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Long-term antihormonal therapy for breast cancer — Orlando, July 1991
The Breusr (1992)
1.51
I Conference
report
I
Long-term antihormonal therapy for breast cancer - Orlando, July 1991 R. A. Hawkins University Department
of Surgery, Royal Infirmary of Edinburgh,
The objective of this conference was to review the effects/problems/benefits/potential of long term antioestrogen treatment in breast cancer. The endocrine profile of a new, pure antioestrogen (ICI 182,780) with theoretical advantages over currently available antioestrogens such as tamoxifen, which are partial agonists, was described by Alan Wakeling (ICI, Macclesfield, UK); it probably acts by blocking dimerisation of the oestrogen receptor, as discussed by Malcolm Parker (London, UK). Roger Blarney (Nottingham, UK) reported that for premenopausal women with advanced breast cancer, either oophorectomy or the gonadotrophinreleasing hormone agonist, Zoladex, were equally effective but a small number of patients progressing on Zoladex appeared to show a benefit on cross-over to surgical oophorectomy. When Zoladex alone was compared with a combination of Zoladex and tamoxifen, response rates were similar, although the length of response appeared greater in the combination group. Marc Lippman (Washington DC, USA) demonstrated in nude mice that breast cancer cells, which normally required oestrogen for growth, could be maintained by infusing conditioned culture medium containing secreted growth factors. He reported that the growth factor or ligand for the erb B2 product will stimulate erb B2positive cell lines and that this stimulation can be inhibited by an antibody against the erb B2 product, or receptor. This has potential clinical implications as erb B2-positive breast cancers have a poor prognosis and clinical trials of antibodies raised against erb B2 are planned. Interference with other growth factors such as fibroblast growth factor, which may be involved in the vascular changes associated with invasion, offers another potential method of treatment for breast cancer. Michael Baum (London, UK) discussed the CRC tamoxifen trial which has shown improved survival in both pre and postmenopausal women treated by tamoxifen. Tamoxifen reduced the frequency with which contralateral breast cancer developed, this effect diminishing with time and being significant only in postmenopausal women; premenopausal women receiving tamoxifen had a slightly but non-significantly increased
Edinburgh,
EH3 9YW. UK
risk of contralateral breast cancer. Results from Scottish Cancer Trials (Helen Stewart, Edinburgh, UK) showed the benefits of adjuvant tamoxifen appeared greatest in node-negative, oestrogen receptor-rich and postmenopausal patients. Deaths from myocardial infarction were significantly reduced in the tamoxifen group. A Stockholm trial (Lam Rutqvist, Stockholm, Sweden) has also shown a reduction in contralateral breast cancers with tamoxifen; the breast cancers which did develop in patients on tamoxifen were significantly more likely to be oestrogen receptor-negative. An increased incidence of endometrial cancer in patients on tamoxifen was recorded (relative hazard 6.4) which may be related to the increased dose of tamoxifen used, 40 mg versus 20 mg in other studies. Richard Love (Wisconsin, USA) reported that in postmenopausal women taking tamoxifen, there was a doubling in the SHBG level, a 12% fall in total plasma cholesterol with a fall in the LDL/HDL cholesterol ratio, a modest rise in triacyl glycerols and a fall in both serum osteocalcin and alkaline phosphatase with a rise in bone mineral density in the lumbar spine. Gynaecological sideeffects were identified in a fifth of patients at six months and in 5%, these side-effects were severe. Kent Osborne (Texas, USA) indicated that current data support the value of adding endocrine therapy to chemotherapy in postmenopausal but not premenopausal patients. Studies of mechanisms by which tumour cells might become resistant to tamoxifen indicate that changes in both uptake and metabolism of tamoxifen may be involved in the development of resistance to this drug. Craig Jordan (Wisconsin, USA) concluded that the benefits of adjuvant tamoxifen were clearly established but the length of time it requires to be given is a question still to be answered. Antioestrogens are likely to have their major effect on oestrogen receptor-positive breast cancers and it is now possible to transfect oestrogen receptor-negative cells with DNA coding for the oestrogen receptor, thus rendering such cells sensitive to oestrogen/antioestrogen. This in theory, could result in all cancers, even those of non-breast origin, under hormonal control!
1.51
I Conference
report
I
Long-term antihormonal therapy for breast cancer - Orlando, July 1991 R. A. Hawkins University Department
of Surgery, Royal Infirmary of Edinburgh,
The objective of this conference was to review the effects/problems/benefits/potential of long term antioestrogen treatment in breast cancer. The endocrine profile of a new, pure antioestrogen (ICI 182,780) with theoretical advantages over currently available antioestrogens such as tamoxifen, which are partial agonists, was described by Alan Wakeling (ICI, Macclesfield, UK); it probably acts by blocking dimerisation of the oestrogen receptor, as discussed by Malcolm Parker (London, UK). Roger Blarney (Nottingham, UK) reported that for premenopausal women with advanced breast cancer, either oophorectomy or the gonadotrophinreleasing hormone agonist, Zoladex, were equally effective but a small number of patients progressing on Zoladex appeared to show a benefit on cross-over to surgical oophorectomy. When Zoladex alone was compared with a combination of Zoladex and tamoxifen, response rates were similar, although the length of response appeared greater in the combination group. Marc Lippman (Washington DC, USA) demonstrated in nude mice that breast cancer cells, which normally required oestrogen for growth, could be maintained by infusing conditioned culture medium containing secreted growth factors. He reported that the growth factor or ligand for the erb B2 product will stimulate erb B2positive cell lines and that this stimulation can be inhibited by an antibody against the erb B2 product, or receptor. This has potential clinical implications as erb B2-positive breast cancers have a poor prognosis and clinical trials of antibodies raised against erb B2 are planned. Interference with other growth factors such as fibroblast growth factor, which may be involved in the vascular changes associated with invasion, offers another potential method of treatment for breast cancer. Michael Baum (London, UK) discussed the CRC tamoxifen trial which has shown improved survival in both pre and postmenopausal women treated by tamoxifen. Tamoxifen reduced the frequency with which contralateral breast cancer developed, this effect diminishing with time and being significant only in postmenopausal women; premenopausal women receiving tamoxifen had a slightly but non-significantly increased
Edinburgh,
EH3 9YW. UK
risk of contralateral breast cancer. Results from Scottish Cancer Trials (Helen Stewart, Edinburgh, UK) showed the benefits of adjuvant tamoxifen appeared greatest in node-negative, oestrogen receptor-rich and postmenopausal patients. Deaths from myocardial infarction were significantly reduced in the tamoxifen group. A Stockholm trial (Lam Rutqvist, Stockholm, Sweden) has also shown a reduction in contralateral breast cancers with tamoxifen; the breast cancers which did develop in patients on tamoxifen were significantly more likely to be oestrogen receptor-negative. An increased incidence of endometrial cancer in patients on tamoxifen was recorded (relative hazard 6.4) which may be related to the increased dose of tamoxifen used, 40 mg versus 20 mg in other studies. Richard Love (Wisconsin, USA) reported that in postmenopausal women taking tamoxifen, there was a doubling in the SHBG level, a 12% fall in total plasma cholesterol with a fall in the LDL/HDL cholesterol ratio, a modest rise in triacyl glycerols and a fall in both serum osteocalcin and alkaline phosphatase with a rise in bone mineral density in the lumbar spine. Gynaecological sideeffects were identified in a fifth of patients at six months and in 5%, these side-effects were severe. Kent Osborne (Texas, USA) indicated that current data support the value of adding endocrine therapy to chemotherapy in postmenopausal but not premenopausal patients. Studies of mechanisms by which tumour cells might become resistant to tamoxifen indicate that changes in both uptake and metabolism of tamoxifen may be involved in the development of resistance to this drug. Craig Jordan (Wisconsin, USA) concluded that the benefits of adjuvant tamoxifen were clearly established but the length of time it requires to be given is a question still to be answered. Antioestrogens are likely to have their major effect on oestrogen receptor-positive breast cancers and it is now possible to transfect oestrogen receptor-negative cells with DNA coding for the oestrogen receptor, thus rendering such cells sensitive to oestrogen/antioestrogen. This in theory, could result in all cancers, even those of non-breast origin, under hormonal control!