Fertility Preservation for Women With Breast Cancer

Introduction

Nearly 100,000 reproductive-age women are diagnosed with cancer annually in the United States, with the most common malignances being breast, hematologic, gynecologic, and central nervous system cancers. Approximately 25,500 cases of breast cancer are diagnosed annually among reproductive-aged women, with the majority of women having local (64%) or regional (27%) disease at the time of diagnosis. Almost all of these women require chemotherapy with or without endocrine therapy for cure. The majority of young women who undergo breast cancer treatment survive their disease, with an approximate 95% 4-year relative survival for patients diagnosed with stage I breast cancer across all subtypes.

Curative treatments can lead to a delay in childbearing and/or render a patient infertile. Chemotherapy drugs, and particularly alkylating agents, result in a significant depletion of the primordial follicle pool and a considerable compromise in the ovarian reserve. Even low-risk chemotherapeutic regimens can compromise fertility and result in primary ovarian insufficiency (POI) as determined by antimullerian hormone (AMH) levels, antral follicle count (AFC), and/or clinically evident amenorrhea and subfertility.

Importantly, trends in delayed childbearing mean that women are completing their families at a more advanced reproductive age, with an average age of first birth peaking at 26.3 years in the United States and continuing to rise. Female fertility is known to decline significantly with age, while the risk of miscarriage rises steeply in an inverse fashion. Both patients and providers overestimate the age at which fertility declines, as well as the ability of assisted reproductive technology to overcome age-related fertility decline. Many women diagnosed with cancer will not yet have begun or completed childbearing, making fertility preservation a priority during treatment planning. This is particularly problematic for cancer patients facing not only acute gonadotoxic therapy, but also prolonged endocrine therapy, which may span their remaining reproductive years.

Many women express concerns regarding treatment-related infertility, allowing this risk to influence the pursuit of potentially life-saving chemotherapy and/or endocrine therapy. The concerns are not unwarranted, as female cancer survivors are significantly less likely to achieve parenthood, with the probability of a first child after cancer diminished by 50% compared with the general population. Improved cryobiology techniques have led to the increasing success of fertility preservation techniques such as oocyte and embryo cryopreservation, with these techniques now considered standard of care.

We thus address fertility preservation as a critical part of comprehensive breast cancer care.

Ovarian Biology and Gonadotoxicity

Gonadotoxicity of Chemotherapy

The risk of ovarian injury due to chemotherapy is age-, agent-, and dose-dependent. Treatment-associated mechanisms of oocyte depletion have been linked to damage to the granulosa cells or to the oocyte itself, resulting in follicular apoptosis, vascular damage, fibrosis of the ovarian cortex, and “follicular burn-out” with accelerated activation of the dormant primordial follicle pool. Alkylating agents such as cyclophosphamide, known to be among the most gonadotoxic agents, cause DNA breaks at any stage of the cell cycle and negatively affect both the oocytes and ovarian function. Cyclophosphamide-based treatment regimens lead to a significantly higher incidence of amenorrhea compared to regimens without cyclophosphamide (OR 2.25; 95% CI 1.26–4.03, P = 0.006).

Taxanes, such as paclitaxel and docetaxel, inconsistently result in chemotherapy-induced amenorrhea. Platinum agents and capecitabine result in lower rates of chemotherapy-induced amenorrhea, but patients should be counseled regarding the impact of age, additional therapies, and need for endocrine suppression.

Less is known regarding the impact of monoclonal antibody treatment on fertility. The monoclonal antibody trastuzumab is used as targeted treatment against Her2/neu, a transmembrane protein that is overexpressed in approximately 20% of patients with breast cancer. The APT trial evaluated menstrual impairment in premenopausal patients receiving weekly paclitaxel with trastuzumab for 3 months, followed by trastuzumab monotherapy for 1 year of anti-HER2 therapy. This treatment resulted in a lower rate of POI compared to the expected incidence of POI with other adjuvant chemotherapy regimens. Given the paucity of data surrounding monoclonal antibody treatment, conclusions can not yet be drawn regarding their impact on fertility.

PARP inhibitors, which may be clinically appropriate for those with germline pathogenic BRCA1/2 mutations with a breast or gynecologic cancer, may result in greater depletion of the primordial follicle pool compared to cyclophosphamide, doxorubicin, or other antineoplastics alone. These data warrant further investigation.