Subscribe to The Podcast by KevinMD. Watch on YouTube. Catch up on old episodes!

Physician and clinical researcher Chris Apfel discusses his article, “Functional precision oncology: a game changer in cancer therapy.” Chris explains that functional precision oncology takes a highly personalized approach by testing a patient’s live tumor cells outside the body (ex-vivo) against a panel of cancer drugs to directly observe which treatments are most effective against that specific cancer. This method, he argues, can significantly improve cancer response rates and survival while reducing costs and unnecessary side effects, by moving beyond the limitations of standard pathology (which identifies cancer type but not optimal treatment) and genomic sequencing (which identifies mutations but provides actionable targets for only a minority of patients). Chris recounts the history of functional testing, its initial promise, its decline with the rise of next-generation sequencing, and its current resurgence, supported by studies demonstrating its high predictive accuracy for clinical outcomes. Despite its potential to complement genomics and truly personalize care, he notes that functional precision oncology faces slow adoption due to its general absence from standard NCCN treatment guidelines, hospital restrictions on external tissue testing, and a systemic preference in health care for standardization over innovative, individualized approaches. Chris strongly encourages patients, particularly those facing difficult or unresponsive cancers, to educate themselves about functional precision oncology and actively advocate for access to these tests.

Our presenting sponsor is Microsoft Dragon Copilot.

Want to streamline your clinical documentation and take advantage of customizations that put you in control? What about the ability to surface information right at the point of care or automate tasks with just a click? Now, you can.

Microsoft Dragon Copilot, your AI assistant for clinical workflow, is transforming how clinicians work. Offering an extensible AI workspace and a single, integrated platform, Dragon Copilot can help you unlock new levels of efficiency. Plus, it’s backed by a proven track record and decades of clinical expertise and it’s part of Microsoft Cloud for Healthcare–and it’s built on a foundation of trust.

Ease your administrative burdens and stay focused on what matters most with Dragon Copilot, your AI assistant for clinical workflow.

VISIT SPONSOR → https://aka.ms/kevinmd

SUBSCRIBE TO THE PODCAST → https://www.kevinmd.com/podcast

RECOMMENDED BY KEVINMD → https://www.kevinmd.com/recommended

Transcript

Kevin Pho: Subscribe at KevinMD.com/podcast. Today we welcome Chris Apfel. He is a physician and clinical researcher. Today’s KevinMD article is “Functional precision oncology, a game changer in cancer therapy.” Chris, welcome to the show.

Chris Apfel: Thank you very much for having me.

Kevin Pho: So before we talk about your article, just briefly share your story and journey.

Chris Apfel: OK. As you may have already recognized from my accent, I was made in Germany over half a century ago. I have done a lot of clinical work and a lot of research to see how we can really improve patient outcomes. I did a lot of research, published over a hundred papers, and at some point, a paper in the New England Journal of Medicine.

I had a nice offer at the Cleveland Clinic. I then had an offer at Harvard and Stanford and decided to go to UCSF, the University of California, San Francisco. I continued with my research until my dad was diagnosed with lung cancer. I got a call on a Monday morning and learned he apparently had stage four lung cancer.

I was not aware of that. Because I was on the cancer IRB at the University of California, I asked my oncologist what we should do, and he said he probably needs cisplatin Paclitaxel. I said, well, he may not. He may refuse. What’s the evidence that this works? Because when he took care of my mother who had ovarian cancer, the treatment didn’t work in her last months of life and only made her more miserable, he said, unless you can promise me this is going to work, I don’t want it.

And that’s actually what happened. I said, wait a minute. I thought the future is here now. I thought we are all talking about precision medicine. I thought that we have it all under control. Can’t we do genomic sequencing? Yes, we can, but only one out of four patients has actionable mutations.

That’s actually where the story started, where I realized the public doesn’t know that when tissue is examined and a biopsy is done, you do histology, or pathology, which is better understood in layman’s terms. You try to classify the tumor to get an understanding of what could or could not work. And it’s based on many, many studies that really compare groups of patients. But every patient is different. And that’s actually where the journey started.

Kevin Pho: So tell us how that leads into your KevinMD article, “Functional precision oncology, a game changer in cancer therapy.”

Chris Apfel: So with the recognition that if we just look at the genome, we are only looking at a very small snippet of the cancer biology. The cancer biology is not driven by a single mutation; the cancer biology is much more complex. As I’m also an adjunct professor of biostatistics and epidemiology, and I love clinical trial design, the best way to predict the future is actually to create it.

So I said to my oncologist, why can we not take the tissue, put it ex vivo in the lab, and put different drugs on it to see which of the treatment options is really best for that individual patient? This idea is not new, and I actually only came upon this because in the ICU when I have been treating patients with sepsis, you always do an antibiotic sensitivity test.

You always want to know which antibiotic works best. It’s the same principle. Why should this not work? This is biologically and medically plausible. And the answer I got is, people have tried this before, but it has never worked.

I said, that’s odd. So I looked into it and spent about a year reviewing all the data that has been published, some dating back to the eighties, and it turns out that you can actually double the patient’s chance of a tumor response if you know ahead of time which therapy is most likely to work. That’s a big deal. That’s a bigger deal than any drug that’s in development, and yet it’s not the standard of care.

There were a number of reasons for this, why this is not standard of care. One of these was that in the early phases, they were trying to grow tumors. If you have an aggressively growing tumor, you can do that and you can compare how you can slow down the tumor growth. The problem is it takes months to grow the tumors, and by that time, the disease has progressed in the patient.

So with such a clonogenic assay, it’s hard to really make a difference for patients. And then if you have the other extreme, when the tumor is a slow-growing tumor, low-grade tumors, they sometimes grow very slowly. You can’t grow them at all. You don’t have a test result then. So we do know that in principle, you can replicate the biology ex vivo and it correlates with patient outcomes. But if you try to grow tumors, it comes too late to really have a clinical impact.

Now there has been a lot of NIH research on organoids and there has been a lot of progress made. But all these academic spinouts that are based on NIH-based research don’t really have an impact on patients. The way was, and that’s actually very interesting, Larry Weisenthal and Robert Nagourney started off saying, well, we need to actually see whether we can kill the tumor. And so they developed a technology, the disc assay, where they could actually, within a week or 10 days, see whether they could kill the tumor.

And they did a lot of studies on this and were actually able to show it. And were active in the nineties until the two-thousands. And then what actually happened was genomic testing came along. Genomic testing is interesting because it’s mechanistically plausible. It’s fascinating.

It has been developed as a companion diagnostic. So the FDA approval of a drug is dependent on the mutation you have. Suddenly, big pharma was highly dependent because it was harder and harder to develop a drug that can work on a patient population. Genomic testing was kind of the ideal tool for drug development to better identify patients who would benefit from a targeted therapy. And so the FDA approval and with that, reimbursement was tied to genomic testing. And that’s actually why genomic testing took off. And that’s also why functional testing has fallen by the wayside.

But what’s interesting is that now people are more and more recognizing the limitations of that. I mentioned the National Cancer Institute’s MATCH trial that Keith Flaherty from Harvard published a couple of years ago where they looked at actionable mutations of over 5,000 patients, I believe.

They could find that only in one out of four patients can you match it to a targeted therapy; for everybody else, it is basically still a hit-or-miss or trial and error.

Kevin Pho: Let me jump in here. For the physicians listening, could you provide a case study of a specific cancer that illustrates this functional precision oncology approach?

Chris Apfel: Yes. At Sage, what we have developed is a technique where we can actually create hundreds of 3D micro-tumors that reflect the tumor heterogeneity and variability within each of the wells. And we can create those within one day through disaggregation. Then we drug them for roughly a week, and then we assess how they are affected, whether they are completely killed or not affected at all.

What we can see is we had, for example, an ovarian cancer patient who had failed first-line treatment. Second-line treatment had failed. She had failed carboplatin, paclitaxel, has failed PARP inhibitors, and was really progressing. So we were testing a wide range of drugs after we got the sample shipped overnight.

We also interestingly tested VAC, which is a combination of Vincristine, dactinomycin, and cyclophosphamide. It showed great effectiveness. The reason why we tested this was because it was in the NCCN guidelines as a salvage therapy. It’s rarely given. But interestingly, a week later, the histology report came back and was actually showing this patient’s tumor had sarcomatoid components.

And VAC is a typical combination therapy for sarcoma. It’s very interesting. So that’s a nice success. The other part is a lady out of San Diego, a music teacher, who presented with ascites. Ascites is not a good sign at the initial stage. And interestingly, out of the ascites, from the paracentesis, we were able to get tons of tissue, so no extra biopsy was needed, no extra surgery was needed. And it was highly sensitive to the standard therapy of carboplatin paclitaxel. She got this as neoadjuvant therapy and responded beautifully. But we also saw that because our test can actually test both cytotoxicity and anti-proliferation, there is a subset of tumors that is likely resistant to it, that is sensitive to a different combination. And those are things that you cannot know ahead of time unless you really test the tumor and you can’t get it with a traditional genome-driven precision medicine approach. And that is functional precision medicine, where you really look at how the tumor is responding to the various treatments.

Kevin Pho: So what used to take months for a tumor to grow under the traditional functional precision technology you mentioned earlier, you’ve now compressed into a timeframe of, say, a week, and then you’re able to determine which specific treatments affect that specific individual patient’s tumor.

Chris Apfel: Well said.

Kevin Pho: So does this apply to most cancers? You mentioned ovarian cancer. Are there specific cancers that are more amenable to this approach versus others?

Chris Apfel: Yes. I think it applies for a wide range of tumors. It applies for all solid tumors that we can get our hands on. We have done a lot with sarcomas, also in children and minors.

We have also done colorectal, lung, and liver mets, for example, of breast cancer patients, and glioblastoma. And the interesting thing is we can test both the FDA-approved drugs, and we can also test drugs that are in development. So if the patient is considering going on a clinical trial, one can actually think about what the different drugs are that are currently in development from which the patient would be most likely to benefit. We can test that.

And then there is actually interest in looking at repurposed drugs. You are familiar with Lovastatin and Avastin. And we have seen those being effective in sarcoma patients. We have seen Desuranib, we have seen a bunch of drugs, Metformin. And if you go into the literature, there is ample research on it, what the mechanisms are, how they affect cancer metabolism and the cancer biology. So that’s actually quite intriguing. They don’t always show up, I would like to say in probably five percent of cases.

But that’s an additional thing, not a replacement of course, but these are additional options that we can see in our lab.

Kevin Pho: Now, what are some of the reasons behind the resistance some hospitals and oncologists have to this approach?

Chris Apfel: That’s a very important part, and what is often not recognized is that oncologists and medicine have become overregulated. I would like to say if you are in one of the NCCN cancer centers, you are expected to practice by the guidelines that you and your colleagues have set up. These are 33 cancer centers in the U.S. They basically define the standard of care and so they are encouraged to practice within those walls, and they don’t carry any benefit from going beyond that.

That’s one part. The other part is it’s not reimbursed by insurance at this point. So we are working on a health economic analysis to demonstrate that it can actually benefit patients so that they are not getting treated with therapy that can’t be effective.

So that’s the second one. Then there is a question also on liability. What if I do something else? And so one of the things that is important to explain to oncologists is you can actually provide superior care within the standard of care. If I use the ovarian cancer sample I mentioned, when we get the tissue, the first-line treatment may still be carboplatin, cisplatin, and Paclitaxel. But very often tumors respond in ovarian cancer; you have a 75 percent response rate, but then you also have over 80 percent of patients who reoccur within the same year. And then the big question is: what next?

We can already test this ahead of time so you can provide superior care with better outcomes within the standard of care. Because the standard of care is not fully developed. But for an oncologist, because the guidelines have become more and more complex, it adds another layer of complexity, and most oncologists are overworked and just want to get through the day.

Kevin Pho: So in terms of macro-level outcomes data for this functional precision oncology approach, you mentioned anecdotal success cases, but on a more macro level, are there any survival benefits when contrasted to guideline-driven standard of care? What are some of the differences in terms of survival and outcome benefits?

Chris Apfel: So normally in medicine, we want randomized controlled trials. That’s the state of the art and ideally even meta-analyses of randomized controlled trials. And one of the criticisms and pushbacks was, there aren’t really randomized controlled trials for this functional precision medicine approach yet.

There has been a randomized controlled trial from Daniel Von Hoff in the nineties, and that failed for the reason that I said: it took too long to get the results and so the treatment came too late. Interestingly, and by the way, many things and many approvals occur in the oncology field without RCTs, without randomized controlled trials.

And an assay is actually not a drug. So requesting a randomized controlled trial for an assay is suddenly a very high bar, which I think is politically motivated. Because if you think about ER/PR-positive breast cancer, there are no prospective trials that show that if you measure ER/PR you have improved outcomes.

That’s caveat number one. Number two, I think last year the first paper was published that looked at recurrent glioblastoma patients. It was a company out of the Midwest and they showed, I think, over six months progression-free survival and overall survival difference in the range of about half a year when patients got therapy according to the assay-guided therapy as opposed to the standard of care.

So that evidence is growing.

Kevin Pho: You mentioned some of the obstacles that prevent the spread of this technology. What do you propose to overcome some of these limitations and get wider adoption of this approach?

Chris Apfel: It’s very interesting. Patients need to be empowered, and their right over their tissue and their body needs to be respected. Very often, especially in larger centers, there is pushback. The patient says, “I want to have the Sage Onco test.” They may even have a physician’s order, and the pathology department says it’s against our policy.

So in order to overcome this, patients need to be aware that the glamorous precision oncology approach that only uses DNA and the approach that NCCN cancer centers are taking is a very confined approach that doesn’t always consider the best possible treatment options for that individual patient. And patients often believe if they go to an NCCN cancer center, then they get the best possible care because they also have clinical trials, et cetera.

They are on the cutting edge. The problem is because of these guidelines, even at NCCN Cancer Centers, the practice is really restricted to the guidelines. And so the therapy from a medical oncology perspective you get is almost identical to what you get at the NCCN cancer centers as opposed to in community practice; there is likely no difference.

There is a firewall between research and clinical care. So you may have a researcher who’s working on a novel compound, but unless there is really a clinical trial on which he or she can enroll you, he or she would not use it if other treatments have failed. And NCCN cancer centers argue that they have the latest and greatest, but this is also financially motivated because the clinical trials are usually paid for very well by industry.

If you get $50,000 per patient to enroll in a clinical trial, it’s very clear why you can say, well, our center is the best, you get the latest, you have access to the latest innovation. But in a way, it’s an academic-industrial complex that is at work here, and patients are not aware of it. And so patients need to know that they have a right to determine what will be done with their tissue when they get a biopsy or when they get surgery and that they actually have the right to determine and say, “I want the Sage Onco test,” or “I want to have a functional profiling test because I don’t want to fly blindly when it comes to subsequent therapy.”

Kevin Pho: We’re talking to Chris Apfel. He’s a physician and clinical researcher. Today’s KevinMD article is “Functional precision oncology, a game changer in cancer therapy.” Chris, let’s end with some take-home messages you want to leave with the KevinMD audience.

Chris Apfel: Yes. The take-home message is if you are a patient and you’re diagnosed with a serious cancer, you need to be your own advocate. You need to think about what the treatment options are and cast a wide net, get a second opinion. And don’t just blindly rely on a big brand. You also need a support network that helps you emotionally and helps you look beyond the normal horizon that people normally look at if you want to have an outcome that’s better than average.

Kevin Pho: Chris, thank you so much for sharing your perspective and insight, and thanks again for coming on the show.

Chris Apfel: Thank you very much for having me.