Molecular medicine in lung cancer

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Published: 4 Jul 2017
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Dr Reinhard Büttner - University Hospital of Cologne, Cologne, Germany

Dr Büttner speaks with ecancer at WIN 2017 about determining vulnerabilities to targeted or immune therapeutics in lung cancer through Network Genomic Medicine.

He discusses the landmark successes of PD-1 checkpoint therapy for lung cancer, and futher mutational markers of resistance and vulnerability.

Dr Büttner considers the comparable incidence of lung cancers resulting from germ-line mutation and those arising from environmental factors, with emphasis on early detection and diagnosis to alleviate disease burden before advanced disease

The data that I will be presenting is of a large initiative in Germany called Network Genomic Medicine. The basic idea is to profile lung cancer patients for genomically actionable mutations or for vulnerabilities for immune oncology therapies. We think lung cancer is a specific challenge in oncology because it’s the most deadliest cancer disease worldwide with the highest mortality. Usually patients are diagnosed in advanced stage disease and it’s clear we need better and more effective therapies. In the last years we have seen the introduction of targeted therapies which specifically address genomic mutations or immune oncology therapies which specifically address immunological vulnerabilities. Thereby the majority of lung cancer patients today can be treated in first line therapies by more specific, more targeted therapies than chemotherapy alone.

Has PD-L1 made an impact on lung cancer treatment?

Actually you’re totally correct, PD-L1 has made a huge impact on lung cancer treatment and there is now a subgroup of patients that can be treated by a PD-1 antibody specifically as first line therapies rather than by chemotherapies. So we have initiated also a German-wide initiative to harmonise testing and reporting for PD-L1 status but also we have implemented testing for the mutational burden as we know that that is also a very good prognostic indicator for patients that are susceptible. So it’s a convergence in molecular diagnostics: on the one side you have a read-out for specific mutations, translocations, amplifications, gene alterations, but on the other hand you get an oversight of the total mutational burden of a patient and its drug vulnerability to immune oncology.

Are there any thoughts about the development of resistance?

That is an absolutely important aspect because once you have an effective therapy, let’s say by targeting EGFR, ALK, BRAF, MET, it is very important to monitor these patients for acquired resistance because in most of these cases we have very, very good second or even third line therapies that will address the resistance mechanism. All the data from our network show that when these patients are carefully monitored, if they are applicable for a second line therapy with another TKI or another antibody, they have a huge increase in overall survival and quality of life also.

Is there any research to try and find high risk genes for lung cancer?

In lung cancer we have this huge group of patients that are exposed to environmental toxic agents like smoking for example. So the number of patients with germline mutations is much less although they exist. There is [?? 3:44] for example, patients that get also lung cancers; there are germline carriers of EGFR mutations that exist but considering the total amount of patients that’s a very minor fraction. So the huge challenge is the tremendous risk for smokers, prevent smoking actually.

How is the allocation of resources in terms of prevention versus treatment?

There are three areas, I would say, where we need progress for lung cancer patients at the moment. One is prevent smoking, that certainly would be a very effective means. However, if the entire world would stop smoking, quit smoking now, it would still mean that lung cancer would be the seventh deadliest cancer worldwide. So the amount of non-smokers that will develop lung cancer is considerable and large. The other is early diagnostics, to increase the number of patients that can be treated by surgical resection and thereby we have now seen new technologies like detection of mutations in the peripheral blood, trying to select the risk patients for surveillance strategy, low dose CT and so forth, and there is a big consortium in Germany also that surveys super-high risk patients, patients that have asbestosis and are concurrent smokers. The third area is the advanced stage patients where we try to find and deliver better and more effective therapies. So all these three areas have to cooperate to address the huge problem of lung cancer.

Any final thoughts?

One aspect, important aspect, I will also show in my presentation is that we need to enable the pathology labs to go further, to go beyond a mere histological diagnosis, because the immune landscape and the genomic landscape is an important aspect that needs to be integrated into daily diagnostics.