50 Genes? 150 Genes? 500 Genes? Multi-Gene Cancer Panels – How Big Can We/Should We Go?

I first started in my current lab back in 2008. At that time, we did not have a separate section for testing solid tumors in our lab. The small amount of testing we did have were for three different types of sarcomas, and we still used a thermal cycler that didn’t have a heated lid, so we had to put mineral oil over the top of the reactions…

Fast forward eleven years and we now have a “bench” dedicated to solid tumor testing with next generation sequencing as a major part of this testing. We have been running our current solid tumor assay, a hotspot panel of fifty genes, for almost five years now and it has served us well. However, many of our oncologists have been starting to ask for more. We have begun the search for a larger panel to fulfill the needs of our oncologists and our patient population. As a smaller lab, we are somewhat limited in resources and are not quite ready to go completely custom, so we are left with kitted options from major vendors. As we research and evaluate these options, though, certain questions come to light. These panels have more than 150 genes and upwards of 500 genes in order to cover the most relevant genes in a number of different cancers. The areas tested in these genes are important for therapy and/or prognosis, but with the sheer number of bases we are looking at, we are bound to find many variants that do not have a known significance.

So, question one, how do the pathologists deal with trying to interpret the large number of variants of unknown significance (VUS’s)? Currently, with our very limited 50 gene panel, we may get one or two VUS’s, so it doesn’t take much time to assign significance and sign out the report. Our myeloid panel, which is a larger panel of 40 genes, some with full gene coverage, though, can sometimes result in reports with eight to ten VUS’s. These reports take a lot of time to research the potential impact each of these variants will have in the disease. I have seen reports from some of these large gene panels that have upwards of 25 or more VUS’s detected in a single specimen. How are these handled in the pathologists’ workflow? Can time be taken to investigate each of these, or are they just placed in a list in the report?

Question two, how do the oncologists feel when they receive a report with few, if any, variants with known significance, and many variants with unknown significance? Does this help at all, or make it more difficult and frustrating? I’d be interested if anyone has feedback in this area. In our internal tumor boards, when we review testing done at other locations, a great deal of time is spent trying to filter through the results to see how they can help point to the best possible treatment for the patient. If the variants do not point to therapy or clinical trials, those variants are not currently helpful.

Lastly, if and when we bring up a larger panel, do we keep running our smaller 50 gene panel? We believe the answer to this one is easy – yes. The amount of DNA needed for some of these larger panels is more than what we can get sometimes from the smaller biopsies. Also, insurance may not always cover the larger panels. The information we get from the 50 gene panel is still very useful and can point the oncologists to therapy options, as well as clinical trials, so we believe the smaller panel will still have a place in our lab.