Breast cancer is the most common malignancy in women of reproductive age, and about 13% of all breast cancer diagnoses are made in women younger than age 45 years 1. In Germany, the average age of primiparas is 29.8 years 2, which means that many breast cancer patients have not completed their family planning and wish to have children after the diagnosis of breast cancer. The majority of women diagnosed with early-stage breast cancer today have an excellent long-term prognosis, but many of them will undergo a temporary or permanent cessation of menses. Although premature ovarian insufficiency can improve the breast cancer prognosis for women with hormone-positive breast cancer, these women have to face subsequent infertility and many psychological problems 3.

In the present review, we discuss the effect of the most up-to-date chemotherapy regimens for breast cancer on fertility, and we analyze the options for fertility preservation, as well as the various in vitro fertilization (IVF) protocols that can be applied in this specific patient group. Finally, a review of the available studies on the effect of a subsequent pregnancy on the outcome in breast cancer survivors is conducted.

This section discusses the effect on fertility of chemotherapy for breast cancer (Table 1) 45678910111213. The risk of chemotherapy-related amenorrhea depends on the patient's age, on the specific chemotherapeutic agents used, and on the total dose administered. Older women have a higher incidence of complete ovarian failure and permanent infertility in comparison with younger women 14. This higher incidence can be explained by younger women's larger primordial follicle reserve, which declines with age.

With regard to the chemotherapy regimen, according to Meirow, alkylating agents (for example, cyclophosphamide) involve the greatest risk for inducing ovarian failure among all chemotherapeutic agents (odds ratio 3.98 in comparison with unexposed patients) 15. The higher the cumulative dose of cyclophosphamide, the higher the observed incidence of menopause. Goldhirsch and colleagues reported that, with the classic cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) regimen, the incidence of amenorrhea was 61% in patients aged < 40 years and was 95% in patients aged > 40 years 4.

The classic fluorouracil, epirubicin, and cyclophosphamide regimen (intravenous administration on day 1 of all drugs for six cycles, cyclophosphamide 600 mg/m², epirubicin 60 mg/m², fluorouracil 600 mg/m²) induces menopause in 60% of patients 11.

The National Cancer Institute of Canada adjuvant trial comparing CMF with the fluorouracil, epirubicin, and cyclophosphamide regimen indicated that the incidence of amenorrhea was slightly higher in the fluorouracil, epirubicin, and cyclophosphamide arm (51%) in comparison with the CMF arm (42.6%) 6. This arm was a dose-intensified fluorouracil, epirubicin, and cyclophosphamide regimen (cyclophosphamide 75 mg/m² orally on days 1 to 14, epirubicin 60 mg/m² intravenously on days 1 and 8, and fluorouracil 500 mg/m² intravenously on days 1 and 8), given for six cycles.

Most anthracycline-based regimens are associated with a lower incidence of amenorrhea, most probably due to the lower cumulative cyclophosphamide dosages used in comparison with the classic CMF regimen. The doxorubicin and cyclophosphamide regimen (adriamycin (doxorubicin), and cyclophosphamide) has been reported by Bines and colleagues to result in amenorrhea at a rate of 34% 5.

With regard to the taxanes, a study including 191 patients showed that older age and the addition of taxane to adriamycin and cyclophosphamide increased the risk of chemotherapy-induced amenorrhea, and that the amenorrhea was more likely to be irreversible for women over 40 years old 13. Younger women often resume menstruation even after 6 months of amenorrhea, and the addition of a taxane does not play a role 13. Some other studies have evaluated the impact of the addition of paclitaxel or docetaxel 91012161718. These limited data suggest that, when age is controlled for, adding a taxane to adriamycin and cyclophosphamide-type chemotherapy has little if any effect on the subsequent risk of chemotherapy-related amenorrhea. Taxanes inhibit the function of the mitotic spindle and appear to have an even lower likelihood of resulting in persistent ovarian dysfunction 19.

With regard to trastuzumab, a preliminary study evaluating the risks of the most up-to-date treatment modalities found that the addition of trastuzumab did not have a detrimental affect on fertility 18.

Another recent prospective cohort survey study evaluated 595 women aged 25 to 40 years who were treated for early breast cancer with different chemotherapy regimens 12. The study found that menstrual cycles were more likely to persist among women treated with regimens that contained less total cyclophosphamide, such as adriamycin and cyclophosphamide, or taxol (paclitaxel), adriamycin, and cyclophosphamide, or docetaxel, adriamycin, and cyclophosphamide. While women who were on CMF treatment were more likely than those on adriamycin and cyclophosphamide, those on docetaxel, adriamycin, and cyclophosphamide, or those on taxol, adriamycin, and cyclophosphamide to bleed during the first month following chemotherapy (approximately 50% versus 20%; odds ratio, 2.9; 95% confidence interval (CI), 1.7 to 5), the likelihood of menses 1 year later was lower in the CMF group (odds ratio, 0.37; 95% CI, 0.37 to 0.67). The study also revealed that tamoxifen accounted for a modest but significant decrease (15%) in menstrual cycling at 1 year and 2 years, regardless of the chemotherapy program. Premenopausal women generally continue to menstruate while receiving tamoxifen, although menses can become irregular. The effect on the ovary is assumed to be reversible and temporary 12.

The most effective approach to date is embryo cryopreservation. The human embryo is very resistant to damage caused by cryopreservation. The post-thaw survival rate of embryos is in the range of 35% to 90%, while implantation rates are between 8% and 30%; if multiple embryos are available for cryopreservation, cumulative pregnancy rates can be more than 60% 20. Delivery rates per embryo transfer using cryopreserved embryos are reported to be in the range of 18% to 20% 20. This approach, however, requires IVF and a participating male partner. If many mature oocytes are retrieved, there is an opportunity to carry out several attempts at embryo transfer from a single cycle. This option may not be acceptable for prepubertal adolescent girls 21.

An increase in estradiol during controlled ovarian hyper-stimulation may not be safe in women diagnosed with estrogen-sensitive breast cancer who are seeking fertility preservation. It has been clearly shown that estrogen stimulates breast cancer cell growth, even at low concentrations 4950.

The embryo yield with natural-cycle IVF (without hormone stimulation), however, is very low 51. In such cases, alternative stimulation regimens can be used – for example, tamoxifen 52 or aromatase inhibitors 53 – although these regimens are less effective without added gonadotropins. Although these medications should not be used during pregnancy, studies with tamoxifen and letrozole have demonstrated that their short-term use for ovulation induction does not adversely affect oocyte and embryo development. Moreover, no detrimental effects on fetal development have been demonstrated. In any case, clomiphene, a compound related to tamoxifen, has been safely used for ovulation induction for almost four decades 54.

In a study by Oktay and colleagues, tamoxifen 40–60 mg was started on day 2 or day 3 of the cycle and was administered daily for 5–12 weeks. The control group consisted of patients with an unstimulated IVF cycle. The tamoxifen group had a significantly higher number of mature oocytes, higher peak estradiol, and a higher number of embryos (mean of 1.6 embryos versus 0.6 embryos) than the natural-cycle group 52.

Third-generation aromatase inhibitors (letrozole, anastrozole, and exemestane) entered clinical practice initially as first-line and second-line agents for the treatment of breast cancer 5556. The use of aromatase inhibitors for ovulation induction was first reported in 2001; letrozole was reported to provide superior results to clomiphene and was associated with 50% lower estradiol levels 57. Many groups are currently testing the feasibility of ovarian stimulation with aromatase inhibitors in patients with breast cancer and in patients with endometrial cancer. The patient is stimulated with gonadotropins, and an aromatase inhibitor is simultaneously introduced to reduce serum estradiol levels. Oocyte development is unaffected. A luteinizing hormone-releasing hormone antagonist is also used to prevent a premature luteinizing hormone surge 58.

Oktay and colleagues compared the combination of tamoxifen or letrozole with FSH for stimulation in women with breast cancer, with very promising results 51. Letrozole-FSH and tamoxifen-alone stimulation were associated with significantly lower peak estradiol levels than tamoxifen-FSH stimulation. The combined letrozole-FSH protocol resulted in peak estradiol levels close to those seen in unstimulated cycles, and breast cancer recurrence rates were not increased compared with controls 59. The same group also reported the first pregnancy from cryopreserved embryos generated after tamoxifen stimulation 51, and reported that breast cancer patients who underwent ovarian stimulation with anastrozole had a significantly higher exposure to estradiol than those who were stimulated with letrozole 60.

Nevertheless, Partridge and Winer have listed a series of questions that remain unanswered 61. How does even brief exposure to high estrogen levels through tamoxifen or FSH-letrozole stimulation affect the risk of breast cancer recurrence? Does brief exposure to tamoxifen or letrozole before treatment compromise the effect of chemotherapy? Finally, do these substances have any influence on the quality of the oocytes harvested?

Pregnancy after breast cancer is another area of investigation (Table 3) 6263646566676869707172. The incidence of live births after breast cancer is very small. Among women < 45 years of age at diagnosis, only 3% have full-term pregnancy 70; and among women < 35 years at diagnosis, 8% give birth to a liveborn infant 71. There has been concern that continued menstrual cycling or pregnancy after breast cancer may worsen the prognosis, since breast cancer is often hormone sensitive.

Chemotherapy-induced amenorrhea may be reversible; however, the vast majority of women who remain amenorrheic 1 year after treatment do not regain ovarian function. Less than 11% of women over 40 years old and only 12% to 15% of younger women experience a return of menses after 1 year of amenorrhea 7.

Ovarian estrogens play an important role in the oncogenesis and development of breast cancer. The positive effect of ovarian hormone suppression in the preventive situation, the adjuvant situation, and also the palliative situation has been adequately proven. There is no doubt that, particularly in very young patients, chemotherapy acts at least partially via chemotherapy-induced amenorrhea 79808182.

The fact that both ovarian suppression and chemotherapy produce an improvement in the disease-free survival for premenopausal women poses the question of whether this effect is mediated at least partly by the same biochemical pathways – a hypothesis that may be supported by the following four points 83.

First, cytotoxic chemotherapy will induce amenorrhea in a proportion of premenopausal women, ranging from about 15% to close on 100%, depending on age. The younger the woman, the greater the resistance to the castrating effect of cytotoxic drugs 5.

Second, the endocrinological profile of a woman exposed to cytotoxic chemotherapy is similar to that of a castrate woman. In other words, estradiol levels fall and gonadotropin levels rise 8485.

Third, there is now extensive literature illustrating the fact that the induction of amenorrhea by adjuvant cytotoxic chemotherapy or endocrine therapy is in itself a prognostic factor. Those women who develop permanent amenorrhea fare better than those whose menstrual periods return during or after the completion of the course of treatment. This association is seen most clearly amongst women whose tumors express the estrogen/progesterone receptors 868788. A meta-analysis on the influence of chemotherapy-induced amenorrhea on the prognosis has demonstrated a significant advantage of survival for amenorrheic patients in 15 of 23 studies included 89. Similarly, a meta-analysis of randomized studies including 3,307 patients confirmed a significant difference in the overall survival (15% reduction, P = 0.04) with GnRH therapy after chemotherapy 90. Altogether, the available data allow the conclusion that chemotherapy-induced amenorrhea or amenorrhea after GnRH therapy following chemotherapy improves the prognosis.

Finally, there have been trials that have attempted to carry out a direct comparison of endocrine therapy and chemotherapy in premenopausal women. In a recent meta-analysis, data from 11,906 premenopausal women with early breast cancer who were randomly assigned to treatments in 16 trials were examined. When used as the only systemic adjuvant treatment, luteinizing hormone-releasing hormone agonists did not significantly reduce the recurrence rate (28.4% relative reduction; 95% CI consistent with a 50.5% reduction to a 3.5% increase; P = 0.08) or the rate of death after recurrence (17.8%; 95% CI consistent with a 52.8% reduction to a 42.9% increase; P = 0.49) with hormone-receptor-positive cancers. The addition of luteinizing hormone-releasing hormone agonists to tamoxifen or chemotherapy, or to both, reduced the recurrence rate by 12.7% (95% CI, 2.4 to 21.9; P = 0.02) and reduced the rate of death after recurrence by 15.1% (95% CI, 1.8 to 26.7; P = 0.03). Luteinizing hormone-releasing hormone agonists showed similar efficacy to chemotherapy (recurrence, 3.9% increase; 95% CI consistent with a 7.7% reduction to 17.0% increase; and death after recurrence, 6.7%; 95% CI consistent with a reduction, 20.7% reduction to 9.6% increase; neither significant). No trials have assessed a luteinizing hormone-releasing hormone agonist versus chemotherapy with tamoxifen in both arms. Luteinizing hormone-releasing hormone agonists were ineffective in hormone receptor-negative tumors 34.

Young female breast cancer patients are still being poorly counseled with regard to the negative impact of the treatment on their fertility and on their options for fertility preservation. Although there have been a few studies that show a positive effect of GnRH analogues on fertility preservation, there is insufficient evidence to establish the use of GnRH analogues as a first-line therapy. There are currently a few ongoing prospective randomized studies on the topic, but their long-awaited results will probably not yet be published for several years. In the meantime, the use of GnRH analogues in breast cancer patients should be offered in the context of clinical trials after adequate counseling of the patients with regard to the possible influence of this treatment on the effectiveness of chemotherapy. Other methods of preserving fertility, such as ovarian tissue cryopreservation, in vitro maturation, and IVF after ovulation induction with aromatase inhibitors, should also be discussed with the patient. Pregnancy after breast cancer treatment does not appear to limit the prognosis.

The present review has focused both on the effects of cancer treatments on fertility and on the various assisted-reproduction innovations that are available to provide the breast cancer patient with the option of future pregnancies. We are currently passing through a period of uncertainty and change with regard to the role of ovarian suppression and other fertility preservation measures in the management of early breast cancer, but developments in the near future promise to be very exciting.

CI = confidence interval; CMF = cyclophosphamide, methotrexate, and 5-fluorouracil; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; IVF = in vitro fertilization.

The authors declare that they have no competing interests.