Drug used to treat women with advanced ovarian cancer can kill immature eggs and reduce fertility, study suggests
- Cancer treatment drug shown to damage store of immature eggs in mice ovaries
- Fertility preservation counselling should be considered before olaparib is taken
- Women who have taken the drug may appear to have regular menstrual cycles
- However they could ‘unknowingly’ have a significantly depleted ovarian reserve
A drug that is used to treat patients with advanced ovarian and breast cancer can adversely affect a woman’s fertility, scientists warn.
Researchers in Australia found that olaparib, which is known by the brand name Lynparza, damaged the store of immature eggs in the ovaries of mice.
Olaparib, which comes in tablet form, can destroy more than a third of the immature eggs that are contained in structures called primordial follicles, they said.
Women are born with a limited number of follicles in their ovaries where eggs are stored, and damage to these follicles or eggs may lead to fertility issues.
Olaparib has not been used on young women long enough to see how it affects their fertility – meaning this study could be an important indication of its effects.
The drug was approved last year by the European Medicines Agency to treat women with advanced breast cancer, without knowing its effect on fertility, scientists say.
Two healthy primordial follicles containing eggs are seen in this normal mouse ovary (control, left). But after olaparib (right) primordial follicle remnants lacking eggs are abundant, suggesting this new breast cancer drug kills eggs
The team recommend fertility preservation counselling for young women before they are treated with the drug.
Those who are treated with the drug may appear to have regular menstrual cycles while ‘unknowingly’ having a significantly depleted ovarian reserve, which can lead to infertility and premature menopause.
Anti-Mullerian Hormone (AMH) levels – which are often used to assess the reserve of follicles in a woman’s ovary – also appeared to be within the normal range after olaparib treatment.
This could lead to a false sense of reassurance among women and their fertility doctors, researchers said.
‘Fertility is very commonly overlooked in many safety tests in pre-clinical studies in animal models and also in human clinical trials for new cancer drugs,’ said study first author Dr Amy Winship at Monash University in Melbourne, Australia.
‘But 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 and normal hormone levels.
‘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.’
If a drug kills growing eggs, ovulation and fertility might be temporarily impacted, but more eggs can be activated from the immature primordial stockpile and ovulation will resume as normal.
However, if primordial eggs are killed, this can lead to complete infertility and early menopause once the stockpile is gone.
As well as killing primordial eggs, olaparib causes DNA damage in some eggs that survive, suggesting they will either soon die, or be too poor quality to give rise to a healthy baby, the team said.
A box of the drug (pictured above) has been hailed as a wonder drug that slashes the risk of death from ovarian cancer
Olaparib works by interfering with the way cancer cells repair themselves in patients who carry a faulty version of the ‘BRCA’ or breast cancer gene.
Immature eggs are contained in structures called primordial follicles.
An ovarian follicle progresses through several distinct phases before it releases its ovum.
During the first five months of development, a finite number of primordial follicles form in the fetal ovary.
These follicles consist of oocytes surrounded by a single layer of squamous follicular cells.
These primordial follicles remain in the process of the first meiotic division.
At puberty, they begin to develop further and become primary follicles.
Source: Yale University
One in six ovarian cancers are caused by faulty genes such as BRCA1 and BRCA2 mutations, which prevent cells repairing damaged DNA.
The drug blocks the action of a family of enzymes called poly(ADP-ribose) polymerase, or PARP, that cancer cells need to repair themselves.
In 2018, olaparib was approved for use in women with BRCA1 and BRCA2 breast cancer that had spread to other parts of the body.
In 2019, the drug was approved in England through the Cancer Drugs Fund for use in women with advanced ovarian, fallopian tube or peritoneal cancer as a way to prolong the effects of initial treatment.
The ‘pioneering’ drug is now available on the NHS for women with ovarian cancer who have inherited mutations to the BRCA genes.
The drug is currently being used by women with early, potentially curable BRCA1/2 breast cancer that has not yet metastasised, as part of a randomised controlled trial called OlympiA.
Many of these will be young women who have yet to start or complete a family.
However, there is no preclinical or clinical information regarding the potential impacts of olaparib on the ovary or on female fertility, the research team said.
The team of scientists gave mice a single dose of chemotherapy or a placebo, followed by a daily dose of either olaparib or a dummy drug for 28 days.
In normal mouse primordial eggs (stained green), scientists never detect DNA damage. But, on top of killing primordial eggs, olaparib causes DNA damage in some eggs that survive, suggesting they will either soon die, or be too poor quality to give rise to a healthy baby
The team then counted the number of primordial follicles – structures that contain immature eggs – in the ovaries.
‘We found that olaparib significantly depleted primordial follicles by 36 per cent compared to ovaries of mice who had not received the drug,’ said Dr Winship.
‘We detected a significant accumulation of primordial follicle remnants in mice given olaparib, while these were rarely detected in the ovaries of the untreated mice, indicating that olaparib is likely to destroy immature eggs.
Losing primordial follicles could ‘ultimately lead to complete infertility and early menopause once the stockpile is gone’, she said.
The researchers recommend using fertility preservation methods such as removing and freezing ovarian tissue, follicles or mature eggs before treatment with olaparib for breast cancer.
Olaparib (pictured) was hailed as having the ability to save thousands of people from ovarian cancer
Fertility preservation can include removing and freezing ovarian tissue, follicles or mature eggs before treatment with chemotherapy, olaparib or other anti-cancer treatments.
‘In future olaparib and similar drugs may be approved for use in young women, with the intention of curing them of the disease, and for these women fertility preservation is an important consideration,’ said study author Professor Kelly-Anne Phillips at the Peter MacCallum Cancer Centre in Melbourne.
‘Therefore, it is very important to understand its effects on ovarian function and we encourage researchers to consider measuring ovarian function and fertility in future clinical trials so that we have data from humans to support or refute the findings of our study in mice.’
The study has been published in the journal Human Reproduction.
OLAPARIB: HISTORY AND EFFECTS
Olaprabic, or Lynparza, was developed by researchers based at the Francis Crick Institute in London and Oxford University.
The scientists discovered a weakness in cancer ‘s defence.
Cancer grows when a fault in normal DNA stops it from repairing itself.
But even tumour cells need DNA repair mechanisms to survive, so they use a ‘back-up’ repair process – a protein called Pol-theta – that healthy cells do not usually need.
This reliance on Pol-theta leaves cancer vulnerable to attack because if scientists can block its one survival route the cancer cannot recover after being blasted with radiation.
Olaprabic, takes as a capsule, blocks the ability of tumour cells to repair themselves.
They hope this will mean a lower dose of radiation can be used, sparing healthy tissue while having a greater effect on the cancer.
It is the first of a group of drugs called PARP inhibitors.
Like any drug, it has side effects, including headaches, nausea, skin reactions and dizziness.
The drug has now been approved for women with ovarian cancer and inherited mutations to the BRCA breast cancer genes, and clinical trials are continuing in other groups of patients.