Molecular Profiling and the Promise of Precision Medicine

Roughly 26% of global cancer incidence and 35% of all cancer-related deaths worldwide are related to gastrointestinal (GI) disease.¹ Traditional treatment—consisting of surgery, radiotherapy, and chemotherapy—has shown limited efficacy and is accompanied by toxicities that often negatively affect a patient’s quality of life. However, the rise of molecular profiling and next-generation sequencing has allowed investigators to identify and characterize genetic mutations, amplifications, and protein expression, leading to a new era of targeted and personalized therapy for patients with GI cancers. The ability to more accurately profile tumors has led to dramatic increases in survival and quality of life while reducing adverse effects (AEs)— so much so that the American Society of Clinical Oncology has named molecular profiling in GI cancers as its 2021 Advance of the Year.²

In a recent interview with ONCOLOGY®, John L. Marshall, MD, chief of the Division of Hematology/Oncology at Medstar Georgetown University Hospital and director of the Ruesch Center for the Cure of Gastrointestinal Cancer as well as co-chair of the 6th Annual School of Gastrointestinal Oncology® (SOGO®), hosted by Physicians' Education Resource, LLC (PER®), discussed the importance of profiling every patient and the improved outcomes made possible by the use of immunotherapy.

Q: In your opinion, what is the biggest story in GI cancers right now?

MARSHALL: Molecular profiling continues to be the story. How do we subdivide our patients into their different molecular subtypes for therapies? With multidisciplinary care, how do we approach neoadjuvant therapies and combined modality approaches? We’re all trying to put each other out of business: We’re trying to put the surgeons out of business with [more effective] chemoradiation; we’re trying to put the radiation oncologists out of business with better chemotherapy and better surgery. So, we’re all trying to make the same or better outcomes while affecting patients less: fewer AEs, shorter treatments, less toxicity. So [the question becomes,] “How do we do that? How do we deliver the same or better outcomes with less patient toxicity?”

Q: Use of immunotherapy has become more and more important in treating GI cancer. What are you learning that’s allowing you to make more use of the immune system?

MARSHALL: We have to remember, first, that only 10 years ago, no one on the planet, except for a few people, thought immunotherapy would ever have an impact at all. We thought that idea was crazy. Why bother? But these checkpoint inhibitors were [such an incredible] breakthrough, to the point where now we say, “How come they’re not working everywhere?” We should get them to work in every cancer, but we know that that’s not happening so far. With GI cancers—unlike, say, lung cancer, melanoma, or kidney cancer, in which major breakthroughs have occurred quickly—it’s been a little bit of a slower set of stairs to climb. We have made a landmark breakthrough with microsatellite instability (MSI)–high cancers. So, with MSI-high colon cancer, in terms of frontline therapy, immunotherapy is beating chemotherapy. That’s big news because lots of our GI cancers are MSI high. Then, when it comes to PD-L1 positivity, it’s gotten kind of confusing for us in GI cancers. Do you need any PD-L1 expression? Do you need a combined positive score of greater than or equal to 1, 5, 10? The answer is different for different settings. So, there’s a lot of confusion right now, even among the GI oncology leaders, about who should get immunotherapy and when they should get it, depending on Molecular Profiling and the these molecular markers. But what we really need is a way to turn on what we’re calling “cold tumors,” tumors that don’t seem to be responding to immunotherapy. Are they not responding because the immune system is not seeing the tumor? Or is it because the defenses against the immune system are so strong that the immune system just can’t get to the tumor? But our drugs currently are [starting to] break through. So, what we’re seeing in liver cancers and bile duct cancers and some others are combinations of immune therapies resulting in improved outcomes. The holy grail right now, however, is in microsatellite-stable colon cancers and pancreatic cancers. These are tough nuts to crack with regard to immunotherapy. A lot of research is ongoing in that field, but so far, we’ve had no major breakthroughs.

Q: With confusion around the specifics of immunotherapy use, what do you recommend when other physicians come to you and ask when these drugs should be used?

MARSHALL: It all depends on the biomarkers of the patient. Sometimes, you get a result back that would make you say, “Stop everything and give [the immunotherapy to] him now.” Other times, you might have a setting where [the treatment is] much less likely to work, where the benefit is lower. So, you save it for later. Patients are highly enthusiastic about these medicines: They watch TV, they watch the advertising. They see the remarkable outcomes from friends and neighbors who are getting these uncertain diseases. So, they want [those outcomes,] too. There has never been a higher awareness of the kind of treatment [than with these immunotherapies]. Doctors want to see the positive outcomes, [too]; we love it when treatments work. But we also know that these medicines are expensive and that in certain circumstances, they are “hail Marys” and they don’t work all that well. So, every physician needs to make that a decision that is [individualized for each] patient. Is the treatment approved? Will guidelines support it? Will insurance cover it? What are the chances that it will work?

Q: You mentioned TV advertising and awareness. How do you manage the treatment of a patient who comes in and says they want pembrolizumab (Keytruda)? Or one who says they’ve seen the latest study and now wants to deviate from their treatment plan?

MARSHALL: Well, it’s not difficult to manage, if you just tell them the truth. Tell them, “we’ve tried it in your cancer, and it didn’t work, and there are AEs and risks.” To me, it is a fairly easy answer. It doesn’t mean you’re happy about it. [It’s no different than] if a patient came in and said, “Why can’t you do surgery on that?” I don’t think we as oncologists are obligated to provide a therapy that doesn’t work just to maintain hope or to make peace with a patient’s soul. It’s our job to talk them off that ledge and explain to them why that really is not appropriate or feasible.

Q: In which specific areas do you see immunotherapy having the biggest impact?

MARSHALL: Immunotherapy is having a significant impact on liver cancer. I never thought I would say as a GI cancer expert that the disease we’re making the most progress in is liver cancer, because it’s been among our most difficult cancers to treat [for a very long time]. So, we’re excited about that. We already knew immunotherapy frontline has been showing some benefit, but now evidence from new studies supports first- and second-line [treatment] with checkpoint inhibitors. This just adds to the strength and the focus of [these treatments] being the appropriate therapy. Now, not many oncologists deal with liver cancers (although they are increasing in incidence), so many oncologists out there would send their patients with liver cancer to specialty centers, for example, for transplants or liver-directed therapies. I think, with these new therapies and immunotherapies in the hands of oncologists, we’re going to see a lot more liver cancer being treated primarily in the community. The esophageal study [CheckMate 577; NCT02743494] is also exciting because we know that gastroesophageal junction cancer is a difficult disease to start with. Here, we’re talking about a surgery that can be a big deal for patients. So, what I’m [wondering is whether, as a] next step, something like [immunotherapy could be used] after chemoradiation to replace surgery. That would be something I would love to see. But for right now, after surgery, the patient who hasn’t had full or complete response to the chemoradiation is a candidate for immunotherapy. And the data are impressive, indicating that more people are cured of their disease and progression-free survival is quite positive. So, I think it immediately becomes a new standard of care for that subpopulation of patients. It’s been really fun. We’ve been jealously watching as the lung cancer pie chart gets more and more subsections, showing how different drugs are working for different kinds of lung cancer. We’re finally getting that pie chart with colon cancer and other GI cancers getting divided [by druggable targets], with BRAF being the latest major addition. But honestly, right on its heels, is HER2 targeting. There is a new exciting recent approval for HER2-targeting agents. In gastric cancer, and we think that will quickly follow in colorectal cancer. So, it is very important for us as oncologists to make sure we’re doing good molecular testing. You need to do it right from the beginning of metastatic disease; you need to know MSI, HER2, RAS, BRAF—and there’ll be others. Broad molecular profiling is quickly becoming the standard of care. Whether it’s a [suspected] NTRK- or HER2-positive colon cancer or whatnot, you [have] got to look into every single patient. And you need to track [results] in your chart, because they can get lost in the electronic medical record somewhere. In your history of present illness, [you have to] make sure you have listed the molecular positives and negatives. For every single patient with every GI cancer, this is critical to making sure you’re delivering the best care, given so many new approvals in all of these spaces, and so many options for all of these patients that can have major benefits. You can’t miss these opportunities. They won’t come every day. But when you find them, it’s pretty cool.

Q: Breakthroughs in the treatment of some of the more difficult GI cancers are notable, but other areas, such colorectal cancer, seem to be just holding steady. Why do you believe that is the case?

MARSHALL: Well, we go through spells, if you will. You understand the biology better, and then you go after it. Despite all the energy in pancreas cancer, there really hasn’t been a lot of progress. Liver cancer is an exception; maybe gastric cancer is an exception; and neuroendocrine cancers are an exception. But we are bringing these fields along. I actually think the problems are research funding and the understanding of the science behind these diseases. One of the cool new discoveries of late is our microbiome. The bacteria that live in our GI tract, in our mouths, and on our skin clearly [contribute to] our health. And the more we look, particularly for colorectal cancer, the more we’re seeing that it’s that interface between the bacteria and the cancer that might have some special relationship that’s creating this biology. Why is right-sided colon cancer different from left-sided? And why the differential expression? We’re really not even sure of that yet, but the microbiome may be the answer. My guess is that as we continue to look at that microbiome science, we’ll begin to see this explosion of new knowledge, in the next 5 years or so. Maybe we’ll learn how to better control the immune system, or maybe how to eat better, or control our microbiomes so that they are the most balanced, the most healthy for us as individuals. So, I’m excited about that. A lot of that research is being pushed by emotion, in that the funding comes from the emotional reaction [of seeing] young people with colon cancer. We’re seeing 20-, 30-, 40-year-olds getting colon cancer—and we say, wait, that’s not supposed to happen; we should study that. Now we’re starting to see the money come to fund the research, drawn by that emotion, which is then triggering success.

Q: What recently reported or soon-to-be reported data excite you?

MARSHALL: One series of studies is looking at frontline immunotherapy in various patients. We’re seeing more and more studies of combinations of immunotherapies and chemotherapy, or immunotherapies and other [treatments], in earlier lines of therapy; understanding better how to optimize that treatment early on [is important]. I’m looking forward to seeing some of those studies. In the adjuvant and neoadjuvant world, I think we are all struggling with how to incorporate things like microsatellite instability into neoadjuvant approaches. On the one hand, we have data that say chemotherapy is harmful in the space. On the other hand, we don’t [have any better choices], right? We don’t have immunotherapy approval in that space for adjuvant approaches. So those studies will be critical to how we approach those patients from the beginning, not just in the metastatic setting. I think those are the main areas now. All of oncology is shifting [away from] a one-size-fits-all to an individualized approach. So, most of the coolest studies out there now are not big randomized trials. The coolest studies are patients with a particular molecular abnormality and a particular drug. For example, we have drugs now that really do a good job with KRAS mutations. So, we have umbrella studies, these basket studies individualized for the right patient, [the right] molecular biomarker, and the right drug for the best outcome. That’s the coolest thing that’s happening. Again, I think [the future] is all about precision medicine and biomarker-driven therapies. I’d love to be wrong about this, but I don’t see a time when one medicine or another is going to have a dramatic impact on a bunch of different cancers or on a larger underenriched patient population. I think those kinds of medicines are still important, but I think our knowledge about cancer and its variable expression—why your cancer would be different than my cancer—and understanding how to apply that [knowledge] is really where the future is. [More often,] we’re segregating patients into smaller and smaller buckets and treating that very specific disease or that very specific molecule rather than [utilizing] an overarching idea of therapy. It’s more difficult because you have to find those needles in the haystack, but what’s equally encouraging is that we’re seeing a similar phenomenon across different subtypes. [Let’s take] some molecular drivers, MSI and NTRKs, for example: If you have one of those, almost regardless of what kind of cancer you have, the drugs work. So, this was the dream. In fact, we have fights in our own division about [what constitutes] a GI oncologist— [actually,] one member of my division thinks that we should be RAS-ologists or MSI-ologists instead of a GI oncologist or breast oncologist or hematologist. I’m not sure we’re there yet. But you can sort of feel like we’re heading in that direction.

Q: How may other breakthroughs have an impact in the field?

MARSHALL: The biggest new technology that is having [an impact] that we weren’t expecting is the use of artificial intelligence. We now have big data sets, huge sets of molecular data and clinical outcomes, and [although] we’re not smart enough [to interpret all of it], we have machines that are. So, something I’m looking forward to is using artificial intelligence (AI) machine learning to [analyze] what [molecular] profile a patient has and predicting what treatment we should give. I [assure] you that you’re better off receiving treatment [suggested by] this AI profiling than [any] other treatment. My hope is that AI technology will make us smarter in this confusing world of oncology, where we have multiple choices and lines of therapy.

FINANCIAL DISCLOSURE: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Arnold M, Abnet CC , Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology. 2020;159(1):335-349.e15. doi:10.1053/ j.gastro.2020.02.068

2. Smith SM, Wachter K, Burris HA 3rd, et al. Clinical Cancer Advances 2021: ASCO’s Report on Progress Against Cancer. Published online February 2, 2021. J Clin Oncol. doi:10.1200/JCO.20.03420