Here at the ASCO 2023 Conference many important trials have been presented in the breast cancer field and I would be happy to discuss the most important studies presented in the early breast cancer setting, particularly, for the HER2 positive as well as for the luminal-like breast cancer subtypes. I will start with the HER2 positive and with a trial that, to me, is probably one of the best news from this ASCO 2023, which is the PHERGain trial presented by Dr Cortés from Spain. This is a phase II non-comparative trial in patients with HER2 positive breast cancer that wanted to investigate the value of having an early response assessment with a PET-CT scan and for those patients responding after two cycles of anti-HER2 therapy in the early setting the possibility to de-escalate the treatment and potentially not give chemotherapy in this setting. So in this trial patients were randomised to receive a TCHP regimen for six cycles, in the other arm, but this was a non-comparative trial, but in the other arm patients received two cycles of dual anti-HER2 blockade alone, so trastuzumab pertuzumab, with endocrine therapy for those patients with hormone receptor positive breast cancer. We have already the pCR data published in Lancet Oncology, we have already preliminary evidence that those patients responding after two cycles of anti-HER2 therapy may potentially skip chemotherapy. They will still have a significant pCR rate of around 20% for these patients not receiving chemotherapy in the early setting.

What the authors presented at ASCO is an updated survival analysis from this trial in which they have shown that also for the survival endpoint the trial met its survival endpoint in the sense that overall in the patients enrolled in the so-called group B, so those patients receiving anti-HER2 therapy for two cycles and then, based on their response, receiving additional treatment, they had a more than 95% invasive disease free survival rate at three years, which was above the threshold expected in the study. But, to me, the most interesting finding was to look… this is completely exploratory so we cannot make any strong conclusions, but to look at almost 90 patients that did not receive any chemotherapy in the early setting that achieved a pCR and then, following pCR, they did not receive further chemotherapy in the adjuvant setting. So patients that received only anti-HER2 therapy with endocrine therapy if hormone receptor positive. In these cases, small numbers but still very, very good survival outcomes with 100% distant disease free survival at three years and almost 99% invasive disease free survival at three years. So this trial is really giving us a strong rationale to try to de-escalate chemotherapy with optimal anti-HER2 therapy for some selected patients with HER2 positive breast cancer. 

In the HER2 positive field, quickly two other updates, one from the Early Breast Cancer Trials Comparative Group – a very large meta-analysis looking into the potential prognostic and predictive value of tumour infiltrating lymphocytes in the main adjuvant trials of anti-HER2 therapies with trastuzumab. The main conclusion from this very large analysis based on individual patient level data is that these are strongly prognostic in HER2 positive breast cancer and the higher the TIL the better the outcomes. However, in terms of predictive value in this trial there was no association between TIL level and trastuzumab benefit, So apparently there is not a predictive potential there.

Finally, the Short-HER trial, a study from Italy investigating the de-escalation of adjuvant trastuzumab in HER2 positive disease. So this is a study that compared standard anthracycline taxane-based chemotherapy and one year of trastuzumab to anthracycline taxane-based chemotherapy but only three months of adjuvant trastuzumab. The study already is ended and published in Annals of Oncology a few years ago in its primary endpoint. At ASCO the authors presented the ten-year follow-up data. Overall, the study did not meet its pre-specified boundary for the non-inferiority boundary so it cannot be considered a positive trial. However, the interesting finding also at long-term follow-up is that the lower the risk of recurrence apparently the less benefit is observed with longer trastuzumab duration. So if we look at the subgroup analysis of patients with node negative disease, apparently there is no difference between those that received one year of trastuzumab as compared to those that received a short duration of trastuzumab. 

So, overall the trial did not meet its primary endpoint, as per the inferiority definition, so one year of trastuzumab-based treatment is still standard of care in HER2 positive breast cancer. However, this trial is providing more evidence on the possibility to de-escalate trastuzumab when it’s not available, so to have a short course, especially in lower risk patients or in those that develop cardiotoxicity. There probably we should discuss if it’s really relevant to continue the anti-HER2 therapy with optimal cardiac support. 

On the other side, briefly, on hormone receptor positive, HER2 negative disease there are three studies I wanted to mention and two are related to the use of adjuvant CDK4/6 inhibitors. I will start with the NATALEE trial that was probably the most awaited study presented at the ASCO 2023 Conference in the early breast cancer setting. This is a study that included more than 5,000 patients with hormone receptor positive HER2 negative disease that were randomised to receive endocrine therapy with an aromatase inhibitor with or without the addition of a CDK4/6 inhibitor, ribociclib. In this trial, a different ribociclib adjuvant trial, patients with stage 2 disease and some patients with node negative disease could be included in the trial if they had other additional risk factors, including, for example, a high genomic risk. This patient population was not included in the monarchE trial. 

So the authors presented very preliminary results because the median follow-up is still shorter than 30 months. Only 20% of the total number of patients completed adjuvant ribociclib treatment, that was three years in this study, so very preliminary findings. The trial met its primary endpoint showing a significant improvement in invasive disease free survival at three years with around 3% absolute difference and a hazard ratio of 0.75. Again, a positive trial, definitely, but still very early to make a strong suggestion here. We definitely need to wait a bit longer, so to have longer follow-up, and to see what happens when all the patients have completed treatment and a more long-term follow-up. 

In this trial the dose of ribociclib that was used was lower as compared to what we use in the advanced setting – the advanced setting it’s 600mg, early setting 400mg. The idea for a lower dose was to reduce the burden of the side effects. Indeed, for most of the side effects, particularly neutropenia, we saw lower rates of grade 1/2 but also grade 3 or 4 neutropenic events. What apparently did not seem to be lower as compared to what we see in the advanced setting is the hepatobiliary toxicity. Still with a 400mg dose we had around 9% of patients with grade 3 or more hepatobiliary toxicity which is something we will need to manage in the first months of treatment if this treatment will become available in the early setting. 

In the same setting we had additional data from the monarchE trial, very similar design. The CDK4/6 inhibitor was abemaciclib in this trial for two years and not three years as NATALEE. But in the monarchE the patient population included was a bit higher risk of disease recurrence. We already know very well the results on this trial; the updated results at more than 40 months median follow-up were published in Lancet Oncology earlier this year showing a significant improved benefit with the addition of abemaciclib in the long term in this high-risk patient population. Here at ASCO the authors presented more data for the elderly patient population, or not really elderly because the age cut-off used was 65 years of age, so let’s say in patients older than 65 years of age. The results are reassuring in terms of efficacy, the same findings also in terms of toxicity and patient-reported outcomes, no major differences if we compare the more than 65 years of age with the less than 65 years of age patient population. What is different in older patients we may expect to have more dose reduction. But, very importantly, the authors presented also the efficacy data based on the dose reduction. What has been observed is that even when reducing the dose still the benefit was there. So apparently reducing the dose due to side effects does not impair treatment efficacy. We need probably more data on that; these are the first evidence that reducing the dose in the early setting does not seem to impact in a negative way the outcomes for the patients.

A final abstract I wanted to discuss is the EBCTCG meta-analysis investigating the role of ovarian function suppression in the early breast cancer setting. A very large analysis including many trials, also trials done many years ago when the treatment of chemotherapy, endocrine therapy, we had different treatments as compared to our current standard of care. But the reason why I wanted to highlight it is that this meta-analysis really provides further evidence of the great value, of the important value, of adding ovarian function suppression for premenopausal women with early breast cancer at risk of disease recurrence. In this case overall we have almost 10% absolute benefit at 15 years with the inclusion of ovarian ablation or ovarian function suppression in this patient population. So for premenopausal women, with the only exception of patients with very low risk of disease recurrence where Tamoxifen alone is still standard of care, these data will reinforce that for all the other patients ovarian function suppression should be considered as a key component of the adjuvant endocrine therapy backbone. 

So ASCO 2023 has been a great conference for the early breast cancer setting and thank you very much for listening.