Breast cancer is the most frequently occurring cancer in women of developed countries, and as a result of new developments in breast cancer treatment, more women are cured after being diagnosed with this disease. It is important that fertility preservation strategies are addressed before chemotherapy, because chemotherapy may induce premature ovarian failure (depending on the woman’s age, the drugs used, the dosage and duration of treatment). Among possible solutions are embryos or oocytes cryopreservation, ovarian tissue cryopreservation–freezing with a subsequent orthotopic and heterotopic autotransplantation, whole ovary cryopreservation, ovarian suppression with gonadotropin-releasing hormone (GnRH) analogues, which inhibit ovarian follicular depletion induced by chemotherapeutic agents and in vitro fertilisation (IVF) after ovulation induction with aromatase inhibitors or tamoxifen.
Breast cancer and future fertility
Cancer is the leading cause of death among women of reproductive age. Over time, great strides are being made in the care of cancer sufferers. The longevity and quality of life of patients with cancer continues to improve and the term cure is being used more commonly. In a similar manner, there is also much reason for optimism regarding the future fertility options for female (and male) patients with cancer.
Breast cancer is the most frequently occurring cancer in women of developed countries. A total of 12% of breast cancer occurs in women aged 20–34 years. As a result of new developments in breast cancer treatment, more women are cured or remain in long-term remission after being diagnosed with the disease. Although young women constitute a minority of breast cancer patients, these women commonly have more distinct concerns and issues compared with older women, including queries regarding fertility and pregnancy.
Nowadays, more cancer patients want to have children after the diagnosis of such a disease. Taking into account that the mean age at first pregnancy continues to rise worldwide, the question of pregnancy after breast cancer is thus raised more frequently. Similarly, survival from breast cancer has significantly improved, and the potential late effects of treatment and the impact on quality of life and fertility have become increasingly important.
Chemotherapy for breast cancer and impact on reproduction
Some studies have already reviewed the possibility and risks of giving birth among women with breast cancer previously treated by chemotherapy. Reproductive medicine specialists and gynaecologists commonly see these young women either shortly after initial diagnosis or following adjuvant therapy and should be aware of current management of breast cancer, the prognosis of patients with early stage breast cancer and how adjuvant systemic treatments may impact reproductive function. It must be emphasised that the majority of women, younger than 35 years of age experience only temporary amenorrhoea due to chemotherapy and can maintain fertility. On the other hand, in premenopausal women with breast cancer, it was shown that cytotoxic chemotherapy is beneficial because it causes premature menopause. Evidence appears to support the hypothesis of a dual mechanism of action of chemotherapy in this patient population: direct cytotoxicity and ovarian suppression resulting from chemotherapy-induced ovarian failure. There is ample preclinical and clinical evidence to support a direct cytotoxic mechanism of action. The evidence supporting the gonadotoxic mechanism of action of chemotherapy is indirect but biologically compelling. Chemotherapy, particularly with alkylators such as cyclophosphamide, can cause ovarian fibrosis with a concomitant loss of function. Furthermore, amenorrhoea and premature menopause are well-known side effects of adjuvant chemotherapy for breast cancer. The onset of ovarian failure and amenorrhoea is accompanied by increased follicle stimulating hormone (FSH) and decreased inhibin B, anti-Mullerian hormone (AMH) and oestradiol. Amenorrhoea occurs after a median of two cycles of chemotherapy (range: 1–6 cycles). In women aged less than 35 years, amenorrhoea is induced in less than 10% of the cases. In the rest of the patients, median resumption time of menstruations is 3.5 months (range: 1–10 months). In women aged >40 years, most chemotherapic regimens induce premature ovarian failure or premature menopause.
The rates of chemotherapy-induced amenorrhoea are shown in Table 1 .
| Chemotherapy | Percentage (%) of permanent or temporary amenorrhea |
|---|---|
| Doxorubicin/ A driamycin- C yclophosphamide | >30 |
| C yclophosphamide- M ethotrexate- F luorouracil | < 35 years: > 10 |
| > 35 years: > 65 | |
| C yclophosphamide- E pirubicin- F luorouracil | > 50 |
| Doxorubicin/ A driamycin | > 55 |
| F luorouracil-Doxorubicin/ A driamycin- C yclophosphamide | > 30 |
| Docetaxel/ T axol-Doxorubicin/ A driamycin- C yclophosphamide | > 50 |
Nevertheless, it seems that chemotherapy-induced ovarian failure would confer benefit, particularly in patients with hormone receptor-positive disease. On the other hand, target therapies, such as trastuzumab (Herceptin), lapatimib (Tykerb) and bevacizumab (Avastin), used as anti-neoangiogenetic agents have no impact on fertility.
It is important that fertility preservation strategies are addressed before chemotherapy, because chemotherapy regimens (including paclitaxel (Taxol), cyclophosphamide, methotrexate, epirubicin, fluorouracil and adriamycin) may induce premature ovarian failure (depending on the woman’s age, the drugs used, the dosage and duration of treatment).
Chemotherapy for breast cancer and impact on reproduction
Some studies have already reviewed the possibility and risks of giving birth among women with breast cancer previously treated by chemotherapy. Reproductive medicine specialists and gynaecologists commonly see these young women either shortly after initial diagnosis or following adjuvant therapy and should be aware of current management of breast cancer, the prognosis of patients with early stage breast cancer and how adjuvant systemic treatments may impact reproductive function. It must be emphasised that the majority of women, younger than 35 years of age experience only temporary amenorrhoea due to chemotherapy and can maintain fertility. On the other hand, in premenopausal women with breast cancer, it was shown that cytotoxic chemotherapy is beneficial because it causes premature menopause. Evidence appears to support the hypothesis of a dual mechanism of action of chemotherapy in this patient population: direct cytotoxicity and ovarian suppression resulting from chemotherapy-induced ovarian failure. There is ample preclinical and clinical evidence to support a direct cytotoxic mechanism of action. The evidence supporting the gonadotoxic mechanism of action of chemotherapy is indirect but biologically compelling. Chemotherapy, particularly with alkylators such as cyclophosphamide, can cause ovarian fibrosis with a concomitant loss of function. Furthermore, amenorrhoea and premature menopause are well-known side effects of adjuvant chemotherapy for breast cancer. The onset of ovarian failure and amenorrhoea is accompanied by increased follicle stimulating hormone (FSH) and decreased inhibin B, anti-Mullerian hormone (AMH) and oestradiol. Amenorrhoea occurs after a median of two cycles of chemotherapy (range: 1–6 cycles). In women aged less than 35 years, amenorrhoea is induced in less than 10% of the cases. In the rest of the patients, median resumption time of menstruations is 3.5 months (range: 1–10 months). In women aged >40 years, most chemotherapic regimens induce premature ovarian failure or premature menopause.
The rates of chemotherapy-induced amenorrhoea are shown in Table 1 .
| Chemotherapy | Percentage (%) of permanent or temporary amenorrhea |
|---|---|
| Doxorubicin/ A driamycin- C yclophosphamide | >30 |
| C yclophosphamide- M ethotrexate- F luorouracil | < 35 years: > 10 |
| > 35 years: > 65 | |
| C yclophosphamide- E pirubicin- F luorouracil | > 50 |
| Doxorubicin/ A driamycin | > 55 |
| F luorouracil-Doxorubicin/ A driamycin- C yclophosphamide | > 30 |
| Docetaxel/ T axol-Doxorubicin/ A driamycin- C yclophosphamide | > 50 |
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