New Pathways: Researching and Innovating Pancreatic Cancer Treatment


Dr. Gulam Manji is an oncologist and director of medical oncology and translational research at the Columbia Pancreas Center. His passion is clinical research, and one of his specialties is pancreatic cancer treatment.

Dr. Manji joined Dr. Hyesoo Lowe on an episode of Columbia Surgery’s podcast Conversations and Curbsides. The two doctors covered topics related to the past, present, and future of pancreatic cancer, from the role that genetic mutations play in illness and treatment to the importance of increased awareness about clinical trial-awareness in the pancreas community to the personalization of individual treatment and the emergence of targeted therapies.

The following is a transcription of the discussion, and is lightly edited for context and clarity.

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Introduction

Dr. Hyesoo Lowe

Our topic today is pancreatic cancer innovations. And I'd like to welcome Dr. Gulam Manji, oncologist and director of medical oncology and translational research at the Columbia Pancreas Center. Thank you so much for coming on today.

Dr. Gulam Manji

Thanks for the invitation, glad to be here.

Pancreatic Cancer Overview

Dr. Hyesoo Lowe

Of course. I'm going to start off by having you talk a little bit about your research. Sometimes discussions of pancreatic cancer have a little bit of a tone of discouragement at the difficulties in things like early detection, difficult surgeries, maybe limited treatment options. And I wanted to see if you could shed some light on some updates on the frontier of pancreatic cancer treatment.

Dr. Gulam Manji

Sure. I think this is an excellent question. And as you point out, many patients and many folks, when they find out that somebody has been diagnosed with pancreas cancer, they realize the aggressiveness of the disease. They realize the tough road that that patient, and actually also the loved ones are going to be facing. And there are times when, maybe a decade ago, where we didn't have as many treatment options. People sometimes jump to the worst conclusion. And happy to say that we have now gone much further in our ability to treat pancreas cancer.

The Importance Of Early Detection

Dr. Gulam Manji

And the other thing that's really important to say is that pancreas cancer starts off as different stages. It is so important that, when patients get the diagnosis of pancreas cancer or when they get a scan, even if there's a hint that there's something that's an issue with their pancreas, what they really should do is seek highly specialized opinions.

That means going to a center that's a high volume center, which focuses on pancreas cancer so that they can get the expertise so that a correct diagnosis is made. Because remember, if there's an issue with a pancreas it doesn't automatically mean that they have been diagnosed with pancreas cancer. It can be pancreatitis, et cetera.

Treatment: Surgery & Chemotherapy

Dr. Gulam Manji

Let me jump to the treatment now. There are excellent surgical options now in patients who have pancreas cancer when it's diagnosed and that's limited to the pancreas. And the important thing is that it's really a multidisciplinary approach that needs to be taken, meaning that you need to have a gastroenterologist, you need to have an expert surgeon. And regardless of the stage of diagnosis, be it localized where surgery is an option, you may need to have radiation oncology involved. You definitely need an interventional gastroenterologist involved. And you will also need a medical oncologist, because even if there's a surgical option there which is of curative intent, meaning that hopefully the cancer will never come back, we now know that pretty much all patients who undergo surgery will benefit from additional chemotherapy afterwards.

And many patients will ask, "Well, it doesn't make sense. I went for the surgery, the cancer was removed. Why do I need chemotherapy?"

The reason for that is twofold. There might be small, tiny cells left behind that the surgeon and the radiologist are unable to see. Really effective chemotherapies can potentially cure them.

There is also the case of micrometastatic disease, where the tiny cells may have escaped the pancreas and have gone to additional sites. And it may be that this chemotherapy can cure those and allow a longer life, and also an increased potential for cure.

Dr. Hyesoo Lowe

Terrific. It sounds like there's definitely a lot of things to be hopeful for, even after getting a diagnosis of pancreatic cancer. Now, what part of that treatment plan is your main focus and what are the things that you're studying now?

Targeted Therapy

Dr. Gulam Manji

By clinical training, I'm a medical oncologist, which means that I give systemic treatments. And “systemic treatments” doesn't always mean chemotherapy, it can mean targeted therapy.

The importance of a multidisciplinary approach is that you need multiple experts. You need an expert surgeon, but you also need a medical oncologist ideally who really focuses on GI oncology, if not just pancreatic cancer. Because now we know that pancreas cancer is not just one disease: there are many different errors that can occur in the DNA that result in propagation of that cancer.

Personalized Treatment

Dr. Gulam Manji

We know that a little over 10 to 15% of patients with pancreas cancer, depending on where you live and the ethnic background of that population, may be the result of a mutation a person may have inherited from their parents called BRCA1, BRCA2, or BRCA-like mutations. BRCA has gained its “fame” and has been discovered in breast cancer and ovarian cancer.

Many people don't know, and even many oncologists may not be as familiar, that there's an association between pancreas cancer and breast cancer and ovarian cancer. And there might be a minority of pancreatic cancer patients who have a BRCA mutation.

Clinically this is important because the choice of chemotherapy that those patients should get may be a little bit different. There is a seminal clinical trial of patients who have Stage 4 cancer and have a BRCA mutation (which they inherited). Some of them benefited from chemotherapy at a certain stage, wherein the cancer did not grow. What the study shows is that giving that group a targeted therapy that affects the BRCA pathway (or that mechanism which is thought to continue the propagation of the tumor) shows benefit.

Imagine, we never thought that this would be possible a decade ago, where patients with pancreas cancer would stop their chemotherapy and go on a pill. And we have patients that have been on this specific agent without any chemotherapy and just on a pill for an extended period of time with tolerable side effects and deriving benefits.

Dr. Hyesoo Lowe

I think you're absolutely right. A decade ago I think it would've been a pie-in-the-sky thought to think that you could take a pill to treat your pancreatic cancer. But the name of the game here appears to be mutational analysis, targeted treatment based upon the particular mutations that a pancreatic cancer may have. And again, personalized medicine that is always entering into many of our conversations, including pancreatic cancer.

Genetic Mutational Analysis

Dr. Hyesoo Lowe

One question is, do all pancreatic cancer specimens get treated or get tested for molecular markers or mutational analysis?

Dr. Gulam Manji

Yes. Here at Columbia University, every patient who has a cancer diagnosis for pancreas cancer will get two different kinds of testing done. One for germline testing, which means looking at the mutations that you may have inherited from your parents, regardless of whether there is a strong family history of breast cancer or ovarian cancer or pancreas cancer or not.

And then what we do here is that we also do mutation analysis on the tumor specimen. Sometimes when it's difficult to analyze the tumor specimen, we now can also get peripheral blood, and from the peripheral blood, identify mutations that occur in the tumor.

We've had significant success where, for some patients, we've identified a sporadic mutation in the BRCA gene. And that may have a discussion further as to whether a different type of chemotherapy should be used, and then maybe even targeted therapy. And that type of analysis in sporadic mutations with BRCA1 or BRCA2—meaning that you have not inherited the mutation but the tumor has that mutation—is being tested in a clinical trial.

Clinical Research: Immunotherapy

Dr. Hyesoo Lowe

Terrific. Can you tell us about some of your trials that you're currently conducting?

Dr. Gulam Manji

Sure. My passion really lies in research. Even though we've made significant progress in pancreas risk cancer, unfortunately it is not where we need to be. We haven't made as much progress in pancreas cancer as other fields have made, such as in breast cancer or lung cancer or kidney cancer. And my focus really is in learning why immunotherapy—which has really revolutionized how we treat certain cancers such as melanoma and lung, liver and others—why immunotherapy has in general been ineffective in pancreas cancer.

Research from our group and others here at Columbia and elsewhere are identifying new mechanisms which the tumor manipulates, preventing the immune system from recognizing and killing cancer cells.

What I do in the lab—using specimens from mice and historical samples from patients who have undergone surgical resections, and even on patients who undergo biopsies—is to understand these different pathways that exist in the pancreas tumor that may interfere in allowing the immune cells to recognize and kill the tumor, and then identify drugs that may interfere in these pathways, and, finally, testing the combination in mice to show that there is some improvement.

The next step is that I write my own clinical trials to then test them in patients with pancreas cancer to see whether there is a potential benefit. We also do biopsies on these patients who are undergoing these clinical trials to confirm that we are truly interfering in the pathways that we intend to. The hope is to learn from both successes and failures to continue to optimize the treatment options that we're trying to get to our patients with pancreas cancer.

Why Is Pancreatic Cancer Treatment So Elusive?

Dr. Hyesoo Lowe

It seems like there's something elusive about the pancreatic cancer cell. Is it because of these different pathways? They're just resistant in certain ways to the usual immune targets that we've seen so successfully in other cancers, as you said? What is it about pancreatic cancer that's just a little bit mysterious, do you think?

Dr. Gulam Manji

Excellent question. It's the “million-dollar question.” I think that there are multiple things. The first thing is the diagnosis of pancreas cancer. We don't have a screening tool, like a mammogram or a colonoscopy, which could identify pancreas cancer at an early stage where we can go ahead and get these patients to surgery and then get them adjuvant chemotherapy to increase a cure rate. That is one thing.

The second thing is the symptoms. The median age of diagnosis of pancreas cancer is in the mid-sixties, and what are your symptoms? Epigastric, abdominal discomfort, back pain. At that age, unfortunately, many patients have that so the physicians don't think of pancreas cancer right away. And then that leads to the disease, unfortunately, progressing and moving to stage four.

Third, looking at the tumor itself. The way that I describe a pancreas tumor to our patients, is that if I told you that we need to go to a neighborhood and we need to go ahead and do some construction, and we are going to go ahead and clear out a block of a neighborhood. Well, you're going to ask, "Are we going to a suburb? Are we going to a New York City block? Or are we going to a fort?" Because the amount of effort that's going to take to clear that block is going to be significant.

Unfortunately, pancreas cancer is in a gated community and it's like a cell, it's like a fort. And what happens is that it's not a sheet of tumor cells that are right next to each other. It is tumor islands that are surrounded by a gated community. And unfortunately, many of the neighboring cells or the supporting structure have these alarm systems that do not allow the immune cells to enter. So multiple different pathways, and a very immunosuppressive environment such that the immune cells do not recognize a tumor. And that's what's so challenging.

The fourth issue that has been a challenge is that nearly 90% of the patients with pancreas cancer have a mutation in KRAS, a mutation that is a switch that turns the cell on, and tells the cell to continue to divide.

Until recently we have not had targeted drugs that inhibit and block the signal. As you may know, a specific mutation, KRAS G12C, which has already been approved in lung cancer, has been tried in patients with pancreas cancer. A small clinical trial has shown that there might be an effective option there. There are also some other drugs that are currently in development that hopefully will target more and different types of KRAS mutations. It is an aggressive area of research.

Dr. Hyesoo Lowe

It seems like there's a lot more to know. With technology blowing open the door of molecular testing and genetic mutational analysis, things like the finding of a KRAS mutation and the targets to intervene upon such a mutation, this seems like just the beginning and like there's more to come. We are at the forefront of learning about these mutations in ways that we were never before able to know.

Dr. Gulam Manji

Exactly. And so it's an exciting time, believe it or not, in pancreas cancer. I can feel the pulse. I can feel that there are multiple clinical trials, and many of the trials are showing these glimpses of hope.

I think the other area to pursue is to not treat pancreas cancer as one disease, but to understand more about the tumor and the tumor microenvironment or the “neighborhood,” so that you know whether you're going to a “suburb” or you're going into the “city” or you're going to a “fort.” Then you can determine what tools you will truly need to attack and control the tumor.

And then, like you said, identify personalized treatment options for these patients for better successes.

Dr. Hyesoo Lowe

It seems like there's a lot of hope on the horizon because there's more to come, in terms of what exactly these pancreas cancer cells are made of and how they will behave and hopefully things that will predict their behavior.

Next Steps: Enrolling in Clinical Trials

Dr. Hyesoo Lowe

Dr. Manji, what do you think is the next step? What do centers like ours and other researchers need in order to really go to the next level and make a meaningful impact on patient care?

Dr. Gulam Manji

The one thing that we need, and really the pancreas community needs at large—including the patients, the researchers, and the providers—is to have every pancreas cancer patient enroll onto a clinical trial.

Not just to any trial, but a trial that is ideally specifically designed for patients with pancreas cancer, targeting the pathways that are involved in pancreas cancer, so that we can truly learn from every patient as to whether we are making progress or we need to optimize therapy.

Then we can distribute this information across the community so that we know, for instance, that “this or that pathway looked very interesting in the lab, but doesn't really translate to the patients.”

We need to educate patients that many clinical trials add new drugs to existing therapy in hopes to make current therapies work better. Hence, in many trials, effective therapies are not being witheld.

Trials in patients who have never received FDA approved therapies do not give untested drugs alone. For example, patients in first line trials will pretty much get chemotherapy, which is standard, in combination with an investigational agent.

There is often a fear that, "I'm going to be a guinea pig. I might get something, right from the very beginning, which may not even be effective." That is unlikely to be the case. If someone were to be newly diagnosed with Stage 4 pancreas cancer, the trial is likely to include standard chemotherapy in addition to new agents.

Only patients who have exhausted standard available therapy, may then encounter a clinical trial which may use placebo or a "sugar pill". Patients should ask their oncologist regarding what potential arms may be randomized to, and always seek a second opinion at another high volume pancreas cancer site.

Dr. Hyesoo Lowe

Very well said from a very premier physician scientist here. And I think that's a very important distinction to make.

In the course of treating a patient with pancreas cancer, we are giving the patient, as well as the medical community an opportunity to improve care moving forward for the patient and for many, many others.

Dr. Gulam Manji

People can reach out to PanCan (Pancreatic Cancer Action Network) and the Lustgarten Foundation (the largest private funder of the world’s preeminent pancreatic cancer researchers).

These organizations can help patients and direct them to centers with clinical trials.

Dr. Hyesoo Lowe

I just want to thank you so much for joining us today and I really definitely learned quite a lot.

Thank you, Gulam. That was really great.

Dr. Gulam Manji

Thank you so much for having me.

FURTHER READING


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