In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer. The prespecified secondary analysis from the POSITIVE study demonstrates that younger age is the main determinant of shorter time to pregnancy in premenopausal patients with breast cancer temporarily interrupting adjuvant endocrine therapy to attempt pregnancy. Type of endocrine therapy or the use of gonadotropin-releasing hormone agonist (GnRHa) with chemotherapy did not appear to have an important impact.
These findings are important in counselling young patients with breast cancer considering future pregnancy according to Dr. Hatem A. Azim, Jr of the Cairo Cure Oncology Center in Cairo, Egypt and Breast Cancer Center, Hospital Zambrano Hellion, School of Medicine, Tecnologico de Monterrey in San Pedro Garza Garcia, Mexico and colleagues who published the findings on 29 May 2024 in the JCO.
The authors wrote in the background that retrospective data have demonstrated the safety of pregnancy after breast cancer, even in patients with hormone receptor (HR)–positive disease. However, the optimal duration of adjuvant endocrine therapy of 5-10 years, during which pregnancy is contraindicated, substantially challenges the feasibility of future pregnancies given the decline of fertility potential over time.
Recently, the primary results of the POSITIVE study demonstrated that temporary interruption of endocrine therapy to attempt pregnancy does not increase the short-term risk of disease recurrence. However, other challenges still exist regarding the likelihood of becoming pregnant, including the detrimental impact of chemotherapy on ovarian reserve and the uncertainty regarding safety and efficacy of assisted reproductive technologies in this population.
Embryo cryopreservation and oocyte cryopreservation are considered as reliable tools to preserve fertility in young women with breast cancer, but concerns remain regarding the potential detrimental effect of the use of ovarian stimulation required for embryo or oocyte cryopreservation, particularly in the setting of HR–positive breast cancer. Prospective data are lacking on the efficacy and safety of ovarian stimulation and other assisted reproductive technologies strategies in young breast cancer survivors.
In POSITIVE, the study team investigated time to pregnancy, efficacy, and safety of fertility preservation, and assisted reproductive technologies in women with early HR–positive breast cancer desiring future pregnancy. It is an international, single-arm, prospective study, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. The study investigators evaluated menstruation recovery and factors associated with time to pregnancy and investigated if assisted reproductive technologies use was associated with achieving pregnancy. The cumulative incidence of breast cancer free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months.
A total, 273 patients (53%) reported amenorrhea at enrolment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients aged <35, 35-39, and 40-42 years.
A total of 179 patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrolment. Cryopreserved embryo transfer was the only assisted reproductive technology associated with higher chance of pregnancy (odds ratio 2.41, 95% confidence interval [CI] 1.75 to 4.95). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI 6.0 to 15.4) compared to 8.7% (95% CI 6.0 to 12.5) with those who did not.
This study provides important insights into patterns of premature ovarian insufficiency and infertility in young patients with breast cancer. At study entry, around 50% of patients had amenorrhea. This is not unexpected given that more than half of the patients received GnRHa as part of adjuvant endocrine therapy. Importantly, menses resumed in more than 90% of amenorrheic patients, mostly during the first 6 months. As expected, patients who did not receive chemotherapy had faster time to menstruation recovery.
Most patients (74%) achieved a pregnancy; this relatively high proportion is likely due to the inclusion of highly motivated women into the study. While pregnancy rates were largely age-dependent, older premenopausal patients of age 40-42 years still achieved a pregnancy rate of almost 50%. This information is highly relevant in managing the expectations of premenopausal women inquiring about their chances of future conception.
The study data provide evidence on the efficacy and short-term safety of different fertility preservation and assisted reproductive technologies options and add to the primary results of the POSITIVE study as an important resource for the oncofertility counselling of young patients with breast cancer. This is the only prospective study to date to evaluate oncologic and reproductive outcomes of women attempting pregnancy after breast cancer.
The study was previously presented at the 2023 San Antonio Breast Cancer Symposium (San Antonio, TX, US; 5-9 December 2023).
The study was was sponsored by the International Breast Cancer Study Group (IBCSG), which is responsible for data management and statistical analysis. It was supported by the ETOP IBCSG Partners Foundation (globally) and the Alliance for Clinical Trials in Oncology (in North America), in collaboration with the Breast International Group (BIG), the BIG cooperative groups, and the National Clinical Trials Network of the US National Cancer Institute. Globally, the study receives grant support from the IBCSG; Frontier Science and Technology Research Foundation, Southern Europe (Frontier Southern Europe), Pink Ribbon Switzerland, Rising Tide Foundation for Clinical Cancer Research, Swiss Cancer League, San Salvatore Foundation, Swiss Group for Clinical Cancer Research, Clinical Cancer Research Foundation of Eastern Switzerland, Ms Elisabetta Pavesi, Roche Diagnostics International, Verein Bärgüf, Swiss Cancer Foundation, Piajoh Fondazione di Famiglia, Gruppo Giovani Pazienti “Anna dai Capelli Corti,” and Schweizer Frauenlauf Bern, all in Switzerland; BIG Against Breast Cancer and the Baillet Latour Fund in Belgium; Gateway for Cancer Research and Breast Cancer Research Foundation in the US; C & A, Germany; Dutch Cancer Society, the Netherlands; Norwegian Breast Cancer Society and Pink Ribbon in Norway; ELGC K.K. and Pink Ring in Japan; Mr Yong Seop Lee, Ms Sun Hee Kang, and Korean Breast Cancer Foundation in South Korea; and other private donors. In North America, the Alliance for Clinical Trials in Oncology, Eastern Cooperative Oncology Group–American College of Radiology Imaging Network, SWOG Cancer Research Network, NRG Oncology receive support from the National Cancer Institute of the National Institutes of Health. Canadian Cancer Trials Group (CCTG) participation in the study was supported through its grant from the National Cancer Institute of the NIH. Funding support from the Dutch Cancer Society, the Netherlands. Additional programmatic funding support for the CCTG is provided by the Canadian Cancer Society and the Canada Foundation for Innovation. In addition, the study receives support from RETHINK Breast Cancer, Canada, and the Gilson Family Foundation, US.
Reference
Azim HA, Jr., Niman SM, Partridge AH, et al. Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy. JCO; Published online 29 May 2024. DOI: https://doi.org/10.1200/JCO.23.0229