New role for tamoxifen as fertility drug for breast cancer patients?

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In a study of 12 breast cancer survivors they found that stimulating the ovaries with a short, carefully timed course of tamoxifen boosted the number of eggs they could retrieve. Every patient had one or more embryos either for freezing for later attempts at pregnancy, or for immediate transfer. One patient who had two fresh embryos transferred has already given birth to twins. Another patient conceived on her second attempt although she miscarried. None of the patients with frozen embryos has yet attempted pregnancy.

Lead researcher Professor Kutluk Oktay said that the experiment arose from a desire to find a safe way of preserving fertility among the 15% of breast cancer patients - around 27,000 annually in the USA - who were still of reproductive age when they were diagnosed.

Chemotherapy causes ovarian failure in many patients - nearly as many as four out of five women in the case of those given cyclophosphamide. Even those who remain fertile or don't have chemotherapy face the problem of needing a recurrence-free period of perhaps two to five years before trying to conceive, bringing them up against the barrier of infertility due to ageing and diminishing ovarian reserves.

"These women can try natural cycle IVF without ovarian stimulation, but typically, no more than a single embryo can be achieved for immediate use or freezing. So, we need to find a safe way of increasing the number of embryos to give these women a better chance of having a baby," said Professor Oktay, assistant professor of Reproductive Medicine and Obstetrics and Gynaecology at the Center for Reproductive Medicine and Infertility, Weill Medical College of Cornell University.

Tamoxifen was developed in the UK in 1966 as a contraceptive, but found to stimulate ovarian follicle growth and became used in Europe as an ovarian stimulant. (A related compound, Clomiphene, is usually used in the USA). It wasn't until 1976 that tamoxifen's suppressive, anti-estrogenic effect on breast cancer was discovered. Since then it has become the world's most successful anti-cancer drug, saving the lives of thousands of breast cancer patients every year worldwide.

"Sometimes the best ideas are the obvious ones and tamoxifen seemed the obvious choice of drug to test, although, to my knowledge, no one has tried it before in breast cancer patients," said Professor Oktay. "We hypothesised that tamoxifen stimulation would result in higher numbers of embryos compared with natural cycle IVF, while theoretically shielding breast cancer cells against oestrogen."

A retrospective group of five breast cancer patients who had undergone nine cycles of natural cycle IVF was used as a control for the 12 study patients. The 12 patients were given 40-60 mg tamoxifen for around seven days on days 2-3 of their menstrual cycle (a total of 15 treated cycles). The tamoxifen patients produced a greater number of mature eggs than the controls (1.6 versus 0.7) and embryos (1.6 versus 0.6). All tamoxifen patients generated embryos compared with three out of five controls. After a mean follow up of around 15 months none of the study patients has had a recurrence of cancer.

"This is a novel use of tamoxifen to attempt to preserve fertility and treat chemotherapy-related infertility via IVF embryo cryopreservation and embryo transfer after breast cancer," said Professor Oktay. "We exploited tamoxifen's dual action as an ovarian stimulating drug and an anti-cancer agent."

Because most patients in the tamoxifen group froze their embryos while most in the control group had fresh embryo transfer it has not been possible yet to compare pregnancy rates between the two protocols or to provide long-term data on the effects of tamoxifen on pregnancy. However, long-term experience of the drug in ovulation induction did not suggest an embryo-damaging effect. In any case its use was discontinued prior to ovulation and egg retrieval and IVF embryos were never exposed to it as fertilisation took place in vitro.

Professor Oktay said the study had limitations with its short follow-up and its retrospective, small control group, but a larger study was planned with modifications to the protocol to include low amounts of follicle stimulating hormone (FSH) in addition to tamoxifen.

"I am optimistic," he said. "Many of my patients tell me that just doing something to address the issue of loss of reproductive function makes it easier for them to deal with breast cancer. It connects them to their future and underlines that because they have breast cancer it does not mean they have a terminal illness.

"It would be especially fitting if a drug that has saved so many women's lives should also turn out to be a means of preserving their fertility," he added.

He urged all breast cancer physicians to be aware of the effect of chemotherapy on women of reproductive age and to refer them to an appropriate assisted reproduction centre as soon as a diagnosis was made so that options for preserving fertility could be discussed.

[1] Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen. Human Reproduction. Vol. 18. No 1. pp 90-95.

MW Communications