With improved early detection and treatment, the majority of women diagnosed with early-stage breast cancer will survive their disease. The majority of younger women will be offered adjuvant chemotherapy, and those whose tumors express estrogen receptors (ER-positive) should receive hormonal therapy for at least 5 years. Recent data suggest a benefit of extending hormonal therapy beyond 5 years, and often chemical ovarian suppression is added in young patients. As mortality has become less of an immediate threat, minimizing short-term and permanent long-term side effects should be a central goal when choosing adjuvant regimens. In addition to the risks of leukemia and heart failure, chemotherapy-induced premature ovarian failure must be considered. The insult to the ovaries by cytotoxic agents has been linked to the patient’s age at diagnosis, the type and dose of regimen used, likely genetic determinants of the host, and lifestyle factors.
There is still uncertainty about which are the most predictive biomarkers of poor ovarian reserve and impending infertility, and how to interpret their changes during adjuvant therapy for breast cancer. Several genetic markers predicting a higher likelihood of ovarian damage from treatment with specific chemotherapeutic agents are emerging and under clinical evaluation, but large randomized studies will be needed for validation.
The two most challenging groups of patients with whom to discuss fertility preservation are probably the patients whose tumors are ER-positive, as the induction of amenorrhea has been associated with better breast cancer–related outcomes, and patients with a genetic predisposition to ovarian cancer, such as women with mutations in BRCA1/BRCA2 or with Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) genes. In women with BRCA mutations, removal of the ovaries has been strongly associated with better breast cancer outcomes and prevention of ovarian cancer.
Little is still known about the emotional toll on patients who must navigate this very complex problem with conflicting priorities in a very short time. Access to novel technologies in fertility preservation prior to the start of chemotherapy is often not facilitated or thought feasible, because of perceived and actual risks to the patient, as well as costs and time constraints.
Care providers and patients should be informed about the risks, benefits, and likelihood of success in preserving ovarian function so they can make the best informed decision at a time that is stressful for the patient.
Fertility and natural risk factors for premature ovarian failure
Each year in the United States, more than 200,000 women are diagnosed with breast cancer, of whom over 50,000 are under 50 years of age, with over 11,000 under age 40. Hence, at diagnosis an increasing number of young patients with breast cancer have not ever conceived or completed family planning.
One of the most important natural factors when considering fertility preservation is the age at breast cancer diagnosis and at the anticipated completion of adjuvant therapy. Changes in lifestyles over the last 3 decades have led to a delayed onset of childbearing, and there has been a steady increase in the number of children born to women over the age of 35. Nonetheless, the number of children born to women over age 35 is considerably lower than that in younger women. Whereas 97 children are born to 1,000 US women aged 30 to 34, this rate drops to 47 births at ages 35 to 39, to 10 at ages 40 to 44, and to 0.7 in women over 45 years of age, despite many recent advances in assisted reproductive technology (ART). ART has become an integral factor in childbearing. In 2011, an estimated 15 in 1,000 children in the United States were reported to be born through use of ART.
Fertility is strongly linked to the onset of menopause. In the United States, the median age of menopause, the permanent cessation of menstruation and completion of natural fertility, is estimated to be 51 years; however, natural fertility rates decrease much earlier. A steady decrease in ovarian reserve and fertility is expected to occur after age 30, with a sharp drop after age 37.
Premature menopause, defined as menopause occurring under the age of 40, is seen in about 1% of women. The likelihood of premature or early menopause (before age 45) is impacted by family history, smoking, ethnicity, and socioeconomic status.[4,5] These underlying risk factors should be considered in each patient when assessing the risk of chemotherapy-induced amenorrhea and the potential for successful fertility preservation.
Risk of chemotherapy-induced amenorrhea
The rate of chemotherapy-induced amenorrhea, the commonly used surrogate for infertility after chemotherapy and hormonal therapy, has been described in several excellent reviews.[6-9] Amenorrhea rates are frequently reported as secondary endpoints in large randomized studies evaluating novel therapeutic interventions for premenopausal patients with breast cancer. The induction of amenorrhea is dependent on the agent, dose, and duration of therapy; reported rates of post-treatment amenorrhea range from 10% with newer regimens and shorter durations of therapy to close to 100% in earlier studies. In addition to the aforementioned factors, the amenorrhea incidence rate is strongly associated with advancing age. Frequently, the reported data are further confounded by short follow-up of the respective study and the considerable reversibility of the chemotherapy-induced amenorrhea.
Several reports have suggested that addition of paclitaxel and trastuzumab (Herceptin) do not add to the amenorrhea risk of doxorubicin and cyclophosphamide. Patients treated with tamoxifen in addition to adjuvant chemotherapy, on the other hand, may have a decreased chance of recovering their regular menses.[7-9]
This wide range of therapy-induced amenorrhea points to the need for well-controlled randomized studies when assessing the risk of therapy-induced amenorrhea, and the potential benefits of interventions to preserve fertility and protect against ovarian damage during adjuvant therapy.
It further outlines the need for biomarkers to assess the individual ovarian reserve at time of diagnosis, to facilitate a personalized calculation of the risk imposed by the cancer therapy.
Predictors of ovarian damage and permanent therapy-induced amenorrhea
FSH and inhibin. Follicle-stimulating hormone (FSH) levels and inhibin A and B levels have been used in many studies to assess and predict therapy-induced ovarian failure.[10,11] However, the fluctuations of these markers between and within cycles render them less predictable, and often both high FSH levels and low inhibin levels after chemotherapy are reversible over time and revert to pretreatment levels when menses recover.[12-14]
Anti-Mllerian hormone. Recent studies have suggested that anti-Mllerian hormone (AMH) levels may be predictive of ovarian reserve and the response to ovarian stimulation. AMH belongs to the transforming growth factor beta (TGF-β) family and is expressed in the ovarian granulosa cell of antral follicles but not in larger developing follicles.[15,16] In contrast to FSH and inhibin levels, AMH does not fluctuate during the menstrual cycle and should not be greatly influenced by the temporary cessation of menses. Several small studies have pointed to the value of AMH as a more reliable predictive marker of permanent chemotherapy-induced amenorrhea.[17-20] Assessment of AMH levels should therefore be incorporated in future studies evaluating interventions to preserve fertility in patients undergoing chemotherapy.
Antral follicle count. In addition to laboratory studies of levels of FSH, inhibin, and AMH, sonographic assessment of antral follicle counts (AFC) have recently been found to be predictive of ovarian reserve and predictors of impending menopause.[21-24] A small study suggested that the assessment of both AMH and AFC were most reliably linked to a positive response to letrozole for ovarian stimulation and the successful embryo/oocyte preservation in patients with breast cancer.
It is hoped that using this approach in addition to assessing levels of AMH, inhibin, and FSH will increase the value of any of these markers in predicting the likelihood of permanent ovarian damage induced by chemotherapy in individual patients.
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