Dr. Tania Small sits down with Dr. Heinz-Josef Lenz, one of the world’s greatest minds in gastrointestinal medical research, for a thought-provoking conversation on the future of colorectal cancer (CRC) care. Together, they unpack the rising incidence of early-onset CRC and the factors driving the surge of new cases in younger patients. This conversation dives into cutting-edge innovations that are reshaping detection and treatment: • ctDNA liquid biopsies and minimal residual disease testing - revolutionizing how relapse is detected. • Next-generation diagnostics and precision screening, including AI-assisted colonoscopies - enabling earlier, more accurate identification. • Methylation profiling, tumor microenvironment and epigenetic therapies - advancing personalized therapy and novel treatments. • Immunotherapies and targeted agents - moving to the “front line” with the potential to transform treatment approaches into organ-preserving strategies. But the conversation doesn’t stop at science. Together, they examine the influence of lifestyle, disparities in access, and patient-driven data on survival. If you're driving change in oncology, this episode offers practical insights on integrating molecular testing, rethinking prevention, and preparing for the innovations ahead.
Dr. Tania Small sits down with Dr. Heinz-Josef Lenz, one of the world’s greatest minds in gastrointestinal medical research, for a thought-provoking conversation on the future of colorectal cancer (CRC) care.
Together, they unpack the rising incidence of early-onset CRC and the factors driving the surge of new cases in younger patients. This conversation dives into cutting-edge innovations that are reshaping detection and treatment:
But the conversation doesn’t stop at science. Together, they examine the influence of lifestyle, disparities in access, and patient-driven data on survival.
If you're driving change in oncology, this episode offers practical insights on integrating molecular testing, rethinking prevention, and preparing for the innovations ahead.
About Dr Heinz-Josef Lenz
Heinz-Josef Lenz, MD, is an award-winning trailblazer and mentor whose pioneering work in colorectal cancer gene regulation, drug resistance, early detection and surveillance has reshaped the field of oncology. He is the recipient of multiple prestigious honors, including the ASCO Young Investigator Award, Career Development Award and the USC Mentoring Award, celebrating his excellence in both research and mentorship. Dr Lenz also serves on national committees including SWOG, NCI Task Forces and advisory boards and has authored numerous peer-reviewed publications.
Dr Lenz is a professor of medicine, Preventive Medicine and Cancer Biology J Terrence Lanni chair in Cancer Research. He is also deputy Cancer Center director at USC Norris and co-director of USC Brown Center for Cancer Drug Development.
Dr. Heinz-Josef Lenz is a paid BMS consultant.
Dr. Small (00:00):
The script has changed. Colorectal cancer used to be the 50 and up disease. Today it's surging in young adults and devastating multiple communities. But it's not just about who's getting sick. We're now unraveling the root cause drivers.
Dr. Lenz (00:20):
We identified the gene and this gene is highly predictive and prognostic for outcome.
Dr. Small (00:24):
And rethinking what true prevention can look like.
Dr. Lenz (00:27):
Colon cancer is the most preventable cancer of all
Dr. Small (00:30):
Today. We define what that is now and into the future,
Dr. Lenz (00:35):
And the future will lie in the tumor microenvironment as targets for novel treatment.
Dr. Small (00:40):
It is my honor to welcome a true pioneer of colorectal cancer care, Dr. Heinz-Josef Lenz. He's led one of the largest translational colorectal cancer research programs and defined the molecular subtypes guiding today's therapy. There's no one better to lead us into the next frontier. I'm Dr. Tania Small, and this is Doctors Unscripted.Now let's get started.
Dr. Small (00:40):
So welcome, Dr. Lenz to Doctors Unscripted.
Dr. Lenz (01:14):
Thank you very much for having me. I'm very excited about today's show and to really talk about colorectal cancer.
Dr. Small (01:21):
Well, in that case, I ask the hardest question first.
Dr. Lenz (01:24):
Okay.
Dr. Small (01:25):
Do you remember when you were in med school and you knew you could predict where other people, what other people are going to become? So your professors or colleagues, what specialty did they expect you to go into and how did you get into GI Oncology?
Dr. Lenz (01:42):
I had no idea I would be an oncologist. I liked a lot of different areas. I thought I would end up as an internist or general practitioner in the village I grew up. That was actually how I started. And during medical school you have to study a lot. You don't see the world. So, I decided doing to hold medical school to do all my rotations abroad. I ended up in a very interesting ward on hepatology in University of Vienna and next to the ward was an outpatient clinic and it was a breast cancer clinic. And I started going there and I knew this is the right thing for me because the patients were extremely kind. You developed a relationship, you talked, you got to know the patient and their families. So before I decided to go really in oncology, I said I will do a rotation in the US—three months oncology at George Washington University. And then I decide to choose oncology and I had a blast. And after that I applied only for hematology/oncology fellowships. But, the university I choose, University of Tübingen in the south of Germany, the professor was very famous. He discovered glucose six phosphate dehydrogenase. In the SHA family.
Dr. Small (03:15):
So you went from that to GI Oncology? So tell me more.
Dr. Lenz (03:20):
I was basically trained as a hematologist in oncology. There was very little, so I knew I wanted to always do some bench research. And the professor who was at Tübingen, the boss, I worked on his private ward, I think he was very happy with my clinical service. So I went to him and saying, I want to do some research in the lab science. He says, you will not succeed. You're very good clinically you should do continue what you do good.
(03:51):
And I thought, I don't believe him. So I wrote a grant to the German National Science Foundation. I got the money for two years. I was all set up to go to Sloan Kettering and about three months before my friend who was still in the lab said, don't go to Sloan Kettering. Go to USC because there is a laboratory which develops novel technologies. This was in 1990. They were already doing PCRs on genes from endoscopic biopsies. So I contacted them, read their research, and I knew this is the wave for me to go. Now we started doing this research on colon cancer and gastric cancer samples and that was for me the beginning to work on GI Oncology
Dr. Small (04:48):
I’m going to go into a question that everyone is asking now, and that is early onset colorectal cancer. And you look at the data, if you look back in what, 1995, what about 11% of patients under 55 were diagnosed? Now you're up to 20%.
Dr. Lenz (05:05):
Yes.
Dr. Small (05:06):
Besides I guess more the sensitivity of diagnosis, what is it? Is it biology? Is it environmental? What is causing this increase?
Dr. Lenz (05:16):
Yeah, I think this is still a mystery. There are a lot of research groups around the world working on it because it's not genetic or we know this is not a genetic predisposition leading to early onset because when you have a 20-year-old or 25-year-old or an 80-year-old patient coming in, you think it is a family inheritance, but it's not. And it's very interesting because certain ethnic groups have different onsets of early onsets. So Hispanics are by far the highest early onset incidents from any ethnic groups. Our patient population in LA County is 90% Hispanic. So we see that. We saw that many years ago that we already had young Hispanic patients with colon cancer. No one else saw and we didn't know why. We did always genetic testing. It was not it. Then we thought the tumors developing in young would be different, but there are no big differences.
(06:16):
Very small one would not explain the early onset. Now, one of the interesting aspects is that the patients I see in the early twenties look not high risk. They're not obese, they're often high school athletes. They are fit.
They're not fitting a risk profile which we usually associate with colon cancer. There is a question if metabolic pathways are involved, the glucose and fructose metabolism in the colon is a very unique pathway, but it has not been proven yet. So we are looking is metabolic pathways responsible for early onset? Now there are also very interesting and new data because when it's not genetic, can it be epigenetic? Meaning there are no mutations, no genetic inheritance, but there are ways which can silence genes which may have the same effect as mutation. Now, epigenetic regulation could be done by outside factors or by behavior, by food, by exposures. And there are a lot of new risk features we now know. Very obvious is food and exercise and so on, but also plastic material.
Dr. Small (07:40):
Is there a way to measure to see if there's something unique about that population? Was there a unique difference?
Dr. Lenz (07:45):
So we have to be very unique to look, can we test for epigenetic regulation? And there are tests available called methylation. Methylation was not in pursuit even the data in the tumor genome atlas, but there are very little. So we are now doing a large study, the biggest ever done on whole genome sequencing, whole transcriptome analysis, DNA methylation from over 500 patients with Hispanic. We already have 260 and a third of us of these patients are early onset. We can estimate the exposure from environmental factors including PFAS, including work environment, inverting air pollution and so on. And we will capture with them with surveys and questionnaires, what they do, what they eat, how much they eat, how much exercise they do. There are all this information captured on exposure environment as well as the potential outside way in order the family history. Or when you look at coronary artery disease, we know when the parents have it, even the kids are not risk and obese at higher risk. That is considered epigenetic. So I think we're getting very close to better understand because this is an epidemic.
Dr. Small (09:08):
So there's an increased risk in Hispanics, but also I was looking Native Americans as well as African-Americans are also disproportionately increasing with colorectal cancer. Do we know any reason why? Is it biology in that case or environmental?
Dr. Lenz (09:23):
I think we already knew when we looked at all the different ethnic groups for patients with disease, the African Americans usually have the poorest prognosis and there are some genetic differences when they develop colon cancer compared to the white or the Asians because the Asians usually do the bestfollowedby the Hispanics, followed by the Caucasians or whites followed by the African Americans. So we know there are biological differences. They have often genes in their tumor, which is more difficult to treat. They have less response to treatment, they have differential response to immunotherapy. So there are biological differences. I think at the end of the day, the goal of personalized medicine, forget the ethnicities, you need to treat individually the tumor, doesn't matter who has it that you have the most optimized treatment. For early onset, we don't know what the treatment would be or now there is a little bit move on the epigenetic regulation because the group in China who is very well established scientifically, they have tested a drug which modulates epigenetic regulation and combined it with immunotherapy and combined it with
anti-VEGF treatment and showed incredible response rate. This is for me a proof that going down that road to change the genetic and epigenetic regulation with immunotherapy and anti-VEGF or bevacizumab treatment is, and this is an MSS tumors? Yes.
Dr. Small (11:03):
Really?
Dr. Lenz (11:04):
Yes. Now what we already know, the methylation stages of African-Americans versus Hispanic versus white is completely different. I mean it's almost black and white. You understand. Completely different. Can this explain the differential outcome? We don't know yet. We hopefully see it, but this is for the first time we do a methylation signature, which has not been done in any major patient population.
Dr. Small (11:32):
So if we look at clusters, do you think we'll see a similar response beyond ethnicity?
Dr. Lenz (11:38):
So I think if all this environmental factor really go through the epigenetic regulation, we would be able to identify these patients by the methylation signature. So I think when we find this link, it doesn't matter anymore how they got it. It is
Dr. Small (11:56):
As long as they have it. Yes, yes.
Dr. Small (12:04):
So we know that. Now we've obviously lowered the age in terms of when one should get a colonoscopy. I had to get mine earlier than I planned, but now we looked at the data in terms of colonoscopy, what it’s like 90% sensitivity rate as well as specificity versus a stool DNA sample with Cologuard, I'm looking at the sensitivities about what 90% as well. However, the specificity is a little less. At what point do we say that it's okay to use Cologuard or those type of stool DNA approaches versus a colonoscopy?
Dr. Lenz (12:43):
So I think first of all, colon cancer is the most preventable cancer of all because you have precursors, you have the polyps. The development of colon cancer takes five to 10 years, which is the reason the interval of the colonoscopy is 10 years because it takes so long. Or the exception is MSI high, they can develop within a year. That's the reason they get it yearly. So because you have all these precursors, you can prevent colon cancer a hundred percent today if they do colonoscopies. Because of the early onset we get down to 45, I still don't think this is…
Dr. Small (13:18):
You think we need to go earlier?
Dr. Lenz (13:19):
Yeah. And colonoscopy at the moment is the gold standard. Okay. Now there are certain populations, groups, religious issues to see, I don't want to do a colonoscopy because just the thought of that would be for them enough to say I will not do that.
Dr. Small (13:40):
By the way, that means everyone here please get your colonoscopies.
Dr. Lenz (13:43):
That's correct. We will do it afterwards. Okay. Is that the difficulty and that they should do like a Cologuard or something else, but there is a problem or because the specificity is not there and the reason is that polyps already have mutations which can mimic colon cancer. So that's the reason when you have a positive test, you need a colonoscopy. There's no way around it. It's a compromise. Even not the best. But because you miss, I think it's better than to do nothing. I try always to do colonoscopy because it's actually not so bad, you know? I mean the first thing is the prep. Prep. The prep…
Dr. Small (14:30):
The prep. The prep is the worst.
Dr. Lenz (14:32):
The colonoscopy is not. The prep is like the worst. Yes. I think they should develop something better.I mean we're flying to the moon and cannot have a good colon prep.
Dr. Small (14:40):
Exactly.
Dr. Lenz (14:41):
I mean…
Dr. Small (14:41):
And then now even moving into colonoscopy and AI assisted colonoscopy, now that I'm excited about, I think they said there's about a 10 to 20% increase in pickup in adenomas. If that's the case, why have we not done more of it? Why are most academic centers not using AI guide?
Dr. Lenz (15:00):
I think the AI system is not there yet because the intraluminal processes like a polyp or cancer are not easy to see on any imaging. That's the reason CT scan will not help. CT scan cannot detect colon cancer. So with AI, you need still the clearance, you need still the whole prep. Okay,
Dr. Small (15:21):
The wonderful prep,
Dr. Lenz (15:22):
Yes. So it does not change. And then the flat tumors you may not find and identify. So I think if AI doesn't change dramatically, I don't think that's a good substitute.
Dr. Small (15:41):
So we know that with ctDNA, we're able to now detect these molecular, I mean even relapse months before imaging. And based on DYNAMIC we saw that you can actually use CT guided MRD to determine whether you're going to escalate or deescalate treatment. I guess at what point do we really start implementing ctDNA-based treatment decisions?
Dr. Lenz (16:06):
I do it already.
Dr. Small (16:07):
You do, really? Actually this morning I was on a call with a physician. They saw a molecular relapse based on ctDNA imaging was still stable. So, there's still a lot of debate whether or not they trust or should you wait for imaging?
Dr. Lenz (16:22):
Yes. So I think it's probably not as straightforward as it sounds, I think I do liquid biopsy for MRD minimal residual disease on all my patients after surgery, not only from the primary tumor but also resection of metastatic disease. Now in the setting of a primary tumor or when you get a positive liquid biopsy test, we do not know what the time interval is from a positive test to see the disease developed on imaging or visible on imaging. It could be three months, six months, nine months, 10 months. So the argument is would you do treatment early when 10 months nothing is visible and would you create and expose a patient to chemo he may not need at least as long. Now the argument against it that all the studies we have seen is that the conversion of a positive liquid biopsy to a negative one with chemo changes the prognostic outcome of this patient into a situation where it is the same prognosis as it would have been negative. So we know that there is a potential benefit, but there is always argument when do you start treatment with a positive or do you seek increasing? Now there's also one lesson we learned about 10 to 15% of liquid biopsy for MRD is false positive. So you don't want to treat a false positive. So when the number is low for the ctDNA count, I check it again four weeks later to make sure this is for real positive and it's going up.And then I discuss with the patient because there is no consensus that we should treat. Now there are clinical trials developed which look for MRD positive colon cancers after resection of the primary tumor to treat with novel treatments. What was a little bit of setback was at ASCO in the positive deescalation of treatment did not make a difference. The chemo is effective but not escalating because what do we call a positive liquid biopsy is this metastatic disease, but you cannot see it. We know that small minimal residual disease requires different treatments. When you look at the adjuvant setting, all the new drugs have failed. FOLFOX is the standard of care. They try to add bevacizumab, they add cetuximab, they try to do FOLFIRI, all failed in the adjuvant setting. Meaning if you have really not well established tumor volume, these treatments do not work as well. Now you and I know ATOMIC was presented, this is the first trial for MSI high in the adjuvant setting. But there are big problems with this trial, not with the trial itself, but the trial was developed before we had the IDEA trial, before we know about neoadjuvant immunotherapy for MSI high. So I think a lot of my colleagues including me struggle what to do in the adjuvant setting for MSI high. And I think the NCCN has also issues how to put it that we don't overtreat patients for wrong reason because these patients are resistant to chemo and here we would give six months. So I think however, the proof of principle is that the immuno component seemed to work in the adjuvant setting, but there is no doubt, I think that's the wrong approach. It has to be in the neoadjuvant setting.
Dr. Small (20:15):
So let's talk about that and I want to get your thoughts on organ sparing type of treatment for neoadjuvant.
Dr. Lenz (20:19):
I think there is a paradigm change.
Dr. Small (20:21):
Yes.
Dr. Lenz (20:22):
Okay. And it's happening everywhere. Okay. Because the first start was that with a chemo radiation chemo prior to surgery, we are now able to spare sphincter and preserving technologies. And this is amazing. But the future is beyond chemo and chemo radiation. And I think we will talk a little bit about MSI high, but we should also include MSS because in my opinion, everything will change for colorectal and colon cancer moving in the neoadjuvant setting. And not only MSI high but also MSS. The combination of immune checkpoint inhibitor with CTLA-4 and other immune checkpoint inhibitor will in the future become standard of care. With its efficacy, we will do less surgery, less radiation, and less chemotherapy. The challenges are can be stage a colon cancer, not imaging, but we colonoscopy. But this is all possible and feasible. We just need a better immune combination. Everyone will get neoadjuvant immuno and then evaluate if we need surgery or if we need radiation or we need chemotherapy. And the patients with rectal cancer have the biggest benefits because they don't need a really stoma placement, that can sphincter sparing. Now I think this is even underrated because when you don't need radiation of the pelvis, all your sexual function for the young patients is a big thing.
Dr. Small (22:04):
Yes. Maybe you could take the listener through what the side effect is when you have surgery plus radiation.
Dr. Lenz (22:12):
I think there is no doubt that radiation leaves scars or in the area of the radiation field, which includes the rectum, includes the vagina, includes the bladder. So you can have all irritation in these different organs massively lasting for a long, long time. So you don't want to do that if you really don't need to. And I think we need to learn better in order to really avoid radiation treatment. Now chemo is a little bit easier because you get sick, but it's getting better and has not often so long-lasting lifelong side effects. But I'm very optimistic with a new immunotherapy combination. We will replace many of these treatments, which is considered standard of care. We just need to advance.
Dr. Small (23:04):
And the data are great for MSI high. Let me ask you, MSS, where do you think it's going in terms of neoadjuvant therapy?
Dr. Lenz (23:12):
I think this will be possible personally. When you look at the metastatic refractory setting, look at the BOT/BOL data or the Adagene data, they see in extrahepatic disease, 40% response rate. You show me new adjuvant chemo radiation with 44%. So what I'm saying is it's not the end, but when this is used earlier, not in refractory setting, the efficacy should go up, not down
Dr. Small (23:45):
And many people when they think about colorectal cancer, they don't realize how heterogeneous it is. And even learning this and understanding that the differences we're developing better targets. Again, if you think through immunotherapy, you saw the data, initially you'd look at a six month PFS, now you're looking at greater than 50-month progression-free survival. Tremendous.
Dr. Lenz (24:10):
Yes. So I think we have come a long way or we have now molecular-defined subgroup where the treatment has changed, including since ASCO. We have the HER2 with the data of HER2-targeted treatments. So I think we have exhausted the targets within the tumor we've mentioned. I think the future will come from targeting metabolic pathways. All the, when you think about all this new information, exercise, and diet, it's a metabolic pathway. So what do we need to do to mimic what we achieve with this diets and exercise, or what can we modulate in the patient or impacting indirectly than the tumor and the sensitivity? I think that the immunotherapy basically enables the microenvironment to attack the cancer. It's not attacking directly. It goes to the immune cells, which are part of the tumor microenvironment. I think that we are only starting to understand where the resistant mechanisms are. We don't even know what the immunesuppressive natures are in the MSS tumors in liver. There are a lot of hypotheses, but we really don't know. I think these are the areas which would make the big impact because 90, 95% are MSS tumors. I think the biggest change in our view is can some of these treatments or some of these pathway we identify being used to prevent it in the first place, the treatment is very good, but this needs to move into
Dr. Small (26:04):
Prevention.
Dr. Lenz (26:05):
So do we will have a concept of diet and exercise. And I think that some people need medications, and I don't mean drugs, but some targeted medication to enhance that effect and prevent it. And when we identify patients at risk, we can easily identify if this works or not. So I think that in this situation that targeting metabolic pathways, targeting structures, we enhance or potentially inhibit development of cancer will be the next success. It will not be broccoli. It'll be not just fiber diet that is not good enough. This does not really reach the tumor microenvironment. Or it is local, it creates a little bit activity and make the bowel move faster and more often where you have less exposure. But we need something which really interferes with metabolic pathways or the changes of the tumor microenvironment really early on. There is the NIH network called HTAN, which I think is absolutely phenomenal because they look not at the tumor, they look at the normal tissues which will develop the tumor. What are the earliest changes? Molecular changes, pathway changes in order to develop drugs to prevent the sequence of pre-cancerous lesion going into cancerous lesion.
Dr. Small (27:42):
So then let me even take you to treatment.
Dr. Lenz (27:45):
Yes.
Dr. Small (27:46):
Now when you and I spoke on the phone, one of the things you were adamant about was sequencing. You have a window of opportunity for maximum tumor vulnerability. Maybe you could take us through why sequencing is important, and what do you recommend?
Dr. Lenz (27:59):
I was always convinced that the sequence of treatments you choose is absolutely critical for the outcome. You cannot save a successful treatment for later because sometimes we start a little bit here and then when we really need it.
Dr. Small (28:16):
You want to reserve it.
Dr. Lenz (28:17):
Yes, when you really need it.
Dr. Small (28:18):
Yes.
Dr. Lenz (28:19):
That does not work. The treatment pressure on tumors changes the biological makeup of the tumors which are resistant in a dramatic, specific way. And the sensitivity changes usually for the worst, or when you do first-line treatment, it's about 50, 60% in second-line, 10 to 20 and then to two or three. This is not because you do the wrong treatment, is that the tumors have cross-resistant pathways. So you need to make sure that you do the best treatment first. And we have learned that now recently in BREAKWATER, we know BAF mutant tumors have usually overall survival median about 12 to 15 months. And that's actually the standard of care arm. Now when you do the encorafenib cetuximab chemo, it's 30 months. It's as good as any normal tumor without this bad mutation. So this is the proof that you need always to give the first treatment and not save something for later. So that's one important lesson. Now, what I think is very unique, because we will also talk about immunotherapy, is that immunotherapy plays a significant impact on subsequent treatments, because immunotherapy remodels and changes the tumor microenvironment. And I know we will talk probably about it that we have almost exhausted our identification of targets on the tumor by sequencing to the death for certain mutations in the tumor and have completely neglected themicroenvironment.
Dr. Small (30:15):
So maybe you could give an overarching view on the tumor microenvironment, what that is and why it's important, and then how do we leverage it to actually attack the tumor.
Dr. Lenz (30:25):
So I think in the beginning of our research we were trying to avoid to have any normal cell or from the tumor in our sequencing tissue because it would have diluted it. We didn't realize that these cells are all very important. The tumor microenvironment depend where you are, the liver, the lung, the bone, the gut. When I throw you in the water, you're not still the same person, but your activity is different.
Dr. Small (30:51):
Yes.
Dr. Lenz (30:52):
And the tumors is the same. When you throw it in a different environment. It will drive or drive faster or not as fast. But we now realize that there is significant communication networks in the microenvironment is blood vessels, there are fibroblasts, there are nerves, and there are immune cells. All these communicate directly with the tumor cells and with each other. It is an incredible network. Okay. So interfering with that will be the future of new treatments.So the cancer-associated fibroblasts play a big role in controlling inflammation and immune cell trafficking. The blood vessels are absolutely critical for the activation of certain immune cells. The nerves talk to the blood vessels, the nerves talk to the immune cells. So if we understand that communication network and how we interrupt it, that will be a new treatment option. And I'm convinced that will happen, because we now have the capacity to dissect out the microenvironment and better understand the role of these different functions. Now we all talked about the brain-gut connection. It's all nerves talking to each other in order to do the inflammation and do the blood vessel formation and so on. So it comes together at some point. But the microenvironment is the new frontier for cancer research, not the tumor.
Dr. Small (32:29):
So this whole, I guess, gut-brain axis, a big discussion has been microbiomes and how do we modulate the microbiome since it is part of the tumor microenvironment. What are your thoughts on that and how do we do it well?
Dr. Lenz (32:42):
So, I think there is, we are just a little bit scratching the surface on understanding what the microbiota in the gut does. Now we know when you have bad bacteria that they create a lot of inflammation, and inflammation is not good. Or when you have chronic inflammation, you can cause eventually cancer. Patients with ongoing colitis develop that. We know that very well. We have even identified the bacteria which are the worst one to create inflammation. The fusobacteria. And the fusobacteria were shown that they're not only sit in the gut, they can travel into the tumor, and these fusobacteria, high check cancer cells and travel to the liver. So they're part of the metastatic spread.
Dr. Small (33:35):
Interesting.
Dr. Lenz (33:36):
They're looked in a mouse model where this happened and then they're treated with antibiotics, and the tumors in the liver stopped growing. So I think it's all a little bit simplified. I think it's much more complicated because we tend to believe and we have bad bacteria, they're responsible for everything. Personally, I don't think that's the major story about it. Bacteria are natural and we all need, we have four or five pounds of bacteria in our gut. It’s not little, but these bacteria not only in the gut, we are dependent on them. Without them we would not survive. But some of these bacteria are also potentially communicating with cancer cells and they may in the tumor and we have some data showing that. And this bacteria communicate again in a very unique way with the tumor cells, but also the tumor microenvironment. We actually have started a collaboration with a microbiologist who does on focus on core cultures of bacteria with cancer cells. And I was shocked how sophisticated this bacteria communicate with cancer cells to two major pathways. One is metabolic and one is neurotransmitter. Yes, I had the same look on my face, thinking bacteria produce neurotransmitter? So there is very unique things. I think these are all things we have never thought about and just going to develop. So when you think about it, that neurotransmitter play a role, there are no drugs targeting neurotransmitter. Now we have done over the last probably four or five years, incredible research on neurotransmitter and tumors. There was a publication out in Cell many years ago. Because it was in a pancreas cancer model, and this pancreas cancer was not able to produce an essential amino acid. So it triggered a nerve cell from the spinal root to grow an exon into the tumor to produce this essential amino acid.
Dr. Small (35:59):
So let me ask you this question. So, how do we then address it?
Dr. Lenz (36:02):
So we don't know fully what these drugs do. So we did a very easy experiment, or we gave a mouse with colon cancer, dopamine like we treat Parkinson and the tumors decreased their growth in a significant way.
Dr. Small (36:20):
Wait, sorry, you gave it dopamine and it decreased
Dr. Lenz (36:23):
Yes.
Dr. Small (36:23):
So we want to increase the release.
Dr. Lenz (36:26):
Remember Parkinson is a lack of dopamine. We gave the dopamine like we treat Parkinson's medication, we gave medications which change the dopamine metabolic pathway and they have an antitumor effect. It doesn't melt away, but it is almost the opposite that you would think.
Dr. Small (36:47):
But that's interesting. So basically if we modulate the release of dopamine is basically what we're saying, we may be able to actually help with
Dr. Lenz (36:57):
I think right now there are potential values for treatment. But I think where this plays a big role is for prevention.
Dr. Small (37:05):
Yeah. Yeah.
Dr. Lenz (37:07):
When we can understand the regulation of neurotransmitter, if Parkinson's patient or neurogenerative disease, it's not all dopamine, it's really protective. If we can create a pathway which mimics this without the side effects, we would prevent colon cancer. In the moment we are looking for a better target in the neurotransmitter network in order to have more effect. And we identified a overarching gene. We are working on this, but I think this is the frontier. This is where I think the future may have more promise than the classical treatments we are giving now, because at the end of the day, metastatic disease still has a median survival of 10% after five years. We need to do something different. Now I think what is very important for colon cancer discussion is we talked about always the best treatment first. Because if you shrink colon cancer metastases and it comes to a resectable stage, there is a curative attempt. You can cure some of these patients. That's not possible in breast cancer. Or if you're metastatic, you can't do anything anymore. In colon, you can. So the intervention in identifying to have a shrinkage or a significant shrinkage and you can resect, you see big differences in outcome.
Dr. Small (38:30):
A lot of data have recently come out about fecal transplants, and we're seeing that, with fecal transplant, you have increased, you can have increased sensitivity to some therapies. What is your take on fecal transplant as you're talking about the whole tumor microenvironment and microbiome?
Dr. Lenz (38:50):
So I don't use it in my clinic, but it's used for colitis patients very successfully. But I'm fully convinced I put all my patients on the probiotics and everybody says, what should I take? Or I don't need it. I eat yogurt. And it's interesting, the cheap yogurt has one bacteria. The middle yogurt has about two or three, and the expensive yogurts have six. When you count, you look at the ingredients, you see the diversity and the frequency of your acidophilus, the bifido, the thermophiles, and so on. So I recommend a probiotics which has at least 10 different species.
Dr. Small (39:34):
Okay.
Dr. Lenz (39:34):
To really look for calming down and controlling the inflammatory environment. So all my patients are on probiotics, with a big, high impact. It's not the 20 billion, it's the diversity which counts.
Dr. Small (39:47):
Ah,
Dr. Lenz (39:48):
Okay.
Dr. Small (39:49):
Because I saw one with just one. To your point, even some
Dr. Lenz (39:51):
Don’t buy a yogurt with one.
Dr. Small (39:52):
Now I'm learning that.
Dr. Lenz (39:54):
Yes,
Dr. Small (39:56):
It tastes good, though.
Dr. Lenz (39:57):
No, the other one tastes much better.
Dr. Small (40:05):
So I know that challenge as well as SWOG. This ASCO’s presented data on exercise and eating anti-inflammatory diets.
Dr. Lenz (40:16):
So interestingly, all these factors—inflammatory, anti-inflammatory diet, exercise—is all the microenvironment. You change not the tumor, but you change where the tumors, what environment the tumor lives, what the host is changing. So I'm a big believer. So we have now started with that. We actually give our patients information on anti-inflammatory diet. I tell all my patients not to eat red meat, to avoid refined sugars, to supplement diet with vitamin D3, to exercise, drink coffee, no cream tea. We try to guide them through in order to have a framework. I think knowing that this particular, the extent of exercise is not known or I think it's important that all my patients do some exercise. I say 20 minutes, 30 minutes a day is good. Or you can also not overdo it depending on chemo. You cannot run around and do a half-marathon when you get chemo, but you can't walk around the block twice a day, to walk about three, four miles. So I try to make sure that they do that. It's also good to get out and see something. Have sun. This is all important for your rhythm. I think for the food it's a little bit more complicated.
Dr. Small (41:42):
Well, I've noticed many things had to be erased from my diet when it comes to anti-inflammatory.
Dr. Lenz (41:46):
So we are working, actually, we have a little team who's working on potentially to have a better understanding what diet and what that would mean for the food you can eat and avoid. But I am a big believer in it because this is what you change the microenvironment. Now I tell you we did an incredible experiment. We work with our specialist, Dr. Cohen, from the school of gerontology. So aging. We took young mice and 1-year-old mice, which was a hard thing to get by. We put the same tumor in the young and old.And we gave them high-fat diet, regular diet and calorie restriction. And we looked at the stool microbiota, we looked at the cytokines in the blood, and we looked at the tumor, and the data are amazing. So young mice, the microbiota is angry, very inflammatory high cytokines. The high fat diet, these mice died within days. When they had calorie restriction, they lived much longer. Much longer. The young ones. The old ones, the stool was much nicer, diverse, not so inflammatory. The cytokines were lower and the diet did not make too much difference. A little bit if you had high-fat diet, a calorie restriction a little bit, but not even compared to young. And some you would have expected it and some you haven't. But then we looked at the tumor and here came the big surprise. The same tumor changed in the old versus the young. The tumor makeup and intratumoral thickening changed.
Dr. Small (43:40):
Interesting. Interesting.
Dr. Lenz (43:42):
The tumor. So the host,
Dr. Small (43:43):
Based on the host
Dr. Lenz (43:44):
Changed the tumor. That's what you do with your diet. And we identified the major pathway which changed. We identified the gene. And this gene is highly predictive and prognostic for outcome. So a host can change the tumor. So exercise, food, I'm
Dr. Small (44:04):
Critical. Critical.
Dr. Lenz (44:04):
In no doubt that it can do it because we can see it.
Dr. Small (44:09):
So then in that case, as we think about prevention and those that are predisposed to colorectal cancer, should we be pushing those people to really make sure that they are, their diet is anti-inflammatory diet and all the lists that you
Dr. Lenz (44:24):
Yes, absolutely.
Dr. Small (44:26):
But, I mean, are people counseling them about this? Because I have not heard a lot about this until after you've been diagnosed.
Dr. Lenz (44:33):
Yes. So I think we have always counseled them on healthy diet. We have never had a very specific diet for anti-inflammatory or pro-inflammatory, what to avoid. That's what we are at the moment changing in our counseling. I do the meat and on the alcohol.
Dr. Small (44:51):
So if we look at other lifestyle behaviors that resulted in increased risk, curious to see what your lab had discovered.
Dr. Lenz (44:59):
Yeah, so I think we have seen and that has been published that certain professions have higher risk, including pilots, night shift nurses, and it becomes very apparent that the disruption of regular night sleep is increasing risk for colon cancer. So the circadian clock, which regulates night and day shifts, is very poorly understood in cancer situations. So knowing that the administration schedule and knowing that certain professions who cannot sleep at nighthave a higher risk of colon cancer or different outcomes, we started looking at the regulation of the clock. We studied these genes in many phase three clinical trials, including 80405, FIRE-3, and you name it, in thousands of patients, since we have large clinical databases, molecular characterized, and the data were amazing. We were completely blown away because many of these circadian genes predicted efficacy of two targeted drugs, one immune checkpoint inhibitor and one the anti-VEGF bevacizumab-based treatment. We confirmed that in multiple trials. We even confirmed that in a Japanese cohort. So this is for real. So I thought, wow.
Dr. Small (46:31):
Yes.
Dr. Lenz (46:32):
So is that an effect on the tumor? Is this effect on the tumor microenvironment? What is it all? So we did very simple tests all. So we knocked out the gene, we overexpressed it, okay. And it changed the growth pattern of the tumor cells dramatically. So at this point I wanted to know more about the mechanism and are there drugs available? And it happened to be that one of the pioneers of circadian clock, Dr. Steve Kay is at USC, and he's a metabolic guy, a plant biologist, nothing with cancer. So I showed him all this data, predictive and outcome and prognostic, and he was saying, oh my god, that is incredible. We should work together because I have a drug which targets the clock. He developed it for metabolic disorders. So after mechanistic knocking it out and knocking it in, we use this drug in our animal models. And combined it with immune checkpoint inhibitors and combine it with bevacizumab. And there was traumatic change in efficacy. So just a very non-toxic drug changed the efficacy of immune checkpoint inhibitor inhibitor significantly and increased the efficacy of bevacizumab I have never seen before. So it is the microenvironment which I think plays a bigger role, but we don't know for sure what the particular targets in the tumor microenvironment is.
Dr. Small (48:19):
I know as we start thinking, wrapping up, there's a couple of things I want to really pick your brain on. Crystal ball. If you look five to 10 years out, where do you think the field is going to go when it comes to colorectal cancer?
Dr. Lenz (48:34):
I think we will cure much more patients. We will use less chemo, we'll use less surgery, less radiation treatment. We will optimize immunotherapies in a way that we will use it in most of the majority of the patients. I think that there will be new drugs developed, taking advantage of targets in the tumor microenvironment, which we just start to believe. I think that epigenetic treatments will be part of our treatment strategies, and I'm very optimistic that all this research will hopefully translate into better prevention drugs, which we have not seen. So I think these targets, which are now the new frontier, will hopefully translate into very effective prevention studies and treatments.
Dr. Small (49:22):
What are three things you want the listeners to take away after listening to this show?
Dr. Lenz (49:27):
First, colon cancer is preventable. Do the screening with any kind of unexplainable symptoms in a young patient. Don't wait because there are too many mistakes done thinking this is hemorrhoids, this is stomach upset and month and month go by without a colonoscopy. Second, do molecular testing on the tumor, if patients develop colon cancer. That will guide the best treatment options. Do it at the time of diagnosis, not later. Because with molecular-defined subgroups, now we have treatment options. We can completely change the outcome, including curative attempts. To miss an MSI high would be a crime, okay, because we can cure these patients. Third is you need to make sure you really watch for the sequence of your treatments. The best treatment first, and the future will lie in the tumor microenvironment as targets for novel treatment or novel treatment combinations. So I did four
Dr. Small (50:32):
For the physiciansstarting out in their career who are now walking into GI oncology. Any advice?
Dr. Lenz (50:39):
Yeah, I think listen and don't be shy to ask questions. Be curious, okay. Don't be shy to question decisions or ask why because only that way we find better answers, okay. And I think sometimes people think these are weird ideas and they are actually very interesting and they lead to novel questions. So work with your mentor, work with your professor, reach out to basic scientists, open up that communications. You will be very surprised how much more information you gain and you better understand why you're doing and why certain drugs work. I think sometimes we drown in the clinics because of clinical issues and we need to look beyond what we do, but better understand why this happens, what can be improved. So I think open-minded, listen, look and go to meetings and talk to others, particularly the basic scientists. It's not easy but it's very rewarding.
Dr. Small (51:45):
And I remember when you were on the phone with me, you told me that as you were looking and seeing the differences, the question you asked is why? Now
Dr. Lenz (51:53):
Yes. Yes.
Dr. Small (51:53):
Let’s figure out the why because that's the root of everything.
Dr. Lenz (51:55):
And I mean we stumbled really on the night shifts all, but take it from there and go back and thinking because I think what the basic scientists are missing to know what's happening in that clinic, what do we see different? What makes them different in the way? It was so funny because I think we talked on the phone about this. We stumbled on the location right versus left.
Dr. Small (52:21):
Yes, yes.
Dr. Lenz (52:22):
Okay. Because we had a postdoc and looking and I said, can you check out ER alpha and ER beta in colon because we know premenopausal women have less colon cancer, but only on the right, not on the left. So we started looking at ER beta, which is expressed only in colon, not ER alpha. And sadly we clearly see there is a difference. Postmenopausal woman, you prevent colon cancer on the right, not on the left. So now we knew and checked on the location as a predictive and prognostic marker, and it is, it's all in the guidelines. So the clinical observation follows biology because it's a different disease, midgut versus end gut that explains why the prognosis is different. This explains why certain drugs will not work. So be minded, be curious, ask why. I completely agree.
Dr. Small (53:22):
Yeah. My old mentor used to say, there isn't a problem that we can't solve. You have to ask why and then go figure it out.
Dr. Lenz (53:29):
I agree.
Dr. Small (53:30):
Yeah.
Dr. Lenz (53:31):
He's a smart man.
Dr. Small (53:33):
So one of the things I like people to realize that the reason why this is so important is because there's always people behind this disease. There are people that we fight for. There's a reason why we cannot stop, why we have to continue to ask why and then try to seek the answer. So we all have people or that person that we are fighting for. Is there someone that you're fighting for or
Dr. Lenz (53:55):
Yeah, I have wonderful patients. I love them all. I think one of the biggest rewards for me is that many of them go out and do communities and create national support groups, advocacy group, and they're doing an amazing job because I think physicians are all very busy in the clinic and cannot explain everything, and information about clinical trials is not so easy to communicate. The patient advocacy in the US is unparalleled in the world and what they do for our communities and our patients is completely underrated. They help so much to better show the patients what they need to do, what they have to ask, what clinical trials are out, please look for out for this. I am so impressed by them and that's what I'm fighting for, that they have all the information to share and be able and amplify what we know to make access to people who otherwise would not have access to that information.
Dr. Small (54:56):
Yeah, I agree. In the US particularly, I mean this is a powerful group and we have to continue to support them.
Dr. Lenz (55:01):
Yeah, I mean Colontown and Colon Cancer Alliance and WunderGlo Foundation, they have impacted so many patients and people around the world. I'm very minimal for my impact compared to them. I'm so impressed with that, that they are able to do that.
Dr. Small (55:19):
Well thank you so much for your time and thank you for your fight and just to our listeners and remember always why we fight and who we're fighting for and ask why
Dr. Lenz (55:29):
And fight on
Dr. Small (55:30):
And fight on. Thank you so much. It's been such a pleasure.Such a pleasure.
Dr. Lenz (55:37):
It was a pleasure. My village, we were 90 people in the class. Okay. I'm the only one who went to university. I'm the first one in our family and I left to the university and I was just happy to made it. If you would have said I would become a physician and would study abroad and would be in the US in the major cancer center, I would say, are you nuts? Are you on medications? I just went whatever was fun.
Dr. Small (56:05):
What makes your practice unique in LA?
Dr. Lenz (56:06):
I think USC is an incredible university because we have the private practice, we have the rich and famous, and we have also a county hospital where people come who have no insurance, who are the underserved. And I love it to have my feet in both worlds. We make no differences how we treatpatients. And that's the reason I stayed. The patients, the county, they are so lovely and so grateful. Just that you help them and you're there for them. Yes. I think it keeps you humble.
Dr. Small (56:39):
You have one of the largest patient populations. I guess, samples in the US I'm curious to know.
Dr. Lenz (56:44):
Over the last 20 years we had postdocs from different countries and the people who came to me wanted to do research. So I said, you can come, but bring me your clinical trial samples. Bring me your databases. And that's what they did. That makes a difference not only for them, but it has impact for patients everywhere or it's a global impact.