Expert Highlights Emerging Areas of Research in CRC

Heinz-Josef Lenz, MD

Heinz-Josef Lenz, MD

In the field of colorectal cancer (CRC), findings from clinical studies on liquid biopsies, Immunoscore^®, and primary tumor location have been garnering a lot of interest.

Heinz-Josef Lenz, MD, associate director for Adult Oncology and co-leader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, shared his excitement over these new areas of development in an interview withTargeted Oncologyduring the 19th World Congress on Gastrointestinal (GI) Cancer.

Lenz also discussed his study of molecular variations between small bowel adenocarcinomas, right-sided colon cancers, and gastroesophageal cancers.

TARGETED ONCOLOGY:You chaired the colorectal cancer abstract session at this meeting. What studies stood out to you?

Lenz:In the oral session of the CRC part at this conference, there were very interesting abstracts looking at liquid biopsies and Immunoscores^®. These new areas will develop into very important research, which will impact clinical practice.

One abstract from Dr Aparna Parikh showed that doing liquid biopsy, which evaluated the monoclonal makeup on the cell-free DNA, was able to detect the mechanism of resistance. She was checking DNA alterations under treatment and was able to show—in most of the cases—the reason that the drug did not work anymore.

This is fascinating because that will determine subsequent treatments depending on way of molecular space. So, when you have an upregulation of c-Met or an upregulation of FGFR inhibitors or HER2, you could target these molecular pathways. However, the most fascinating part of this abstract was that the liquid biopsy detected these mechanisms more effectively than re-biopsying the primary tumor on the metastatic site.

Therefore, the sensitivity of a liquid biopsy is significantly better because when you do a biopsy you only get a little bit of the tumor—which is very heterogeneous. So, you may miss molecular mechanisms of cells that only survive in the blood. Only the surviving resistance cells are found. That is very important because there was so much anxiety that maybe the liquid biopsy will maybe not capture the mechanisms of resistance, as well as the tumor biopsy.

There are also 2 abstracts looking at Immunoscores^®. We are learning more that immunotherapies will become part of our treatment armamentarium for GI cancer, particularly CRC. Last year at the 2016 ASCO Annual Meeting, there was a big presentation in the oral session on Immunoscore®, an independent prognostic marker for outcomes in stage II and stage III disease composed of staining for CD3-positive and CD8-positive T cells.

However, this did not really change the way we are looking at stage II and stage III disease. Therefore, this year we have validation in an American clinical trial, showing that the Immunoscore^®is a significant prognostic marker. It validates that the presence of CD3-positive and CD8-positive cells in the tumor, as well as in the invasive margin, are very important. The nice part of this presentation is that the CD3 presence in the invasive margin of the tumor seemed to be the most important information. It is not necessarily the most important regarding CD3 and CD8 ratios, but really CD3 in the invasive margin. This is the first step in using immuno-related markers to better characterize our patients.

There is another interesting paper looking at the ratio of neutrophils and lymphocytes. It looks and sounds very general to do this ratio. However, in the literature, there are many clinical trials showing the normotension ratio is very important and is a very important prognostic marker.

But, why is this? When you look at it, this ratio goes along with a very important cytokine profile. Looking at the ones that have a high and low ratio, which is highly prognostic, the cytokine profile is completely different. This is another way to look not at the ratio as a prognostic factor, but the reason why the difference in prognosis exists, and dissecting out if these cytokine signature may give us some idea to how we would treat these tumors differently in the future. These are very exciting new data characterizing tumors away from the classical DNA/RNA signature, and going into the immuno-characterization, which is only the beginning.

To round out the session, 2 presentations were focused on the location of the primary tumor. It has become more and more accepted that the location of the primary tumor is a significant prognostic marker, but it can also be predictive. We had 2 presentations from the adjuvant setting from Dr Julien Taieb showing that the location [of the tumor] is not associated with recurrence. However, if the tumor recurs, the survival after recurrence is identical to the previously reported prognostic feature of primary tumor location—which is very consistent with the data.

TARGETED ONCOLOGY:Are there any new or emerging agents in CRC that warrant attention?

Lenz:With the better understanding of the monoclonal characterization, new treatment strategies have been developed. We know that left-sided tumors respond better with cetuximab (Erbitux). We know that for patients with right-sided tumors that are microsatellite instability (MSI)-high, an immune checkpoint inhibitor is the next step of treatment. Now, with the MSI prognostic factor, the checkpoint inhibitors are moving into the frontline setting. There is a complete change in paradigm.

The biggest challenge right now is to find an immune-modulatory combination for the microsatellite stable (MSS) population, which could be effective. There are a lot of different efforts combining classical immune checkpoint inhibitors with additional immune modulators to overcome the potential immune resistance in MSS disease.

We just heard that patients withBRAFmutations have new treatment options. When you combine a BRAF inhibitor with cetuximab and irinotecan or a MEK inhibitor, there is significant and promising efficacy in a tumor that has very poor prognosis. HER2 is an escape to EGFR inhibition, and there are now clinical trials addressing HER1 and HER2 inhibitors in this patient population.

We now understand the monoclonal characterization better and we have better targets. The fragmented subgroup are molecularly defined, which benefit from very specific tailored treatment. This trend will continue to involve fragmenting out tumors that benefit from very specific combinations of targeted therapies.

TARGETED ONCOLOGY:Currently, what is the biggest unmet need in the CRC landscape?

Lenz:Patients who cannot be treated with immunotherapy all eventually fail classical chemotherapy treatment. The first-line therapy response rate is about 50% to 60%, and it drops to 10% or 20%, and then it drops to 2%. So, we ultimately always fail.

The immunotherapies are an exception because they have long-lasting durations of response or durations of stable disease. They are not following the course that chemotherapy does.

In order to overcome this, we need to develop new and better treatment strategies because part of this acquired resistance is really a selection of subclones of cells, which are stem cell—like and are ultimately resistant to all of our treatments. So, a stem cell-targeting approach would be the most effective treatment to potentially increase efficacy and even cure patients.

TARGETED ONCOLOGY:You were a lead author on a study of molecular variations between small bowel adenocarcinomas. Could you recap the significance of that study?

Lenz:We know that right-sided versus left-sided CRC cancers are different. This data showed that the molecular differences are on a DNA level. There is even a difference in the left side between the left side of the colon and the rectum. The prognosis is different, so there are different mutations found.

The small bowel is a very unique cancer, and we do not understand why. That is the major take-home message from this study. Many of them have very unique genetic alterations—we know they can be MSI, or have HER2 application or upregulation. Knowing these, which we did not originally think about when we see a small bowel cancer, can completely change treatment options.

The problem for small bowel cancer is that we do not have approved standard-of-care treatments because it is so rare; clinical trials have not been done in the past. With an understanding that they have very unique characteristics, it may actually allow for novel treatments such as immunotherapy or HER2-targeted treatment in this patient population.

When oncologists see small bowel cancer, a light should go on. We really need to test these tumors because they are very unique and have very defined molecular subgroups that could benefit from very specific treatments.

TARGETED ONCOLOGY:What further investigation would you like to see in small bowel cancer?

Lenz:This study is a very good basis in which to do clinical trials. It will depend on the international community—we must look for molecular-specific alterations such as MSI orHER2