Fertility after breast cancer.

The desire to have a child after a diagnosis of breast cancer in women raises two central questions:

* can breast cancer survivors conceive, and

* should breast cancer survivors conceive?

Breast cancer per se does not influence female fertility. Similarly, surgery and radiotherapy for breast cancer do not affect fertility, although both these interventions may affect a woman's ability to successfully breastfeed. In contrast, adjuvant chemotherapy can be highly gonadotoxic, resulting in a loss of oocytes and primordial follicles. The extent of this reduction in ovarian reserve (which reflects the ability of the ovary to respond to gonadotrophin stimulation and which is in turn a marker of the remaining number of follicles) will determine whether women experience irregular menstruation, temporary amenorrhoea or permanent ovarian failure. Amenorrhoea extending beyond 12 months after adjuvant chemotherapy is often a sign of irreversible ovarian failure; however, the return of menstruation does not necessarily reflect normal fertility potential. Chemotherapeutic agents and combination regimens vary in their impact on ovarian reserve, but generally speaking cyclophosphamide and doxorubicin have the greatest gonadotoxic effect. Moreover, the risk of premature ovarian failure is influenced by the total cumulative dose of the cytotoxic drugs as well as the woman's age at the time of treatment, with women over the age of 40 years being particularly at risk. Subject to these variables the risk of premature ovarian failure can range from below 10% to over 90%. Furthermore, adjuvant endocrine therapy, such as tamoxifen, can also affect ovarian reserve, not through a direct drug effect but through the long duration of treatment during which time the pool of remaining follicles undergoes further decline.

The second question, whether pregnancy is safe and advisable in breast cancer survivors, has been the subject of considerable debate. Due to the concern that oestrogen, which is a carcinogen in the pathogenesis of breast cancer, may have a negative impact on survival (by stimulating local recurrence or the growth of micrometastases), many women have been advised against pregnancy in the past. To date we still lack prospective data on which to base the counselling and management of this group of women. There are, however, a number of retrospective studies which have documented the outcome of pregnancy in breast cancer survivors. Collectively, these studies showed either no difference in breast cancer-related outcome between women who did and who did not have a subsequent pregnancy, or they documented improved survival following pregnancy. Moreover, there is no evidence to suggest that the exposure of oocytes to chemotherapeutic drugs causes an increased risk of congenital abnormalities in subsequent pregnancies. Similarly, maternal pregnancy complications do not appear to be increased in breast cancer survivors. It would therefore appear that pregnancy after breast cancer is not detrimental and may indeed be beneficial.

Caution needs to be exercised, however, when interpreting these retrospective and heterogeneous data. The apparent survival benefit derived from pregnancy may be due to a selection bias in that women who conceive after breast cancer are healthier and have a better prognosis than those women who do not have a subsequent pregnancy. Alternatively, it has been hypothesised that breast cancer cells share common antigens with fetal cells, which trigger an immune response during pregnancy. This immune response may be protective against the growth of micrometastases.

At a practical level most experts advise that pregnancy should not be considered within the first 2-3 years of initial diagnosis, as this is the period with the highest incidence of recurrence. Waiting times of up to 5 years may be recommended for women with more advanced disease and/or who are advised to complete adjuvant endocrine therapy. However, these recommendations are not free of controversy, as some authors regard them as outdated. At all times delay in childbirth must be considered against the backdrop of reduced ovarian reserve as outlined above.

It is important that the issue of subsequent conception should not be approached when cancer therapy has been completed but discussed upfront in order to explore options for fertility preservation. Strategies include modification of the adjuvant chemotherapy regimen (such as choosing less gonadotoxic agents) or the addition of a GnRH analogue given at the same time as chemotherapy. Alternatively, patients may undergo assisted reproductive techniques just prior to chemotherapy with the option of freezing embryos or unfertilised oocytes, although the latter is currently not part of routine clinical practice due to, as yet, limited success. These modalities are rarely used as they result in the patient delaying the commencement of her treatment and receiving oestrogen.

When fertility-preserving strategies fail or are not feasible and premature ovarian failure ensues, egg donation or adoption are remaining options.

Further reading

Calhoun K, Hansen N. The effect of pregnancy on survival in women with a history of breast cancer. Breast Dis 2005-2006; 23: 81-86.

Gaducci A, Cosio S, Genazzani AR. Ovarian function and childbearing issues in breast cancer survivors. Gynecol Endocrinol 2007; 23(11): 625- 631.

Partridge A, Ruddy K. Fertility and adjuvant treatment in young women with breast cancer. Breast 2007; 16: 175-181.

Sonmezer M, Oktay K. Fertility preservation in young women undergoing breast cancer therapy. Oncologist 2006; 11: 422-434.

SILKE DYER, MB ChB, MMed, PhD

Associate Professor and Head, Reproductive Medicine Unit, Department of Obstetrics University of Cape Town.