In General Session 3 of the 2025 San Antonio Breast Cancer Symposium we presented the first multicentre data from the PREFER study, pregnancy and fertility study, which is a large Italian multicentre prospective cohort study looking into optimising oncofertility care in premenopausal women with early breast cancer.

What was the study design?

In this prospective study we aimed to improve awareness and referral to proper fertility and ovarian function preservation care in premenopausal women with early breast cancer aged 45 years or less at the time of diagnosis of early breast cancer. What we suggested is that all the oncologists will discuss with patients the risk of chemotherapy-induced premature ovarian insufficiency and potential subsequent infertility. We will also discuss with the patients the potential interest in preserving ovarian function and/or fertility.

In terms of preserving ovarian function the standard strategy is GnRH agonist during chemotherapy. In terms of fertility preservation, the standard strategies are oocyte or embryo cryopreservation or ovarian tissue cryopreservation. In my country embryo cryopreservation is not allowed by law in patients with cancer so we can only offer oocyte or ovarian tissue cryopreservation as fertility preservation procedures. But all these options, including a GnRH agonist during chemotherapy, are fully covered by the Italian national health system.

So in this study we really wanted to look into the patient needs towards the different strategies, so what’s the actual interest of patients into these different options. So what’s the uptake of the different strategies? Then also we looked specifically into the safety of oocyte cryopreservation which is a strategy that many colleagues are still not offering to patients because we are concerned that giving a two-week stimulation to a newly diagnosed patient with breast cancer may potentially increase the risk of recurrence. So far we have had mostly retrospective studies looking into the safety of controlled ovarian stimulation for oocyte cryopreservation.

What were the results?

In this study we included 746 patients and 533 of them were aged 40 years or less at the time of diagnosis. What we have observed if we look specifically at the young patient population, so 40 years or less at the time of diagnosis, which is the patient population to whom we normally refer to both fertility preservation as well as ovarian function preservation, we observe that the vast majority of patients, almost 90% of them, accepted the use of a GnRH agonist during chemotherapy as a way to preserve ovarian function, so as a way to reduce the risk of early menopause and all the side effects of early menopause. We observed that 25%, so one out of four patients, accepted to receive a cryopreservation procedure for fertility preservation, meaning that we can estimate that if we counsel 100% of the patients, 25%, so one out of four, will be interested in fertility preservation and the vast majority will be interested in ovarian function preservation.

The other important findings from this analysis is that this is the first multicentre analysis looking to the safety of offering ovarian stimulation for oocyte cryopreservation. So we compared the outcomes of the 127 patients that underwent ovarian stimulation for oocyte cryopreservation with the 406 patients who did not receive ovarian cryopreservation before starting chemotherapy.  At the median follow-up of 3.8 years we did not observe any difference in disease free survival, nor in overall survival, between patients who received or did not receive ovarian stimulation for oocyte cryopreservation before starting chemotherapy.

We also looked into the subgroup of patients with hormone receptor positive disease, which was the vast majority, more than 70% of them had ER+ disease. Also in this case there was no signal of a potential detrimental effect of this short-term stimulation before initiating chemotherapy.

So we hope that this data may provide evidence and support the importance of improving oncofertility care in premenopausal patients with breast cancer and will convince all the oncologists that are still concerned in offering this option for a potential increased risk of recurrence. We do now have prospective data from a multicentre study showing that there is no alarming signal of this short-term stimulation before initiating chemotherapy.

What is the clinical significance of these results?

In terms of clinical significance, these results are important on two main aspects. The first is how to improve the oncofertility path and the oncofertility care in premenopausal women with breast cancer, highlighting the importance of the concept of ovarian function preservation on the one side, which is GnRH agonist during chemotherapy, and fertility preservation on the other side, which is the use of cryopreservation procedures. So a GnRH agonist is not a replacement for cryopreservation procedures for fertility preservation because it’s not a fertility preservation strategy but it’s an ovarian function preservation strategy.

So there are patients that are interested in fertility preservation, so they are interested in increasing chances to have a future pregnancy, and we have observed that it is around 20% of newly diagnosed young women with breast cancer.

On the other side there are around 90% of the patients that will be interested to reduce the risk of early menopause which is the use of a GnRH agonist during chemotherapy. These numbers are important from a research allocation perspective in implementing the so-called oncofertility unit, so the connection between oncologists and gynaecologists experienced in fertility preservation.

The second important news is the safety part, and particularly the safety of controlled ovarian stimulation for oocyte cryopreservation because we now have prospective data from a multicentre study that, despite the relatively short follow-up, still there is no signal of potential detrimental effect of this short-term stimulation before initiating chemotherapy. So for those patients that are interested in fertility preservation before chemotherapy there is no reason not to propose the use of controlled ovarian stimulation for oocyte cryopreservation if the patient is interested in this strategy and is going to receive chemotherapy following the cryopreservation procedure.

So overall I believe that this data may help improve the oncofertility counselling of premenopausal women with early breast cancer.

What is next for this study?

I think it’s important to further continue the research into the oncofertility field, particularly looking into all the new treatment options that are now available in the early setting beyond chemotherapy. For most of these new therapies we don’t have any data on the potential risk of gonotoxicity, the potential additional risk of treatment-induced premature ovarian insufficiency and infertility. We have no data on the outcomes of the pregnancy, the feasibility and the outcomes of the pregnancy, following these new treatment options. I’m thinking about, for example, immunotherapy, PARP inhibitors, CDK4/6 inhibitor, ADCs come into the early setting. We need to provide evidence on the risk to the ovaries associated with the use of these new agents, the indication to fertility procedure with these new techniques and also the feasibility and outcomes of post-treatment pregnancies.

At the San Antonio Breast Cancer Symposium we had some preliminary data on the potential risk of immunotherapy on the ovarian function and ovarian reserve of our patients but these are very small analyses so we do need to do more into this space to improve our oncofertility counselling beyond chemotherapy.