Age, Parental Status Influence Ovarian Function Preservation Strategies in Premenopausal Breast Cancer

Findings from the Premenopausal Breast Cancer Patients’ Fertility Preservation (PREFER; NCT02895165), a large Italian multicenter prospective cohort, demonstrated that the majority of premenopausal women with early breast cancer underwent gonadotropin-releasing hormone agonist (GnRHa) therapy during chemotherapy to preserve ovarian function compared with a lower uptake of cryopreservation strategies in older premenopausal patients.

The prospective cohort evaluated oncofertility strategies in this patient population, and data were shared at the 2025 San Antonio Breast Cancer Symposium.

Among patients age 41 to 45 years old, 75.1% received GnRHa alone, and 24.9% declined any procedure. Among patients aged 40 years or younger, 89.3% received GnRHa, 25.0% underwent cryopreservation, and 9.2% underwent no procedure. Acceptance varied according to hormone receptor (HR) status, with higher GnRHa uptake in patients with HR-positive disease. Factors associated with cryopreservation acceptance included younger age, absence of prior children, more recent year of diagnosis, and lower tumor grade.

“Most premenopausal women with early breast cancer accepted the use of a genetic agonist during chemotherapy to preserve ovarian function... Factors associated with acceptance [included] younger age at diagnosis, [absence of] prior children, more recent year of diagnosis, and lower tumor grade,” Matteo Lambertini, PhD, explained in the presentation of data.

Lambertini is an associate professor and a consultant in medical oncology at the University of Genova and IRCCS Policlinico San Martino Hospital in Genova, Italy.

Importantly, controlled ovarian stimulation for oocyte cryopreservation did not negatively impact disease-free survival (DFS) or overall survival (OS).

PREFER Study: A National Oncofertility Initiative

Oncofertility counseling is recommended for all premenopausal women with newly diagnosed early breast cancer who are candidates for chemotherapy. Standard approaches include cryopreservation of oocytes, embryos, and ovarian tissue, with concurrent GnRHa therapy recommended during chemotherapy to preserve ovarian function. However, data on the uptake of these strategies and reasons for patient refusal are limited.

The analysis shared at the 2025 symposium represents the first multicenter evaluation of patients enrolled in the PREFER study between November 2012 and December 2024.

PREFER was conducted at 23 Italian centers. Inclusion criteria for the prospective trial was stage I, II, and III invasive breast cancer, premenopausal status at diagnosis, being 18 to 45 years old, and candidacy for neoadjuvant or adjuvant chemotherapy. Contrarily, exclusion criteria included stage IV disease, prior chemotherapy or radiotherapy, severe psychiatric disorders, and inability to provide written informed consent.

The primary objective of PREFER was to evaluate patient needs and choices regarding ovarian function and fertility preservation, assessing both the percentage of acceptance and reasons for refusal. Secondary objectives included assessment of the safety of controlled ovarian stimulation for oocyte cryopreservation in patients 40 years or younger at diagnosis, with DFS and OS as end points. Predefined subgroup analyses were performed according to HR status.

Key Findings: Fertility Preservation Status by Age and HR Status

Fertility Preservation Strategies: GnRHa Among Patients Aged 41 to 45

When stratified by HR status in patients ages 41 to 45, 77.9% of patients with HR-positive disease chose GnRHa alone and 22.1% had no procedure; 68.8% of patients with HR-negative disease received GnRHa alone and 31.3% declined any fertility-related intervention. The most frequently reported reason for refusal in this age group was completion of family planning (11.3%).

Among patients with HR-positive disease age 40 or younger, 90.2% received GnRHa, 8.0% had no procedure, and 26.2% used cryopreservation. Patients with HR-negative disease had slightly lower GnRHa use at 86.9%, with 12.4% receiving no procedure and 21.4% undergoing cryopreservation.

Fertility Preservation Strategies: Cryopreservation Among Patients Aged 40 Years or Younger

Younger age was a strong predictor of oocyte cryopreservation, with each 1-year decrease generating an odds ratio (OR) of 1.25 (95% CI, 1.18-1.32). Having no prior children significantly increased cryopreservation uptake compared with having 1 or more children (OR, 13.39; 95% CI, 7.73-23.21). Year of diagnosis also influenced decisions: compared with 2012 to 2015, patients diagnosed from 2016 to 2020 had an OR of 1.37 (95% CI, 0.74-2.51), and those diagnosed from 2021 to 2024 had an OR of 2.06 (95% CI, 1.15-3.67).

Patients with grade 1/2 tumors had higher odds of using cryopreservation compared with grade 3 (OR, 1.82; 95% CI, 1.18-2.82), while those with unknown tumor grade had lower likelihood (OR, 0.88; 95% CI, 0.50-1.55). HR-negative status was associated with lower uptake relative to HR-positive disease (OR, 0.76; 95% CI, 0.48-1.20). BRCA-negative status had an OR of 0.78 (95% CI, 0.44-1.38) vs BRCA-positive, and patients not tested for BRCA had reduced odds of pursuing cryopreservation (OR, 0.53; 95% CI, 0.34-0.84).

Neoadjuvant chemotherapy compared with adjuvant had an OR of 0.74 (95% CI, 0.50-1.09) and tumor size greater than 2 cm vs 2 cm or smaller showed an OR of 0.90 (95% CI, 0.60-1.34).

Fertility Preservation Strategies: Oocyte Cryopreservation Among Patients Aged 40 Years or Younger

Patients who underwent oocyte cryopreservation (n = 127) were younger, with a median age of 33.0 years (IQR, 29.0-36.0), compared with 36 years (IQR, 33.0-39.0) among those who did not (n = 406; P <.001. Year of diagnosis differed significantly between groups.

Parental status strongly separated the groups. Among those who pursued cryopreservation, 86.6% had no prior children compared with 34.7% of those who did not (P = .0127). Tumor grade distributions also differed: grade 1 tumors represented 3.1% of oocyte cryopreservation done vs 1.2% of oocyte preservation not done; grade 2 tumors represented 41.7% vs 27.6%, respectively; grade 3 tumors represented 47.7% vs 48.8%; and GX tumors represented 13.4% vs 22.4% (P = .0041).

HER2-positive disease was present in 27.6% of patients undergoing cryopreservation compared with 30.8% of those who did not (P <.001). Adjuvant chemotherapy was used in 57.5% vs 46.5%, respectively (P = .0315). The type of chemotherapy also varied: anthracycline- and taxane-based regimens were used in 70.0% vs 81.8%, respectively (P = .0123).

Patient Demographics and Tumor Characteristics of PREFER

Among 746 patients included in the analysis, the median age at diagnosis was 38.0 years (IQR, 34.0-41.0). Patients aged 41 to 45 years (n = 213) had a median age of 43.0 years (IQR, 42.0-44.0), and those aged 40 years or younger (n = 533) had a median age of 36.0 years (IQR, 32.0-38.0). Regarding year of diagnosis, 19.3% were diagnosed from 2012 to 2015, 34.0% from 2016 to 2020, and 46.7% from 2021 to 2024. These proportions were comparable across age subgroups: 19.2%, 27.2%, and 53.5%, respectively, among those aged 41 to 45 years and 19.3%, 36.8%, and 43.9% among those aged 40 years or younger.

Tumor size measured 2 cm or less in 37.3% and more than 2 cm in 62.6%, with similar distributions by age. Nodal involvement occurred in 57.2%, was slightly higher among patients aged 41 to 45 years (62.9%), and lower among those aged 40 years or younger (55.0%). Negative nodal status was recorded in 40.7% overall, including 36.1% of patients aged 41 to 45 years and 42.6% of those aged 40 or younger.

Parental status varied: 42.8% had no prior children and 57.2% had 1 or more. Among patients aged 41 to 45 years, 31.9% had no children and 68.1% had at least 1. Among those aged 40 or younger, 47.1% had no children and 52.9% had 1 or more. Tumor grade included 1.7% grade 1, 31.2% grade 2, 47.3% grade 3, and 19.7% with a tumor grade unknown (GX). Distributions were similar between age groups.

Most patients had HR-positive disease (72.0% overall; 70.0% age 41 to 45 years; 72.8% age 40 or younger). HER2 positivity occurred in 28.3% overall, including 23.9% in the older subgroup and 30.0% in the younger subgroup. Data collected on BRCA status revealed 12.5% pathogenic variants, 46.6% BRCA-negative results, and 40.9% not tested. Younger patients were more frequently BRCA-positive (15.2% vs 5.8%), and patients aged 41 to 45 years were more often untested (58.2%).

Chemotherapy timing was evenly divided between adjuvant and neoadjuvant therapy (50.0% each), with similar distribution across age groups. Anthracycline- and taxane-based regimens were used in 79.4% overall, including 80.3% among older patients and 79.0% among younger patients. Taxane-only therapy accounted for 8.8%, and other regimens for 11.8%.

Safety Outcomes and Next Steps Based on Clinical Implications

Among patients age 40 years or younger, DFS remained high in both groups, with a 4-year DFS of 94.8% (95% CI, 86.3-98.1) in patients who underwent oocyte cryopreservation and 87.2% (95% CI, 82.8-90.5) among those who did not (adjusted HR, 0.78; 95% CI, 0.27-2.26). The 4-year OS rate was 97.4% (95% CI, 89.9-99.3) in those who had oocyte cryopreservation done vs 96.0% (95% CI, 92.8-97.8) in those who did not (adjusted HR, 0.53; 95% CI, 0.06-4.73).

“Results from the PREFER study may provide novel prospective evidence to improve the oncofertility counseling of premenopausal women with early breast cancer and, from a public health perspective, they may help optimize the network between oncology and fertility units, including resource allocation,” Lambertini concluded in the presentation of data.

Reference

Lambertini M, Blondeaux E, Fontana V, et al. Fertility and ovarian function preservation in premenopausal women with early breast cancer: results from the multicenter prospective PREgnancy and FERtility (PREFER) study. Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract GS3-02.