BRITISH MEDICAL JOURNAL
30 OCTOBER 1976
Endocrine adjuvant therapy in breast cancer SIR,-I have received numerous inquiries on this topic since my unpublished address was quoted in a recent leading article in your journal.' It may be useful, therefore, to summarise the main points I made in an address to the Annual Meeting of the Royal College of Radiologists in June 1976. (1) Randomised trials of cytotoxic agents such as thiotepa and melphalan as adjuvant therapy in "early" breast cancer2 3 have shown decreased recurrence and metastasis in the first two or three years after surgery, but only in those node-positive patients who were premenopausal. These results are remarkably similar to those reported from surgical or x-ray castration carried out in premenopausal or perimenopausal women at the time of primary breast surgery.4 7 The most recent reports of Bonadonna's trial of adjuvant therapy by a combination of cyclophosphamide, methotrexate, and fluorouracil8 are already showing an advantage for premenopausal patients. These results all suggest that at least the major part of the cytotoxic action must be to depress ovarian activity, especially as amenorrhoea is reported in the vast majority of treated premenopausal patients. (2) New antioestrogens such as clomiphene, nafoxidine, and tamoxifen have in recent years been under clinical trial in the treatment of advanced breast cancer. Tamoxifen (Nolvadex) causes tumour regression in 30 to 40'" of postmenopausal cases'-" and three series have reported it effective also in premenopausal cases. 12-14 The agent is singularly free from side effects even when given continuously for periods of two to three years.12 Its action appears to be by inhibiting the replenishment of oestrogen receptor protein in the tumour, and if given continuously it should be able to stop oestrogen stimulation of the tumour for a prolonged period. (3) The biological rationale for expecting better results in the presence of a small tumour burden applies equally to endocrine therapy as to cytotoxic therapy in mammary cancer. Observations on the DMBA-induced rat mammary cancer model show that a proportion of tumours can be extinguished completely by endocrine therapy.'5 1'; Moreover, oophorectomy, androgen, or antioestrogen treatment is most effective when carried out earlier in the development of the tumour.1 18 (4) Most cytotoxic agents depress the immune response in the human, especially if the drugs are given in small repeated doses."9 On the other hand, steroidal agents such as oestrogens and androgens appear to stimulate the host defence mechanism.21 Whereas the anabolic effects of many steroidal agents are of benefit to the patient, the administration of currently used cytotoxic agents is associated with immediately unpleasant and damaging side effects. They are selective for proliferating cells whereas hormonal agents seem to be selective for mammary cancer cells. (5) We now have a means of recognising those tumours which are more likely to be sensitive to hormonal manipulation. About 70"