Leveraging Endoscopic Ultrasound in Pancreatic Cancer: Utilizing Genetic Testing Results

In this third episode of OncChats: Leveraging Endoscopic Ultrasound in Pancreatic Cancer, Toufic A. Kachaamy, MD, of City of Hope, Madappa Kundranda, MD, PhD, of Banner MD Anderson Cancer Center, and Tamas A. Gonda, MD, of NYU Langone, share how they would best utilize genetic testing results obtained from endoscopic ultrasound (EUS)–guided biopsies in pancreatic ductal adenocarcinomas (PDACs).

Kachaamy: When you [detect] an actionable mutation, [how] are oncologists using the information? In a locally advanced pancreatic cancer, is there any evidence that it makes a difference for the patient? Any evidence of downstaging [or] making them more [amenable to surgery].

Gonda: For many reasons, and this is certainly always something that we do in concert with the oncologist, often the initial biopsy is [done] at the beginning of the patient’s journey or diagnosis. It often does not necessarily impact the first-line treatment of patients with pancreatic cancer. Nearly everyone is receiving chemotherapy as their first treatment modality. I think these “actionable mutations” are really impactful in patients when there isn’t sufficient response [to first-line treatment]. Unfortunately, we know that the majority, if not nearly all patients who don’t have surgically resectable disease, will have some element of progression on first-line therapy. As such, it’s really the second-line choices that [are particularly affected by the knowledge of] these actionable mutations.

There are some scenarios where there may be exceptions to that, but I think that’s [true for] the majority [of cases]. In our experience, for many reasons, at least half of the “actionable mutations” end up being “acted upon.” It’s unfortunately still a relatively small number, and of course, that’s because of pancreatic cancer biology in that there aren’t that many actionable targets. However, in about half of those patients identified with an actionable mutation, we will be able to potentially translate that into an actual therapeutic impact.

Kachaamy: Thank you. Dr Kundranda, any comments on this from the oncologist’s perspective? How would you use this information early in the disease?

Kundranda: Thank you, Dr Kachaamy. I want to start off by saying we’re not talking about pancreatic neuroendocrine tumors. However, I think it’s worthwhile to mention that pancreatic neuroendocrine tumors tend to be very bland—even blander in the context of the genomic landscape, in the context of actionable mutations. When we look at 90% of the tumors, which are PDACs, the landscape there is a little bit different and it’s evolving. What do I mean by that? The traditional conventional thought is that [more than] 90%, some would say closer to 100% of these tumors have a KRAS mutation. We thought KRAS was a pathway that was not druggable. That has changed over the past couple of years, wherein we now have drugs [targeting] specific KRAS mutations that are now FDA approved. As this is evolving, I think we’re using this in treating pancreatic cancer under the umbrella of clinical trials; none of them are standard of care at this time.

The truly actionable mutations, as Dr Gonda alluded to, [the ones that] make a difference in some of these earlier-stage diseases, [include] BRCA mutations. We have drugs such as olaparib [Lynparza] and [other] PARP inhibitors, which are used and approved [for use] in the maintenance setting in PDACs, [that] tend to improve survival. Then you have about 0.5% to 1% of PDAC [cases] that [are] microsatellite instability high. Prior to us being able to obtain adequate amount of tissue with EUS-guided biopsies, we were still confined to getting percutaneous biopsies. There were several studies, including the COMPASS study [NCT02750657], which demonstrated that yes, you could get enough tissue [with] a percutaneous approach. However, as we know, the complication rate can be as high as 20% [in terms of] pancreatitis. In experienced hands, such as yours, with an EUS-guided biopsy of the pancreas, the [incidence of] pancreatitis is 5% or lower. So truly, by doing this, the paradigm has shifted toward using EUS-guided biopsies to obtain tissue for molecular testing.

However, I truly think that today, when we look at locally advanced unresectable pancreatic cancer or metastatic pancreatic cancer, the treatment paradigm is the same from a systemic therapy standpoint; because if the role is not with curative intent, which is the case with locally advanced unresectable pancreatic cancer, the treatment paradigm hasn’t changed a whole lot. Some of the local modalities are still in the experimental phase. [We’re trying] to see whether locally advanced PDACs tend to respond better to some local measures once we’ve started [patients] on systemic therapy, because as we know, pancreatic cancer is a systemic disease and not a local disease.

Kachaamy: Do you find the molecular analysis more helpful if you’re treating [patients with] metastatic [disease]?

Kundranda: Correct. [For those with] locally advanced unresectable [disease, molecular analysis is] certainly very helpful. Because in those cases, they do not have a liver lesion or a lung lesion that’s amenable to percutaneous biopsy. As such, in those cases, we are limited to basically having this EUS-guided biopsy, and that is certainly very helpful [for these patients].

Check back on Tuesday for the next episode in this series.