In HER2-positive early breast cancer, with the new introduction of anti HER2-based therapies, we have been able to obtain dramatic responses and great clinical outcomes. This opened the opportunity to deescalate chemotherapy, to deescalate treatments for patients with early breast cancer. We have been doing many, many trials to try to deescalate this.

PHERGain, basically, was one of the first trials based on a trial design and strategy design to deescalate treatment. In brief, patients received all of them, the combination of trastuzumab and pertuzumab, and after two cycles we did a PET scan to see if these patients achieved a response or not. Depending on the response, patients continued or not with trastuzumab and pertuzumab only without chemotherapy or we added chemotherapy to our patients. After surgery, patients who did achieve a pathological complete remission did continue without chemotherapy.

This means that about, more or less, one-third of the patient population who achieved at the end a pathological complete remission never received chemotherapy. So this is a very elegant way to deescalate chemotherapy, to deescalate the treatment, and many of these patients will be able to be cured without the need of a chemotherapy. This is a concept of the PHERGain study at the end.

The results are very, very interesting. So for all patients, patients who received trastuzumab and pertuzumab independently, if they received chemotherapy or if they did not receive chemotherapy, primary endpoint was invasive disease-free survival at 3 years. And we achieved this primary endpoint. The 3-year IDFS was 95.4%, so achieving the pre-specified PFS events. And what was very, very important for those patients who did never receive chemotherapy, those patients who achieved pathological complete remission after trastuzumab and pertuzumab, showed the great news that we did not have any metastatic events for these patients. The invasive disease-free survival was 98.8%. Only 1 patient did have original recurrence, showing that this strategy was very safe.

And what about the toxicity? As we might expect, patients who started in this strategy have much lower adverse events compared with patients who usually received chemotherapy, trastuzumab, and pertuzumab. Just for us to remember, the related treatment emergent adverse events was in the range of 65% grade 3 and grade 4. And with this strategy it was 41. For those patients who never received chemotherapy, it was only 13%. So clearly this might highlight the importance of the escalation treatment in terms of quality of life.

So one of the questions that we asked ourselves is about the use of PET scan. It is true that this is not a very practical assessment, and remember that in the PHERGain study, we conducted the PET scan at baseline and after two cycles after 6 weeks. So what happened in those centers is that this is not available or it is unlikely to be done. So, clearly this study was designed with a PET scan, but I think that if we do other assessments, maybe a breast ultrasound, maybe a breast MRI, that is something that also could be useful and could be good enough to apply the PHERGain strategy.

What are the next steps? I think that, in my opinion, at least, for patients in the clinical practice that maybe do have T2 N0 tumors, we could start applying this strategy in the clinical practice. It is true that this PHERGain study did use the PET scan to observe the response, but I think, and that's my absolutely personal opinion, in the clinical practice, maybe if we observed a response by breast MRI or another response by ultrasound, I think that is also something that we can apply for the clinical practice.

So, summary. I think that deescalation is key for our patients. This is something that can be done and this is one of the strategies that we might apply to do something important in the clinical practice.