Anti-oestrogen Therapy for Breast Cancer: A Trial of Tamoxifen at Two Dose Levels

Ward, H. W. C.

doi:10.1136/bmj.1.5844.13

Cited by 353 publications

(126 citation statements)

References 2 publications

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“…The antiestrogen produced response rates of 25-35% in unselected patients comparable to diethylstilbestrol and high dose androgen therapy, the standard endocrine therapies at the time [9,10]. However, fewer side effects were noted with tamoxifen [9,10]. As a result, the drug was approved as a palliative option for the hormonal treatment of breast cancer in the UK in 1973.…”

Section: Tamoxifen the First Sermmentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

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Section: Tamoxifen the First Sermmentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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“…Studies from our unit have indicated that relapse is not often due to proliferation of an oestrogen-receptor negative (RE-) cell population, since most relapsing tumours contain significant quantities of RE (Taylor et al, 1982). We therefore examined whether relapse or non-response was due to an inadequate effect of endocrine agents on gonadotrophins and steroid hormones in patients treated with tamoxifen, aminoglutethimide (AGT) and danazol, all of which are effective endocrine agents (Ward, 1973;Smith et al, 1978;Coombes et al, 1980a) and are known to lower hormone concentrations (Golder et al, 1976;Santen et al, 1977;Franchimont & Cramilion, 1977).…”

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confidence: 99%

Tamoxifen, aminoglutethimide and danazol: effect of therapy on hormones in post-menopausal patients with breast cancer

Coombes¹,

Powles²,

Rees³

et al. 1982

Br J Cancer

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Summary.-Gonadotrophins, oestradiol, androstenedione, testosterone and dehydroepiandrosterone sulphate (DHAS) were measured sequentially in 72 patients with advanced breast cancer receiving endocrine therapy of various types. Tamoxifen significantly reduced gonadotrophins but did not effect other hormones. Danazol also reduced gonadotrophins. Aminoglutethimide (AGT) reduced oestradiol and DHAS but had no effect on gonadotrophins. The effects of administering tamoxifen, AGT and danazol together (TAD) together were therefore examined. This combination reduced gonadotrophins, oestradiol and DHAS, but no further than tamoxifen and AGT alone.The degree and duration of hormone suppression were similar in both responders and non-responders to tamoxifen, AGT or TAD, though patients responding to AGT showed more complete suppression at the end of the course of treatment, perhaps because they were treated longer. On relapse, adequate gonadotrophin and steroid suppression was demonstrated in patients receiving tamoxifen and AGT respectively.We conclude that (a) response to endocrine therapy is unlikely to be related to the degree of endocrine suppression produced by the therapy; (b) combination endocrine therapy does not further reduce serum-hormone concentrations and (c) relapse is unlikely to be due to escape from the hormone-inhibitory effects of endocrine agents.ENDOCRINE THERAPY is an effective form of treatment in patients with advanced breast cancer. However, only a proportion of patients respond, and their response is often transient. Patients whose tumours contain a high concentration of oestrogen receptor are more likely to respond to endocrine therapy (McGuire et al., 1975) but a moderate proportion of patients whose tumours contain receptor do not respond, and it may be that in these patients inadequate hormone suppression by endocrine therapy is responsible for lack of effect in these patients.Few studies have been carried out to elucidate the mechanism of relapse. It is not known whether endocrine therapy is still effective at the time of relapse, nor whether relapse is due to premature inactivation of endocrine agents. Studies from our unit have indicated that relapse is not often due to proliferation of an oestrogen-receptor negative (RE-) cell population, since most relapsing tumours * Priesent address:

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“…The anti-oestrogen drug tamoxifen, and the aromatase inhibitor aminoglutethimide, have been extensively tested in metastatic breast cancer with overall objective remission rates of around 30% (Cole & Todd, 1976;Ward, 1973;Murray & Pitt, 1981; Harris et al, 1986a,b). The lack of serious toxicity in the case of tamoxifen has made this a particularly attractive therapy where quality of life was as important as prolongation (Stewart et al, 1980).…”

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Epidermal growth factor receptor (EGFr) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer

Nicholson

Halcrow²,

Sainsbury³

et al. 1988

Br J Cancer

103

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There was a significantly higher proportion of EGFr+ tumours in the endocrine failure group compared with the control population (P<0.001).EGFr status is a marker for rapid early progression on primary endocrine therapy and the development of non-excisional methods of EGFr analysis would allow better directed therapeutic decisions.The anti-oestrogen drug tamoxifen, and the aromatase inhibitor aminoglutethimide, have been extensively tested in metastatic breast cancer with overall objective remission rates of around 30% (Cole & Todd, 1976;Ward, 1973;Murray & Pitt, 1981; Harris et al., 1986a,b). The lack of serious toxicity in the case of tamoxifen has made this a particularly attractive therapy where quality of life was as important as prolongation (Stewart et al., 1980). In advanced disease ER status predicts response to endocrine therapy (Block et al., 1975;McGuire et al., 1975;Roberts et al., 1978).The proportion of patients with ER positive primary breast cancers increases with age such that about 70% of patients over 70 years of age have ER positive tumours (Allegra et al., 1979; Elwood & Godolphin, 1980). These observations may in part account for the relatively good prognosis for some elderly patients with breast cancer.Tamoxifen had proved useful in the treatment of many elderly patients with advanced or metastatic breast cancer (Ingle et al., 1981;Legha et al., 1978). The use of pharmacological endocrine manipulation as the sole treatment of primary operable breast cancer in the elderly has been reported in several small studies (Preece et al., 1982;Hellenberg et al., 1982;Bradbeer, 1985;Allan et al., 1985;Horgan et al., 1986), and in one randomised prospective study (Gazet et al., 1988), to be an alternative to surgery. Steroid receptor status at relapse was not reported in these studies but in one (Allan et al., 1985) the response rate for ER positive tumours was found to be similar to the overall response rate.The use of primary endocrine therapy for many elderly patients with operable breast cancer became our standard practice in mid-1984. However, not all elderly patients will respond to tamoxifen and some relapse rapidly (within 6 months) without any initial control of tumour growth. We have shown previously that EGF receptor status is a strong prognostic factor in primary breast cancer (Sainsbury et al., 1987 EGFr to age, relapse in elderly patients on primary endocrine therapy, and its role in predicting tumour recurrence in elderly patients treated by primary surgery. Patients and methodsFifty-one patients over seventy years and ten in their late sixties with severe intercurrent medical illness or severe psychological aversion to mastectomy who were otherwise considered to have primary operable breast cancer were offered primary endocrine therapy. Patients with proven distant metastases at the time of presentation, as assessed by biochemical and clinical criteria, were excluded from this study.The study population comprised 61 patients. The median age was 77 years (range 64-96) and all patients ...

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Anti-oestrogen Therapy for Breast Cancer: A Trial of Tamoxifen at Two Dose Levels

Cited by 353 publications

References 2 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

Tamoxifen, aminoglutethimide and danazol: effect of therapy on hormones in post-menopausal patients with breast cancer

Epidermal growth factor receptor (EGFr) status associated with failure of primary endocrine therapy in elderly postmenopausal patients with breast cancer

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