Yesterday I had my presentation, my oral presentation, about applied precision cancer medicine in biliary tract cancer in a metastatic setting. All in all we included in our platform for precision cancer medicine 30 patients, 16 men and 14 women. We identified in these 30 patients who were all in a metastatic setting 35 molecular alterations. The most frequent alterations were seen in KRAS, TP53, IDH2 and IDH1; we had also two cases of BRAF mutation, one of them had a BRAF V600E alteration and was included in the ROAR phase II trial, and two months ago Wainberg et al had a sub-analysis of the ROAR trial which showed disease control over 80% for patients who were treated with dabrafenib and trametinib who had a BRAF V600E mutation.
In our platform we could suggest in 60% of all cases, so this means 18 persons, we could suggest or recommend a targeted therapy based on their specific molecular profile. The molecular profile also included the immunohistochemistry which revealed an over-expression of EGFR and phosphorylated mTOR in the majority of the patients, so over 25 of the patients had EGFR or phosphorylated mTOR. Four patients had HER2 expression and, notably, six patients had over-expression of PD-L1, so that’s remarkable because these are druggable alterations which can be targeted, for example by trastuzumab, pertuzumab and PD-L1 can be targeted by immunotherapy, for example by pembrolizumab.
What are the results so far?
Our analysis was a primary feasibility analysis. We wanted to show that nowadays it’s quite possible, technically feasible, to perform precision cancer medicine analyses for patients for whom we do not have a standard therapy regimen any more. We wanted to show that and the concrete numbers are that from the time of analysis, from the time of biopsy to the mapping of the molecular profile we needed 18 days. And from time of biopsy to the initiation of the recommended targeted therapy we needed a little bit more than three weeks, so exactly 23 days. So this means that nowadays it’s implementable and applicable into clinical routine that’s possible.
In seven patients we could apply the targeted therapy, so eventually seven patients received it. Unfortunately three patients died prior to restaging, so four remained and out of these four two had disease control and the two others experienced progressive disease. What I want to stress and point out that these analyses were not an interventional or prospective trial, it was a feasibility analysis of our platform of precision cancer medicine. I mentioned the turnaround time from biopsy to analysis and to the initiation of targeted therapy to give you an overview about the possibility nowadays. But this also shows a disadvantage of biopsy because it takes a lot of time so that it can perform the biopsy and perform the molecular profiling and to eventually recommend or initiate the targeted therapy because we always have to discuss the results in a multidisciplinary tumour board and we see or we check whether we can offer a targeted therapy or not. It would be better in the future to maybe avoid biopsies, to reduce the turnaround time from three weeks nowadays to maybe only one week to initiate the targeted therapy at an earlier time point because, particularly in this quite rare entity, the prognosis is quite dismal and poor. Despite therapeutic efforts the prognosis of biliary tract cancer in the metastatic setting is below one year. So when weeks pass and you cannot offer a targeted therapy the health condition of these patients aggravates and you cannot initiate the targeted therapy due to the deteriorated health condition, that’s the problem.
So in the future it would be great if we can have a follow-up molecular liquid biopsy, on the one hand to monitor the therapy response by, for example, assessing the tumour mutational burden and, on the other hand, we could reduce the turnaround time to see whether the therapies have an effect or not.
What role do available resources and costs play in providing precision cancer medicine?
Regarding the costs and expenses in precision cancer medicine, I can tell you that at our centre the expenses are covered but at general hospital the patients are in a setting for whom we cannot offer a standard therapy regimen anymore. For those patients the general hospital is willing and is ready to cover the expenses for the mapping of the molecular profile which includes the gene sequencing, which includes the immunohistochemistry, FISH and the RNA fusion panel for detection of gene fusions, which is quite important for metastatic biliary cancer because FGFR2 gene fusions are typical of intrahepatic cholangiocarcinomas.
Is there anything you would like to add?
I think in the future we will have the possibility of novel therapies which are molecularly driven and tissue agnostic therapy approaches. We’ll target in a specific manner FGFR2 mutations, BRAF V600E alterations and also IDH1 and IDH2. There are upcoming drugs and we will apply them in the foreseeable future to help our patients.
What I also think will play a significant role are cell adhesion molecules which are also the subject of intense research focus. We will have in the future drugs which will target cell adhesion molecules and will maybe help to improve the outcome in these patients.