You have all already mentioned immunotherapy for breast cancer. You are a major expert in cancer immunotherapy, focusing on breast cancer but also other solid tumors. Some breast cancer types are more susceptible to immunotherapy compared with other types. How do you use immunotherapy for breast cancer patients? Can you give an overview of how to approach this situation?

What you need to do, of course, is to select cancer patients according to the immunological milieu. So let's say they should be really enriched in tumor-infiltrating lymphocytes or PD-L1 expression. Personally, I believe is that the more you are the tumor immune-enriched, the more benefit you will have from immunotherapy. Some data are coming from the neoadjuvant setting of breast cancer treatment, wherein reaching by PD-L1 expression, you also increase the rate of pathological complete response. And potentially, you can also have a better outcome.

Does immunotherapy work better in the neoadjuvant setting in breast cancer in the adjuvant setting of breast cancer?

Potentially, you can cure some patients in the neoadjuvant therapy setting. So my advice is, let's use immunotherapy in the early breast cancer setting. We also have data on overall survival in the metastatic setting. But ideally, our aim should be to cure all patients with the early diagnosis of breast cancer.

You already mentioned some on that topic. But immunotherapy can help patients with early triple-negative breast cancer. However, immunotherapy is often part of the neoadjuvant chemotherapy regimens for the triple-negative breast cancer for patients who are just diagnosed. What is known about the efficacy and particular challenges for immunotherapy in the new diagnosis of triple-negative breast cancer?

The most advances, I believe are coming from the neoadjuvant treatment setting, combining the chemotherapy plus immune checkpoint inhibitors. But I am sure that in the future, for those patients with residual disease after neoadjuvant chemotherapy, there will be really the opportunity also to use antibody-drug conjugates. There is a very interesting clinical study ongoing actually for patients with residual breast cancer disease comparing adjuvant capecitabine to adjuvant sacituzumab govitecan. In my personal opinion, in the future, we will have a combination of antibody-drug conjugates plus immune checkpoint inhibitors for early triple-negative breast cancer therapy.

Will they be used together? Yes, they will be used together. Yes. So immunotherapy is effective in many cancer types. But sometimes, immunotherapy is not as effective as expected in those tumors which are supposed to be susceptible to immunotherapy. What could explain such resistance to immunotherapy? What are the strategies to overcome resistance to immunotherapy in those tumors that are considered, perhaps overall to be immunotherapy-sensitive?

So you have cold tumors, where immunotherapy doesn't work, and hot tumors that are infiltrated by lymphocytes. In hot tumors, immunotherapy is very effective. How to overcome these mechanisms of resistance in cold tumors? Maybe what we can do is inject cold tumors with immunomodulators that may attract tumor-infiltrating lymphocytes. We are doing some studies now with toll-like receptor four (TLR4) or toll-like receptor seven (TLR7). You can demonstrate that by injecting the tumor you may increase the number of tumor-infiltrating lymphocytes. So the strategy is to infiltrate the tumor with toll-like receptor agonist and then boost the immune system with immune checkpoint inhibitors.

So in this way, you make the tumor more susceptible to the immune checkpoint inhibitors.