Thejus Jayakrishnan, MD: [00:00:00] Those of you who have listened to the keynote address today by Dr. Ng from Dana Farber, she highlighted how there is an increasing incidence of early onset GI cancers. In fact, we’re seeing more and more young patients Young people developing cancers and the largest increase is happening in GI cancers and specifically in cholangiocarcinoma.
So over the years we’ve seen more and more patients dying from cholangiocarcinoma and we do not know what is the reason for this and we also don’t know are there any features that are unique to young patients compared to older patients. And this is important because in cholangiocarcinoma especially, we are identifying mutations that can be used for targeting treatments, called targeted therapies.
up To 30 to 40 percent of the patients with cholangiocarcinoma have mutations that can allow us to use.[00:01:00] More like a precision, like targeted therapies. The goal of our project, of my research, was to use the real world data from CARIS Biosciences, which is a molecular laboratory that helps in analyzing, characterizing molecular features with cancer.
Was to collaborate with them. to use the data to identify molecular differences between young patients with cholangiocarcinoma carcinoma compared to older patients so that we can establish some benchmarks and also identify if there are any unique features for young patients compared to older patients. Can you
OncologyTube: explain the clinical implications of differences in molecular characteristics between early onset cholangiocarcinoma carcinoma and the average onset cholangiocarcinoma carcinoma especially in terms of targeted therapies like FGFR2 fusions.
Thejus Jayakrishnan, MD: Absolutely. So as I mentioned, one of the reasons why we did this study was to look at molecular differences that can be targeted with treatments. And one of those options is [00:02:00] FGFR diffusion. Like studies have shown that patients with FGFR diffusion type cholangiocarcinoma, when they receive these agents, they have good response rates and have like shrinkage of tumor, which may last really long.
The study is trying to look at if we can utilize these agents even before doing chemotherapy because they are much better tolerated. And so what we found was in younger patients there’s a higher prevalence of these mutations up to 15 percent compared to like older patients around like 5% of these mutations, which is important because that means Younger patients may have more options in terms of FGFR diffusion targeted treatments.
Obviously we need to validate these results and see if there are differences in outcomes, but this is definitely a promising finding.
OncologyTube: The study highlights that patients with EOCCA experience better outcomes with immunotherapy despite immunotherapy related markers [00:03:00] favoring AOCCA. What might explain this discrepancy and how should these findings influence treatment decisions for patients with
Thejus Jayakrishnan, MD: EOCCA?
That is a great question. As you pointed out we found that based on our mutation analysis using the transcriptomic space signaling pathway analysis and gene set enrichment analysis. Several biomarkers such as T cell inflamed score, interferon gamma response, inflammatory response, or angiogenesis enrichment.
Several of these factors favored older patients with immunotherapy. But when you look at the real world data in terms of survival younger patients seem to have better outcomes with immunotherapy. We think it is partly because of the fact that younger patients though the population comprised those with MSI high tumor, which were more likely to respond to immunotherapy and also they probably may have received immunotherapy.
Earlier on as compared to say, an older patient who received later on during their course of treatments. It’s, it is also [00:04:00] possible that there are other confounding factors which were not adequately captured in our study. So I think it’s mainly adjusting for those factors. And then, once we establish what the exact outcomes are, we need to figure out if there are ways to improve outcomes for either of these subsets.
OncologyTube: Given the rising rates of early onset cholangiocarcinoma carcinoma, how can the identification of specific molecular characteristics and potential age tailored therapeutic strategies impact the management and prognosis of patients with this cancer subtype?
Thejus Jayakrishnan, MD: Yeah, that’s a good question too. One of the things that I mentioned earlier on is the difference in the FGFR diffusion.
So that is definitely something we should have clinical implications and therapeutic relevance since there are like all this. targeted therapies available, specifically targeting that mutation. It was disappointing that we did not see any significant differences in the other targetable agents.
But at least, there are targetable agents available [00:05:00] and, We did not see that young patients have significantly lower prevalence of targeted these mutations that are targetable. So that is reassuring. In terms of the immunotherapy, like as I mentioned, we found biomarkers of relevance that could predict response.
We need to investigate that. further in trials are looking at immune checkpoint inhibitor therapies for cholangiocarcinoma. If there are differences between young patients and older patients when we can adjust for the confounding factors that may be present in real world analysis.
The other thing is we really identified that patients with FGFR diffusion had better survival outcomes especially in early onset patients. But in general, those with FGFR diffusion had better survival outcomes. So that holds promise as a prognostic factor as well in terms of survival. And we also found that there was clear difference in mutations in FGFR2 fusion negative versus positive patients.
[00:06:00] And what I mean is so patients with FGFR2 fusion negative type cancer harbored more unfavorable type of mutations such as KRS mutation, SMAD4 mutation, TB53 mutation, so which are all associated with poor prognostic features. Knowing these different molecular features, which are also unique in young versus average onset, can help us in developing prognostic biomarkers.
Those are the clinical relevance. If you could
OncologyTube: give us the key takeaways for our oncologists and our GIs that are not here with us, but are on the internet.
Thejus Jayakrishnan, MD: Yes, absolutely. The key takeaway is the significant difference in FGFR2 fusion prevalence which is a targetable mutation which we noticed in young versus average onset patients.
And what it implies is that, Because of this difference, we should consider NGS testing as a standard for all these patients without any delay. Especially with the FGFR2 targeted agents holding promise even in the first line setting, [00:07:00] getting those mutations analyzed, they earliest possible time frame would be helpful.
We noticed significant difference in immune oncology relevant biomarkers. It did not pan out in terms of the survival analysis as we expected better outcomes for older patients, but in the survival analysis it was better for early onset patients. But as I mentioned, it could be related to different confounding factors that was not probably, properly addressed in the survival analysis.
However, we also found that the FGFR2 alterations can have unique molecular markers that can impact outcomes. bad mutations. And the significance of that is that, there are studies that are looking at combining FGFR diffusion targeting agents with immunotherapy and knowing that FGFR diffusion may be associated with a immune cold or non inflammed type tumor, which is what we observe in young patients, [00:08:00] combining FGFR to targeting agents with the Immunotherapy may help improve outcomes for people with cholangiocarcinoma.
I think that would be another aspect to look at or investigate. Those are the key takeaways.
OncologyTube: All right, this has been an interview with Dr. Thejus Jayakrishnan, MD medical doctor, fellow at Cleveland Clinic in Cleveland, Ohio. Dr. Jaya Krishna, thank you so much for sitting down with us today. Absolutely.