New Research on Follicular Lymphoma Subtypes

The journal Cell Reports Medicine has a very interesting article this month, reporting on some research that might have significant implications for those of us with Follicular Lymphoma.

The article is called "Whole-genome sequencing reveals three follicular lymphoma subtypes with distinct cell of origin and patient outcomes."

Basically, the article is suggesting that Follicular Lymphoma is not one disease, but three different subtypes. Those three subtypes have different outcomes, and would require different treatments. The idea that FL isn't just one thing really is not new. As I wrote in reviewing an ASCO presentation, FL is considered heterogeneous -- it shows up in each of us a little differently. That makes it tough to figure out how to treat it. There have been many attempts (including that ASCO research) at finding biomarkers to help with this -- some kind of biological signal that will help guide treatment decisions. So far, those attempts haven't been completely successful.

That's where we are with this research. It describes an attempt at finding gene-based biomarkers that will guide treatment for Follicular Lymphoma.

First, some more background about where the study is coming from. Cancer research took huge steps forward when the human genome was finally mapped about 25 years ago. The human genome is the complete set of all 62 million or so genes in a person's DNA. Mapping out the genes is a first step. Once researchers knew where they were, they could start to examine what happened when they were damages, or switched places, or did things they weren't supposed to do.

Cancer researchers have been trying to use this knowledge to develop new treatments since that time. A well-known example is HER2-positive breast cancer. HER2 is a protein that is the result of someone having extra copies of a specific gene. It can result in a type of aggressive breast cancer. There are now treatments that can target this type of breast cancer, and the prognosis has greatly improved as a result.

I'm using breast cancer as an example because, so far, we don't really have that kind of success story for FL. There aren't any reliable biomarkers to guide research and treatment. 

And that's what this research is hoping to do -- identify biomarkers that can distinguish different subtypes of Follicular Lymphoma.

The early results of the research look good, hough, as I'll explain, I'm still a little skeptical.

(And this is a good time to give you the reminder that I give to you frequently -- I am not an oncologist or a cancer biologist. I'm just a Cancer Nerd -- a patient who reads a lot. Keep that in mind, always.)

The researchers looked at 131 samples from FL patients from China and conducted Whole-Genome Sequencing (mapping out the entire DNA of each sample so they could be compared to one another to see how they were specifically different from one another). They determined that there were 3 different subtypes, based on differences in the DNA. Recognizing that there are possible differences based on geography, they repeated the same process with 227 samples from outside China, and found the same results.

At the risk of being too general, I'm not going to get too heavily into the details of what they found. Genetics is fascinating, and if you want a deep but understandable introduction, I recommend The Gene: An Intimate History, by the oncologist Siddhartha Mukherjee. If I got too much into the details of the genes, I'd mix up you and me both. Here's a sample from the article: "K1 is related to the activation-induced cytidine deaminase (AID) activity and is enriched in activation B cell-like (ABC) DLBCL, whereas K2 is associated with POLH activity and is enriched in GCB-like DLBCL.The majority of the kataegis events were concentrated in specific genomic regions, notably the IGH, IGK, and IGL genes, along with the transcription start site (TSS)-proximal regions of genes such as BCL2, BCL6, BCL7A, CXCR4, and BTG2." I lost track myself of which gene or protein they're talking about.

More important are the results -- the three subtypes that they are proposing.

They call them C1, C2, and C3.

C1 is high grade (fairly aggressive) but has a ow risk of POD24 (the disease returning within 24 months after successful treatment), and has a good Progression Free survival (a long time between treatments). 

C2 is low grade (less aggressive, probably more likely to watch and wait), with low chance of POD24, and moderate PFS. 

C3 is high grade, with a high chance of POD24, and poor PFS.

Looking at those differences on the surface, they seem to capture FL patients pretty well. It's a heterogeneous disease.

The details of how they got to these three categories are interesting, though pretty dense. They provide a very convenient chart in the article (Figure 7, if you want to take a look yourself).

 Each of the three types has its own biomarkers. C1, for example, is more likely to have BCL6, or the B Cell Lymphoma 6 gene (as well as a few others). There seem to be differences in the Tumor Micro-Environment for each type as well (this is what is happening in the area around the cancer cell, which can be just as important as the cancer cell itself). C1, for example, tends to have "hot" tumors, meaning there are lots of immune cells in the tumor. This means it is more likely to respond well to immune therapies, for example.

The summary for all of this is that the researchers did a bunch of different tests on the genome to figure out which genes were different and why that mattered, and then suggested that certain treatments would work on the different subtypes based on those differences. C1 may respond well to PI3K inhibitors, BTK inhibitors, IRF4 inhibitors, and immune therapies. C2 may respond well to BCL2 and EZH2 inhibitors. C3 may respond to PI3K, BTK, IRF4 inhibitors, but not immune therapies.

It's all very encouraging. The testing they did was pretty extensive, and the fact that they tested it on a second cohort helps to make their results more encouraging still. 

But as I said, I'm skeptical. Maybe "skeptical" is the wrong word here. I don't doubt their results. But I've been following the search for FL biomarkers for 15 years, and I haven't seen any real results yet. Maybe this will be the one that gives it to us? Or at least moves us on that path?

As a start, it's going to take a much larger sample with the same results to really get the attention of the Lymphoma community. Then there will have to be actual trials, where a large number of FL patients are divided into subtypes, and then treatments are given to them based on their subtype to see if, for example, the EZH2 inhibitors really do work better than an immune therapy for the C2 patients. 

It's going to take come time to test all of this out. Years.

But that's OK. I can wait.

I am encouraged by it, and hopeful. It all makes sense. Some patients in a trial respond really well to a treatment, and some don't respond at all. They were all put into the trial based on having some things in common. But maybe the traits that they have in common aren't the ones that matter. Maybe this research has identified the things that really do matter.

I'll definitely keep an eye on this one. It's been published in a peer-reviewed journal, so it has been seen by other experts, which means it is less likely to be presented at a conference like ASCO or ASH. But an update to the research cold be presented there. 

I'll keep looking. You keep hoping.