Fertility Preservation in Breast Cancer Patients

Hady El Hachem; David Atallah; Michael Grynberg

Disclosures

Future Oncol. 2014;10(10):1767-1777. 

In This Article

Impact of BC Treatment on Reproductive Function

Following a diagnosis of BC, the risks of fertility loss and premature ovarian failure (POF) depend primarily on the chemotherapy regimen used (type of agent, the duration and the total cumulative dose administered), the patient's age and her baseline ovarian reserve (OR).[6,8]

Chemotherapy agents cause direct ovarian toxicity, which affects both somatic (pregranulosa and granulosa cells) and germinal (oocytes) cells, leading to a dose-dependent apoptosis of primordial follicles and acute ovarian vascular damage.[8] A recent hypothesis also suggests that an increased activation of follicles from the resting pool, results in accelerated follicular atresia, and eventually a premature 'burn out' of the primordial follicle reserve.[9]

Of the chemotherapeutic agents used for BC treatment, alkylating agents, such as cyclophosphamide, are associated with a high risk of gonadotoxicity, while anthracyclines (e.g., doxorubicin) and antimetabolites (e.g., 5-fluorouracil) are associated with moderate and low risks, respectively. Studies regarding the gonadotoxicity of taxanes have yielded conflicting results.[10]

The rates of POF following chemotherapy for young patients with BC vary between 0 and 70%, and are dependent on both the protocol used and the patient's age. The cyclophosphamide, methotrexate and 5-fluorouracil (CMF), cyclophosphamide, epirubicin and 5-fluorouracyl (CEF) and cyclophosphamide, adriamycin and 5-fluorouracyl (CAF) chemotherapy protocols induce amenorrhea and POF in less than 20% of women younger than 30 years, 30–70% of women between the age of 30 and 39 years, and in more than 80% of women over the age of 40 years.[3,7–10] By contrast, either four cycles of adriamycin and cyclophosphamide (AC) or four cycles of docetaxel have been shown to be less gonadotoxic, causing amenorrhea in 6% of women younger than 31, 12% of women aged 31–39 years and 35% of women over the age of 40 years.[11]

Although pelvic radiation has been shown to have a negative impact on ovarian function, the standard radiation therapy used for BC may not be gonadotoxic. Of the 50 Gy dose commonly delivered during BC radiation therapy, only 2.1–7.6 cGy reach the pelvis and the ovaries, which is well below the dose required to induce POF (15 Gy).[9,12] Finally, for women with estrogen receptor-positive (ER+) BC, pregnancy is precluded during treatment with tamoxifen, a known teratogenic.[13] Treatment duration has conventionally been 5 years and could be extended to 10 years based on the recent ATLAS trial that showed a further reduction in recurrence and mortality with a 10-year therapy.[14] Delaying conception during the 5–10 years of treatment with tamoxifen results in a physiologic decline of ovarian function with age, and is especially impactful in women over the age of 35 years.[15]

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