At the ASCO 2021 conference we presented the final results of the PROMISE-GIM6 phase III trial which is the largest trial that addressed the role of using GnRH agonists during chemotherapy as a strategy to preserve ovarian function and potential fertility in premenopausal early breast cancer patients. This is a very important topic, so preventing the risk of gonad toxicity, preventing the risk of developing premature ovarian insufficiency, is of high importance to many premenopausal women. We have to remember that developing these side effects does not only mean infertility but it is also associated with the potential development of many other side effects, menopause related side effects, that have a major negative effect on the quality of life of young survivors. So it’s important to discuss fertility preservation and cryopreservation options but it’s also highly relevant to discuss how to reduce the risk of premature ovarian insufficiency, of entering menopause at an earlier age than physiologically with all our premenopausal women.
The use of GnRH agonists during chemotherapy is nowadays recommended as a standard strategy for ovarian function preservation in premenopausal women with early breast cancer. It’s not an alternative to cryopreservation options for fertility preservation but it is a standard approach for reducing the risk of premature ovarian insufficiency. However, there are some unmet needs, there are some uncertainties in this area that we try to address with the long-term follow-up data from the PROMISE-GIM6 phase III trial that we presented at ASCO.
In this trial 281 premenopausal women with early breast cancer stage 1-3, hormone receptor positive and hormone receptor negative disease, that were candidates for adjuvant or neoadjuvant chemotherapy were randomised to receive chemotherapy alone or chemotherapy plus concurrent use of triptorelin that was started at least one week before chemotherapy initiation and was prolonged for the whole duration of chemotherapy. The majority of patients, more than 80%, had hormone receptor positive disease, different from other trials like the POEMS study that included only patients with hormone receptor negative disease.
The primary endpoint of the study saw premature ovarian insufficiency one year following chemotherapy completion was already published in JAMA in 2011 showing a significant improvement with the use of GnRH agonists during chemotherapy. Then in JAMA in 2015 we published the ovarian function recovery over time up to five years following diagnosis, showing again positive results favouring the use of GnRH agonists during chemotherapy.
However, there is some concern amongst physicians to give a hormone during chemotherapy, especially in patients with hormone receptor positive disease because we all know the negative effect of giving tamoxifen concurrently with chemotherapy. So the main reason for providing long-term outcomes was to provide some safety information on the use of GnRH agonists during chemotherapy, particularly for patients with hormone receptor positive disease.
At the time of the current analysis at 12.4 years median follow-up, so a very long follow-up also for patients with hormone receptor positive disease, we could not observe any difference in survival outcomes – disease free survival, overall survival – between patients who received chemotherapy alone or chemotherapy plus concurrent use of GnRH agonists. At the subgroup analysis there was no significant interaction observed between treatment effect and hormone receptor status, particularly for the cohort of patients with hormone receptor positive disease which is the largest cohort in the study, more than 80% of the patients had hormone receptor positive disease, in this setting there was no signal of potential worse outcomes for patients that received GnRH agonists – very similar survival outcomes between the two treatment arms.
For the small cohort of patients with hormone receptor negative disease there was a trend towards worse outcomes for patients that received GnRH agonists during chemotherapy, however, this is based only on a small subgroup, it was not statistically significant and this has to be put in place also with the other data available like those from the POEMS study that included only patients with hormone receptor negative disease, more than 200 patients, and observed better outcomes for patients that received GnRH agonists during chemotherapy.
So we believe that these long-term data are particularly important to counsel premenopausal women with early breast cancer wishing to preserve ovarian function during chemotherapy. With this data we can be reassured that the use of this approach is safe also for patients with hormone receptor positive disease. This is also confirmed by the SOFT and TEXT data where we have observed no difference in survival outcomes between patients that started GnRH agonists before chemotherapy as compared to those who started ovarian suppression following chemotherapy completion.
Our data at a follow-up of more than ten years, data from the PROMISE-GIM6 study, are reassuring in this regard and reinforce the current recommendation to offer GnRH agonist use during chemotherapy to all premenopausal women with early breast cancer that wish to reduce their risk of premature ovarian insufficiency. All women, irrespective of hormone receptor status of their tumour.