor-positive participants in both trials likewise revealed that the time to progression was significantly longer with anastrozole than with tamoxifen (10.7 vs 6.4 months, respectively, P = .022).

“These data highlight the importance of hormone-receptor assessment prior to initiation of endocrine therapy,” Dr. Buzdar commented.

Anastrozole was associated with significantly fewer episodes of thromboembolism (4.5% vs 7.6% with tamoxifen, P = .0056) and vaginal bleeding (1.0% vs 2.2% with tamoxifen, P = .0083).

“These data clearly support the use of anastrozole as front-line therapy in metastatic disease,” Dr. Buzdar said. “I think that the ultimate test of the value of these compounds will be in the adjuvant setting.” To this end, the ongoing ATAC study is assessing the efficacy of anastrozole vs tamoxifen vs the combination of both drugs in 9,000 women with invasive breast cancer.