Prevention Trial of Tamoxifen in Postmenopausal HRT Users
Prevention Trial of Tamoxifen in Postmenopausal HRT Users
A basic principle of clinical endocrinology indicates that hormone deficiency should be replaced when it is clinically relevant. Although life expectancy has dramatically increased over the last century, age at menopause has shown only a small increase. The aim of this pragmatic trial was to assess the efficacy of 5 mg/day of tamoxifen in reducing breast cancer in recently postmenopausal women treated with different HRT forms for menopausal symptom relief. We found a nonsignificant 20% reduction of breast cancer with low-dose tamoxifen, a figure similar to that obtained with 20 mg/day in hysterectomized women. Unfortunately, the negative impact of the WHI findings on HRT prescriptions in recently postmenopausal women despite the different indications and age range heavily hampered our recruitment capability. Subgroup analyses showed that tamoxifen exhibited a favorable trend on luminal-A tumors and tumors expressing PgR, which are known to be associated with HRT use and to be highly endocrine responsive. Tamoxifen also showed a lower breast cancer risk in women on HRT <5 years, who had the highest risk among HRT users, consistent with the gap-time effect, and among ERT-alone users, where the long-term risk of breast cancer incidence and death is decreased, at least with CEE. In contrast, tamoxifen had no effect in the combined HRT subgroup, where the risk of breast cancer incidence and mortality is increased. Sensitivity analysis adjusted for nonadherence and restricted to women who took treatment for more than 1 year yielded a 50%, borderline significant reduction of breast cancer by low-dose tamoxifen. All these subgroup analyses have limited power, however, and none were significant at P < 0.01, so the results should be interpreted with caution.
We found no excess of cardiovascular events and VTE on tamoxifen, in line with the observation that the risk of VTE under tamoxifen is attenuated by concomitant ERT use and in premenopausal women. Also, the rates of serious adverse events seem to be lower with 5 mg/day than with 20 mg/day in a similar population, possibly because tamoxifen estrogenicity is attenuated by a lower dose. Although significantly more endometrial polyps were noted on tamoxifen, no increase of endometrial cancer was observed, again suggesting a protective effect of progestins against tamoxifen endometrial effects. However, a clear relationship between endometrial polyps and subsequent endometrial cancer under tamoxifen has not been established.
Despite the concomitant use of HRT, low-dose tamoxifen increased the rate of grade 2–3 hot flashes by ~50% (from 64/1000 to 97/1000 per year). An indirect comparison suggests that this rate is lower than that observed with tamoxifen at 20 mg/day in our prior trial in hysterectomized women (from 67/1000 on placebo to 119/1000 on tamoxifen), but it is still of concern given the notion that hot flashes are a major reason for dropout in prevention trials. In both the studies, women were on HRT because of menopausal symptoms or early surgical menopause, and thus represent a selected population with a higher rate of symptoms than the average population treated with tamoxifen. An increase of hot flashes under 20 mg tamoxifen in HRT users has also been reported in the IBIS trial. Because women were not randomly assigned to HRT, however, we cannot determine the magnitude of the effect of HRT on tamoxifen-induced menopausal symptoms. The 5-year compliance was slightly over 50% in our trial, in line with most breast cancer prevention trials. Yet the high dropout rate remains an important issue that may jeopardize efficacy, as suggested by our sensitivity analyses.
Although our study cannot directly apply to different categories such as gene mutation carriers undergoing risk reduction salpingo-oophorectomy, our findings seem to provide safety reassurance on the addition of low-dose tamoxifen to estrogen-alone therapy for menopausal symptom relief in these specific women's populations where there is a clear unmet medical need. A properly designed clinical trial may be warranted.
Our population was mostly composed of recently postmenopausal women undergoing HRT for menopausal symptoms, in contrast to the WHI trials which addressed the preventive effect of HRT in a much older and asymptomatic population. Moreover, only a minority of our participants used oral CEE (8%) and MPA (15%), reflecting the limited prescription of both the drugs in Europe. Admittedly, the lower risk of breast cancer death associated with estrogen therapy alone versus the increased risk in the combined HRT may have contributed to the heterogeneity of our findings. Since subgroup analyses of the WHI trials indicated that estrogen therapy alone has an overall health benefit in women aged <60 years, it is possible that the use of most recent forms of HRT that avoid the systemic effects of MPA will regain consensus in the treatment of recently postmenopausal women. If this is the case, our results are useful as they provide a clue to reduce breast cancer, the major risk associated with HRT use, in a broad population composed of recently postmenopausal women. Although tamoxifen is currently not available as 5 mg tablet in the market, its prolonged half-life allows for alternative schedules with retained activity, such as 10 mg every other day.
Our findings in primary prevention cannot be compared with the HABITS and Stockholm trial, which assessed the effect of HRT in breast cancer survivors, some of whom were being treated with tamoxifen as an adjuvant treatment. The Stockholm trial did not show any difference between HRT arms in tamoxifen users (5 versus 4), whereas in the HABITS trial there was a higher risk of recurrence in the HRT arm among tamoxifen users. However, the proportion of tamoxifen users was lower in HABITS (33% versus 52%). Moreover, because tamoxifen use was not randomized, women may have received the anti-estrogen tamoxifen because of their higher risk of recurrence.
Our study has several important limitations, including the limited statistical power and the marked heterogeneity of HRT types having different risks of breast cancer. For these reasons, reliable conclusions cannot be drawn. However, our trial suggests that the addition of low-dose tamoxifen to HRT may reduce the risk of breast cancer in recently postmenopausal women. This hypothesis should be assessed in a larger study.
Discussion
A basic principle of clinical endocrinology indicates that hormone deficiency should be replaced when it is clinically relevant. Although life expectancy has dramatically increased over the last century, age at menopause has shown only a small increase. The aim of this pragmatic trial was to assess the efficacy of 5 mg/day of tamoxifen in reducing breast cancer in recently postmenopausal women treated with different HRT forms for menopausal symptom relief. We found a nonsignificant 20% reduction of breast cancer with low-dose tamoxifen, a figure similar to that obtained with 20 mg/day in hysterectomized women. Unfortunately, the negative impact of the WHI findings on HRT prescriptions in recently postmenopausal women despite the different indications and age range heavily hampered our recruitment capability. Subgroup analyses showed that tamoxifen exhibited a favorable trend on luminal-A tumors and tumors expressing PgR, which are known to be associated with HRT use and to be highly endocrine responsive. Tamoxifen also showed a lower breast cancer risk in women on HRT <5 years, who had the highest risk among HRT users, consistent with the gap-time effect, and among ERT-alone users, where the long-term risk of breast cancer incidence and death is decreased, at least with CEE. In contrast, tamoxifen had no effect in the combined HRT subgroup, where the risk of breast cancer incidence and mortality is increased. Sensitivity analysis adjusted for nonadherence and restricted to women who took treatment for more than 1 year yielded a 50%, borderline significant reduction of breast cancer by low-dose tamoxifen. All these subgroup analyses have limited power, however, and none were significant at P < 0.01, so the results should be interpreted with caution.
We found no excess of cardiovascular events and VTE on tamoxifen, in line with the observation that the risk of VTE under tamoxifen is attenuated by concomitant ERT use and in premenopausal women. Also, the rates of serious adverse events seem to be lower with 5 mg/day than with 20 mg/day in a similar population, possibly because tamoxifen estrogenicity is attenuated by a lower dose. Although significantly more endometrial polyps were noted on tamoxifen, no increase of endometrial cancer was observed, again suggesting a protective effect of progestins against tamoxifen endometrial effects. However, a clear relationship between endometrial polyps and subsequent endometrial cancer under tamoxifen has not been established.
Despite the concomitant use of HRT, low-dose tamoxifen increased the rate of grade 2–3 hot flashes by ~50% (from 64/1000 to 97/1000 per year). An indirect comparison suggests that this rate is lower than that observed with tamoxifen at 20 mg/day in our prior trial in hysterectomized women (from 67/1000 on placebo to 119/1000 on tamoxifen), but it is still of concern given the notion that hot flashes are a major reason for dropout in prevention trials. In both the studies, women were on HRT because of menopausal symptoms or early surgical menopause, and thus represent a selected population with a higher rate of symptoms than the average population treated with tamoxifen. An increase of hot flashes under 20 mg tamoxifen in HRT users has also been reported in the IBIS trial. Because women were not randomly assigned to HRT, however, we cannot determine the magnitude of the effect of HRT on tamoxifen-induced menopausal symptoms. The 5-year compliance was slightly over 50% in our trial, in line with most breast cancer prevention trials. Yet the high dropout rate remains an important issue that may jeopardize efficacy, as suggested by our sensitivity analyses.
Although our study cannot directly apply to different categories such as gene mutation carriers undergoing risk reduction salpingo-oophorectomy, our findings seem to provide safety reassurance on the addition of low-dose tamoxifen to estrogen-alone therapy for menopausal symptom relief in these specific women's populations where there is a clear unmet medical need. A properly designed clinical trial may be warranted.
Our population was mostly composed of recently postmenopausal women undergoing HRT for menopausal symptoms, in contrast to the WHI trials which addressed the preventive effect of HRT in a much older and asymptomatic population. Moreover, only a minority of our participants used oral CEE (8%) and MPA (15%), reflecting the limited prescription of both the drugs in Europe. Admittedly, the lower risk of breast cancer death associated with estrogen therapy alone versus the increased risk in the combined HRT may have contributed to the heterogeneity of our findings. Since subgroup analyses of the WHI trials indicated that estrogen therapy alone has an overall health benefit in women aged <60 years, it is possible that the use of most recent forms of HRT that avoid the systemic effects of MPA will regain consensus in the treatment of recently postmenopausal women. If this is the case, our results are useful as they provide a clue to reduce breast cancer, the major risk associated with HRT use, in a broad population composed of recently postmenopausal women. Although tamoxifen is currently not available as 5 mg tablet in the market, its prolonged half-life allows for alternative schedules with retained activity, such as 10 mg every other day.
Our findings in primary prevention cannot be compared with the HABITS and Stockholm trial, which assessed the effect of HRT in breast cancer survivors, some of whom were being treated with tamoxifen as an adjuvant treatment. The Stockholm trial did not show any difference between HRT arms in tamoxifen users (5 versus 4), whereas in the HABITS trial there was a higher risk of recurrence in the HRT arm among tamoxifen users. However, the proportion of tamoxifen users was lower in HABITS (33% versus 52%). Moreover, because tamoxifen use was not randomized, women may have received the anti-estrogen tamoxifen because of their higher risk of recurrence.
Our study has several important limitations, including the limited statistical power and the marked heterogeneity of HRT types having different risks of breast cancer. For these reasons, reliable conclusions cannot be drawn. However, our trial suggests that the addition of low-dose tamoxifen to HRT may reduce the risk of breast cancer in recently postmenopausal women. This hypothesis should be assessed in a larger study.
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