Fertility and Pregnancy in Young Patients with Breast Cancer

Use of assisted reproductive technology (ART) to facilitate pregnancy is safe in women taking a break from endocrine therapy (ET) for breast cancer, as in pregnancy in BRCA carriers who have been treated for the disease. So say findings from two international trials co-authored by Cleveland Clinic researchers and presented at the 2023 San Antonio Breast Cancer Symposium.

The data about ART are from a secondary analysis of the prospective POSITIVE trial. Evidence on pregnancy post-breast cancer in BRCA carriers is from a retrospective, multicenter trial. The results are of paramount importance to clinicians for oncofertility counseling of young patients with breast cancer, according to the investigators.

“This analysis from the POSITIVE trial suggests that ART may allow patients with breast cancer to become pregnant more quickly, and therefore, be off endocrine therapy for less time,” says Halle Moore, MD, Director of Breast Medical Oncology at Cleveland Clinic’s Taussig Cancer Institute and co-author of both studies. “It also appears, based on large, global retrospective study, that pregnancy post-BC in BRCA carriers has no detrimental impact on maternal prognosis or fetal outcomes.”

ART and ET interruption to attempt pregnancy

Participants in POSITIVE were women aged ≤42 years with stage 1 to 3 hormone receptor (HR)-positive breast cancer who received 18 to 30 months of ET before temporary interruption. Endpoints for the secondary analysis were menstruation resumption and safety of ART, as well as time to pregnancy.

A logistic regression model was used to evaluate whether ART was associated with achieving pregnancy, with controls for age and receipt of chemotherapy with or without gonadotropin-releasing hormone analogues (GnRHa). Cumulative incidence of breast cancer-free interval (BCFI) events was estimated, based on whether a patient had undergone ovarian stimulation for cryopreservation at diagnosis. The authors performed a 24-month landmark analysis of the safety of ART use, with median follow-up of 41 months.

At enrollment, 53% of the patients (273) were amenorrheic. Six months later, menstrual recovery had occurred in 90% of those who had not received chemotherapy, versus 85% and 81% of the patients who had received chemotherapy with or without GnRHa, respectively.

“Rates of recovery of menstrual function after endocrine therapy interruption were very high, regardless of whether patients had been taking tamoxifen or tamoxifen or an aromatase inhibitor with a GnRH analog,” says Dr. Moore. “This is novel information, in that we might have expected ovarian ablation to delay recovery of menstruation.”

At 12 months, cumulative incidence of pregnancy was:

• 64% in patients aged <35
• 54% in those aged 35 to 39 years
• 38% in those aged to 40 to 42 years

Youth was the only factor associated with shorter time to pregnancy in a multivariable analysis that included use of chemotherapy, GnRHa plus chemotherapy, type of ET and prior parity.

Of the participants, 36% had ovarian stimulation or embryo/oocyte cryopreservation at breast cancer diagnosis, 37.9% of whom underwent embryo transfer during POSITIVE. ART was used by 43.3% of patients, 37.2% of whom underwent ovarian stimulation for in vitro fertilization (FIVET) or intracytoplasmic sperm injection (ICSI).

Overall, 74% of patients became pregnant at least once. The pregnancy rate was 82.4% with embryo transfer and 67.5% with FIVET/ICSI. In a multivariate model, embryo transfer was the only ART modality associated with a higher likelihood of pregnancy.

At three years, cumulative incidence of BCFI events was similar in patients who had undergone ovarian stimulation (9.7%) versus who did not (8.7%). The 24-month landmark analysis showed that ovarian stimulation for FIVET/ICSI had no impact on BCFI.

“Based on short-term follow-up, use of assisted reproductive technology did not appear to increase the risk of recurrence of breast cancer,” says Dr. Moore. “We will continue to follow these patients for 10 years to gather long-term safety data.”

Safety of pregnancy after breast cancer

More than 4,700 patients were enrolled in the 78-center study of pregnancy safety in women aged ≤40 years with BRCA1 or BRCA2 mutations. All had been diagnosed with stage 1 to 3 breast cancer between January 2000 and December 2020.

The primary endpoints were pregnancy rate and disease-free survival. Overall survival and breast cancer-specific survival, pregnancy and fetal and obstetric outcomes were secondary endpoints.

Two survival analyses were performed: an extended Cox model with occurrence of pregnancy as a time-varying covariate; and a case-control analysis with 1:3 matching of patients with and without a pregnancy for type of BRCA pathogenic variant, HR status, nodal status and year at diagnosis.

Of the patients, 659 had ≥1 pregnancy and 4,073 did not. Patients with pregnancies were significantly younger at diagnosis and more likely to be BRCA1 carriers and to have node- and HR receptor-negative breast cancer.

The overall pregnancy rate was 22% at 10 years, versus 18% and 26% in patients with HR-positive and HR-negative breast cancer, respectively. Median time from breast cancer diagnosis to conception was 3.5 years, and was significantly longer in patients with HR-positive breast cancer (4.3 vs. 3.2 years).

Incidence of induced abortion and miscarriage were 6.8% and 9.6%, respectively. Of the 78.5% of patients with completed pregnancy, 10.4% had twins and 78.5% delivered at term. Congenital anomalies occurred in 0.9% of the 571 live births. At median follow-up of 7.8 years, there was no significant difference in disease-free survival in the patients who became pregnant and those who did not. Rates of breast cancer-specific survival and overall survival were both significantly better in the patients who became pregnant.

“The survival benefit was a bit a surprise, but it needs to be taken with a grain of salt because this was a retrospective study,” says Dr. Moore. “Nevertheless, the data provide reassurance about the safety of pregnancy after breast cancer, even in patients with pathogenic BRCA mutations.”