Australian researchers have demonstrated that the breast cancer drug olaparib destroys immature eggs, known as oocytes, which exist within ovarian primordial follicles. Women are born with their entire store of ovarian follicles, and during their reproductive years, a selected oocyte matures to be released from the follicle as a mature egg each month, ready for fertilisation. The study found that olaparib depleted over one-third of primordial follicles in mice treated with the drug when compared to mice given a placebo dose.
These findings could represent a significant side effect for women, explained first author of the study, Dr Amy Winship from Monash University in Melbourne: 'Although there are differences between species, such as the number of eggs ovulated in a menstrual cycle, there are many important similarities that make the mouse an excellent model for studying the human ovary. The storage of primordial follicles, and the processes of activation, growth and ovulation are all the same.'
Olaparib, which prevents cancer cells from repairing themselves and being able to grow and spread by inhibiting a class of enzymes known as poly (ADP-ribose) polymerase, is currently used to treat women with metastatic breast cancer who carry certain mutations of the BRCA1 or BRCA2 genes. However, the OlympiA randomised control trial is currently in the process of assessing olaparib as a potentially curative treatment for early BRCA1/BRCA2 breast cancer which has not spread. Therefore, the drug may eventually be used to treat women who have not yet completed their families.
'Fertility is very commonly overlooked in many safety tests in preclinical studies in animal models and also in human clinical trials for new cancer drugs,' said Dr Winship. 'We know this is an important and valid concern of young cancer patients and survivors, particularly as survival rates for many cancers are improving. We show for the first time that olaparib is harmful to the immature eggs stored in the ovaries that will give rise to the mature eggs required to sustain fertility.'
While olaparib depleted primordial follicles, it was not found to impact the number of ovarian corpora lutea, which reflect active ovulation and play a crucial role in fertility, nor the level of anti-Mullerian hormone (AMH), which is often used as an indicator of fertility. Therefore, women may still experience regular menstrual cycles and have normal AMH levels following their cancer therapy, which may lead to false reassurance about their fertility status.
Results of this study, published in the journal Human Reproduction, may impact future clinical practice. 'Diminished ovarian reserve leads to infertility and premature menopause. Therefore, fertility preservation counselling should be considered for young female patients prior to olaparib treatment,' suggested Dr Winship.