Biological activity of all-trans-retinoic acid with and without tamoxifen and alpha-interferon 2a in breast cancer patients

In addition to suppressing breast cancer cell growth, retinoids potentiate growth inhibition in human breast cancer when tested in vitro and in vivo w ith tamoxifen and/or interferon. The purpose of this study was to ascertain the biologic effects of all-trans-retinoic acid (ATRA) administered alone and with tamoxifen +/- interferon and to identify the relationship between ATRA plasma concentrations and optimal biological dose (the lowest dose tha t produces a biological response). Three consecutive groups of 15 patients with locally advanced operable breast cancer were treated, in accordance wi th good clinical practice (GCP) requirements, with ATRA at 3 dose levels al one or with tamoxifen +/- alpha-interferon 2a at flat doses. After 3 weeks, the tumors were surgically removed. Biological parameters measured at the beginning (in biopsy tissue) and end (in surgical tissue) of the study were compared. The optimal biological dose for ATRA was 15 mg/m(2)/day. Treatme nts influenced tumor grade but not cell cycle kinetics (G(0)-G(1) phase) or proliferation (Ki67 levels). ATRA induced progesterone receptors independe nt of dose level and co-administered drugs, but did not induce estrogen rec eptors when administered alone. Retinoic acid receptor (RAR)-alpha was not affected by treatment and RAR-alpha was moderately influenced whereas RAR-b eta (concomitantly with transforming growth factor-beta) was induced in 33% of patients by ATRA alone. ATRA pharmacokinetics were dose- and time-depen dent. Neither the ATRA + tamoxifen nor the ATRA + tamoxifen + interferon co mbinations potentiated the ATRA-induced biological changes. Future studies evaluating the role of RAR-beta as a biological marker of retinoid activity are warranted.