Biomarker analysis of the NeoALTTO trial provides oncofertility insight for younger breast cancer patients

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Published: 6 Jun 2022
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Dr Matteo Lambertini - San Martino Hospital, Genoa, Italy

Dr Lambertini discusses his biomarker analysis of the NeoALTTO trial, loooking at the impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer.

This study explored for the first time the short-term impact of anti-HER2 therapy alone and then combined with weekly paclitaxel on ovarian reserve.

It found that anti-HER2 therapies alone have limited gonadotoxicity and addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

The analysis provides novel important information to share with premenopausal breast cancer patients in order to improve their oncofertility counselling.

At ASCO 2022 we have presented an abstract on the gonotoxicity of anti-HER2 therapy plus chemotherapy which is a very relevant issue for many premenopausal patients receiving this with HER2 positive disease. We have clear data how to counsel in terms of oncofertility counselling patients receiving standard chemotherapy, however, it’s not really clear how to counsel patients receiving targeted agents where we have very limited information on the ovarian toxicity of these targeted agents.

So at this ASCO we presented a biomarker analysis of the NeoALTRO trial. I’ll just remind the design of this study – this was a neoadjuvant trial in which patients received a couple of cycles of anti-HER2 therapy alone before adding weekly paclitaxel on the top of anti-HER2 therapy before surgery then after surgery patients received anthracycline based chemotherapy. The three arms of the trial were three different anti-HER2 agents: trastuzumab alone, lapatinib alone or the combination of the two anti-HER2 agents, trastuzumab and lapatinib. 

So we collected blood samples of premenopausal women; around 130 patients had samples available and were premenopausal at the time of diagnosis. We collected a sample at diagnosis, after two weeks of treatment, which is the so-called biological window, so patients received anti-HER2 therapy alone without chemotherapy, then the samples at the end of weekly paclitaxel plus anti-HER2 therapy, so the time of surgery. We assessed the so-called anti-müllerian hormone which is the best biomarker for assessing ovarian reserve. 

We saw the dynamics of this biomarker across the three different time points and what we have seen is that there is a decline of these hormones, meaning a potential gonotoxicity, also with the use of anti-HER2 therapy alone. This is something that it’s the first time that we have such type of information. Then if we add weekly paclitaxel on the top of anti-HER2 therapy we have a major decline of these hormones. 

This is important because the only data we have with weekly paclitaxel and trastuzumab, which is one of our standards of care in the clinic, for low risk patients, we have amenorrhea data in this setting. So we know that this regimen is associated with a low risk of chemotherapy-induced amenorrhea. However, these data provide more insights on the gonotoxicity of these agents and the fact that there is such a major AMH decline with the use of this single agent chemotherapy plus anti-HER2 therapy in this case, means that these agents are also gonotoxic. So we need to counsel also patients receiving this regimen in terms of potential risk of infertility as a consequence of the use of this treatment.

In terms of anti-HER2 therapy alone, of course it’s a small study, it’s a small cohort, but we have some insights that potentially also anti-HER2 therapy can impact on the ovarian reserve. Unfortunately we don’t have samples in the long term so we don’t know what is the long-term impact of this regimen and then patients in any case receive anthracycline-based treatment later on. So this is something that we don’t know. But I think that this study can provide important information in the clinic to share with patients that are young at the time of diagnosis, that potentially are interested to have a pregnancy following treatment completion and that should be counselled about the possible risk of gonotoxicity also with this regimen and so the potential need to access fertility preservation options if they are interested in increasing their chances of a future pregnancy.