Polymorphisms May Offer Promising Biomarkers to Predict Outcomes in Colorectal Cancer

Francesca Battaglin, MD

Francesca Battaglin, MD

Although biomarker discovery has been a challenge in colorectal cancer, new findings suggest the presence of select polymorphisms may be promising in predicting treatment outcomes in patients with colorectal cancer.

In 2 studies presented during the 2019 Gastrointestinal (GI) Cancers Symposium, Francesca Battaglin, MD, and fellow researchers at The University of Southern California, analyzed different types of polymorphisms, including in the lipopolysaccharide (LPS) receptor and telomerase complexes. According to their early findings, these germline variants can impact treatment outcomes and thus, may be a promising biomarker for guiding treatment selection.

“Biomarker discovery is a very challenging field because it's very difficult to get a validation of very interesting preliminary results that you can find. All these results I have been talking about are preliminary data, so they are very interesting findings, but need further validation,” said Battaglin.

In an interview withTargeted Oncology, Battaglin, a postdoctoral fellow at the University of Southern California Norris Comprehensive Cancer Center, Keck School of Medicine, discussed the findings from these 2 studies that explored polymorphisms as biomarkers in colorectal cancer.

TARGETED ONCOLOGY:Can you provide some background on your research?

Battaglin:My current work is focused on the study of biomarkers, predictive and prognostic biomarkers, mainly in patients with colorectal cancer, although we work with a large spectrum of GI malignancies. I am working in a research lab in Southern California with Dr Heinz-Josef Lenz who is a leading physician-scientist in GI oncology. We are trying to find new biomarkers to predict treatment effectiveness and treatment activity, and, generally speaking, outcomes in patients with colorectal cancer.

This year at the ASCO GI Conference, I am presenting 2 posters, one is focused on the LPS receptor complex, so using the receptor as a predictive biomarker in patients with colorectal cancer treated with first-line cetuximab (Erbitux)-based treatment. This is an interesting study because it focused on genetic polymorphisms, which are germline variants that the patients have, and how this can impact their response to treatment. 

The other one is similar in the basic science behind it, because it's another study of polymorphisms as biomarkers in patients with colorectal cancer, but the second one is focused on telomere and telomerase. This is an enzyme which has the role of guarding the length of human DNA. At the end of DNA there are these sequences called telomeres, and the length of these telomeres is involved in cellular senescence and it's involved in the immortalization of cancer cells and the development of cancer. Telomere length is a biomarker that has been studied in colorectal cancer and different cancer types, and we are analyzing polymorphisms’ genetic variants in these genes for patients with colorectal cancer in terms of treatment outcomes. 

TARGETED ONCOLOGY:Canyou expand on these 2 studies?

Battaglin:Our research with cetuximab-based treatment is focused on this series of genes, which participate in creating the LPS receptor complex. LPS is a component of gram-negative bacteria and microbiota. The gut microbiota is emerging as a very important player in colorectal cancer development. We already know that high expression levels of toll-like receptor 4 (TLR4), which has a key role in recognizing the gram-negative bacteria LPS and activating the innate immune system, is implicated in colorectal carcinogenesis mediated by gut microbiota, which can start colorectal cancer development. 

We analyzed some polymorphisms in TLR4 and other components of the LPS receptor and, in addition, we analyzed gene expression levels of TLR4 in tumor samples. Patients enrolled in the phase III FIRE-3 trial, which was a head-to-head comparison of bevacizumab (Avastin) and cetuximab-based first-line treatment for metastatic colorectal cancer. We analyzed genetic polymorphisms in about 240 patients enrolled in this trial across the 3 genes in the LPS receptor complex, including TLR4. About half the patients were treated with cetuximab and about half the patients were treated with bevacizumab and we compared the effect of this polymorphism in the 2 different arms and we found that loss-of-function polymorphism in TLR4 and other functional polymorphisms in the other genes of the receptor complex were associated with shorter progression-free survival (PFS) to cetuximab-based treatment, which did not happen for bevacizumab-based treatment.¹

The second study I am presenting is a study about telomere capping complex gene and telomerase polymorphism in patients with colorectal cancer. This time we analyzed patients from 2 different trials, the FIRE-3 trial and the TRIBE trial, both phase III trials for first-line treatment in metastatic colorectal cancer. We have cohorts of patients treated with bevacizumab-based chemotherapy and cetuximab-based chemotherapy. This time we are looking at outcomes and how this polymorphism could affect patient outcomes.

We found that telomere capping genes and telomerase were associated with different PFS in our patients. These were patients treated with bevacizumab mainly, so significant results were [seen] in the bevacizumab-treated patients. We found that in the TRIBE trial in the discovery cohort, polymorphism was associated with a longer PFS. On the other hand, in the cetuximab cohort of the FIRE-3 trial, we found that a different type of polymorphism in the same genes were associated with shorter PFS to cetuximab-based treatment.²It seems like these genes can impact either targeted treatment outcome. Of course, in a different way, according to bevacizumab or cetuximab treatment.

TARGETED ONCOLOGY:Whatare the challenges that exist within this space?

Battaglin:Biomarker discovery is a very challenging field because it's very difficult to get a validation of very interesting preliminary results that you can find. All these results I have been talking about are preliminary data, so they are very interesting findings, but need further validation. In our case, we were not able to validate some of these results in other cohorts for now, but that is because we are dealing with very small patient numbers and very small data sets. That is challenging from a statistical point of view from the methods that you can use to do the analysis to have reliable results and to be able to repeat and validate your findings. Of course, we are trying to find more tailored statistical methods to perform these types of analyses in order to exploit this patient population that we have access to that are limited but are very important.

Specifically, a challenge is the molecularly selected patients, because sometimes this effect can be seen in some defined molecular subgroups and they are more relevant according to the molecular subgroups. This is very important because now we are talking about precision medicine. A very interesting talk here was about precision medicine in upper GI cancer. Precision medicine means that you are going to tailor your treatment based on the molecular characteristics of the patient and of the tumor in the patient. We are going to have to work with very small data sets because they will be more and more selected from a molecular point of view and we will have to find a way to get reliable analyses and get new tools to analyze these small sample sizes.

TARGETED ONCOLOGY:Is there any other research you are working on that you would like to discuss?

Battaglin:I am actually working on furthering our understanding of the role of clock genes in colorectal cancer as well. That was a project that I presented at the ASCO Annual Meeting this year about starting with a single nucleotide polymorphism in clock genes. These are genes that regulate the circadian rhythms in every cell of our organisms. These genes regulate the cellular function, which is different during the day and during the night. We know now that disruption of these genes and disruption of this circadian cycle is associated with cancer development. It started with an observation in breast cancer, but then moving from that first observation, different cancer types of been associated with disruption of circadian rhythms and colorectal cancer is one of these. We analyzed single nucleotide polymorphisms in the clock genes, the core clock components of this mechanism in patients with metastatic colorectal cancer treated with first-line chemotherapy and we found that actually one of these genes, which is called CLOCK and is the main gene of this pathway. Polymorphism in this gene was associated with treatment outcome.

Starting from that point, we are now trying to figure out the details of the biology and the mechanism involved in the specific effect that we see in colorectal cancer and trying to exploit this pathway as a therapeutic target for colorectal cancer.

References:

1. Battaglin F, Puccini A, Cao S, et al. Genetic variants in the lipopolysaccharide (LPS) receptor complex and TLR4 expression levels to predict efficacy of cetuximab in patients with metastatic colorectal cancer: data from the FIRE-3 phase III trial. Presented at: the 2019 Gastrointestinal Cancers Symposium; January 17-19, 2019; San Francisco, CA. Abstract 564.
2. Battaglin F, Loupakis F, Stinzing S, et al. Polymorphisms in the telomerase complex to predict outcome in patients with metastatic colorectal cancer: Data from TRIBE and FIRE-3 phase III trials. Presented at: the 2019 Gastrointestinal Cancers Symposium; January 17-19, 2019; San Francisco, CA. Abstract 566.