I think we are living in a very exciting time, in a molecular revolution where we have an increased understanding of the molecular make-up of colorectal cancer. Because with this increased understanding we now know that certain patients with very specific mutations benefit more from very specific treatment. It’s absolutely critical that at the time of diagnosis of metastatic disease patients undergo genetic testing. Preferably we like to have a big panel testing like next generation sequencing panel which tests between 500-700 different genes, but the minimum to make good treatment decision is RAS, BRAF, microsatellite instability and HER2 because they have implications on the decision of what first line chemotherapy is the most effective for an individual patient.
The challenges are often payment – depending on where you live in the world this testing may be covered or not. So the financial resources can be a limitation factor to do this testing. However, without testing you may not get or recommend the most effective treatment for an individual patient. Colon cancer is like no other, the decision of your first line treatment is the most important decision you make, you cannot make up the efficacy in later lines of treatment because under treatment pressure molecular make-up changes depending on your first line choice. So you need to have the best benefit and potentially convert a tumour into a curative resection the molecular make-up to make the decision on the most effective treatment.
How can we address the challenges?
It’s not easy to address the challenges, it has to do with health societies, what insurance carries their cover. But in the US for the first time FDA and Medicare now pay for NGS testing, realising that molecular testing in the long-run will be cost effective, avoiding drugs which are not beneficial, expensive drugs, and avoiding significant toxicities. So when everyone is tested the prices go down and the efficacy of your treatment choices goes up.
Do we have any known predictive markers?
The known, most common, predictive marker is KRAS or NRAS mutations - we know EGF receptor inhibitors do not work. When we have a BRAF mutant we know EGF receptor inhibitors also have no activity. But for BRAF we now have treatment options – the NCCN guidelines now recommend a BRAF combination like the BEACON trial triplet or vemurafenib and irinotecan and cetuximab. MSI high we have immunotherapy approved in second line and even to first line, depending on if the patient is a candidate for chemotherapy. But there are now increasing new molecular markers – fusions such as NTRK which is present only in 1% but if you have it larotrectinib can be extremely effective and would be used in second line. So we are now embracing even very rare mutations with incredible impact of treatment opportunities like ROS1, ALK1 or the NTRK fusions.
How does the future look for this field?
My dream is that everybody will be screened, not only with next generation sequencing but whole genome, that we know everything about the tumour and everything about the patient. Because that will allow us to really tailor and personalise treatment the best we can. The limit will be the availability of drugs which are specific for certain genetic signatures but we are getting closely there so I am very optimistic that the refined technology will help us further to really select more effective and less toxic treatments.
