Cancer treatment and tumor-informed residual disease testing [PODCAST]

Listen and followApple PodcastsSpotifyYouTubeMore apps · Browse all episodes

“Life can feel full of uncertainty when battling cancer, with few guarantees. ‘Is there still cancer in my body?’ and ‘Will it come back?’ are common questions that have long been difficult to answer confidently until recently. Advances in next-generation sequencing — and a growing understanding of how our bodies respond to illness and treatment — have brought us closer than ever to predicting our individual futures, at least when it comes to cancer.

In recent years, cancer researchers have embraced new noninvasive technologies that can detect small amounts of DNA shed by tumors into the blood, also known as circulating tumor DNA (ctDNA). This is no easy feat, as ctDNA is extremely scarce after surgery and treatment — as low as a single molecule in a tube of blood. But by broadly sequencing one’s tumor, we can identify its unique genetic signature, allowing for the creation of a highly sensitive and personalized assay that can track cancer in the body over time.”

Alexey Aleshin is a hematology-oncology physician and health care executive. He can be reached on Twitter @aaleshin.

He shares his story and discusses his KevinMD article, “Tumor-informed residual disease testing can help inform cancer treatment.”

Did you enjoy today’s episode?

Rate and review the show so more audiences can find The Podcast by KevinMD.

Subscribe on your favorite podcast app to get notified when a new episode comes out.

Reflect and earn 1.0 AMA PRA Category 1 CME for this episode.

Also available in Category 1 CME bundles.

Powered by CMEfy – a seamless way for busy clinician learners to discover Internet Point-of-Care Learning opportunities that reward AMA PRA Category 1 Credit(s)™. Learn more at about.cmefy.com/cme-info

Do you know someone who might enjoy this episode? Share this episode with anyone who wants to hear health care stories filled with information, insight, and inspiration.

Hosted by Kevin Pho, MD, The Podcast by KevinMD shares the stories of the many who intersect with our health care system but are rarely heard from.

Transcript

Kevin Pho: Hi, and welcome to the show, where we share the stories of the many who intersect with our health care system but are rarely heard from. My name is Kevin Pho, founder and editor of KevinMD. Today on the show we have Alex Aleshin. He is a hematology-oncology physician and health care executive, and he wrote the KevinMD article “Tumor-informed residual disease testing can help inform cancer treatment.” Alex, welcome to the show.

Alexey Aleshin: Thank you, Kevin. Glad to be here.

Kevin Pho: We’ll get into the article in a little bit, but first off, can you share your story and journey to where you are today?

Alexey Aleshin: Absolutely. Originally I’m from Iowa, so I grew up in the Midwest, and I moved out west for college. I finished UC Berkeley and then went to UCLA for medical school. Then, unlike some of your readers, I actually took some time off and got my MBA, and that was my first exposure to the business world, where I actually spent some time helping launch what’s called the next-generation sequencing device, to really identify the genomic basis of cancer to help better inform clinical decisions.

After that, I actually went back into medicine and did my internal medicine and hematology-oncology training at Stanford. After that, I actually made a big decision: I left academia and joined a company called Natera to lead the medical team, to really develop and clinically validate what are called minimal residual disease tests for patients with solid tumors.

Kevin Pho: I always like to ask physicians who straddle that line between clinical medicine and academia and the business side: What are some of the challenges when you made that transition from clinical medicine onto the business side, and how did you overcome those challenges?

Alexey Aleshin: I think the biggest challenge is trying something new, right? Stepping into the unknown. Having invested so much time into clinical training, walking away from the practice of medicine that we all went into medicine to do is very scary, right? And I think making that switch really took a lot of soul-searching for me, and really making sure that I was doing it for the right reasons, and that on the business side I was going to be able to still stay involved in what I trained in, and really, hopefully, try to make a big difference to how we manage patients with cancer.

Kevin Pho: Now, for those physicians who are interested in making a similar jump out of clinical medicine onto the business side, what are some pieces of advice that you could share with them, having made that journey yourself?

Alexey Aleshin: Yeah, I think the biggest piece of advice is to really figure out why you’re making that switch. Is it really because you don’t like to practice? I mean, are you burned out? I think if that’s really the reason, there are better ways, to maybe cut down on time, maybe switch groups. But if there’s really a curiosity about how tests are developed, how pharmaceutical drugs are developed, or really, there are multiple other things that can be done on the business side of medicine, then I think the biggest piece of advice is to really talk to as many people as possible.

It is a completely different field. As physicians, we know medicine very, very well, but the business side sometimes can be opaque. Talking to people who made that switch, and really figuring out what you’re getting into, I think is very, very important. And if you still like what you hear, I think that career transition can be the right one for many people.

Kevin Pho: As for working with a health technology company, has it been what you expected?

Alexey Aleshin: I think for me it has. Even before I made the transition, I was involved on the research side, on the consulting side, working in this space. I was very, very familiar with the diagnostic industry, very familiar with some of the technologies being developed. For me, it was the right decision to make, looking back in retrospect. And the last few years, having been involved in developing the device that we’ll spend some time discussing, have been extremely rewarding.

Kevin Pho: All right, let’s talk about your KevinMD article. It’s titled “Tumor-informed residual disease testing can help inform cancer treatment.” Now, for those who do get a chance to read your article, can you just walk my audience through it and share the story of why you decided to write it?

Alexey Aleshin: Yeah. I think even for folks who are listening to this who may not be oncologists, we see patients with cancer, cancer survivors, pretty much on a weekly basis across any specialty. And really, I think the biggest issue with many cancer survivors is: Is my cancer coming back? Did we get it all? Up to this point, historically, we’ve relied on things like staging and risk factors to say, “Gosh, your risk is a little bit higher,” or, “Your risk is a little bit lower.” But a patient is not 30 percent likely to recur. So figuring out who’s really going to recur from cancer and who’s not has been the holy grail.

Really, for the first time, the technology has caught up and has allowed us to actually now just look in a patient’s blood with ultrasensitive ctDNA, or circulating tumor DNA, technologies and ask the question: Do we see residual pieces of the tumor in the patient’s plasma? And if we do, that is a sign that the cancer is still present in the body, and without additional therapy, it has close to a 100 percent, if not 100 percent, probability of coming back. On the oncology side, this can be very helpful to decide who should or should not get adjuvant therapy after surgery.

But really, I think across all of medicine, these tests are going to be popping up. Patients are going to be coming in and saying, “I had this,” at least the test we make is called Signatera, “I had a Signatera test. It’s negative. What does that mean?” Or, “My test is positive. What does that mean?” So I think getting familiarity with these so-called minimal residual disease tests is going to be important, especially since there are over 10 million cancer survivors living in just the U.S. alone.

Kevin Pho: So give us an example story or case study of how this test could be used in clinical practice today.

Alexey Aleshin: Yeah, so I’ll start from diagnosis and go all the way into the surveillance setting. I think we interviewed a patient, actually, for a news story recently, who had early-stage colon cancer. She had surgery, and I think it was stage two. For stage two colon cancer today, especially if it’s low-risk, the recommendation is actually not to give chemotherapy in the adjuvant setting, and what that means is that you’re basically assuming the patient is cured with surgery alone.

She was young, I think in her late 30s, with young kids, and she said, “Well, I still know that even without adjuvant chemotherapy, and even for an early-stage cancer, my risk of recurrence is still not zero. It’s around 20 percent. Is there anything new out there?” And the answer is yes. There is a test called Signatera that can actually look for residual tumor DNA in your system. She had the test done, and it was positive. Based on all of the validation studies, what that suggests is that the risk of the cancer coming back without additional therapy is 100 percent, because what this is basically saying is that you have micrometastatic disease in your system, even if we can’t see it on the scan. She actually elected to then receive adjuvant therapy, and it was really satisfying seeing that ctDNA signal go from detectable to undetectable and actually stay negative throughout her follow-up. So that’s an example of how the test is used by oncologists to really make that adjuvant decision.

But for surveillance, similarly, you just do the test every few months, and if you ever see the ctDNA become detectable again, you know the cancer is coming back, and you can really try to intervene early by doing scans to try to find a recurrence, hopefully at a stage that is still manageable surgically with curative intent.

And then lastly, I will say that the pharmaceutical industry has also kind of embraced this, and they started doing trials, which are currently occurring not just in the U.S. but around the world, where patients who become ctDNA-positive, and you can’t find something on the scan, because there’s a significant lead time between molecular and clinical recurrence, patients who are otherwise destined to recur can actually get novel therapies on a trial and get a second chance at cure, which is really our goal, to test that.

Kevin Pho: Now, does this test apply to all solid tumors? Are there any particular cancers that are more amenable to this test than others?

Alexey Aleshin: Yeah, absolutely, great question. This test has been most heavily studied in colorectal cancer. I think that’s where the most literature is, and that’s where the test is currently reimbursed by CMS. But it does apply to other cancer types as well, and there’s significant data now in breast cancer, significant data in melanoma, and also bladder cancer. So those are the next cancer types where we are foreseeing the test is going to be heavily utilized clinically and reimbursed.

I will say that the last indication the test is reimbursed for, which will only really be familiar mostly to oncology practitioners, is in the immune therapy treatment response monitoring setting. These are patients with typically advanced metastatic disease, who again will be mostly managed by the oncologist, who are getting immune therapy, and the question there is: Is the tumor responding or not to treatment? You would think that would be easy to assess, but actually, with immune therapy, it can be tricky. There’s something called pseudoprogression, where the tumor may initially swell when it’s responding. So on imaging, it looks like you’re progressing, while in effect the tumor is actually growing in size because of the immune infiltrate, because the tumor is actually responding so well to this type of treatment. And ctDNA can be used there to dynamically track the molecular tumor burden, to really understand who’s responding or not to these novel classes of agents.

Kevin Pho: Any downsides to the test? What’s the rate, for instance, of, say, false positives?

Alexey Aleshin: Yeah, so I think the data is slightly different for all cancer types. It is definitely a nuanced field. I will say that for most oncologists, the important thing to remember here is that the specificity of these tests is really, really high. So if somebody is ctDNA-positive, that’s not a false positive like you may see with, for example, CEA. We all order CEA. Sometimes it’s a little elevated, and I think, “Gosh, is that colon cancer coming back?” for example. But then we say, “Well, actually, the patient had a few drinks,” or, “They have some liver dysfunction.” The specificity of many tumor markers that traditionally have been utilized has not been great. With tests like Signatera, it’s close to 100 percent, since we’re looking almost for a fingerprint of the tumor in the blood.

The sensitivity can be variable, and sensitivity is not perfect, so patients who are ctDNA-negative still may have a small chance of having a recurrence, but that recurrence risk is markedly reduced.

A good example I like to give is thinking about just how staging of cancer is now being redefined with these assays. If we take a stage one colon cancer patient, who would not typically be recommended chemotherapy and has a really good prognosis at five years, if that patient were ctDNA-positive, that individual had a markedly higher risk than a patient with stage three, kind of the highest stage before being metastatic, who has all the high-risk features, like a perforation and obstruction and close surgical margins, a patient that traditionally we would say, “Well, gosh, we’re really worried about you.” But if that patient was ctDNA-negative, that individual will have a markedly lower risk of recurrence than the stage one patient who is ctDNA-positive. So the staging criteria of oncology are also being redefined. There are now discussions about going from TNM staging, tumor, nodal status, and metastatic sites, to TNMB, where the B is going to stand for blood-based MRD assessment.

Kevin Pho: So you mentioned that this test is being covered by Medicare. Where do you see the future in terms of this test being covered by not only Medicare but private insurers as well?

Alexey Aleshin: Yeah, and I think really we’re seeing this expanding beyond stage two, stage three, and oligometastatic stage four colorectal cancer to include stage one disease. We’re also, hopefully in the future, seeing this being expanded to breast cancer, where again survivorship is a really, really big patient population. There’s currently a lot of anxiety about cancer recurrence.

We’re also seeing this moving into the bladder cancer space, where currently, after cystectomy, it’s very difficult to decide who should get either chemotherapy or adjuvant immune therapy, which has recently been approved, or who should just be observed. So those are the next areas where we see that the test is going to hopefully be reimbursed. But the way the test is designed, it can be applied to any cancer type, so really, I think in the future we see this being implemented across all of solid tumor oncology.

Kevin Pho: So today, can you give us a sense of how commonly this test is being ordered by oncologists? I don’t have a good sense of whether this is standard of care yet. And if not, is this something that primary care doctors and patients should ask for?

Alexey Aleshin: That’s a great question. The test was reimbursed by Medicare a little bit over a year ago, and it has seen extremely rapid oncology adoption. In oncology, I think the field typically is very evidence-driven. We typically say that new technologies or new practice patterns may take up to a decade to be adopted fully. We’ve seen this type of testing be adopted much quicker than historical precedent, where today, at least for patients with early-stage colon cancer, I anticipate something like one out of five is probably getting some type of MRD testing, at least in 2022, and I think that number is growing. So it is definitely something I think we’re all going to see in our practices, especially later this year, and then in 2023 for sure.

And I think there are also a lot of clinical trials, and these types of clinical trials, I think, are going to further cement the clinical utility and allow tests like this to be reimbursed more broadly, and also, I think, be definitively integrated into clinical guidelines. The first such study to read out is called the CIRCULATE-Japan study. It’s a very large study, hoping to accrue over 5,000 patients in Japan. Currently it’s already enrolled over three and a half thousand patients, or somewhere around there, and the initial thousand-plus-patient cohort with adequate follow-up was presented just last month at ASCO.

I think that data was profound, in that it’s the first prospective large study that evaluated ctDNA performance in the adjuvant setting, and the data was very clear. If a patient was ctDNA-positive after surgery and did not receive adjuvant therapy, their risk of recurrence was close to 100 percent. If they did receive adjuvant therapy, their risk of recurrence was decreased by almost eightfold, really suggesting that if you’re ctDNA-positive after surgery, you should not be observed. You should really be offered systemic therapy if you currently qualify for that.

And on the flip side, the study also showed that patients who were ctDNA-negative after surgery did not seem to benefit from adjuvant therapy. I’ll preface that with: The follow-up is short. I think this is still the observational portion of the study, and the randomized questions will be read out later. This is extremely encouraging for the field, because what it suggests is that patients who traditionally today are being recommended adjuvant chemotherapy, and this is tens of thousands of Americans every year just for a single cancer type, may in the future be able to avoid that treatment if they are ctDNA-negative. They will really be able to be told, “Gosh, you have a high-stage tumor, but you’re ctDNA-negative. You don’t need adjuvant therapy. You don’t have to develop horrible neuropathy. You don’t have to be coming back every few weeks for six months. You’re done. Get this test done every few months, but likely you’re cured from cancer.”

So I think that is the data that we’re waiting for to fully mature, and I think if it’s consistent with what we’ve seen today, we think at least the practice for colon cancer will be forever changed.

Kevin Pho: We’re talking to Alex Aleshin. He’s a hematology-oncology physician and health care executive. He wrote the KevinMD article “Tumor-informed residual disease testing can help inform cancer treatment.” Alex, what are some of your take-home messages that you want to leave with the KevinMD audience?

Alexey Aleshin: I think since we had a great discussion about career options, the first one is to be curious, right? I think if you’re interested in a career outside of the practice of medicine, there are many options out there. So seek out individuals who’ve made that transition, get their advice, and try to figure out for yourself if that could be the right career path for you.

I think the second one is that the diagnostic field is rapidly evolving, and I think there are just so many new advances in medicine. Sometimes it’s really hard to keep track of everything, and also to really figure out what’s significant. And I think ctDNA MRD testing is a significant advancement. I think, not just from our company, but from other companies, from multiple investigators, all the data has been very, very consistent, really showing that ctDNA is a much more prognostic, and now predictive, marker, for not just cancer recurrence but also benefit from systemic therapies.

So these technologies will be showing up, I think first, right now, with oncologists, but more and more with primary care physicians, right? Because we co-manage many of these patients, and after a few years, the follow-up falls over to the PCP. So really understanding these tests and keeping abreast of the data, I think, is going to be important, because you don’t want to be caught off guard when a patient shows up with one of these tests and asks you to help interpret the results.

Kevin Pho: Alex, thank you so much for sharing your time and insight, and thanks again for being on the show.

Alexey Aleshin: Thank you.

Listen and followApple PodcastsSpotifyYouTubeMore apps · Browse all episodes