Cancer care

Checkpoint inhibitors may impair fertility


Immune checkpoint inhibitors have the potential to impair both immediate and future fertility in women undergoing treatment for cancer, Australian research suggests.

Results from pre-clinical animal models by scientists at  the Biomedicine Discovery Institute at Monash University and the Peter MacCallum Cancer Centre, Melbourne, have shown that CTLA-4 and PD-1 blockers can reduce the number and quality of oocytes, interfere with ovulation, and disrupt  the fertility cycle.

Immune checkpoint inhibition increased immune cell infiltration and TNF-α expression within the ovary, diminished the ovarian follicular reserve and impaired the ability of oocytes to mature and ovulate, the reported in a paper in Nature Cancer (link).

The study investigators say that if confirmed, the findings could add checkpoint inhibitors to the list for referrals for fertility preservation interventions advised for women receiving chemotherapy and radiotherapy, which are already linked to infertility and premature menopause.

Co-lead investigator Lauren Alesi, a PhD candidate in the Monash Biomedicine Discovery Institute Ovarian Biology Laboratory, said human studies must now be prioritised.

“Initially these [immunotherapy] treatments were thought to be less damaging (than chemo and radiotherapy) in the context of off-target effects to the body in general. However, it is now clear that inflammatory side effects in other organ systems are quite common with these drugs,” she said.

“Our study highlights that caution should be exercised by clinicians and their patients, for whom fertility may be a concern. Studies in women receiving these drugs must now be prioritised.”

Other immunotherapy classes also need to be assessed, she added.

“Our results may have implications for other immunotherapies, since our results have revealed a close relationship between immune cells, the communication molecules (cytokines) they release, and regulating many aspects of fertility,” she said.

The authors said studies in female patients are now needed to further explore the findings. In the meantime, fertility preservation through egg or embryo freezing should be considered for women using immunotherapies, said Professor Sherene Loi, medical oncologist at the Peter Mac and a senior author on the study.

Further research into how these drugs impact the ovarian function and fertility of women receiving these drugs must be prioritised and should be included in future clinical trials involving women of reproductive age, she said.

“Our study further highlights that fertility discussions are critical for all age appropriate women who are recommended to receive chemotherapy as well as immunotherapy,” Professor Loi said.

“Appropriate interventions that can preserve fertility and ovarian function can be implemented to facilitate pregnancies in the future, post completion of treatment. These interventions need to be implemented in a timely manner, so as not to delay anti-cancer treatment.”

“Immunotherapy is now becoming a standard of care for many women with curable early stage breast cancer, due to impressive results in reducing breast cancer recurrences, but further research into the long-term effects of immunotherapy is needed,” she added.

Meanwhile, a separate study has provided reassuring evidence about the safety of fertility preservation at time of breast cancer diagnosis.

A population-based Swedish nationwide cohort study that included 1275 women with breast cancer, showed that provision fertility preservation with or without hormonal stimulation at time of breast cancer diagnosis was not statistically significantly associated with any increased risk of disease-specific mortality or relapse.

“Results of this study provide much needed additional evidence on the safety of fertility preservation procedures in women with breast cancer and may influence current health care practice to the benefit of young women with breast cancer who wish to preserve their fertility,” the authors wrote in JAMA Oncology (link).

“Women diagnosed with breast cancer during their reproductive years should be referred, when interested, for fertility counselling and provided with the available information on safety of the procedures that are offered,” they added.

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