My primary interest is skin cancer and skin cancer is a very broad summary of various diseases including malignant melanoma, Merkel cell carcinoma, lymphomas of the skin and non-melanoma skin cancers, EPC types of cancers deriving from skin which are actually the most frequent cancer which humans develop because of sun and immune suppression. So my prime interest is malignant melanoma. Melanoma is the skin cancer which is responsible for 80% of deaths related to skin cancer so it’s a deadly disease which is diagnosed early, actually the median age is around 50 but with a very wide span between the 20s to 80 years of age. If it’s detected early it’s clear you can cut it out, you can cure it that way. In Western European countries this is the common standard so early detected melanoma has a cure rate way above 90%, 95%.

However, as soon as we have spread of the disease prognosis drops. So the first usual spread is into the lymph nodes, so regional disease. You are actually looking for that by a procedure which is called sentinel node biopsy which is a minimally invasive surgical procedure capturing this first draining lymph node. Then if this is not enough then also melanoma cells might spread into visceral organs, distant organs including lung, liver, brain and obviously this is a deadly threat for the patients. For decades as soon as a patient had been diagnosed with advanced metastatic melanoma this was more or less a death penalty because patients had to die within six to nine months, that was the median overall survival time for those patients. This has changed over the last five years and what I have been summarising in my talk here in Portugal was actually the evolving landscape of treatment options for patients with advanced melanoma.

How is the Eurocan meeting helpful to you and your research?

This meeting is actually important to educate the next generation of cancer researchers who have different angles on cancer and the disease, starting from epidemiology, combining it with the newest techniques in epidemiology, statistics, profiling omics technologies but also keeping a translational clinical focus on what is the disease, what are the problems, what is the most urgent medical need. If you are a physician, an MD, looking at your problem you definitely need help using all these new sophisticated techniques and possibilities, platform technologies. On the other hand, if you’re a trained PhD you have possibly all this knowledge in the subset of these new developments but the question is how to apply and bring together in order to improve diagnosis, prognosis and, at the end, outcome of patients suffering from cancer.

What steps have been taken in the creation of this umbrella?

Malignant melanoma is a perfect example that after thirty years of experimental treatment using also chemotherapy we had not made any progress so patients were still dying within a year. Chemotherapy had no effect. What was done at that point is to establish study groups who work together, which is already a key thing, working together, and now we have learned that, for example, chemotherapy is in most of the cases not necessary anymore because we have much more efficacious treatment modalities based on basic discoveries. One example is targeted therapy for malignant melanoma based on a breakthrough paper published in 2002 in Nature discovering BRAF mutations in numerous tumours including melanoma which had the highest frequency. Selective BRAF inhibitors were developed and they have been approved within ten years after description of this basic discovery in Nature and have shown that survival is improved, dramatically improved. And now we have even more drugs targeting this MAP kinase pathway, for example a combination of BRAF inhibitors and MEK inhibitors leading to an even further increase in overall survival of these patients. I mentioned in the beginning the median overall survival time was in the range between six to nine months and now we have median overall survival times well above two years and there are even subgroups who have median overall survival times more than four years. So we’re approaching a significant subset of patients having a survival chance of roughly 50% at five years with all the new drugs available.

So that’s one perfect example. The second perfect example in melanoma is a better understanding of the immune system. We have been busy analysing the immune system and actually also studying the interaction between tumour cells and the immune system quite intensively in the field of melanoma. Based on this research the first tumour associated antigens were discovered and described, SMH [?] antigens recognised by T-cells. Based on that vaccination strategies, various vaccination strategies were developed and all not successful because we didn’t understand how the immune system is really working. We had only a very small subset of patients who had shown a benefit in regard to this experimental treatment modality.

Now we know that the checkpoint control between immune cells are of critical importance for controlling tumour, affecting the tumour, but also keeping autoimmunity in check. Using now checkpoint inhibitors, checkpoint activators for the first time has shown that there is a really dramatic impact on melanoma patients, even in an advanced stage. Three antibodies targeting checkpoint molecules, ipilimumab targeting CTLA4 and the PD-1 blocking antibodies pembrolizumab and nivolumab, have already been approved within the last three years because they have shown dramatic increase in overall survival and possibly we have for ipilimumab already long-term survival data. We are seeing that roughly 20% of these patients seem to be having a long-term benefit surviving five, seven, ten years without relapse of the disease. This is very fascinating.

What’s the take-home message?

The take-home message is pretty clear. We have made some progress for our patients, looking from the clinical perspective. On the other hand, we have generated so many more questions. Obviously we are not curing all patients, whether we are curing patients is still open because the development is still young; not all patients are benefiting. So we have questions on targeted therapy as well as on immune oncology approaches on primary resistance – why don’t patients respond in the first place? Then the question of acquired resistance, so patients have a certain response, have a certain tumour control over a year, two years or even longer, and then the tumour is relapsing, what are the mechanisms? We are seeing that there is an interaction of the immune system and the tumour in the microenvironment and the critical part of the microenvironment. So there is inflammation, the role of inflammation, can we use that also for better understanding patients who are benefitting, who have a better prognosis. So we need to understand if a patient sits in front of us what is the best treatment modality now. How can we select the best treatment option right from the start and not do trial and error and see if it works and then move to the next one. We need diagnostic research in terms of monitoring minimal residual disease in order to follow the disease, also to see as early as possible relapsing disease and to study this minimal residual disease more careful. So we need all these technologies and we have so many questions to ask, to be implemented in our daily algorithms how we would treat and follow cancer patients.