IBCSG Trials of Chemoendocrine Rx

April 1, 2003

SAN ANTONIO-Results of two randomized International Breast Cancer Study Group (IBCSG) trials of chemoendocrine therapy for node-negative breast cancer suggest that adjuvant chemotherapy may provide additional benefit over endocrine therapy alone for patients with estrogen-receptor (ER)-negative, but not ER-positive, tumors.

SAN ANTONIO—Results of two randomized International Breast Cancer Study Group (IBCSG) trials of chemoendocrine therapy for node-negative breast cancer suggest that adjuvant chemotherapy may provide additional benefit over endocrine therapy alone for patients with estrogen-receptor (ER)-negative, but not ER-positive, tumors.

Endocrine responsiveness is an important determinant of treatment response for both premenopausal and postmenopausal patients, according to the studies presented at the 25th Annual San Antonio Breast Cancer Symposium (abstract 11).

The two trials—IBCSG VIII and IBCSG IX—were conducted between 1988 and 1998. Patients in both trials had histologically proven unilateral breast cancer, stage T1a, 1b, 2a, T2, or T3, with negative nodes and no metastases. Tumors could be either ER positive or negative; an unknown designation was permitted only in the absence of material.

The trial results were reported by Monica M. Castiglione-Gertsch, MD, director of the Swiss Institute for Applied Cancer Research Coordinating Center in Bern, Switzerland, and chief executive officer of the IBCSG.

For IBCSG VIII, 1,109 premenopausal or perimenopausal women were randomized to goserelin (Zoladex) 3.6 mg subcutaneously monthly for 24 months; classical CMF (oral cyclophosphamide at 100 mg/m2 on days 1 to 14; IV metho-trexate at 40 mg/m2 on days 1 and 8; and IV fluorouracil at 600 mg/m2 on days 1 and 8) for six courses; or classical CMF for six courses followed by goserelin for 18 months. Median follow-up was 5.7 years.

IBCSG IX randomized 1,669 postmenopausal women to tamoxifen (Nol-vadex) alone (20 mg/d for 60 months) or classical CMF followed by tamoxifen (20 mg/d) for 57 months. Median follow-up was 6 years.

Endocrine Responsiveness

Dr. Castiglione acknowledged that these trials included treatments that are considered by some to be suboptimal. Tamoxifen, for example, was not given to premenopausal women, and anthra-cyclines were not part of the chemotherapy regimen for postmenopausal women. Nonetheless, she noted, the results are important in choosing the focus of current research.

"The key findings of these trials are that in both premenopausal and postmenopausal patients, treatment effects differed according to estrogen-receptor status. Overall results based on a mixture of endocrine-responsive and nonresponsive disease are confounded and, thus, are of limited value in patient care decision-making," Dr. Castiglione said. "We think, therefore, that it is time to move away from treating patients according to risk, to treating patients according to endocrine responsiveness."

IBCSG VIII Results

In trial IBCSG VIII, nearly one third of patients were ER negative; 63% were age 40 to 49, and 20% were age 39 or younger. "On average, for the entire population, chemotherapy alone yielded the same results as endocrine therapy alone," Dr. Castiglione said. "Overall survival differences were not observed."

Among ER-negative patients, as expected, chemotherapy alone was superior to endocrine therapy alone (83% 5-year disease-free survival vs 72% for goserelin alone). Adding endocrine therapy after CMF appeared to provide some additional benefit in this population (88% 5-year disease-free survival), she noted, "indicating some degree of endocrine responsiveness and underscoring the need to improve the ability to distinguish tumors that are endocrine responsive from those that are not."

Among ER-positive patients, there was no significant difference in disease-free survival among the three treatments. The sequential use of chemotherapy followed by goserelin appeared slightly superior, but was significant only in the younger age group, Dr. Castiglione noted.

Five-year disease-free survival in ER-positive patients age 39 or younger was 88% for combination therapy, 62% for CMF alone, and 63% for goserelin alone (P = .04).

Role of Ovarian Suppression

"For endocrine-responsive disease," she said, "considering that no tamoxifen was given in this trial and goserelin was administered for only 2 years, we can conclude that ovarian suppression has a major role and shows a benefit similar to that of CMF, and that the combination of CMF followed by goserelin is better than either modality alone, especially in younger patients."

This raises the question of whether the combination of goserelin and tamoxifen might be effective enough in these patients to avoid the use of chemotherapy. Evidence from IBCSG trial 11-93, Dr. Castiglione said, suggests that this is a question worth asking. In IBCSG 11-93, at a median follow-up of 6 years, patients on doxorubicin (Adriamycin)/cyclophosphamide (AC) chemotherapy plus ovarian function suppression and tamoxifen fared no better than patients who received only ovarian function suppression plus tamoxifen.

Three cooperative trials are currently examining this issue—SOFT (Suppression of Ovarian Function Trial), TEXT (Tamoxifen and Exemestane Trial), and PERCHE (Premenopausal Endocrine Responsive Chemotherapy Trial).

IBCSG IX Results

In IBCSG IX, about 22% of the patients had hormone-receptor-negative tumors. On average, the outcome for CMF followed by tamoxifen was significantly better than for tamoxifen alone. The effects, however, were significantly different according to ER status.

For the 1,217 patients with ER-positive disease, "we observed no survival benefit from the addition of chemotherapy, similar to the results in trial VIII in the older cohort with ER-positive disease," Dr. Castiglione said.

For the 382 patients with ER-negative disease, however, CMF followed by tamoxifen yielded significantly greater disease-free survival and overall sur-vival, she said.