State of the Union: Pancreatic Care Today

An interview with John A. Chabot, MD, Chief of the Division of Surgical Oncology (formerly known as the Division of GI/Endocrine Surgery) and Executive Director of the Pancreas Center.

A Turning Point in Pancreatic Cancer Treatment

A lot has changed since we last spoke. At the time, you were optimistic about where treatment was headed, but much of what we discussed was still in trials. Since then, we’ve seen a new FDA-approved drug (daraxonrasib), extraordinary data around RAS inhibitors, and some remarkable responses to these targeted medicines. Does it feel like a real turning point?

Very much so. All of our progress in pancreatic cancer until this year was very incremental. A little step here, a little step there, making progress, but painfully slow, and each sort of event just a little bit better.

This represents potentially a massive change. And the reason for that is the new drugs are not traditional chemotherapy. They’re drugs that, if necessary, can be taken for a long time. And the response rates with just a single agent alone have been better than any prior drugs or combination of drugs.

So this first phase is sort of a sea change. And I think we’ll start to make incremental progress on top of that. We now have all sorts of trials going on, combining daraxonrasib with other agents that act in a similar way or that are completely different, and combining it with traditional chemotherapy.

You called RAS inhibitors a whole new category of drugs the last time we spoke. What is RAS and what’s so different about finally being able to target it?

The really important difference is that the dominant mutation in pancreatic cancer, a mutation of a gene called KRAS, which is mutated in 87 percent of people with pancreatic cancer, has never been able to be targeted before.

We’ve now got a target that’s almost universally present in pancreatic cancer. That is different from the sort of shotgun approach that chemotherapy takes, which is just going after dividing cells.

And the FDA approval itself reaches beyond the exact group of patients studied in the original trial, correct?

Yes. The good news is that FDA approval is much broader than the initial clinical trials that led to it. In that trial, you had to have failed chemotherapy. The approval is for anyone for whom chemotherapy is not working, whether it’s because of toxicity or because the tumor is not responding.

So they wrote the approval in a way that we can use it in a lot more people than the very restricted category of patients that were in the actual clinical trial. And I think they did that because the results were so dramatically good.

What do you think this could unlock next?

I think, in our smaller world of surgery, expanding this to preoperative patients is going to make a lot more patients appropriate for surgical intervention.

That’s going to be patients whose tumors are involved with critical blood vessels and therefore the surgery is too risky, or patients with very limited metastatic disease that responds to the new approach. Then we can go after the main tumor because we’ve treated the metastatic disease effectively. So in our small world, I think that’s going to be the big difference.

When Treatment Changes What Surgery Can Mean

Last time, you talked about a small number of highly selected patients reaching surgery who never would have been candidates before. How much could that line between surgical and nonsurgical disease move?

I think within a few years, we may double the number of patients that are appropriate for surgery.

After doing this for so long, what does it feel like to see the field changing this significantly?

It’s very, very satisfying.

When a patient has an exceptional response, how do you decide whether surgery becomes the right next step?

It’s actually gotten a lot more difficult. Historically, we would never operate on people with any level of metastatic disease. In the last three or four years, with improvements in other approaches, in the immunotherapy approaches to pancreatic cancer, we’ve dipped our toe in those waters.

And I think this advance is going to bring us to a state where we’re consistently asking the question: should this patient who never would have been offered surgery in the past be offered surgery at this point?

One of the important things is timing. Do we wait a year? Do we wait two years? How much reduction in tumor burden do we need? All of those are moving targets right now that we have to redefine. The better the treatment gets, the harder those decisions become.

Does it change the operation itself, or mostly the decision about who should have one?

Not so much surgical technique, but surgical decision-making for sure.

Surgical technique is about anatomy and avoidance of complications. But the decision-making around who should have an operation can change very significantly.

And imaging itself can make this difficult. For surgical planning, we’re stuck with imaging. We have to depend on it. But after treatment, pancreatic tumors can be particularly difficult to interpret because much of what you see is scar tissue and fibrous tissue. Killing the cancer cells doesn’t necessarily make all of that disappear on a CAT scan or MRI.

So you have to have a healthy skepticism of what you’re seeing on imaging, and yet you have to have some respect for the possibility that it’s going to be right. It can be very, very challenging decision making.

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Moving Toward the Biology of the Tumor

Are we also getting closer to a world where the biology of the tumor matters as much as where the cancer started or what stage it is?

It doesn’t replace the stage. But I think we will almost certainly move toward treatments that are based on biology rather than organ of origin.

Eighty-seven percent of pancreatic cancers have this KRAS mutation, but about 15 percent of lung cancers have it. Will this drug prove as effective in those categories of lung cancer? Are we going to be treating more based on molecular analysis and less based on organ of origin? I do believe that’ll come to pass.

And it’s already happening to some extent. A lot of phase 1 clinical trials for new drugs don’t care where the cancer started. They say, if you have this marker, you’re a candidate for our trial. On the research side, it has already begun.

Does that mean simply saying someone has “pancreatic cancer” may eventually tell us less than it once did?

I think it tells us less, yes. We used to be able to predict with a reasonable degree of accuracy that most patients were going to die of this disease. I don’t know if I’ve said this to you in the past, but I used to tell people, “We’ll keep you alive as long as we can. And we’ll make sure that if further treatment is futile, we won’t push you too hard.”

Now I tell them, “Listen, you need to live long enough to get to the next great discovery.” It’s a completely different message.

What Has Yet To Change

Treatment is moving quickly. Has early detection kept pace?

It hasn’t. There haven’t been anywhere near these kinds of advancements in early detection. That still would be a game changer if we can detect this disease consistently when it’s curable, rather than designing strategies to go after more aggressive disease. But we have not seen anywhere near the kind of change that we’re seeing at the treatment level.

We’ve spoken before about AI and the potential to identify pancreatic cancer earlier. Has anything changed there?

Not since we spoke last. There was a flurry of activity, but there hasn't been much since that initial foray. I do think it will bear fruit, but I think the roadblocks at this point are not scientific; they’re social.

To apply that technique, you need to open up people’s medical records. Then you have the issues about privacy and who owns the medical record. Can you only apply these techniques to people in the medical records in your hospital system? Do you have to get permission from the patient every time? There are huge social issues. It’s not a scientific issue any longer.

We’ve talked about personalized pancreatic cancer vaccines. Where does that research stand now?

It has taken a bit of a backseat to daraxonrasib, because daraxonrasib has sucked all the oxygen out of the room. There are still lots of immunotherapy trials going on. And I believe firmly that ultimately it’ll be a combination of immunotherapy and drugs that act directly on the tumors that will be the combination that we use.

But right now, all the excitement is on daraxonrasib.

A Different Conversation About Cure

You’ve compared the direction of pancreatic cancer treatment to diseases like breast cancer, where patients may stay on therapy for years. Does that change the way you think about cure itself?

Well, it becomes less critical. If we can keep people alive for 10 or 20 years, then perhaps we don’t take as much risk in attempting to achieve a cure. Surgical decision-making, at its core, is risk-benefit.

When the only opportunity to live more than a couple of years is a curative operation in an appropriate patient, you’re willing to take a lot of risk. And more importantly, the patient is willing to take a lot of risk.

Even now, the conversations with patients who are in their 40s and 50s and facing a very, very high-risk operation are different with the opportunity to take a drug that they may be able to take for many years. Those conversations have already changed.

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When one patient responds exceptionally well, what can you learn from that person that may eventually matter for everyone else?

We do a lot of patient-back-to-the-lab analyses. When we have exceptional responders, the opportunity to get tissue from those patients and study it in the lab is really important. We’ve built a system to be able to do that both when we remove tumors surgically and when we do biopsies.

There’s a unique situation with people whose pancreatic cancer, when it becomes metastatic, only goes to the lung. It’s not the most common scenario at all, but those patients do much better than people whose metastatic pancreatic cancer goes elsewhere. So we’re much more aggressive in that setting. If a lung metastasis shows up a year after surgery, we remove it consistently.

When we get the opportunity to do that, we get that tissue into the lab and study it. We now have a whole collection of those kinds of tumor cells, trying to figure out what the consistent findings are that really change the natural history of the disease.

It’s only a guess, but there may be a different way that the tumor cells interact with the immune system. Is the immune system more active in lung tissue than it is in the other tissues that pancreatic cancer typically metastasizes to? That’s sort of our leading hypothesis.

More Options, Harder Decisions

With all of these new options, has multidisciplinary care changed too?

Not in my mind. For the last 25 years, we have focused on being highly collaborative in our clinical decision-making. That’s as important now as it was 15 years ago. We have dedicated tumor boards for each individual organ system. For us, that’s the best-attended conference of the week, every week. It’s actually listed for a two-hour session because we want to cover all of the patients who have critical decision-making going on.

We present every new patient who comes into the system. Then, at any point that there’s a critical decision to be made, they get represented. You can’t function effectively on behalf of your patients if you make decisions about their care in a vacuum.

We’ve talked before about one surgeon calling a case inoperable when another center might see it differently. As treatment becomes more complex, could those differences become even greater?

It very well may. It can be very confusing for patients because they can get very, very different answers depending on who they talk to. Then they’re struggling to decide, well, this sounds really good, but is it true?

It puts patients in a difficult position. And they’ll ask me, “How do I make this decision?” At the end of the day, I tell them, you’re going to go with your gut. You’re going to go with who makes the most sense and who you really believe and trust.

Does the increasing complexity make it even more important for patients to be treated at a center with a lot of pancreatic expertise?

Obviously, I am very, very biased. I think people with these really challenging diseases ought to be treated in a center of excellence, because if you try to do this stuff in a small hospital without the kind of support and colleagues I have access to, you can’t possibly deliver state-of-the-art care. It’s an argument for regionalization. It’s no problem in New York City, obviously. It is a problem in rural areas.

Keeping the Optimism in Perspective

There is so much extraordinary news right now, and patients are hearing words like breakthrough and targeted therapy. What do you want people to remain careful about?

We can’t communicate that we’ve solved this disease. It’s still an evil disease. And all of our treatments, new and old, take a real toll on people. So we can’t communicate, “Raise the flags, we’re done, we’ve won.”

I think communicating optimism and enthusiasm without telling people that this is solved is where we need to be.

Beyond Cancer, A Look at Pancreatitis

The Pancreas Center sees a much broader group of patients than cancer alone. When it comes to noncancerous pancreatic disease, what feels important to talk about right now?

Continuing to highlight the fact that we offer total pancreatectomy with islet cell transplantation (TPIAT) is important [TPIAT is a procedure that involves removing the entire pancreas to relieve pain while transplanting the patient’s own insulin-producing islet cells into the liver where they can potentially produce insulin]. It’s a complex disease. It’s difficult to make the various judgments required, and you want to be in a center of excellence.

When someone is living with pain or repeated symptoms, when do you start thinking about TPIAT?

It’s a tricky question, and it depends on the underlying cause. There are a lot of things that can be done endoscopically to help with those conditions. But there’s a fine line. The worse the condition of the pancreas becomes, the lower the yield of islet cells when you take that pancreas out, process it, and try to give the islet cells back.

So I think the important message is that patients should be evaluated by a surgeon who does this early in the course of the disease. That doesn’t mean it’s time to do it. It means that the communication lines have opened up, and they’re not going to go too far down the road to the point where there’s no value in trying to salvage their islets because the pancreas is already destroyed. An early consultation yields the best results because it lets us optimize timing.

What about pancreatic cysts? As we find more of them incidentally on imaging, is deciding when to intervene still a challenge?

It’s another challenging decision-making area where we’re trying to do prophylactic operations that are relatively high-risk operations to prevent a deadly disease. It’s easy to operate too early. It’s easy to operate too late. And our markers of the transition between benign and malignant are still pretty rudimentary. So it’s easy to mistime those operations.

We talk so much about precision medicine in cancer. Are we getting better at bringing that same individualized thinking to pancreatitis, cysts, and other noncancerous conditions?

Not so much. I think with cysts it’ll come. Chronic pancreatitis is a bit of an orphan disease. There are not a lot of people really focused on it. I’m not optimistic that we’ll see big changes there.

For referring physicians, I think the message really is to get these patients evaluated earlier. That doesn’t mean you’re going to lose control of your patient. It doesn’t mean there’s going to be a snap judgment to go to surgery. It just allows for collaborative decision-making.

After everything we’ve talked about, what is your greatest hope for the next five or 10 years?

That I’ll be out of a job.