Preserving possibilities: fertility after breast cancer treatment

Breast cancer is the most common malignancy affecting women worldwide and a leading cancer diagnosis among reproductive-aged women. While incidence increases with age, more than 10% of breast cancers occur in women younger than 45, and incidence in this population is rising annually. Advances in early detection and multimodal treatment have substantially improved survival, resulting in a growing survivorship population who may be eager to pursue family building after gonadotoxic breast cancer therapy.

Prior systematic reviews have demonstrated that fertility preservation is a key component of survivorship care among reproductive-aged women facing a cancer diagnosis (1). Deshpande et al. (1) reported that fertility counseling and access to fertility preservation were linked with improved psychological outcomes, including less decisional conflict about the cryopreservation process, reduced long-term regret about their fertility, and better psychological quality of life. Importantly, patients valued prompt, standardized fertility information addressing their specific concerns about future childbearing.

With a mind toward improving quality of life and family-building options among cancer survivors, the American Society for Reproductive Medicine recommends that reproductive-aged patients with cancer be offered timely fertility counseling and access to preservation options, ideally before gonadotoxic therapy (2). They specifically acknowledge the ability to use modified ovarian stimulation protocols for women with estrogen receptor positive breast cancer, adding letrozole and tamoxifen alongside standard stimulation protocols to reduce estrogen exposure to breast tissue while maintaining adequate follicular response (2). Letrozole inhibits aromatase and lowers estradiol synthesis systemically, whereas tamoxifen antagonizes estrogen receptors in breast tissue. The addition of either medication is intended to mitigate the theoretical risk of estrogen-mediated tumor stimulation during controlled ovarian stimulation.

To evaluate the effectiveness of these adjunctive medications for ovarian stimulation in patients with breast cancer, Balkenende et al. (3) initially published the “STIM-RCT (STIMulation of the ovaries in women with breast cancer undergoing fertility preservation)” randomized controlled trial in 2022, comparing ovarian stimulation with the addition of tamoxifen or letrozole to standard stimulation alone. They demonstrated that the addition of either agent did not adversely affect oocyte yield, maturation rates, or embryos cryopreserved compared with standard protocols. These additional medications were thus illustrated to have no negative effect on stimulation outcomes in patients with breast cancer undergoing fertility preservation.

While the STIM-RCT was designed to address the short-term impact of letrozole or tamoxifen on stimulation outcomes, Paans et al. (4) sought to evaluate the possible long-term impacts of these adjunctive medications on reproductive and pregnancy outcomes in the same population. This long-term follow-up study evaluated women who underwent fertility preservation within the STIM-RCT group or within a parallel observational group, the STIM-cohort (4). The STIM-cohort was comprised of eligible patients who declined participation in the randomized controlled trial but agreed to allow their data to be used in research. They underwent ovarian stimulation on the basis of their local treating center protocol, which may or may not include tamoxifen or letrozole. The STIM-cohort study objective was to assess after treatment reproductive outcomes among breast cancer survivors who specifically underwent fertility preservation with the addition of tamoxifen or letrozole during standard ovarian stimulation. Eligible participants in both the STIM-RCT and STIM-cohort were 18−43 years of age at the time of breast cancer diagnosis and elected for fertility preservation through ovarian stimulation before cancer-directed treatment. Hormone receptor status specifically was not assessed. Data were collected by a patient-completed questionnaire at a mean follow-up time of 7 years. Reported outcomes included regularity of menstrual cycles, mode of conception, pregnancy rates, live birth rates, and delivery outcomes.

Ninety-five patients from the STIM-RCT participated: 36 (38%) underwent ovarian stimulation with tamoxifen, 32 (34%) with letrozole, and 27 (28%) with standard protocols. Fifty-eight women (61%) reported attempting conception, and 41 of 58 individuals (71%) had at least one pregnancy after cancer treatment, with one additional pregnancy in an individual not trying to conceive. This resulted in a total of 31 live births, for a live birth rate of 74% in the STIM-RCT group. Several women (N = 22) achieved more than one pregnancy. Across 63 total pregnancies, the large majority (N = 48, 76%) were conceived without assisted reproductive technology (ART), while 13 (21%) required ART. Of ART-conceived pregnancies, 7 (53%) utilized previously cryopreserved embryos or oocytes, indicating that most survivors were able to achieve pregnancy without utilizing their banked gametes. When analyzed by intention to treat, the addition of tamoxifen or letrozole to standard ovarian stimulation protocols did not reduce the likelihood of pregnancy (tamoxifen RR: 0.92 [95% CI: 0.54–1.58]; letrozole RR: 0.84 [95% CI: 0.48–1.50]) or live birth (tamoxifen RR: 0.81 [95% CI: 0.54–1.22]; letrozole RR: 0.82 [95% CI: 0.53–1.26]) compared with standard stimulation alone.

The survey additionally inquired on participant’s future intentions for their frozen oocytes or embryos. While only 12% indicated they had already utilized their frozen gametes, over double that (26%) noted that they planned to use them if they were unable to conceive without medical assistance. This does further support the importance of even longer-term follow-up of these patients, especially those diagnosed in their early reproductive years, to truly elucidate the rates at which patients with breast cancer return to use previously cryopreserved gametes.

The findings from Paans et al. (4) provide long-term data regarding the use of tamoxifen or letrozole to augment ovarian stimulation protocols, specifically that they do not appear to negatively impact an individual’s long-term reproductive outcomes after cancer treatment. However, these data do include patients regardless of estrogen receptor status. Moreover, only a small minority of pregnancies achieved were utilizing previously frozen gametes (n = 7); thus, whether or not these adjunctive treatments affect outcomes of ART-conceived pregnancies specifically warrants further study with larger sample sizes, which may be achievable with longer interval follow-up time than that presented herein. Additionally, future studies should evaluate both stimulation and reproductive outcomes in individuals with estrogen receptor-positive breast cancers, as these patients would theoretically receive the greatest benefit from these adjunctive medications from a cancer standpoint.

When considering all pregnancies from both the STIM-RCT and STIM-cohort, a total of 129 patients participated, with an overall live birth of 67% for those who attempted to conceive. This represents a promising statistic for patients with breast cancer who desire future fertility. The investigators note that this birth rate may be higher than in previous studies because of specific study limitations. These may include self-selection bias given participants with undesired outcomes may not have participated (40% declined or did not respond to the survey). The young mean age of participants (32 years) is a protective factor decreasing the likelihood of after treatment premature ovarian insufficiency or diminished ovarian reserve, which in turn improves the chance of achieving pregnancy without ART. However, after treatment return of menses and ability to conceive spontaneously are highly variable, dependent on the specific gonadotoxic regimen, and the age at which the patient undergoes treatment. This highlights the importance of ovarian stimulation as the first line fertility preservation option, offering a chance at family building for the subset of individuals who will need to use their frozen gametes. Despite these limitations, pregnancy outcomes were consistent with those reported in the POSITIVE trial, with a 63.8% live birth rate among breast cancer survivors attempting pregnancy both with and without ART (5).

These findings highlight the critical role of timely fertility counseling and the offering of fertility preservation care for reproductive-aged patients with breast cancer. Overall, this data support the use of estrogen-modulating medications during ovarian stimulation as lacking a negative impact on long-term pregnancy outcomes, as well as the feasibility of achieving a live birth after breast cancer therapy. Ultimately, breast cancer treatment and survivorship are individualized. Patients with different tumor characteristics, such as stage, receptor status, and tumor biology, may require distinct chemotherapy regimens that affect their ability to achieve pregnancy without ART. Fertility counseling with a reproductive endocrinologist and timely offering of cryopreservation services are essential to support patients in making informed decisions about future family building. While it may be a lofty goal, future studies should aim to stratify reproductive outcomes by breast cancer features and treatment protocols to provide more precise and nuanced guidance for this most common but also varied tumor type.

CRediT Authorship Contribution Statement

Aaron D. Masjedi: Conceptualization, Data curation, Formal analysis, Writing – original draft. Sarah C. Cromack: Conceptualization, Writing – review & editing.

Declaration of Interests

The authors report nothing to disclose.