P-356 Fertility preservation for patients with breast cancer: altered response to ovarian stimulation and loss of cholesterol homeostasis in ovarian follicles
Authors: Poitrinal A , Carlet-Dollet S , Pereira B , Rodrigues C , Lepage M , Gremeau A  S , Marteil G , Brugnon F 
Published: July 2024

Abstract

Study question
Does the presence of breast cancer alter the ovarian response to hormonal stimulation and the cholesterol homeostasis in ovarian follicles?

Summary answer
The deleterious impact of breast cancer on the ovarian response might be link to an alteration of the cholesterol biosynthesis in cumulus cells.

What is known already
Breast cancer is the most frequent cancer in reproductive-aged women. The cancer itself seems to exert a deleterious impact on the ovarian functions. Indeed, cancer patients who undergo fertility preservation before cancer therapy initiation show a poorer response to ovarian stimulation than healthy women. Nevertheless, this impact remains controversial, and the mechanisms by which the cancer impairs the ovarian functions are poorly understood. To our knowledge, no study has yet evaluated the impact of breast cancer on the cholesterol biosynthesis pathway in human cumulus cells, a pathway essential for oocyte competence to maturation and fertilization.

Study design, size, duration
30 patients with breast cancer (10 triple negative (TNBC), 10 hormone-receptor positive (HR+) and 10 HER2 positive (HER2+)) and 30 women oocytes donors undergoing oocyte cryopreservation will be included from January 2019. We assess ovarian response to stimulation (number, quality of retrieved oocytes; total FSH dose). We quantify the level of enzymes and regulators of the cholesterol biosynthesis pathway in cumulus cells (CC) by RT-qPCR. We plan to quantify cholesterol levels in follicular fluids (FF).

Participants/materials, setting, methods
Since January 2019, 25 breast cancer patients (9 TNBC, 8 HR+ and 8 HER2+) and 30 oocytes donors (control group) under 37 years old have been included. Ovarian stimulation was performed with antagonist protocol. Following ovarian pick up and denudation, CC and FF were collected. After total RNAs extraction from CC, the expression levels of enzymes and regulators of the cholesterol biosynthesis pathway were quantified by RT-qPCR. Cholesterol levels will be quantified in FF.

Main results and the role of chance
The clinico-biological characteristics (age, BMI) are comparable between cancer patients and the control group (p &gt; 0.05). Serum AMH levels are lower in the TNBC subgroup (2.3±1.6 ng/mL) than in the control group (4.7±2.8 ng/mL, p = 0.04). A poorer ovarian response to ovarian stimulation is observed in the breast cancer group compared with the control group (number of mature oocytes: 9.4±5.2 vs. 14.5±7.7, p = 0.007). Among the cancer patients group, the TNBC subgroup shows the poorest ovarian response to stimulation (number of mature oocytes: 7.6±4.3 vs. 14.5±7.7 in control group, p = 0.006) despite the highest total administered FSH dose (2480±880 IU vs. 1831±460 IU in control group, p = 0.02).
Dysregulation of the cholesterol biosynthesis pathway is observed in the breast cancer group. For TNBC and HR+ cancer patients, we observed an increase in the transcripts levels of CYP51 enzyme (respectively 3.28±1.69 vs. 1.84±2.33, p = 0.0098 and 1.77±1.78 vs. 1.84±2.33, p = 0.03) and SREBP2 activator (respectively 2.04±0.95 vs. 1.27±1.13, p = 0.003 and 1.12±0.47 vs. 1.27±1.13, p = 0.02) of the cholesterol biosynthesis pathway compared to the control group. In HER2+ cancer patients, a significant decrease in the expression levels of SQLE (0.39±0.34 vs 1.81±3.99, p = 0.001) and DHRC7 enzymes (0.33±0.32 vs 1.21±0.88, p = 0.0002) is observed compared to the control group.

Limitations, reasons for caution
Our preliminary results should be confirmed with the analysis of a larger number of participants.
We should confirm that the observed modulations in the expression levels of enzymes and regulators of the cholesterol biosynthesis pathway led to a loss of cholesterol homeostasis by quantifying cholesterol in FF.

Wider implications of the findings
Our findings strengthen the hypothesis that cancer exerts a deleterious impact on the ovarian functions, as we observed a lower ovarian response in patients with breast cancer. This project will have clinical implications, such as to adapt the fertility preservation approach according to the breast cancer subtype.

Trial registration number
Not applicable