Tag Archive for: somatic mutation

Promising Research and Treatment Updates From an MPN Expert

Promising Research and Treatment Updates From an MPN Expert from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasm (MPN) expert Dr. Mark Heaney shares promising news about about treatments being studied, and how these advances may impact the future of MPN patient care.

Dr. Mark Heaney is a hematologic oncologist and Associate Professor of Medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University. Learn more about Dr. Heaney, here.

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What Are the Goals of ET, PV, and MF Treatment?

What Are the Goals of ET, PV, and MF Treatment? 


Transcript

Katherine Banwell:

When it comes to MPN research and emerging treatment options, what are you excited about specifically?

Dr. Heaney:

I think that there are a lot of exciting treatments in MPNs. Now, I’ve been doing this long enough that when I started, we really didn’t have very many treatments, and I think the last few years has brought a number of very promising treatments, and I think more than that, there’s a buzz and much more interest within the physician investigator community and within pharma to develop treatments for patients with MPNs, recognizing that MPNs are still relatively rare diseases.

I think we’re on the brink of having several new treatments for myelofibrosis, and as of today, they’re investigational, but they may be available even within the next year, and that will give us more opportunities. Drugs like pacritinib and momelotinib, I think, provide effective treatment options for patients who may not be responding optimally to ruxolitinib or in whom ruxolitinib may not be the best choice because of low blood counts.

I think that drugs like ropeginterferon, which may well be approved soon, may provide another treatment for patients with polycythemia vera.

And then, beyond these drugs, which are both – which are all in late-phase investigation, there’s a plethora of drugs that appear really promising that are earlier in evaluation.

I think one of the things that’s been not really attainable with the drugs that we’ve had to date has been to really reduce the contribution of the mutant clone to blood cell production, and this is a concept that has really revolutionized the treatment of patients with another myeloproliferative disease, chronic myeloid leukemia, and we know from that disease patients who had suppression of the malignant clone have done remarkably well and now live lives that are really indistinguishable from patients who don’t have leukemia.

I think the new drugs that are in clinical development are adding to the ability of suppressing them more than clones, and so, we’re getting closer to drugs and drug combinations that may have that ability. There is, for example, a drug that’s in late-stage development, a BET inhibitor – that’s CPI-0610 – that’s now entering Phase III trials that seems to be very promising.

There are other drugs that attack other pathways, like MDM2 and the BTK pathway, that are also very promising.

And, I think they’re also – we’re also on the advent of introducing cellular therapy into myelofibrosis, so that’s another dimension of treatment, and I think all of these will present new opportunities for patients in whom ruxolitinib may not work or may not be the optimal therapy.

Why You Should Understand Your MPN Treatment Plan

Why You Should Understand Your MPN Treatment Plan from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasm (MPN) expert Dr. Mark Heaney discusses the importance of understanding the goals of your treatment plan, including key questions to ask your doctor before beginning therapy.

Dr. Mark Heaney is a hematologic oncologist and Associate Professor of Medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University. Learn more about Dr. Heaney, here.

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How to Engage in Your MPN Treatment Decisions 


Transcript

Katherine Banwell:

Are there questions that patients should ask about their proposed treatment plan?

Dr. Heaney:

Yeah. I think patients should ask a lot of questions. I think a lot of patients don’t ask as many questions as they should, but I think there are a number of things that are important for patients to know. Number one, the question is whether they need treatment at all and what happens if they defer treatment. So, really, what – and, that’s another way of asking what the goal of treatment is going to be. Now, I think patients should have an expectation of what their physician thinks the benefit of starting a particular treatment might be.

I think that they should ask questions about the drugs that they’re taking. Are they new drugs? Are they well established? What are the side effects? And, I think the side effects fall into a number of different categories. Some of the side effects are immediate side effects that patients have and notice soon after they start taking the drugs.

Some of the side effects can be much more subtle, and we know, for example, that some of the agents that are used to treat myeloproliferative neoplasms can suppress the immune system and can make patients more susceptible to infection. Especially today, with lots of infections out there, it’s important for patients to know whether this is something that they should be particularly attuned to. I think that patients should also find out whether there are any lifestyle inhibitions.

So, sometimes, how many times you take a drug, whether the drug has to be taken on an empty stomach or with food – those sorts of things, I think, can be really important in deciding whether this is a treatment that’s right for the individual patient.

Katherine Banwell:

Yeah. Dr. Heaney, how would you define treatment goals, and why is it important that patients understand the goals of their treatment plan?

Dr. Heaney:

Often – often, patients do start treatment without a clear understanding of what the goals are, and I think sometimes, the goals that physicians have may be different than the ideal goals of the patient. I think we’re really fortunate in myelofibrosis today that we now know that ruxolitinib is something that prolongs survival, and we have a drug that has that ability.

And, I think articulating that as a goal to patients is important in their understanding of why a physician might want to push through some toxicities and say, “I know that this may be causing some GI upset, but we’re doing this because we think this is something that may help you to live longer.” So, I think that’s part of – and, that may be the physician’s main goal. That may not necessarily be the patient’s main goal, and the patient’s main goal may be quality of life. And so, having – it goes back to the question about dialogue and understanding what the patient really wants out of his or her treatment and making sure that the patient and the physicians are talking to each other, not past each other.

Will Your MPN Progress? What You Need to Know.

Will Your MPN Progress? What You Need to Know. from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasms (MPN) expert Dr. Mark Heaney discusses how MPNs may progress from one to the next and addresses the possibility of slowing disease progression.

Dr. Mark Heaney is a hematologic oncologist and Associate Professor of Medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University. Learn more about Dr. Heaney, here.

See More from Engage

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Promising Research and Treatment Updates From an MPN Expert

Promising Research and Treatment Updates From an MPN Expert

Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF?

Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF? 


Transcript:

Katherine Banwell:    

Patients living with MPNs are often concerned about disease progression. Will everyone progress?

Dr. Heaney:

Now, we don’t know the answer to that question. There are patients with myelofibrosis and other MPNs who we know live more than 20 years with their disease.

In general, the natural history of the disease is one of gradual progression, and some people have more rapid progression than others. We know that there are patients who will die of complications of their disease, but not everyone will progress, and there are some patients where observation without treatment, even in the face of some progression, may be a very reasonable treatment plan.

There may be times, though, when it’s not really possible to maintain a quality of life without some treatment, and one of the ways of slowing that kind of progression may be with some of the available therapies of – approved therapies and investigational therapies. But, I guess the short answer to your question is not everyone will die of his or her disease, even if the disease does progress, and there are some patients in whom that progression is so slow that they’re able to live really full lives without it – without the disease’s interfering with their lives.

Katherine Banwell:

Is there a way to prevent progression?

Dr. Heaney:

Well, there isn’t a magic pill that stops progression. A lot of my patients ask if there’s some diet, if there’s something that they can do that will change the course of the disease.

And, the short answer for, I think, the overwhelming majority of patients is there isn’t anything that’s a magic bullet. We believe that drugs like ruxolitinib in myelofibrosis can slow the progression of disease.

There are drugs in other MPNs that we also think may slow disease progression even if they don’t completely halt progression. For some patients – admittedly, the minority – who might be candidates for allogeneic stem cell transplant, we know that that can be curative, and so, in that way, that can prevent progression in those patients.

And so, I think it’s important to, again, go back to your physician, understand what progression means, understand what – how the proposed treatment might interact with that progression, and again, getting back to the question of outcomes and goals of therapy, understand clearly what the treatment plan is aimed to do.

How to Partner With Your Doctor on Treatment Decisions

How to Partner With Your Doctor on Treatment Decisions from Patient Empowerment Network on Vimeo.

Myeloproliferative neoplasms (MPN) expert Dr. Mark Heaney explains the role of shared decision-making when choosing therapy and discusses how MPN patients can benefit from taking an active role in their care.

Dr. Mark Heaney is a hematologic oncologist and Associate Professor of Medicine at the Herbert Irving Comprehensive Cancer Center of Columbia University. Learn more about Dr. Heaney, here.

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MPN Caregivers: How to Provide Support During Appointments 


Transcript:

Katherine Banwell:    

 The terms “shared decision-making” is being used lately when we talk about patient care. What does that term mean to you?

Dr. Heaney:

Well, I think it’s really important for patients to be involved in their care, and I think it’s part of shared care, and I think that patients who are really in partnership with their physicians are able to make better choices, and there’s much better communication.

So, to me, that’s the basis of the physician-patient relationship. It’s less of an asymmetrical relationship and much more of an equal relationship.

Katherine Banwell:

Why should patients take an active role in their care? How do they benefit?

Dr. Heaney:

Well, patients who take an active role in their care, I think, provide much more input to their physicians and let them know how they’re feeling, and I think that allows their physicians to know much better what kind of side effects they might be having, whether they’re getting any benefit from the drug, whether they’re having symptoms that are related to the disease, and that kind of communication is really central to patients being able to make the best decisions for themselves and getting the best advice from their physicians.

What Are the Benefits of MPN Inhibitor Treatment?

What Are the Benefits of MPN Inhibitor Treatment? from Patient Empowerment Network on Vimeo.

MPN expert Dr. John Mascarenhas shares an overview of how inhibitor therapy works to treat myelofibrosis (MF) and the benefits of this type of treatment.

Dr. John Mascarenhas is Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai (ISMMS) and the Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai. Learn more about Dr. Mascarenhas, here.

See More from INSIST! MPNs

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Transcript

Katherine Banwell:

Dr. Mascarenhas, what is inhibitor therapy and how does that work?

Dr. Mascarenhas:       

So, inhibitor therapy in general are usually oral drugs for the most part, small molecule inhibitors that are geared and usually specific but not totally specific because then they can have off-target effects, but geared to inhibiting usually an enzyme that is overactive or is contributing to the pathophysiology of the disease.

I think in MF, probably one of the best examples is a JAK2 inhibitor. So, there are a number of JAK2 inhibitors that have been in clinical testing. There are two that are approved, ruxolitinib and fedratinib which are excellent drugs in inhibiting JAK2 protein itself in the cells that could be either upregulated or hyperactive in the signaling pathway, and it quiets down a signaling pathway in the hematopoietic cells that leads to a lot of the manifestations of the disease, namely symptoms and spleen.

So, one of the clear benefits of JAK inhibitors that was established many years ago and reinforced by multiple drugs that are either approved or in late-stage testing is these drugs are excellent in improving the symptom burden in the patients and reducing their spleen. Unfortunately, as a class, we’ve not seen these drugs induce remissions or cure patients. So, there’s still interest in developing, obviously, non-JAK inhibitor therapies. But inhibitors in general are inhibiting proteins that are either inappropriately activated or part of a cascade of signaling molecules that are contributing to the disease.

And they are not chemotherapeutic, which might be an important point to make. In past days, we’ve relied heavily in hematologic malignancies in using chemotherapies which are nonspecific and just kill dividing cells whereas inhibitors typically are targeted, and in some sense, it’s personalized to the disease with toxicity profiles that are usually quite distinct from the traditional chemotherapies that we use.  

 

How Do MPNs Progress From One Disease to the Next?

How Do MPNs Progress From One Disease to the Next? from Patient Empowerment Network on Vimeo.

Understanding how essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF) are connected may be confusing to patients. Dr. John Mascarenhas, an expert in myeloproliferative neoplasms (MPNs), provides an overview of how the conditions are defined and how they may progress from one condition to the next.

Dr. John Mascarenhas is Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai (ISMMS) and the Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai. Learn more about Dr. Mascarenhas, here.

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Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF?

Myeloproliferative Neoplasms Defined: What Are ET, PV, and MF?

Which Gene Mutations Impact Myelofibrosis Treatment Options?

Which Gene Mutations Impact Myelofibrosis Treatment Options?

Which Tests Do You Need Following an MPN Diagnosis

Which Tests Do You Need Following an MPN Diagnosis?


Transcript

Katherine Banwell: 

As we move through today’s program, which is going to cover the three classic MPNs, polycythemia vera, essential thrombocythemia and myelofibrosis. So, for someone who has one of these conditions, can you help us understand how one may progress to the next?

Dr. Mascarenhas:

So, these are a very heterogeneous or variable group of diseases that are under an umbrella called the myeloproliferative neoplasm. So, MPNs can really present and behave and have very different clinical courses. So, I think it’s very important for patients to realize that these are rare diseases, that that has a complexity to it because they don’t always have the ability or the privilege to know other patients or people in their lives that may have these diseases. So, it could be very frightening from a level of feeling isolated or alone with a diagnosis like this and not having familiarity, but also, that these are vague diagnoses in the sense that when you have breast cancer, one can kind of conceptualize that there is a mass in the breast, for example, and that that can be staged. It can go to the lymph nodes in the armpit, it could spread below. And people can kind of understand that concept. I think it’s a little bit more challenging when you talk about MPNs because it’s a little bit more abstract.

These diseases are within the bone marrows at diagnosis. So, they’re not staged in a physical way, and they are complex because they can lead to high blood counts, low blood counts, different types of symptoms, and the approaches really have to be personalized. They are all three interrelated because there are commonalities. So, there are certain clinical commonalities and also biologic commonalities. So, for example, the JAK2 mutation, the JAK2V617F mutation is seen in all three diseases. So, it’s not specific to one or the other.

It’s more common in polycythemia vera, but in about 50 percent of patients with ET, and 50 percent of patients with MF, you can see this mutation. So, the mutation alone doesn’t really tell us what the disease is. It just tells us you have one of these diseases. And, there are other mutations. So, a bone marrow biopsy then becomes integral in helping subtype the patient and then create that treatment plan and that outlook that’s specific for that disease.

And as you mentioned, to make it even more complicated, these diseases can overlap not just biologically, but in a continuum. So, patients with ET or polycythemia vera can progress in some cases to myelofibrosis. And, all three diseases in a minority of patients can progress or evolve into acute myeloid leukemia, which is a more aggressive form of bone marrow cancer.

Which Tests Do You Need Following an MPN Diagnosis?

Which Tests Do You Need Following an MPN Diagnosis? from Patient Empowerment Network on Vimeo.

After a diagnosis of essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), what testing should take place? Dr. John Mascarenhas shares an overview of essential and in-depth testing for patients with myeloproliferative neoplasms (MPNs).

Dr. John Mascarenhas is Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai (ISMMS) and the Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai. Learn more about Dr. Mascarenhas, here.

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MPN Treatment: What Is the Role of Biomarkers?


Transcript

Katherine Banwell: 

What tests are necessary to help understand a patient’s specific disease at diagnosis?

Dr. Mascarenhas:

Usually, the blood counts are the first opening door test that allows some understanding of, again, either an abnormal production of red blood cells, platelets or under production of these cells. And, that’s really where often the evaluation begins. And then, there are further blood tests that often are done.

And I would say almost indefinitely or almost definitely one should have a bone marrow biopsy that helps categorize the type of myeloproliferative neoplasm because there can be overlap in how the blood counts can look from one disease to the next and overlap in the mutations like the JAK2 mutation. So, sometimes, the blood counts and the molecular testing are not enough, and a bone marrow biopsy looking under the microscope at the different types of cells, the proportion of cells, whether there’s fibrosis where there’s others other types of cells that shouldn’t be there and they’re looking at the chromosomes and the flow cytometry, these are associated tests. As well as almost probably anywhere anyone goes at this point, they’re going to get next-generation sequencing, which is looking at multiple genes and mutations, and that gives a more broader, deeper sense of the disease.

So, those really become the integral parts. In some cases, patients will end up getting imaging of their abdomen to see if they have an enlarged spleen or enlarged liver.

Although that’s not always necessary, that is often part of the workup. So, it’s bloodwork, it’s bone marrow biopsy, sometimes imaging is usually the cornerstone.

Katherine Banwell: 

And, what is molecular or biomarker testing?

Dr. Mascarenhas:    

So, molecular testing today really means – at one point, it really meant looking at PCR for specific gene mutations.

So, for example, we would look at the JAK2 and we would say, “In a given person, is this gene mutated?” We all have JAK2 gene, but in patients with these diseases, they’re more commonly mutated which means altered in the blood cells. And, it’s very important for a patient to understand not in every cell in their bodies, but in their blood cell compartment. And, that helps us understand and start characterizing their disease, and sometimes that mutation can be measured. It can be at a low level. It could be a high level. And, that’s all put together in trying to understand the molecular basis of these diseases.

Today, next-generation sequencing has really taken over and that’s looking at more than just one gene.

Its sequencing could be 40 genes, it could be 200 genes, to get a sense of the complexity of the disease and looking for certain mutations which are considered biomarkers that can portend prognosis or I think increasingly, we’ll see may inform treatment decisions and may even be targets themselves of therapies.

Katherine Banwell:              

Right. Should all patients diagnosed with ET, PV, or MF undergo biomarker testing? Is that necessary?

Dr. Mascarenhas:       

I would say it’s part of the modern evaluation and management of patients today. I don’t think that that was true 10 years ago. But, I think the field has matured. I will say I’m the first person to acknowledge to patients that we get a lot of information back, and the truth is we don’t often know what to do with all of that information. So, sometimes we get information back that can cause anxiety because you can see mutations in genes. But they don’t always inform us on how to educate the patient about their disease or tell us what to do with the treatment.

So, there is still a lag as there normally would be between the testing of the results that we get, and then the actual knowledge of what to do with that. And, that’s still a process that’s in evolution.

Which MPN Treatment Is Right for You? What You Need to Know Resource Guide

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Which MPN Treatment Is Right for You? What You Need to Know

Which MPN Treatment Is Right for You? What You Need to Know from Patient Empowerment Network on Vimeo.

What should you know before deciding which treatment is best for YOUR MPN? MPN expert Dr. John Mascarenhas reviews key factors–including essential testing–that guide treatment decisions for essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Dr. Mascarenhas also provides an overview of available treatment types and why he’s hopeful about the future of MPN research.

Dr. John Mascarenhas is Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai (ISMMS) and the Director of the Adult Leukemia Program and Leader of Clinical Investigation within the Myeloproliferative Disorders Program at Mount Sinai. Learn more about Dr. Mascarenhas, here.

See More from INSIST! MPNs

Download Guide

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How Is MPN Treatment Effectiveness Monitored?

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What Are the Goals of ET, PV, and MF Treatment?

What Are the Goals of ET, PV, and MF Treatment?


Transcript

Katherine:

Hello, and welcome. I’m Katherine Banwell, your host for today’s program. Today, we’re going to discuss how to access the most personalized therapy for your MPN and how you might benefit from key testing. Before we get into the discussion, please remember that this program is not a substitute for seeking medical advice. Please refer to your healthcare team about what might be best for you.

All right. Let’s meet our guest today. Joining me is Dr. Mascarenhas. Welcome. Would you please introduce yourself?

Dr. Mascarenhas:

Thanks for having me. My name is John Mascarenhas. I am an associate professor at the Icahn School of Medicine here at Mount Sinai in New York City, and I am a clinical investigator in myeloproliferative neoplasms, and I direct the Adult Leukemia Program here.

Katherine:

Excellent. Thank you so much for taking the time out of your busy schedule to join us today. Before we delve into our discussion, let’s start with a term we’ve been hearing a lot about recently. How would you define “personalized medicine?”

Dr. Mascarenhas:

So, it’s a good question because I think it’s poorly defined in many ways because it can mean different things I think to different people. And, it’s a definition that’s in evolution. So, I think at its core, personalized medicine tries to embody the concept of creating an evaluation and management plan that is specific of tailored to that patient on multiple levels.

On a personal level, on an objective level of what the patient’s objectives are with their therapy or their disease, and then on a biologic level in terms of the type of disease, and now increasingly, on a molecular level. So, in some cases, it may be personalized therapeutics that are specific or targeted to certain mutations that the patient may have. And, that’s kind of where things are evolving from a treatment perspective. And to me, personalized medicine should be the goal of any interaction with a patient that you have to personalize the approach. Because, every patient that we meet is quite different and distinct from the next patient, and their own sensitivities, understandings and desires can be quite different. So, you want to personalize that approach to that patient at the most basic level.

Katherine:

Yeah. Well, that’s really helpful as we move through today’s program, which is going to cover the three classic MPNs, polycythemia vera, essential thrombocythemia and myelofibrosis. So, for someone who has one of these conditions, can you help us understand how one may progress to the next?

Dr. Mascarenhas:

So, these are a very heterogeneous or variable group of diseases that are under an umbrella called the myeloproliferative neoplasm. So, MPNs can really present and behave and have very different clinical courses. So, I think it’s very important for patients to realize that these are rare diseases, that that has a complexity to it, because they don’t always have the ability or the privilege to know other patients or people in their lives that may have these diseases. So, it could be very frightening from a level of feeling isolated or alone with a diagnosis like this and not having familiarity, but also, that these are vague diagnoses in the sense that when you have breast cancer, one can kind of conceptualize that there is a mass in the breast, for example, and that that can be staged. It can go to the lymph nodes in the armpit, it could spread below. And people can kind of understand that concept. I think it’s a little bit more challenging when you talk about MPNs, because it’s a little bit more abstract.

These diseases are within the bone marrows at diagnosis. So, they’re not staged in a physical way, and they are complex because they can lead to high blood counts, low blood counts, different types of symptoms, and the approaches really have to be personalized. They are all three interrelated because there are commonalities. So, there are certain clinical commonalities and also biologic commonalities. So, for example, the JAK2 mutation, the JAK2V617F mutation is seen in all three diseases. So, it’s not specific to one or the other.

It’s more common in polycythemia vera, but in about 50 percent of patients with ET, and 50 percent of patients with MF, you can see this mutation. So, the mutation alone doesn’t really tell us what the disease is. It just tells us you have one of these diseases. And, there are other mutations. So, a bone marrow biopsy then becomes integral in helping subtype the patient and then create that treatment plan and that outlook that’s specific for that disease.

And as you mentioned, to make it even more complicated, these diseases can overlap not just biologically, but in a continuum. So, patients with ET or polycythemia vera can progress in some cases to myelofibrosis. And, all three diseases in a minority of patients can progress or evolve into acute myeloid leukemia, which is a more aggressive form of bone marrow cancer.

Katherine:

Well, let’s turn to testing. And, you did just mention this. You touched on it a moment ago. What tests are necessary to help understand a patient’s specific disease at diagnosis?

Dr. Mascarenhas:

Usually, the blood counts are the first opening door test that allows some understanding of, again, either an abnormal production of red blood cells, platelets or under production of these cells. And, that’s really where often the evaluation begins. And then, there are further blood tests that often are done.

And I would say almost indefinitely or almost definitely one should have a bone marrow biopsy that helps categorize the type of myeloproliferative neoplasm because there can be overlap in how the blood counts can look from one disease to the next and overlap in the mutations like the JAK2 mutation. So, sometimes, the blood counts and the molecular testing are not enough, and a bone marrow biopsy looking under the microscope at the different types of cells, the proportion of cells, whether there’s fibrosis where there’s others other types of cells that shouldn’t be there, and they’re looking at the chromosomes and the flow cytometry, these are associated tests. As well as almost probably anywhere anyone goes at this point, they’re going to get next-generation sequencing, which is looking at multiple genes and mutations, and that gives a more broader, deeper sense of the disease.

So, those really become the integral parts. In some cases, patients will end up getting imaging of their abdomen to see if they have an enlarged spleen or enlarged liver.

Although that’s not always necessary, that is often part of the workup. So, it’s bloodwork, it’s bone marrow biopsy, sometimes imaging is usually the cornerstone.

Katherine:

And, what is molecular or biomarker testing?

Dr. Mascarenhas:

So, molecular testing today really means – at one point, it really meant looking at PCR for specific gene mutations.

So, for example, we would look at the JAK2 and we would say, “In a given person, is this gene mutated?” We all have JAK2 gene, but in patients with these diseases, they’re more commonly mutated which means altered in the blood cells. And, it’s very important for a patient to understand not in every cell in their bodies, but in their blood cell compartment. And, that helps us understand and start characterizing their disease, and sometimes that mutation can be measured. It can be at a low level. It could be a high level. And, that’s all put together in trying to understand the molecular basis of these diseases.

Today, next-generation sequencing has really taken over and that’s looking at more than just one gene.

Its sequencing could be 40 genes, it could be 200 genes, to get a sense of the complexity of the disease and looking for certain mutations which are considered biomarkers that can portend prognosis or I think increasingly, we’ll see may inform treatment decisions and may even be targets themselves of therapies.

Katherine:

Right. Should all patients diagnosed with ET, PV, or MF undergo biomarker testing? Is that necessary?

Dr. Mascarenhas:

I would say it’s part of the modern evaluation and management of patients today. I don’t think that that was true 10 years ago. But I think the field has matured. I will say I’m the first person to acknowledge to patients that we get a lot of information back, and the truth is we don’t often know what to do with all of that information. So, sometimes we get information back that can cause anxiety because you can see mutations in genes. But they don’t always inform us on how to educate the patient about their disease or tell us what to do with the treatment.

So, there is still a lag as there normally would be between the testing of the results that we get, and then the actual knowledge of what to do with that. And, that’s still a process that’s in evolution.

Katherine:

Right. Some patients may not know if they’ve received these important tests. So, what key questions should they ask their physician about testing?

Dr. Mascarenhas:

Well, I think it’s important that the patients feel empowered to understand sort of where the field is and what key questions you would ask a physician, hematologist who’s taking care of you. So, I think all patients should be aware of their diagnosis, the name of the diagnosis, the subtype, but also do they have any of the key driving mutations, the JAK2 mutation, the calreticulin mutation, the MPL mutation, and that’s usually done off of a bone marrow biopsy sample, but it can be done off peripheral blood. And, they may not always know that it’s done. So, I think having a discussion with the position to understand there are criteria that exist called the World Health Organization criteria that are updated frequently and should set a standard throughout the world of how you diagnose and establish these diagnoses.

So, I think it’s important for physicians to be able to convey to the patients with confidence, “We follow these criteria and you have these criteria and we’ve done this testing that shows that you have these mutations.” And not just regurgitate what they found, but help them understand and navigate with that means, which again, I will point out that sometimes we don’t know. But I think it’s important for physicians to convey sometimes that some of the findings that they may see, for example, patients look on portals these days and they can look at their labs and stuff like that. And, we don’t always have a terrific answer or an informed answer for everything that we get back. And, we will potentially in 10 years from now, but sometimes at the moment, we don’t. But I think a discussion about the meaning of the labs that are obtained is probably good for the patient to understand what’s being done.

Katherine:

Absolutely. It sounds like each person’s situation is unique and should be considered before making any treatment choices. Can you talk about how the results of these tests may affect prognosis and treatment?

Dr. Mascarenhas:

So, we do have risk stratification systems that we use for essential thrombocythemia, polycythemia vera, and myelofibrosis. I’ll talk about myelofibrosis because that’s probably a little bit more of a complex and sophisticated model. It’s also changing, and we update it frequently. And, these models are imperfect, so I always warn patients to not put all of their money in one basket when we talk about risk stratification. They broadly help us understand where a patient is in their disease course. So, for example, in myelofibrosis, historically, the DIPSS, the Dynamic International Prognostic Scoring System is used, which considered five clinical variables that have been shown to be independently prognostic. So, at age over 65, the presence of blasts or circulating immature cells in the peripheral blood, anemia, hemoglobin less than 10, symptoms, fevers, night sweats, weight loss or a high white count over 25,000, you those points up.

And patients can do this online. There are calculators that you can calculate your DIPSS score. And, you’ll see that there are four different risk groups that range from low risk to high risk, and they are associated with median survivals. We now know that mutations influence those, have influence on prognosis. So, there are a group of high molecular risk mutations like ASXL1, SRSF2, IDH1/2. So, there are mutations that also have prognostic significance, and we incorporate them into the decision-making.

And, essentially, and this is where I think patients have to be very careful, physicians have to be very careful with conveying this. With these risk models whether they are clinical variable risk models or these integrated molecular risk models, each category is associated with a median survival, that’s based on retrospective studies. But that doesn’t tell the patient specifically what they should expect in terms of survival. And, I always fear that patients, when they look at these things, or even physicians when they convey them that they may inadvertently misrepresent or convey what those really mean.

And, I think the purpose of those risk stratifications is really to help guide a risk adapted treatment approach that’s reasonable and is weighted for benefit to risk of the disease. So, for example, if you have advanced disease with a high-risk score of intermediate to or higher, bone marrow transplant in certain patients may be a warranted therapy to consider. So, they really help inform treatment.

Katherine:

Right. You mentioned a couple of these already. But, outside of testing, what other factors should be considered when choosing treatment?

Dr. Mascarenhas:

I think patient expectation. So, sometimes physicians and family will impose what they want for a patient, and that may not be what the patient really wants. So, I have learned over the years that it’s crucial to make sure that you understand the patient and what the patient’s expectations, desires, and that’s influenced by the life they’ve lead or the remaining life that they want to live and their own personal religious and spiritual beliefs.

] So, I think knowing your patient and understanding what their expectations are, it’s fundamental, and sometimes, it’s overlooked. So, understanding that, I think, is very crucial. And then, dividing what are the objectives of the treatment in a given patient? Is it really to improve anemia in some patient versus perhaps a different patient, it may be to improve their quality of life and reduce their symptom burden. And then in other patients, it may be purely trying to cure the disease with therapies that may be aggressive, which may not be appropriate for an older patient where toxicity could outweigh any potential benefit of survival or longevity. So, you really have to have a discussion with the patient or caregivers, and then define what are the goals in that individual to personalize that approach for that patient.

Katherine:

Right. Right. And, there’s the patient’s overall health, comorbidities, other things like that?

Dr. Mascarenhas:

Yeah, because we are not treating a disease in isolation usually. So, patients come with baggage posed of past diseases, current diseases.

And sometimes patients are not “fit” for certain types of therapies because they may be sick or they may have organ dysfunction that would make certain types of treatment approaches ill-advised because the toxicity could be higher. So, absolutely, you need to know their comorbid index, how much comorbidities they have and also their performance status, how active and how well they are in general.

Katherine:

Right. Are there specific biomarkers that may affect prognosis or treatment?

Dr. Mascarenhas:

So, yes and no. I mean, I think that’s an area of intense interest and research. So, we have identified certain biomarkers that have, as I mentioned, prognostic significance, and that may influence treatment decisions. So, patients who have, for example, as we discussed next-generation sequencing and we see their mutations that are present, if they have an accumulation of high molecular risk mutations, that may give us a sense that perhaps that patient may not enjoy the full benefit and duration of benefit of, for example, a JAK inhibitor as another patient that has a less complex disease.

And, that doesn’t necessarily mean that the therapy is not appropriate for the patient. But it may help us plan and be prepared to move on to the next therapy sooner or to be more vigilant for changes that would tell us it’s time to move on. So, I think they help us maybe get a general sense of things and put things into perspective. They don’t always necessarily inform us on a change in therapy immediately or the next or the most immediate therapy. But I do think that that will change because I would predict in the next five to 10 years, I think that the number of available drugs for myelofibrosis, for example, will likely double from what it is now. I think we will have an armamentarium to choose from, and what we will learn from trials that are ongoing is there may be certain profiles, mutations, chromosomal profiles, other clinical variable profiles that we will learn from these trials that will help us to find upfront, “Well, this profile really should go with his medication. That profile should go with that medication.”

An early of example that would be we’re learning that not all patients with the JAK2 mutation are created equal, that you can have different burdens of JAK2 mutation. And, patients with low burden JAK2 mutation, for example, may fare better with up a specific JAK to inhibitor like pacritinib than patients who get treated with other JAK inhibitors like ruxolitinib.

So, there are differences even within patient defined by mutation that may help us predict which of the JAK inhibitors, as an example, may be more appropriate as a first-line therapy. So, I think that will evolve more so over the next five to 10 years.

Katherine:

Dr. Mascarenhas, what is inhibitor therapy and how does that work?

Dr. Mascarenhas:

So, inhibitor therapy in general are usually oral drugs for the most part, small molecule inhibitors that are geared and usually specific but not totally specific because then they can have off-target effects, but geared to inhibiting usually an enzyme that is overactive or is contributing to the pathophysiology of the disease.

I think in MF, probably one of the best examples is a JAK2 inhibitor. So, there are a number of JAK2 inhibitors that have been in clinical testing. There are two that are approved, ruxolitinib (Jakafi) and fedratinib (Inrebic), which are excellent drugs in inhibiting JAK2 protein itself in the cells that could be either upregulated or hyperactive in the signaling pathway, and it quiets down a signaling pathway in the hematopoietic cells that leads to a lot of the manifestations of the disease, namely symptoms and spleen.

So, one of the clear benefits of JAK inhibitors that was established many years ago and reinforced by multiple drugs that are either approved or in late-stage testing is these drugs are excellent in improving the symptom burden in the patients and reducing their spleen. Unfortunately, as a class, we’ve not seen these drugs induce remissions or cure patients. So, there’s still interest in developing, obviously, non-JAK inhibitor therapies. But inhibitors in general are inhibiting proteins that are either inappropriately activated or part of a cascade of signaling molecules that are contributing to the disease.

And they are not chemotherapeutic, which might be an important point to make. In past days, we’ve relied heavily in hematologic malignancies in using chemotherapies which are nonspecific and just kill dividing cells whereas inhibitors typically are targeted, and in some sense, it’s personalized to the disease with toxicity profiles that are usually quite distinct from the traditional chemotherapies that we use.

Katherine:

Well, outside of inhibitor therapy, let’s review other treatments for patients. Depending on the patient, it seems like ET or PV may be easily managed. So, how are they treated? Let’s start with essential thrombocythemia or ET.

Dr. Mascarenhas:

So, ET is a disease in which first and foremost, we’re trying to reduce the risk of thrombosis, clotting, and/or hemorrhage bleeding. So, typically, ET patients are risk stratified by low risk or high risk.

It’s almost simply based on their age, whether they’ve had a clot in the past, and some systems now even incorporate other factors like mutation status. And, you tailor the treatment based on their risk score. So, low risk ET patients don’t necessarily need to be treated. They can be followed expectantly and watched. The height of the platelet count does not predict thrombotic risk. So, we don’t treat the platelet count per se. A high-risk patient is at high risk for clotting. So, these patients almost invariably are getting aspirin at a baseline, and they are often on cytoreductive therapy. And sometimes, that is chemotherapy like hydroxyurea (Hydrea). Sometimes it’s a non-chemotherapeutic option and like anagrelide, and sometimes it’s a biologic therapy like interferon alfa either 2a, PEGASYS, or 2b ropeginterferon. And, these are therapies that have rationale, that have clinical data, that have demonstrated reduction in risk of clotting, which again is the reason why we treat high-risk ET patients.

Katherine:

And, what about PV, polycythemia vera?

Dr. Mascarenhas:

So, in polycythemia vera, it’s similar to ET. We risk stratify patients low and high risk based on age and clotting histories. And whether you’re low or high risk, we give PV patients aspirin or at least once daily, and we look to keep their hematocrit below a threshold of 45 percent. And sometimes in women, we even go lower, to 42 percent. But the idea is that controlling the hematocrit, which is one of the red blood cells indices, you reduce the risk of having clots, and that’s been shown actually many years ago and reinforced in a very well-known study called the CYTO-PV study in Italy documented that if you keep the hematocrit less than 45 percent, so, stringent control versus allowing for less stringent control between 45 to 50, that you reduce by fourfold the number of cardiovascular events that can occur.

So, we know that controlling the hematocrit is important, and that can be done, again, with hydroxyurea, interferon, and ruxolitinib. The JAK2 inhibitor has also proved specifically for patients who had an intolerance or refractory hydroxyurea, but also importantly as a drug that can address, probably better than most drugs in this field, the symptom burden that could be problematic for some of those patients. But it’s really about controlling the hematocrit.

Katherine:

Yeah. Since myelofibrosis is a progressive condition, I imagine that makes it more difficult to manage. So, what else is available for patients with myelofibrosis?

Dr. Mascarenhas:

The first line of treatment is typically a JAK inhibitor, although I would say that there are a subset of patients – well, there are patients we sometimes meet that have very low risk disease. They don’t have those clinical variables we discussed before that could uptick their risk score, and some of those patients can be watched.

And interestingly, there are a subset of patients that can have an indolent or slow form of the disease where they don’t have aggressive changes in their disease, their blood counts, their symptoms, their spleen, and don’t need immediate treatment. Most patients would benefit from a JAK inhibitor, although there are a subset of patients where their issue is less simple in spleen burden and it’s more anemia.

So, we take those patients where anemia’s the focus, we look at their erythropoietin level, which is their endogenous hormone level that regulates red blood cell production. If it’s low, we give them a lab-based form of erythropoietin, something called PROCRIT or Aranesp. If it’s high, we will move on. We can use a drug called danazol, which is a synthetic male androgen which can improve hemoglobin levels in 20 to 40 percent of patients. Or, we can use a drug called lenalidomide, which is an immunomodulatory drug. And, more recently, there’s a drug in testing called to luspatercept, which is an active activin receptor ligand trap. So, there is a growing armamentarium of drugs that can be used to try to alleviate the anemia which is present and can be a significant issue in about a quarter of patients with myelofibrosis upfront at time of diagnosis or about 75 percent through the course of their disease. So, that’s an unmet need that still requires attention and may alter the treatment plan for a given patient.

Katherine:

What about stem cell transplants?

Dr. Mascarenhas:

So, we relegate stem cell plant transplants for those patients as mentioned before that are higher risk because we think that the potential benefit-to-risk ratio is in favor of transplant.

Transplant is really a modality that is the only modality that offers the potential for cure, but it’s also a modality that poses a significant risk of morbidity and mortality associated with it. So, it has to really be taken very seriously. It can’t be the kind of treatment you would think of as a last resort at the last minute. Once you see a transplanter, if they’re interested in that therapy and see it early on in the disease course, in my opinion, to start that dialog and then figure out when is the optimal time to employ a bone marrow transplant, which is not a surgical procedure. It’s often thought to be surgical. It’s not a transplant of an organ. It’s a transplant of hematopoietic cells. So, it’s really an infusion of stem cells that then end up in the person’s bone marrow, and they create a whole new hematopoietic system and immune system. And with that, you can have an immune system that then goes after the myelofibrosis stem cells.

That’s called graft-versus-leukemia effect. But with that included graft-versus-host disease, which is when the new graft, the new immune system doesn’t always recognize well the person’s own tissues, whether it’s the liver, or the lung, or the skin, and you can have immunologic reactions to that.

So, that’s a complex discussion. But, transplant, typically for patients less than 70 years of age who have high-risk myelofibrosis or even up to 75 if they have a good performance status and as we said don’t have a lot of comorbid issues with a goal of cure. So, if you have someone where their goal is to try to maximize their time out of the hospital and they’re not focused on longevity, they’re focused on quality of life, that may not be an appropriate patient for transplantation. So, I think a very upfront, honest and a transparent discussion with the patient about what to expect with transplant, what are the pros and cons, what are the risks involved, and importantly does it match up with their expectations or their desires.

Katherine:

Right.

We have a question from Mike that we received prior to the program. He wants to know, “What does it mean to have high-risk myelofibrosis?”

Dr. Mascarenhas:

So, high-risk can be defined different ways. For example, if you’re using the DIPSS score, it means that you have enough of those points to put you in a category that would suggest that your disease is more likely in a shorter time period to cause significant morbidity and mortality than someone who has low risk disease. So, it’s really, as we said before, we don’t stage myelofibrosis like stage I, II, III, and IV metastatic disease. But we risk stratify patients. We put them in these categories, and that helps to decide what treatments may be more appropriate. And as we were discussing, transplant is a therapy if you’re a high-risk patient and you’re inclined and you don’t have a lot of comorbidities, and you’re not very advanced in age. That may be a treatment that is appropriate for a high-risk patient, a high risk for having a bad outcome of the disease within a shorter period of time.

Katherine:

Right.

And we have another question from Craig that we received earlier. “I’m currently receiving regular phlebotomies for PV, but my doctor is considering switching me to inhibitor therapy. What can I expect and are there side effects that I should be concerned about?”

Dr. Mascarenhas:

So, for some patients, therapeutic phlebotomy is all that they need, and they do very well with it, and they don’t need to take a therapeutic like a JAK inhibitor or hydroxyurea, which is a non-specific treatment.

But some patients do. So, some patients where if their risk score is higher and their risk for thrombosis, that may be an appropriate indication. And some patients have a lot of symptoms with their PV. So, not all PV patients present and behave the same way. Some patients have a very low symptom burden. Some patients have a very significant symptom burden. Itching, for example can be a very annoying and very troublesome symptom for patients with PV.

And, if you don’t have PV or you don’t know someone with PV, you may not understand or realize the negative impact of having intractable itching, often associated with taking a shower or warm water.

And, that can really detract from quality of life and cause a lot of anxiety. So, that’s an example of where sometimes a JAK inhibitor like ruxolitinib can be really lifesaving in terms of restoring quality-of-life and functionality to a patient.

Usually, drugs like ruxolitinib are very well-tolerated too, which we’re fortunate about. There’s not a lot of toxicity associated with them. So, for example, nausea, vomiting, diarrhea, hair falling out with chemotherapeutics, you really don’t see with ruxolitinib or Jakafi. Easy bruising, headaches and some dizziness up front sometimes may be seen. They’re usually low-grade and they’re usually fleeting. And usually, the benefit, the feel-good aspect of it outweighs toxicity that can be seen with the drugs. They are immunomodulatory drugs. So, ruxolitinib or Jakafi may increase, to some small extent, but likely, real extent, infectious complications like shingles, urinary tract infections, upper respiratory infections. So, sometimes there is this increased risk. It’s often outweighed by the benefit of the drug.

But, there are risks that are associated, and of course the results are not guaranteed. So, I always warn patients, be careful when you look at the package inserts or talk to the physicians. Risks are risks. They’re not guaranteed. So, most patients don’t have these toxicities, but one is at risk for toxicity whenever they take any medication.

Katherine:

Yeah. Before we close, Dr. Mascarenhas, let’s talk about research. Are there new developments that you’re excited about?

Dr. Mascarenhas:

Absolutely. So, what I’m happily interested in and involved in is clinical investigation and moving the field forward, and there are many people out there that are similarly involved and they’re doing really excellent work. So, I am super jazzed and enthusiastic and optimistic, and it’s what gets me work every day and inspires me is all of the effort that is happening. And, it’s a continuum. So, it’s not just one person trying to try a different drug here and there. It’s really a bringing together of many different people because these are rare diseases.

Many different people from many different institutions that have different areas of expertise, but have a common goal of translating from laboratory informed data, so, not just taking a dart and throwing it at the dartboard and hoping it sticks. But actually taking data that we learned from the lab and leveraging that information to develop therapies that are informed, that are targeted, that are personalized and going through a process of evaluating them to get them into the clinic, with the goal of, and I would say ambitiously, our goal these days is moving beyond trying to make patients feel better, which is an important goal, but it’s really can we really target the disease in a more effective way to induce remissions, to, dare I say, cure patients. So, I think the ambitious goal of the clinical investigators and laboratory investigators that are active in MPN research today is really one looking for an understanding at the basis of the biology of the disease to develop curative therapies. And, I am optimistic that that will happen.

And, I don’t mean happen in a hundred years from now. I mean happen in our lifetime. So, that’s where we’re going. There’s a lot of very exciting drugs, oral and intravenous drugs and they target very different types of aspects of the disease, and I think patients and physicians will see that maybe those drugs are used best in combination. So, the idea of using one drug, waiting for it to fail and using another drug is really old news, and much of oncology is combination therapy. So, taking drugs that have different targets or mechanisms of action and non-overlapping toxicity to try to better target and delete what’s called the myelofibrosis stem cell that’s the basic issue here, which we don’t effectively delete other than transplant. So, our goal would be to put bone marrow transplanters out of business.

Katherine:

Well, that’s a great plan. I hope that that can happen one day. Thank you so much for joining us today, Dr. Mascarenhas. We appreciate you taking the time.

Dr. Mascarenhas:

My pleasure.

Katherine:

And thank you to all of our partners.

To learn more about MPNs and to access tools to help you become a proactive patient, visit powerfulpatients.org. I’m Katherine Banwell. Thanks for joining us today. Thank you so much.

 

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Is the COVID-19 Vaccine Safe and Effective for People With Colon Cancer?

Is the COVID-19 Vaccine Safe and Effective for People With Colon Cancer? from Patient Empowerment Network on Vimeo.

Dr. Smitha Krishnamurthi, a colon cancer specialist at Cleveland Clinic, provides vaccine safety information and discusses the effective immune response after COVID-19 vaccination in patients with colon cancer.

Dr. Smitha Krishnamurthi is a gastrointestinal medical oncologist at the Cleveland Clinic. Learn more about Dr. Krishnamurthi here.

See More From The Pro-Active Colon Cancer Patient Toolkit


Related Resources:

Should Your Family Members Be Screened for Colon Cancer?


Transcript:

Katherine Banwell:

Is the COVID vaccine safe and effective for people with colon cancer?

Dr. Krishnamurthi:

Yes. The COVID vaccine is safe. We have no data that patients with colorectal cancer or patients who are undergoing chemotherapy are at any increased risk of any side effects from the vaccine. People should be able to make a good immune response. Patients who are not able to make a good immune response are those who are getting very high-dose chemotherapy, like a bone marrow transplant or an organ transplant. But chemotherapy for colorectal cancer should not be problem. We basically advise – I ask all my patients to get the vaccine. They should just get it whenever they can. They don’t have to worry about timing in regards to their chemotherapy.

Katherine Banwell:

Okay. Dr. Krishnamurthi, thank you so much for joining us today.

Dr. Krishnamurthi:

Katherine, thank you so much for having me. It’s been such a pleasure.

Colon Cancer Treatment and Research News

Colon Cancer Treatment and Research News from Patient Empowerment Network on Vimeo.

What’s the latest colon cancer treatment and research news from the American Society of Clinical Oncology (ASCO) meeting? Dr. Smitha Krishnamurthi shares updates about research findings that were presented at the meeting along with exciting ongoing research in colon cancer.

Dr. Smitha Krishnamurthi is a gastrointestinal medical oncologist at the Cleveland Clinic. Learn more about Dr. Krishnamurthi here.

See More From The Pro-Active Colon Cancer Patient Toolkit


Related Resources:

Should Your Family Members Be Screened for Colon Cancer?


Transcript:

Katherine Banwell:

Welcome, Dr. Krishnamurthi. Would you mind Would you mind introducing yourself?  

Dr. Krishnamurthi:

Sure, it’s my pleasure. Thank you for having me, Katherine. I’m Smitha Krishnamurthi. I’m a medical oncologist. I specialize in taking care of patients who have colorectal cancer and other gastrointestinal cancers. As a medical oncologist, I treat patients with drug therapy like chemotherapy and immunotherapy.  

Katherine Banwell:

And where are you located?  

Dr. Krishnamurthi: I work at Cleveland Clinic in Cleveland, Ohio. 

Katherine Banwell:

Excellent. Thank you so much.  

Cancer researchers came together recently to share findings at the annual American Society of Clinical Oncology meeting, also known as ASCO. Are there highlights from the meeting that patients should know about?  

Dr. Krishnamurthi:

Yes. That’s always such an amazing gathering of knowledge. Thankfully, it’s continued virtually at least due to the pandemic. This past ASCO last month, some of the major highlights in colorectal cancer were the final overall survival results were presented from the study of pembrolizumab versus chemotherapy as first-line treatment for patients with metastatic colorectal cancer with deficient mismatch repair or MSI high status.  

These are the patients who are predicted to benefit from immunotherapy.  

We’d already seen earlier results that the patients who received the immunotherapy up front had a much-improved time for the cancer to regress. Here, they presented the overall survival results, which showed that the median survival for patients who received chemotherapy was three years, meaning half the patients lived shorter time, half lived longer. For the patients who received the pembrolizumab, they hadn’t even reached the median survival at five years.  

So, it looks very important that we know this MSI status or mismatch repair status from the beginning, so that we can offer the right patients immunotherapy first.  

Other highlights were, for example, for patients who have cancers that overexpress HER2/neu. It’s an oncogene. When it’s overexpressed, it tends to drive growth of cancers.  

 We don’t have any FDA-approved drugs for HER2-amplified colorectal cancer, but there are many studies showing that those patients with that type of cancer benefit from targeting this HER2 protein. There are, of course, approved drugs for HER2/neu-amplified breast cancer and stomach cancer. One of these drugs is trastuzumab deruxtecan.   

It’s a drug that targets the HER2/neu protein, but it’s connected with chemo. So, it’s like bringing chemo right to the tumor. The results showed a very high response rate. But it does have a peculiar toxicity of causing inflammation in the lung. So, it’s another treatment option that could be approved. It’s good to see that we’re getting more treatment options there. 

Katherine Banwell:

What are you excited about when it comes to colon cancer research? 

Dr. Krishnamurthi:

There are so many important questions we still need to learn the answers to. I find that patients who have, of course, a mutation of the KRAS or NRAS gene and have metastatic cancer, they have fewer treatment options than when those genes are normal. 

KRAS is a very important oncogene driver of cancer in colorectal cancer, but also in lung cancer and pancreatic cancer. For many decades, it was thought that there was no way to target this protein. Now, we’re seeing that there’s a certain type of KRAS mutation – KRAS G12C – that can be targeted with drugs that now are approved in lung cancer. 

It’s a small fraction of colorectal cancer patients who have that mutation, but it’s like we’re beginning to crack this code. The most common KRAS mutation is G12D. There is a company – Mirati – that has a candidate G12D inhibitor that’s going to enter clinical trials this year. It’s very exciting.   

There was recently a press release onvansertib, which is a polo-like kinase inhibitor, combined with chemotherapy, a second-line treatment for patients with KRAS-mutant colon cancer, showing a much higher response rate than we would expect with the chemotherapy alone.  

That will need to be validated in a large, randomized trial, but that’s looking very exciting. Then the other aspects that I’m most excited about are how to get immunotherapy to work for more of our patients.   

We know that patients who have abnormal mismatch repair or MSI-high cancers can benefit remarkably in the metastatic setting and there are studies going on in the early-stage setting and there are reports of it looking quite promising. But how do we get it to work for the majority of patients who have normal DNA mismatch repair or MSS, microsatellite stable cancers? That’s an area of great interest.  

We’ve seen a study in the Netherlands where they treated patients with normal DNA mismatch repair, early-stage colon cancer, with just two doses of immunotherapy before going to surgery for their early-stage cancer. I was surprised to see like four out of 15 patients responded to the treatment. Perhaps earlier stage cancers may be more responsive to immunotherapy. Definitely looking forward to more updates from that study, which we’ll probably hear in the fall at the European Society of Medical Oncology meeting in fall of 2021. 

Then, of course, the other area that really interests me is what is causing this epidemic of colorectal cancer in young adults? This is really a matter of laboratory studies and epidemiologic studies, but that’s also an area of great interest.  

Katherin Banwell:

There’s an epidemic among younger people?  

Dr. Krishnamurthi:

Yeah. I think of it as an epidemic in that colorectal cancer has definitely been increasing in young Americans and young people around the world in many countries.  

Basically, clearly, there’s been an increase since the 1980s. It seems to be something environmental because it’s related to time. So, it’s not inherited. Some of our patients below the age of 50 diagnosed with colorectal cancer do not have an inherited cause. A study from Ohio State found that 16 percent have an inherited cause. So, 84 percent of them do not. This is definitely increasing, particularly of rectal cancer. I think it must be something environmental. Possibly something like we’re ingesting because our colon is exposed to what we eat. But we really don’t know yet.  

And so, I just advise all my patients and everyone who is interested to just try to eat as much natural food as we can. To try to minimize processed foods and chemicals. 

Because I think that’s the best we can do until we really identify the cause.