Adding Retinoid to Adjuvant Chemotherapy May Improve Outcome in Early Breast Cancer Patients

VILLEJUIF, France--The addition of a retinoid to adjuvant chemotherapy provided a hint of a survival advantage over chemotherapy alone for breast cancer patients, but the difference did not achieve statistical significance, according to 13-year follow-up data from a randomized clinical trial.

Patients who received etretinate in addition to chemotherapy had slightly better metastasis-free, disease-free, and overall survival. Moreover, etretinate-treated patients have yet to reach a median survival, whereas patients treated with chemotherapy alone have a median survival of 14.9 years.

"Due probably to trial design, eligibility criteria, and sample size, the study lacks the statistical power to demonstrate a positive effect of etretinate," Suzette Delaloge, MD, an oncologist at Paul Brousse Hospital, Villejuif, France, said at a poster session of the San Antonio Breast Cancer Symposium. "However, the results cannot be considered negative and must lead to further exploration, especially in the subgroup of patients whose prognosis remains poor despite optimal chemotherapy."

Retinoid derivatives have demonstrated an ability to inhibit the development and growth of a variety of tumors, including breast cancer, in animal and human models, she told Oncology News International. Synergism between retinoids and chemotherapeutic agents has been demonstrated in vitro. Retinoids have been shown to have immunomodulatory properties and to inhibit tumor development, angiogenesis, and invasion.

Collectively, the data make a persuasive argument for use of retinoids in cancer treatment, Dr. Delaloge said. However, few clinical data have been presented to date on the therapeutic potential of retinoids in breast cancer.

Between 1981 and 1985, investigators in the OncoFrance collaborative study group randomized 202 patients with early breast cancer to one of two adjuvant chemotherapy regimens.

One group received six cycles of AVCF, doxorubicin (Adriamycin) (30 mg/m2 IV on day 1), vincristine (1 mg/m2 IV on day 2), cyclophosphamide (300 mg/m2 IV on days 3 to 6), and fluorouracil (400 mg/m2 IV on days 3 to 6). The remaining patients received the identical chemotherapy regimen plus 25 mg of oral etretinate daily for 6 months.

All of the patients had hormone receptor-negative tumors or nodal involvement with unknown receptor status. Initial surgical treatment consisted of removal of the primary tumor and complete axillary node dissection. About 70% of the patients had radical mastectomy.

At randomization, the patients were stratified according to node status, menopausal status, tumor size, and hormone receptor status. About 80% of the patients had T1-T2 cancer. Three-fourths had positive lymph nodes, and 70% to 75% had hormone- receptor-negative cancers.

Of 197 evaluable patients, metasta-sis-free survival at 13 years was 60% to 65%. Disease-free survival was 50% to 55%, and overall survival was 60% to 65%. For all three survival parameters, patients randomized to etretinate did better, but none of the differences was significant.

Subgroup analysis of overall survival suggested a potential advantage of etretinate therapy, especially in premenopausal patients with receptor-negative, node-positive cancer (P = .08).

Patients treated with etretinate did have an unexpected excess of nonbreast second malignancies (12 vs 6), although the difference between the groups was not significant. Dr. Delaloge said the investigators have not found an explanation for the excess in nonbreast cancers. Second breast cancers occurred in five patients in the chemotherapy group and in six patients who received chemotherapy plus etretinate.

"We are continuing to evaluate these patients. Further, we hope to do a new trial that will give us an opportunity to evaluate biologic endpoints, so we can learn more about the effects of retinoids and how to target their use in breast cancer," she said. "We also plan to focus studies on certain patient subgroups."