In an interview with Targeted Oncology, Augusto Villanueva, MD, discussed the role of driver mutations in patients with HCC and how liquid biopsies may help improve the treatment landscape in this patient population.
Augusto Villanueva, MD
Hepatocellular carcinoma (HCC) is lacking in terms of identifying markers of response and genetic drivers. However, liquid biopsies could help play a role in further evolving this treatment landscape, according to Augusto Villanueva, MD.
At the 2020 Gastrointestinal Cancers Symposium, Villanueva discussed the heterogeneity of HCC and the challenges with treating these patients. Although physicians have gained a better understanding over the past few years of driver mutations in HCC, today’s therapies and outcomes are not impacted by these mutations. In order to improve upon treatment, physicians need markers to determine the appropriate treatment for patients with HCC.
Liquid biopsies may be able to help in deriving novel biomarkers in HCC. Analyzing plasma can help physicians detect driver genes more effectively and efficiently, according to Villanueva. In addition, the circulating tumor cells and exosomes can be isolated to help provide more information on potential biomarkers in HCC, according to Villanueva.
In an interview withTargeted Oncology, Villanueva, an assistant professor of the Division of Liver Diseases at the Tisch Cancer Institute of Icahn School of Medicine at Mount Sinai Hospital, discussed the role of driver mutations in patients with HCC and how liquid biopsies may help improve the treatment landscape in this patient population.
TARGETED ONCOLOGY: What gene mutations in HCC appear most problematic?
Villanueva:In the last 10 years, we have gained a significant understanding of the driver mutations in HCC. The most prevalent mutations are TERT promoter, TP53, β-catenin. There is a long tail of low-frequency mutations affecting genes such as AXIN1, ARID1A, and others. The main problem with these mutations is that none of them are [effective] for today’s therapies. Despite having an understanding of what is going on, there are very little things we can do about it.
TARGETED ONCOLOGY: How can the introduction of new drugs impact this challenge in HCC?
Villanueva:With the new drugs that have been approved and have shown efficacy in HCC, there is a rationale to try and understand what the best way is to sequence treatments for patients at advanced stages. That is where mutation analysis or another type of molecular assessment may be able to help us identify who the patients are that would benefit most and how treatments should be allocated for these patients.
TARGETED ONCOLOGY: What did you cover in your presentation at the meeting?
Villanueva:I touched base on 3 major issues. First, I described the mutations, and then I talked about the impact of tumor heterogeneity and the information we can get from single biopsies. Essentially, I tried to address a problem of how heterogenous tumors are in HCC. Depending on where you do the biopsy, you may obtain different genetic information, so we studied that and found that around 30% of the patients had significant heterogeneity at the level of gene expression that connects significance with the degree or the composition of the tumor microenvironment in these heterogenous tumors.
I will also discuss how we can solve or address the issue of heterogeneity, in particular with the role of liquid biopsy to drive novel biomarkers for HCC. Liquid biopsy is the analysis of tumor components that are released into the bloodstream, and we have shown that you can easily detect mutations in driver genes in patients with HCC by analyzing the plasma. Similarly, we know that circulating tumor cells can be isolated and analyzed, as well as exosomes, for mutations released by the tumor cells that contain DNA and RNA; these can be analyzed and can also provide a novel source of biomarkers for liver cancer patients.
TARGETED ONCOLOGY: What are the key takeaways?
Villanueva:The takeaway is that, unfortunately, we still do not have any validated oncogenic markers in HCC. We have a very reasonable understanding of the molecular alterations, but we can do very little about them in terms of mutations. Essentially, the potential role of liquid biopsy is to help us better understand how to stratify patients and how to identify the best responders and inform rationale on how treatments should be sequenced. Liquid biopsy will be very important for that in the next 5 to 10 years.
TARGETED ONCOLOGY: How can some of these new ideas be implemented into clinical practice?
Villanueva:We are still in the data-generation time. As far as clinical practice goes, I think it is important for all the clinical trials that are being conducted now to get liquid biopsies of these patients so we can do molecular analysis and learn from those trials because we need to understand what the main markers are that can help us predict response to different therapies. That is 1 thing that should be done and implemented fairly soon.
Since the new drugs have been approved and show efficacy, we still do not know how to organize these drugs. New biomarkers can help lead us in that direction.
TARGETED ONCOLOGY: What do you think are the next steps towards implementing this?