I will give a presentation of neoadjuvant treatment of triple negative breast cancer; neoadjuvant treatment is the treatment given before surgery. Neoadjuvant treatment is a very interesting approach for many reasons – first of all because it allows to reduce the size of the primary tumour and this can increase the percent of conservative surgery in those cases where radical mastectomy would be necessary because of large primaries. Another very interesting point of primary chemotherapy is that by using drugs with the tumour still on site you can have a direct measure of efficacy of your treatment in individual patients while if you use drugs after removal of the tumour then you only have a statistical estimate of the benefit for the patients. Of course, also by giving treatment before surgery you can also monitor biologically what is happening to your tumour in terms of proliferation, apoptosis, expression of several genes etc.

The neoadjuvant setting has become a standard of care now for the more aggressive breast cancer subtypes such as HER2 positive disease and the triple negative disease. In particular my talk will be on triple negative tumours. It’s now clear that those patients who get the so-called pathological complete remission after neoadjuvant chemotherapy, which means at time of surgery no more viable infiltrating tumour cells are present, neither in the breast nor in the axillary lymph nodes, these patients have a very good prognosis, a significantly better prognosis, than those patients who do not achieve a pathological complete response.

So my talk will focus first of all on the fact that even though we still call these tumours triple negative because they do not express oestrogen receptor, they do not express progesterone receptors, they do not overexpress HER2, these tumours are quite heterogeneous. There are different subtypes within the triple negative subgroup of breast cancers and these different subtypes have different sensitivity to chemotherapy. There are now subtypes which are called basal-like subtypes according to the gene expression profiling which express a high sensitivity to chemotherapy. On the other side there is a subtype which is called the androgen-like subtype which expresses the androgen receptor pathway which is relatively less chemosensitive. So it’s important to identify these different tumours because you can predict the likelihood of getting a pathological complete response.

There is also another subtype which is becoming more and more of interest which are the BRCA mutated tumours. A significant proportion of BRCA mutated tumours, tumours which are the consequence of a germline mutation in BRCA1 or BRCA2 genes, most of these tumours are triple negative as a phenotype. Apart from the chemosensitivity typical with tumour subtypes, these tumours might also benefit from more specific treatments, either in terms of chemotherapy – they have a peculiar sensitivity to platinum sources – or to another category of drugs, the PARP inhibitors. PARP inhibitors are drugs which inhibit a group of enzymes called PARP which is necessary for BRCA mutated cells to repair DNA damage. So by inhibiting these enzymes you can synthetically kill BRCA deficient cells while sparing normal BRCA expressing cells.

Another interesting avenue of research in the field of triple negative breast cancer also in the neoadjuvant setting is the use of immune checkpoint inhibitors. The triple negative breast cancer tumours are highly unstable genetically tumours with a high burden of mutations and with the biological features that make these tumours, theoretically at least, particularly attractive from the viewpoint of immune recognition and also activity of the immune checkpoint inhibitors. In fact, we do have some data coming from advanced disease showing that immune checkpoint inhibitors added to chemotherapy may increase the efficacy of treatment in this tumour type.

Also in the neoadjuvant setting there are very interesting initial data indicating that this tumour type might benefit from the addition of immune checkpoint inhibitors. Of course it will be very important, again, to understand who are the patients who really need this kind of approach because we know that immune checkpoint inhibitors are drugs which can induce also severe toxicities so you don’t want to treat with these drugs those patients who might already be cured with chemotherapy alone; it would be very important to identify predictive biomarkers of activity of these drugs. We do have some initial data indicating that there are some of these biomarkers such as the expression of PD-L1, a biomarker protein expressed on stromal infiltrating lymphocytes, and also the percent of tumour infiltrating lymphocytes is another biomarker which might predict the efficacy of this therapeutic approach.

Also the trial design will be important in this setting because you can either add immune checkpoint inhibitors up front to chemotherapy, so treating all the patients with chemo plus immune checkpoint inhibitors. So we will administer this new drug also to those patients who might still get a pathological complete response by chemotherapy alone or, on the contrary, we might treat with immune checkpoint inhibitors only those patients who do not achieve a pathological complete response with chemotherapy. In this way we might select the patient population who deserves more additional therapies. This is, in fact, the trial which we are running in Italy and in the UK, this is an academic trial sponsored by the University of Padua. There are also, apart from 55 Italian investigational sites there are also ten academic centres in the UK which participate in this trial which is for those patients who do not achieve a pathological complete response to chemotherapy and are randomised after surgery to receive either control, which is the standard of care, or one year of immune checkpoint inhibitor.