At the 2023 ASCO Annual Meeting, Valerie Crolley, MBBS, MRCP, University College London, shares results from translational work done on samples from patients with intrahepatic cholangiocarcinoma enrolled in the phase 3 BILCAP trial. This work investigated alterations in cancer driver genes and other potentially targetable mutations.

In these analyses, Dr Crolley explained, there was a wide variety of potentially targeted mutations. She also stated that FGFR3 fusion, MET amplification, and NTRK1 amplification may be important markers of prognosis and could provide targets for future targeted anti-cancer therapy for intrahepatic cholangiocarcinoma.

Transcript:

Hi. My name's Dr. Valerie Crowley. I work at the University College London Cancer Institute. And I'm a medical oncology registrar, and I'm currently doing my PhD. I'm here at ASCO to present my results of my translational work on the BILCAP clinical trial.

The BILCAP clinical trial was a massive phase 3 clinical trial in the adjuvant setting. What they did is they took patients with early stage resectable biliary tract cancer, and they randomized them one-to-one to receive either adjuvant capecitabine, so chemotherapy after surgery, or observation, which was the standard of care at the time. And they recruited a total of 447 patients. And because it was positive, that's the reason why adjuvant capecitabine is the standard of care for biliary tract cancer in the early stages. BILCAP opened in 2006 and closed in 2014. None of those patients will have received any of the new, novel targeted therapies that are currently available.

There are big questions about the genomic and the transcriptomic landscape of biliary tract cancer in general. And in particular, what the natural history of these patients are. Obviously, we've got these new targeted drugs that we can give to patients, but we don't know whether or not they would do better or worse than people without the targetable patients anyway.

What we've done is we're collecting as many of these BILCAP patients as we can. At the time of the abstract, I had 45 intrahepatic cholangiocarcinoma patients. As of now, I have 98 patients, 47 of which are intrahepatic cholangiocarcinoma, 47 of gallbladder cancer. And we've got 2 distal cholangiocarcinoma and 2 perihilar. We collected the tumor blocks, so the tumor resection blocks from the patients. We processed those, they went for DNA and RNA extraction. And then we did RNA sequencing, we did low-pass whole genome sequencing and we did targeting gene sequencing. We're looking at different mutations, we're looking at different levels of amplification, and we were looking at gene fusions as well. Not only just looking at the incidence and prevalence, we were also there to see whether or not these had any effect on progression-free survival. So the risk of recurrence after surgery and overall survival as well. And we found some interesting things.

One of the most important things that we found was actually looking at FGFR2 fusions. First of all, we found quite a high number of FGFR2 fusions. And because the way we calculated it is we were looking at the RN sequential data. We were truly picking up every patient with a potential FGFR2 fusion. And we found that about 24% of our patients had an FGFR2 fusion. And then when we looked to see if these patients, so did patients with an FGFR2 fusion do better or worse, we found it made no difference. We found it made absolutely no difference whether or not somebody had an FGFR2 fusion at presentation because there'd been some word that maybe those patients did better naturally. And we found that was not the case, which is quite interesting. And honestly, that was the case of most of the amplification and mutations and alterations that we looked at. We found a significant number, for example, of ERBB2 or HER2 amplified patients. And again, there was no difference. Whether or not you had a HER2 amplification didn't make you do better and worse than patients who didn't.

There were a couple of exceptions. The main exception was the EGFR amplified cohort. We found about 15% of patients had amplified EGFR. And for us, we counted amplification based on low-pass whole genome sequencing as copy number of 4 or higher because we didn't have any patients with a total ploidy of 4 or higher. These all had genomically amplified EGFR. And if you had genomically amplified EGFR then you did significantly worse than if you didn't, which was completely unexpected. Hasn't really been found before. There'd been perhaps some discussion about whether or not EGFR amplified patients maybe did worse in upper GI cancers, but definitely hadn't been seen before in biliary tract cancer. That was interesting to find.

Smaller patient numbers, we also found that FGFR3 fusion patients did worse, but we only found I think 2 in our cohort of the 98 so far. And we also found, interestingly, not significant, but we found that with the gallbladder and extrahepatic patients that patients with MET amplification did better than average, but in the intrahepatic cohort, MET amplified patients did worse. Didn't reach significance, but quite interesting.

And I think something, especially that kind of pattern we didn't find with any of the other mutations or alterations that we investigated. But I think it's going to be interesting in the future when we get more patients in this cohort to see if there are any other mutations or amplifications that do have anatomical subtype differences.

What we're going to do next is, as you probably notice, we don't have very many of the extra hepatic cholangiocarcinoma data through yet. We are still sequencing samples from the BILCAP cohort. We are going to get more of the extra hepatic, the distal and the perihilar cholangiocarcinoma is coming through. And when we have that full data set together, we'll do a full multivariate analysis and see whether the EGFR story still hangs true or if there are any other amplifications or mutations or alterations that are coming up as having a survival difference. And see if anything does change with the FGFR2 fusion story. But at this point, that doesn't look like it's going to be the case.

We're also going to be looking similarly in a cohort of patients that were metastatic at presentation. Again, to see if any of the prevalence in mutations and alterations in that group. And again, whether or not that affected length of progression-free survival and overall survival in that cohort as well. And we're looking to get together basically as many adjuvant clinical trials where we can get or have the genomic data and the clinical data. And try and build as a bigger picture of the genomic landscape of biliary tract cancer and really see how that's affecting how patients are progressing in the real world as time goes on.

Source:

Crolley V, Guest R, Beggs AD, et al. Investigating alterations in cancer driver genes and other potentially targetable mutations in patients with intrahepatic cholangiocarcinoma (iCCA) treated on the randomised phase III multicentre BILCAP clinical trial. Presented at 2023 ASCO Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 4019