Trial Information

Antiestrogen vs Aromatase Inhibitor After Chemotherapy for Adjuvant Setting: Efficacy of Endocrine Therapy After Chemotherapy in Postoperative Adjuvant Therapy for Breast Cancer

To investigate the benefit of postoperative adjuvant therapy using sequential administration
of the hormone, toremifene citrate (TOR) or anastrozole (ANA), after chemotherapy in breast
cancer.

TOR is reported to be as effective, or more effective, than TAM on both DFS and OS for
postoperative adjuvant therapy. The incidence rate and severity of its adverse effects are
similar to those of TAM as shown in two clinical trials, the Finnish Breast Cancer Group
(FBCG) and the International Breast Cancer Study Group (IBCSG). Although no significant
difference was observed in these trials, other studies report that TOR produced a lower
number of thromboembolism events compared with TAM, a undesirable side effect seen in
patients treated with TAM. Additionally, compared with TAM, TOR showed less endometrial
hypertrophy which is induced by estrogen.

Endometrial cancer remains one of the significant problems associated with TAM. A TAM
metabolite binds to DNA and forms DNA adducts which damage cells. It is reported that TAM
has an expanded ability to form DNA adducts compared with TOR in vitro. A recent study
compared endometrial cells collected from patients in which TAM or TOR had been
administered. The k-ras gene mutation was investigated in these cases, and it showed that
TAM held a higher frequency of gene mutation. Although we still need to discuss whether or
not k-ras mutation is directly related to the development of endometrial cancer, TAM seems
to have a higher risk of inducing cancer compared with TOR.

In the IBCSG14-93 trials, two chemotherapy protocols were studied subsequent to
administration of TOR. They were doxorubicin and cyclophosphamide (AC) and
cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). These two chemotherapy protocols
were administered in the following sequence: AC four times followed by CMF three times
after administration of TOR. The findings revealed that in estrogen-receptor (ER) positive
cases, DFS equaled 73% in the TOR group, 65% in the TAM group; hormone receptor (HR=0.80
(0.57-1.11); P=0.18). OS was found to total 88% in the TOR group, 84% in the TAM group;
HR=0.78 (0.48-1.27); p=0.32). Although there was no significant difference in two groups,
the TOR group has showed somewhat improved survival.

Based on the information provided above, we consider TAM and TOR to have similar efficacy
with less adverse effects, and this trial will compare the two drugs, TOR and ANA.