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Navigating the Latest Metastatic Colorectal Cancer Treatments and Clinical Trials

Navigating the Latest Metastatic Colorectal Cancer Treatments and Clinical Trials

Edited by:
Katrina Villareal

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Allison Rosen, a colorectal cancer patient advocate, talks with leading oncologist Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center. Gain valuable insights into the latest advancements in the treatment of metastatic colorectal cancer and a deeper understanding of the current treatment landscape, including the most recent FDA-approved therapies that are making a difference.

Learn how biomarkers are revolutionizing the approach to treating metastatic colorectal cancer, potentially leading to more personalized and effective treatment plans. Discover emerging therapies and the most promising clinical trials available, offering new hope and options for patients. Equip yourself with the knowledge to collaborate effectively with your medical team, ensuring the best possible outcomes and quality of life.


We’d like to thank our promotional partners for their continued support of our programs. Please visit the Colon Cancer Coalition and Colontown to learn more about the important work they are doing.

Colon Cancer Coalition

Thank you to Takeda for its support of our patient education program! The Patient Story retains full editorial control over all content.

This interview has been edited for clarity and length. This is not medical advice. Please consult with your healthcare provider for treatment decisions.



Introduction

Stephanie Chuang, The Patient Story Founder

Stephanie Chuang: I’m a blood cancer survivor and the founder of The Patient Story, which I started out of my own experience. I had so many questions and all I found was medical jargon and outdated statistics.

Our goal at The Patient Story is to help patients and care partners navigate life after a diagnosis. What does this mean in human terms? We do this primarily through in-depth patient stories and educational programs. We hope to help connect patients and families to information about topics like self-advocacy and the latest treatment options, which is especially important in colorectal cancer. It makes a difference how early someone can get a diagnosis, how much people know about what’s available to them, and what questions they can ask their healthcare providers.

We want to thank Takeda for its support of our independent educational program, which helps us host more of these free programs for our audience. The Patient Story retains full editorial control of the content. We also want to thank our promotional partner, the Colon Cancer Coalition.

While we hope you walk away with more knowledge, this discussion is not a substitute for medical advice so please consult with your healthcare team.

It’s my pleasure to introduce Allison Rosen, a very well-known and respected individual in the colorectal cancer advocacy space and someone I’m lucky to call a friend. Thank you so much, Allison, for joining us.

Stephanie Chuang
Allison Rosen
Allison Rosen, Patient Advocate

Allison Rosen: I’m a 12-year stage 2C colorectal cancer survivor and a very passionate patient advocate. My treatment consisted of surgery, radiation, chemotherapy, more surgery, and ultimately, a permanent ostomy.

I wanted to meet other young people like me who were diagnosed with colorectal cancer because I felt very alone when I was first diagnosed. When I was being treated at MD Anderson, I asked to talk to another young adult. She was very active in advocacy and introduced me to the advocacy space. Now I volunteer with a lot of national and local advocacy organizations. I get to work with amazing clinicians, researchers, and doctors to help provide the patient perspective.

Dr. Cathy Eng: You are so fortunate to be diagnosed with stage 2 because, unfortunately, most young adults are diagnosed with a much more advanced stage. Stage 2 is a very unique setting because it’s extremely early with regard to prognosis. For the majority of patients, surgical resection is curative. I’m so glad to have you here with us today.

Allison: Thank you. It’s interesting because the reason why I’m so active is because I’m alive. I have a purpose and my mission is to be a part of things like this educational program to talk about what is out there, so people who may not have access to what I had access to can get current information and the best possible treatment.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
Dr. Cathy Eng, Medical Oncologist

Allison: Dr. Cathy Eng is the David H. Johnson Endowed Chair in Surgical and Medical Oncology at the Vanderbilt-Ingram Cancer Center. She’s also the co-leader of the Gastrointestinal Cancer Research Program, co-director of GI Oncology at Vanderbilt, the executive director of the Young Adults Cancers Program, and co-chair of the NCI GI Steering Committee. Dr. Eng, what drew you to this field?

Dr. Eng: What drew me is individuals like yourself. I had a very, very large clinic when I used to work at MD Anderson and I was seeing patients as young as 16. These patients do not have an inherited form of colorectal carcinoma. The majority have sporadic colorectal cancer and, unfortunately, they were showing up in my clinic with very advanced diseases, stages 3 and 4. It’s hard not to be able to appreciate all the hurdles that a young adult has to go through in order to go through their treatment with success and hopefully few toxicities. It’s that communication with the patient and that lives with you as a physician.

Allison: I know many people who are part of the Young Adult Cancers Program and many people who have gone through it. I appreciate everything you’re doing for the young adults who are going through treatment and, unfortunately, the future young adults who will go through treatment. You have to treat the patient as a whole. Things like fertility and body image are so important along with chemotherapy and radiation.

Dr. Eng: Thank you. I want to thank you also for helping promote education and awareness. We don’t know the exact etiology of why this is happening, but in the interim, we can continue to promote awareness so people can be diagnosed earlier.

Allison: Awareness is key.

Dr. Cathy Eng

You don’t need to remove your primary tumor to improve overall survival. In fact, it does not improve overall survival and that’s important to keep in mind.

Dr. Cathy Eng

Latest Treatment Options for Metastatic Colorectal Cancer

Allison: As an advocate, I’ve seen that progress is being made in treating metastatic colorectal cancer, but it’s still challenging. What are the latest treatment options?

Dr. Eng: Oxaliplatin-based and irinotecan-based treatments are still commonly utilized for patients who don’t have a particular molecular marker. We have to recognize that it’s still important to be in contact with the patient because in combination with a fluorouracil-based therapy, those regimens are still the foundation of basic treatment.

Over the past two years, one thing that came out was looking at tumor-sidedness. A patient with a left-sided tumor has a better prognosis overall than a right-sided tumor for a non-inherited form of colorectal cancer. If the patient is RAS wild-type, the data shows that you would probably benefit from anti-EGFR therapy in combination if you’re considering irinotecan- or oxaliplatin-based therapy and that has been shown to improve overall survival. Not everybody loves EGFR therapy because it causes a significant rash, but there are benefits to considering that type of treatment.

A RAS mutation is very common in up to 60% of all colorectal cancer patients. We’re getting so specific that we’re asking what type of RAS mutation you have with regard to KRAS.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

Patients ask if they need to have their primary tumor removed because they have metastatic disease. It’s not like breast cancer where you need to have your primary tumor removed to reduce your tumor burden. That doesn’t benefit a colorectal cancer patient with metastatic disease.

A pooled analysis came out in the Journal of Clinical Oncology. Three presentations from countries all across the world indicated that you don’t need to remove your primary tumor to improve overall survival. In fact, it does not improve overall survival and that’s important to keep in mind.

Sometimes we hear from patients that they’re told they have to remove their primary tumor. You shouldn’t have to unless you have uncontrolled bleeding, near obstruction, or a high risk of perforation. We don’t encourage that for all comers in general. For a rectal cancer patient, if you’re having symptoms, we can give short-course radiation therapy to help alleviate some of those symptoms despite having metastatic disease.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
HER2-Targeted Therapy Combination

Dr. Eng: Tucatinib is the most recent drug that has been approved, which is an oral tyrosine kinase inhibitor of HER2 that prevents downstream phosphorylation and involves the EGFR pathway. These are for patients with RAS wild-type and most often have left-sided tumors.

The best part about the tucatinib study, which shows the relevance of having a rare mutation, is it got FDA-approved based on a small phase 2 study. It wasn’t a giant phase 3 study and that’s important to keep in mind. It showed that these patients, despite heavily being heavily pre-treated, had a great response rate. Progression-free survival was excellent and the overall survival was close to two years.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

HER2 testing is one of the newest things to be considered. We’re very familiar with it in gastric cancer and breast carcinoma, but this is the first time looking at it in metastatic colorectal cancer and making sure that all patients get tested for HER2. It’s extremely important to look at the role of HER2. We have seen that looking at HER2 amplification, which is present in approximately 4% of our patient population, is very, very important.

Looking at HER2 amplification, which is present in approximately 4% of our patient population, is very, very important.

Dr. Cathy Eng
Fam-Trastuzumab Deruxtecan-nxki (ENHERTU)

Dr. Eng: The new drug deruxtecan is an antibody-drug conjugate. It isn’t necessarily new with regard to its presentation but in the sense that it just received tumor-agnostic approval, so it’s approved for colorectal cancer and other tumor types.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

It does best in the IHC 3+ patient population, but it has a benefit with regard to progression-free survival and overall survival. What’s unique about deruxtecan is that the original study that resulted in its approval allowed patients who received prior HER2-based therapy. You could have had tucatinib, pertuzumab, or lapatinib, but you can receive deruxtecan as a single agent.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

They’re moving the G12C inhibitors in combination with chemotherapy to the front-line setting.

Dr. Cathy Eng
CodeBreaK 300 Clinical Trial

Dr. Eng: CodeBreaK 300 was presented at the 2023 European Society for Medical Oncology Congress. It was a phase 3 clinical trial in a previously treated patient population. They looked at dosing as well.

KRAS G12C inhibitors don’t work by themselves. They were evaluated by themselves with a less than 10% response rate. In combination with anti-EGFR (epidermal growth factor receptor) therapy, the combination resulted in an improved benefit for patients. Although it’s not FDA-approved at this time, if you’ve been previously treated, you can inquire about receiving it in combination with anti-EGFR therapy.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

They’re moving the G12C inhibitors in combination with chemotherapy to the front-line setting. In the HER2 setting with newly diagnosed patients, they’re also looking at tucatinib in combination with oxaliplatin-based therapy. The fact that we’ve found molecular alterations that have been positive studies in the refractory setting is exciting. We’re now moving into front-line therapy to see if that is more advantageous for our patient population.

BREAKWATER Trial

Dr. Eng: BREAKWATER is a phase 3 trial for BRAF V600E mutation tumor types, which is about 9% of all of our patients. Encorafenib and cetuximab were approved in the previously treated setting and are now being moved up to the front-line setting in combination with oxaliplatin-based therapy. I’m one of the investigators on that trial and there’s another arm that’s open, which is in combination with irinotecan-based therapy.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

I hope that we will continue to move these rare molecular alteration subtypes earlier on in development because we can get greater outcomes. We hope to improve and break the barrier of overall survival, which is currently about 35 to 37 months for the majority of our patients.

For any metastatic patient, the very first thing they need to ask is their molecular sequencing. It’s critical because it helps create a treatment plan.

Dr. Cathy Eng

Trending to More Personalized Treatment

Allison: You talked about the KRAS, HER2, and BRAF mutations, and about treatment being driven by a particular mutation. Why is biomarker testing important? What would you tell a patient if their doctor hasn’t necessarily brought it up?

Dr. Eng: For any metastatic patient, the very first thing they need to ask is their molecular sequencing. It’s critical because it helps create a treatment plan. Previously, we would look at all metastatic colorectal cancer patients as the same and that’s not the case. Having a molecular marker can make a big difference because it can prevent you from receiving unnecessary toxicities and costs.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
KRAS- and EGFR-Targeted Therapy

Dr. Eng: The most pivotal one was looking at KRAS and anti-EGFR therapy, such as panitumumab and cetuximab. That class of drugs causes a rash in 80 to 90% of patients and depending on where you live, you’re also at a higher risk for having an allergic hypersensitivity reaction to cetuximab.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
Bevacizumab

Dr. Eng: Bevacizumab is an IV drug that’s involved in anti-angiogenic therapy. Anti-angiogenesis or anti-VEGF (vascular endothelial growth factor) therapy means it’s working on the blood supply. Our goal for this class of drugs is to reduce the development of metastatic disease because a tumor needs a blood supply to survive and thrive.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
FRESCO-2 Trial

Dr. Eng: When we designed FRESCO-2, it allowed almost all comers. Patients were allowed to have received prior TAS-102 (trifluridine/tipiracil) and that was before the approval with bevacizumab in combination. They also could have received regorafenib, which has been approved for quite a while now. Patients may have been exposed to either or both of the drugs. It was a trial that allowed almost all patients to participate with the median line of four prior lines of therapy.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

Fruquintinib was compared to a placebo. It was a 2-to-1 randomization. Some people criticize the fact that there was a placebo arm, but there’s no standard of care for fourth-line or fifth-line therapy, so there was nothing to compare it to. Some people say, “Can’t you go back to 5-FU (fluorouracil)?” But the reality is patients have already progressed through 5-FU, so they’re not going to be receptive to 5-FU.

The primary endpoint was met with an improvement in overall survival as well as progression-free survival.

The FDA approval allows patients to receive oral fruquintinib as a potential option for third-line therapy and beyond.

Dr. Cathy Eng
Fruquintinib (FRUZAQLA) Approved by FDA

Allison: With the recent FDA approval of fruquintinib, how can it help address an unmet need in the metastatic colorectal cancer treatment landscape?

Dr. Eng: It’s a drug that I helped bring to the United States. I was involved in the original trial as the senior investigator. This drug is an oral agent, which specifically blocks receptors 1, 2, and 3 of the VEGF pathway. It was originally approved in China in the third-line setting based on a phase 3 trial called FRESCO that was conducted overseas.

FRESCO-2 is specifically trying to address the practice patterns of what we are doing in the United States, which is continuing bevacizumab for front-line and second-line therapy but also trying to ensure the majority of patients had received anti-VEGF therapy as part of treatment, which was the case in 97-98% of patients who participated in FRESCO-2.

Based on the results of both FRESCO and FRESCO-2, the FDA approval allows patients to receive oral fruquintinib as a potential option for third-line therapy and beyond.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

Overall, it was tolerated fairly well. Hypertension is an issue with this class of drugs, but it’s treatable. It got approved in November and we are very pleased to see the FDA approved it. It’s pending the European Medicines Agency’s approval as well as approval in Japan. After that, hopefully, it will be approved internationally so all patients can get access.

At the end of the day, the reality is you need to make sure you have drugs available to the patient. When you ask, “Do you prefer FOLFIRI (folinic acid, fluorouracil, and irinotecan) or FOLFOX (folinic acid, fluorouracil, and oxaliplatin)?” The reality is you’re going to get both regimens. What matters is how well you tolerate the treatment and how you derive the best benefit.

I try not to make it very competitive. I don’t think it benefits anybody. It’s important to recognize that there’s a new drug on the market, it’s available for patients, and it does not require IV therapy.

In a prior study, it was seen that if you have the RAS mutation and receive anti-EGFR therapy, it’s no better than receiving a placebo.

Dr. Cathy Eng

Biomarkers (“Molecular Markers”)

Dr. Eng: There’s a lot of interest with regard to other molecular markers, like a patient’s KRAS status and mutation. KRAS G12C inhibitors are further along in development than G12D. Granted, G12C in colorectal carcinoma is less than 5% of our patient population, but once those patients are identified, they may benefit from therapy.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
Importance of Biomarkers

Dr. Eng: The KRAS mutation is in about 30 to 60% of all colorectal cancer patients. In a prior study, it was seen that if you have the RAS mutation and receive anti-EGFR therapy, it’s no better than receiving a placebo. Why would you want to subject your patient to toxicity, a potential allergic reaction, and extreme financial costs if it doesn’t benefit them?

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
Different Biomarkers

Dr. Eng: KRAS was just the beginning. We are now identifying all these new molecular subgroups, such as HER2, BRAF, and microsatellite instability-high (MSI-H), which is extremely important with regard to the role of immunotherapy. That’s another small patient population, less than 5% of our patients, but that’s where immunotherapy may benefit our MSI-high or mismatch repair protein deficiency (MMR-d) patient population where immunotherapy can have a significant role in potentially curing them.

Tissue molecular sequencing can look at hundreds and hundreds of various molecular alterations, mutations, or amplifications… Information from the blood can be critical in identifying a suitable clinical trial.

Dr. Cathy Eng
Tissue vs. Blood Samples in Biomarker Testing

Dr. Eng: Molecular sequencing can be obtained from tissue and blood. If you’re newly diagnosed, it’s important to send off that tissue as soon as possible before it gets sent off to some warehouse because it can’t sit in the pathology department forever.

Depending on which panel you use, tissue molecular sequencing can look at hundreds and hundreds of various molecular alterations, mutations, or amplifications. Blood sequencing is quicker. You can get it back within less than two weeks, but you’re only looking at 100 different mutations relative to the 500 or so plus potential molecular alterations.

Some places still do it in-house, but the majority of institutions send it out to a third party. Ask for tissue and blood to be sent off because the information from the blood can be critical in identifying a suitable clinical trial for the patient as well. I cannot emphasize enough the importance of participating in clinical trials.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

Allison: I’m very, very passionate about access to clinical trials, education for clinical trials, not being scared, and not thinking that a clinical trial means you’re going to die.

Dr. Eng: Every single FDA-approved drug came from a clinical trial.

Allison: Exactly. It’s the point that I make as an advocate all the time.

Choosing Among Different Treatment Options

Allison: Where do you see fruquintinib fitting in with the current therapies available for metastatic colorectal cancer? Is there a potential for it to be used as a maintenance therapy?

Dr. Eng: My understanding is it’s being investigated as a maintenance therapy. It makes a lot of sense since the majority in the United States use capecitabine, bevacizumab, or 5-FU with bevacizumab for maintenance therapy, so it would make sense to consider this as a potential maintenance therapy.

When thinking about it relative to other agents, such as regorafenib and TAS-102 plus bevacizumab, I talk to the patient. I utilize TAS-102 plus bevacizumab quite a bit. However, some patients are tired of coming in every two weeks for bevacizumab. They want a break and that’s very reasonable.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

With TAS-102, they’re at risk for myelosuppression, so their white blood cell count can drop. That’s a known side effect of that class of drugs, so the patient has to be compliant and not take medications incorrectly. You don’t want a neutropenic patient walking around at risk for other infections.

I don’t offer TAS-102 to certain patients. I had an elderly patient whose platelet count was never above 100,000. He had been on a lot of therapies and came to me for a second opinion. I would be hesitant to give him TAS-102 because I know that his platelet count is going to be a problem, so I chose fruquintinib for him first. Once again, I don’t try to choose one versus the other. I talk to the patient about the potential side effects and see what they’re willing to endure.

Allison: It’s all about shared decision-making. You know about what’s going on and having that conversation with your physician is very, very important.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

Emerging Clinical Trials for Metastatic Colorectal Cancer Patients

Dr. Eng: For the MSI-high patient population, there should be some updates soon regarding NIVO+IPI (nivolumab and ipilimumab). They presented their data at the 2024 ASCO GI (American Society of Clinical Oncology Gastrointestinal Cancers Symposium) looking at NIVO+IPI in combination versus chemotherapy and that was superior, but it was a very rapid abstract presentation, so we don’t have further details. I think there’s going to be an update at the 2024 ASCO, so I look forward to that. Are two immunotherapies better than one for this patient population? What about toxicities? It will be interesting to see.

The CodeBreaK 301 trial is looking at the role of sotorasib, a first-generation KRAS G12C inhibitor, in the upfront setting. Sometimes the next generation may be even better, so I’m looking forward to those trials as well.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
EA2222 (PUMP) Trial

Dr. Eng: The PUMP trial is a new NCI-sponsored study specific for newly diagnosed patients. They will get randomized to having the PUMP versus continuing chemotherapy.

This is an important trial that will answer that question. We know all the data from Memorial Sloan Kettering, but can we validate and replicate that data outside of that institution, especially in an earlier line setting?

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
ERASur Trial

Dr. Eng: The ERASur trial is another NCI-sponsored study that looks at the role of stereotactic radiation therapy, ablation, or some type of liver-directed intervention to improve overall survival.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer
MOUNTAINEER-03 Trial

Dr. Eng: The MOUNTAINEER-03 trial is looking at tucatinib with trastuzumab in the front-line setting.

We cannot make breakthroughs until we get trials completed. It’s very, very important to keep in mind that not all trials involve a placebo.

Dr. Cathy Eng

Importance of Participating in Clinical Trials

Allison: We touched on the importance of clinical trials, but do you have any message about the importance of participating in clinical trials?

Dr. Eng: Focusing on metastatic disease, I encourage all patients to consider participating in a clinical trial. Currently, enrollment across the United States is about 7% for non-NCI cancer centers and up to 20% for NCI-designated cancer centers. We cannot make breakthroughs until we get trials completed. It’s very, very important to keep in mind that not all trials involve a placebo.

All patients should consider getting a second opinion if they haven’t been offered a clinical trial. There are some selective settings where there is no clinical trial available, but you should have that discussion with your provider on your first or second meeting.

It doesn’t take that long to get a second opinion. You want to look at all your options and feel informed. That’s extremely important as a patient and the best way to optimize your care. As a medical oncologist, it’s very, very distressing when I meet a patient who received one cycle of chemotherapy before they walked into my office and find out they would have been a perfect candidate for a clinical trial but now they’re automatically disqualified.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

Allison: Knowledge is power. There are so many amazing trials and the first step is educating yourself on clinical trials. There are a lot of advocacy groups and organizations that are trying to educate patients on what a trial is and having that conversation with their doctors. It’s so important because the last thing you want to do is disqualify yourself for a trial because you did something here versus going there.

Because of my age, I got three different opinions before I decided on where I was going to get treated. For the younger people especially, talk to as many people as you can and educate yourself as much as you possibly can. This program is an amazing start for people to better understand that there are options.

Get a second or a third opinion. I’m not telling you to delay your treatment by months, but give yourself 2 to 3 weeks to make an informed decision by getting another opinion.

Dr. Cathy Eng

Final Takeaways

Allison: What message do you have for metastatic colorectal cancer patients? I always tell them that their lives aren’t over. There are treatment options available. I know quite a few people who were stage 4 who are now in remission.

Dr. Eng: I hear time and time again that they’ve been given a poor prognosis of 6 to 8 months to live; that’s very discouraging and not the right approach. We have so many new options available. Science has advanced so much. If you hear that kind of negative attitude at your first meeting with your physician, you need to go get a second or a third opinion. I’m not telling you to delay your treatment by months but give yourself 2 to 3 weeks to make an informed decision by getting another opinion.

Allison: I agree. The relationship you have with your care team is important. It can spell the difference between a lot of different things that can happen along a journey.

Dr. Eng: It’s also important for people to keep in mind that there’s always hope.

Allison: I was originally diagnosed with stage 3 and they said it was about to break through my colon wall. There’s so much going on and so much information you’re getting when you’re first diagnosed. Talking to someone else who’s gone through it gave me hope. It differs with every stage. I know people who are 20-year stage 4 colorectal cancer survivors. That’s the hope that someone needs.

Latest Treatments and Clinical Trials for Metastatic Colorectal Cancer

Dr. Eng: Your medical oncologist is key. Your radiation oncologist and surgical oncologist are always there, but the captain of your ship, besides your primary care doctor, is your medical oncologist.

Allison: You are an amazing captain of the ship. I know this from hearing from many people and knowing you for as long as I have. Thank you so much for your time and for sharing invaluable information.

Stephanie: Thank you so much, Dr. Eng, for what you do in terms of research, which is critical to advancing care, and the way you’re thinking about patients. Thank you also to Allison for the work you do in advocacy and leading this program, which wouldn’t be the same without the patient perspective.

Thank you to our promotional partner the Colon Cancer Coalition, which was founded by someone who lost her sister to stage 4 colorectal cancer. The Colon Cancer Coalition is celebrating its 20th Get Your Rear in Gear fundraiser in the Twin Cities in Minnesota with other rides and fundraisers happening across the country as well. These fundraisers highlight the need to screen and raise awareness of colorectal cancer. The organization gives more than $1 million every year to local community programs to help fill that need.

We hope that you walk away with a better understanding of what’s out there and something to talk to your own healthcare team about. We hope to see you at a future program.

If you read and/or watched our program, we encourage you to take our program survey to help us improve future programs and answer your questions.


Takeda

Special thanks again to Takeda for its support of our independent patient education content. The Patient Story retains full editorial control.


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Medical Experts Medical Update Article

Colorectal Cancer in Young Adults

Why is Colorectal Cancer Increasing in Young Adults?

A top gastroenterologist explains warning signs, causes and possible prevention

Dr. Toufic Kachaamy is a gastroenterologist trained in advanced endoscopy, including endoscopic ultrasound, he helps care for patients fighting pancreatic, stomach, esophageal, colon, liver or bile duct cancer at our Phoenix hospital. As Chief of Medicine at City of Hope Phoenix, Dr. Kachaamy has clinical leadership responsibilities for several medical departments and supportive care services.

Colon cancer is quickly becoming the number one cancer killer in young adults. An alarming rate of young people are being diagnosed with colorectal cancer according to a new report by the American Cancer Society. An estimated 153,000 will be diagnosed with colorectal cancer in 2023. 

To better understand the causes for the sharp increase and ways to protect against colorectal cancer, we spoke to Dr. Toufic Kachaamy, Chief of Medicine and Director of Gastroenterology at City of Hope, Phoenix.

This interview has been edited for length and clarity. This is not medical advice. Please consult with your healthcare provider for treatment decisions.

Is colorectal cancer on the rise among young people?

Dr. Toufic Kachaamy: New cases of colorectal cancer are actually declining, but that’s not the case with younger people. When you look at the younger population, it’s a completely different story. Over the last one to two decades, there have been year-over-year increases in colorectal cancer, especially rectal cancer, in young adults. In folks [who] are younger than 45, there has been a around 2.2% increase.

Why is colorectal cancer increasing in young adults?

Dr. Toufic Kachaamy: The short answer is we are not sure. I can give you my personal opinion. This is one of the signs we’re seeing, and what we’re doing is not working for us as a species. There’s a price to pay. You might not see it today. But you’re going to see it eventually. Just living an unhealthy lifestyle has consequences.  We have a lot of information available on what’s good for us. But we’re not using that information, you know, So make it a part of your life. 

What helps prevent colorectal cancer?

Dr. Toufic Kachaamy: What we think is good for your heart is also good for your colon. So a diet high in fruits and vegetables, low and processed meat, and probably low in red meat is the best for us. But our diet is going in the opposite direction. People don’t sit down to have a good meal. It’s always on the go. [Some food] has a lot of preservatives and that’s one component. I see rectal cancer in young adults as the canary in the coal mine. Our lifestyle is catching up to us. 

How can we make lifestyle changes to help prevent colorectal cancer?

[For me], instead of grabbing a sandwich, I spend my time with my wife cooking the night before so we can have a fresh meal. That’s time we spend together doing it. And slowly, if you add small lifestyle changes, these are sustainable over the long run and they become habits. Once they’re habits, they’re easier to maintain. And the third is to use the current resources we have to help yourself get better.

How does family medical history and genetics play a role in colorectal cancer prevention? 

Dr. Toufic Kachaamy: Family history is often neglected. We’re a very private society and very few people share. A high-risk [colon] polyp has certain features and characteristics that we know have a high chance of turning into cancer. When we endoscopists remove that polyp, we prevent cancer. Great, but we don’t tell the family members that you are at increased risk. You are at increased risk of cancer and you need to get your screening 10 years earlier. We haven’t changed the genes. We prevented the cancer in a father, but their kids still need to be screened 10 years earlier. We think around 30% of these premature cancers can be detected this way if we pay better attention to the risk factors and their family history. So that’s the gap in our current care that we need to fix.

What are the signs of colorectal cancer?

Dr. Toufic Kachaamy: Any blood in the stool is a reason to be [concerned]. It doesn’t mean you have cancer. But for the small chance that you might have cancer. You want to find that early. These would be the most important things to watch out for and seek an evaluation for versus putting it on the back burner.

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Categories
Gastrointestinal Oncologist

Kimmie Ng, MD, MPH | Colorectal Cancer Treatment

Kimmie Ng, MD, MPH

Colorectal Cancer Treatment

Kimmie Ng, M.D., MPH, started her career with research in mind, but after working with patients, she realized her passion was in helping people directly.

A gastrointestinal oncologist, Dr. Ng also founded the center at the Dana-Farber Cancer Institute that focuses on research specifically for young-onset colorectal patients, people under 50 years old, a growing patient population.

In this interview, Dr. Ng talks about the role of the microbiome, the latest on colorectal cancer treatment in targeted therapy, and gives general guidance to patients and caregivers on questions they should consider at diagnosis.

Dr. Kimmie Ng
  • Name: Kimmie Ng, MD, MPH
  • Specialty: Gastrointestinal cancers and young-onset colorectal cancer
  • Roles
    • Oncologist
    • Co-Director, Colon and Rectal Cancer Center
    • Director, Young-Onset Colorectal Cancer Center
    • Director of Clinical Research, Gastrointestinal Cancer Center
    • Associate Professor of Medicine, Harvard Medical School
  • Experience: 15+ years
    • Dana-Farber Cancer Institute
    • Spends most of week on research, one day a week with patients

Introduction

How did you shift from research to patient care

When I started in college, I actually majored in the molecular mechanisms of biochemistry and really thought that I was going to be in the lab, delving into the intricate complexities of how cells divide and how cancer works and how it spreads. 

But as I progressed through my training, going to medical school, and having increasing interactions with patients, it really struck me that I wanted my work to be more directly relevant to patient care.

I wanted the research that I was doing to be able to have more of an impact on the patients I was meeting and treating than I could do from the laboratory bench.

With that, I shifted more to a clinical and translational type of research where I would work on patient samples and analyze tumors, look at diet and lifestyle factors, and see what of those, in combination or singly, could help to make people’s survival better and help them get through their treatment better.

Describe the work you do at Dana-Farber

When I started in medical oncology,I knew from a very early stage that I wanted to focus on gastrointestinal cancers. Specifically, colorectal cancer because there was still so much to do in terms of improving the outcomes and finding new treatments for patients with these diseases. 

Very early on in my training, I decided to specialize in gastrointestinal cancer and colorectal cancer. Currently, I see patients one day a week and the rest of my time is spent running the Young Onset Colorectal Cancer Center, which really focuses on young people under the age of 50 who are diagnosed with colorectal cancer, as well as conducting research on the diet and lifestyle factors that may impact how long a patient lives with colorectal cancer.

I also study what some of the risk factors are for why more and more young people are developing colon cancer at younger and younger ages. That is still a mystery. We don’t know in the vast majority of patients why it is they became diagnosed with this disease. 

Colorectal Cancer Focus

What’s behind this trend of younger colorectal cancer patients

It isn’t purely a screening effect.

Just to review the overall numbers, colon cancer is the third leading cause of cancer in both men and women in the United States.

When you combine men and women in the U.S., it’s the second leading cause of cancer death. It’s a very big problem that affects thousands and thousands of people every year.

Fortunately, we do have very effective screening programs for people over the age of 50 currently, where they’re able to catch cancers at an earlier stage and also before they become symptomatic, often at the polyp stage where you can completely prevent the cancer.

As a result of those successes of screening, the incidence of colorectal cancer in people over the age of 50, as well as death rates from colorectal cancer have been steadily declining over the years.

Unfortunately, that same improvement has not been seen in people under the age of 50 who are not being routinely screened.

It’s occurring at about two-percent per year in the rise of people, in both men and women, under the age of 50. It’s happening for both colon and rectal cancer, and it’s actually happening in most states in the U.S., as well as many countries around the world.

They’re predominantly higher socioeconomic status countries, and the reasons for these trends are still unclear, but it is a global phenomenon. 

What is driving the increase in young-onset CRC patients

The reason for why this is happening is one of the mysteries of medicine, honestly. We know that diet and lifestyle seem to have a strong link to colorectal cancer no matter what age you are, so we suspect that perhaps it’s diet and lifestyle, perhaps it’s environmental exposures other than diet and lifestyle, such as antibiotic use, that may be influencing whether young people are developing this at younger and younger ages. 

I will have to say that we’ve done a couple of studies that linked obesity and sedentary behavior to a higher risk of developing colon cancer under the age of 50 in cohorts of women.

But the vast majority of patients we see in clinic are not obese and they are active, they eat healthy diets, they follow very active and healthy lifestyles. So clearly, it’s really not just those factors that are leading to this.

How many colorectal cancer patients are under 50

Approximately 150,000 patients are diagnosed newly each year with colorectal cancer. About 18,000 of them are under the age of 50. So it is a small proportion of all colorectal cancer patients right now who are diagnosed at a young age.

But if the trends that we are seeing now continue, it is estimated that by the year 2030, 25-percent of all rectal cancer patients are going to be under the age of 50.

So this is clearly going to be more and more of a problem in young people if the current trends continue and if we don’t start to understand better what the risk factors and causes are.

Patients get bombarded with diet and lifestyle recommendations. Where should they turn for reliable information?

Your experience is exactly the experience of so many of our patients. I think part of the problem is that there isn’t a lot of rigorous research out there to really determine what the ideal diet and lifestyle should be for a person with cancer or to prevent cancer.

This is an area I started working on right out of fellowship and started during fellowship, to study this in a more rigorous fashion. It is true that most of the diet and lifestyle studies out there are still epidemiological. They’re observational.

For the most part, they can only conclude there’s an association between a certain diet and lifestyle factor and risk of developing a cancer or likelihood of surviving that cancer.

It has been something we’ve been focusing on to try and turn those observational studies into randomized clinical trials that will be able to establish causality, a cause and effect relationship, which is the gold standard for determining if something truly has an effect on cancer.

The benefits of Vitamin D

One example is I’ve been working on vitamin D for a really long time. There’s been a lot of evidence in the laboratory that higher levels of vitamin D have been associated with less risk of developing colorectal cancer.

The vitamin D pathways implicated in all kinds of mechanisms that are very relevant for cancer development, so it made sense from the laboratory side that vitamin D may have a role.

We then started to look at this in epidemiological studies. Very consistently, we saw that higher levels of vitamin D in the blood seemed to be associated with a longer survival in patients with colorectal cancer, especially those with more advanced stages of colorectal cancer, stages three and four.

When we saw this and all the consistent evidence supporting such a relationship, we did decide to translate this into the first randomized clinical trial of vitamin D supplementation for treatment of patients with metastatic colorectal cancer. 

This was called the Sunshine Trial and it was published in JAMA  a couple of years ago. We found that adding high-dose vitamin D to standard chemotherapy seemed to allow patients to delay progression of their cancer for longer than a lower dose of vitamin D added to chemotherapy.

That was the first randomized clinical trial of vitamin D in colorectal cancer. The results were really encouraging and has now led to a National Cancer Institute-sponsored phase three clinical trial called Solaris, which is ongoing and enrolling, hopefully by the time it’s done, 400 patients with metastatic colorectal cancer to establish whether high dose vitamin D has a role in the treatment in patients with this disease.

It’s so important to understand the role of diet and lifestyle. These are easier interventions. They’re cost-effective. They’re things patients can do themselves that may perhaps impact how well they do. So it’s very important to study them very rigorously and to have evidence-based recommendations to give to our patients.

The Role of the Microbiome

What is the role of the microbiome in colorectal cancer

This led us to hypothesize that perhaps it’s the microbiome. The microbiome is the trillions of organisms that are living in all of our guts right now that have a profound impact on a variety of different chronic diseases and colorectal cancer is one of the ones that are probably most influenced but the microbiome because the cancer is developing right there in the gut where all the trillions of organisms are living. 

We know that diet and lifestyle very closely shapes the composition of our microbiome and which organisms are in there.

It is therefore likely that diet and lifestyle factors, and environmental factors that may be affecting the microbiome in a way that may be leading to colorectal cancer, and also affecting how well our immune systems are able to either fight off or not fight off the development of a cancer such as this. 

What are you hoping to gain in your newest study of the microbiome

I was very fortunate to get a three-year grant from the Colorectal Cancer Alliance to really study how exactly the microbiome may be influencing the risk of developing colon cancer in young people.

What we’re trying to do is understand how the microbiome is different in young patients depending on how young they are.

We know from clinical experience that it seems like the youngest patients under the age of 30, so in their twenties, even in their teens, may have a different type of colorectal cancer, one that might be a little more aggressive than the colorectal cancers we typically see.

Even compared to patients developing colorectal cancer in their thirties or in their forties are certainly different than those developing colorectal cancers over the age of 50.

We really want to delve deep into how the microbiome is different by what decade of age you’re diagnosed.

We also want to compare microbiomes of healthy, young people, who do not have a colorectal cancer diagnosis so we can get some hints on whether there’s some special microbiome signature that may predict who is at higher risk for developing colorectal cancer.

If it’s true that there is a specific signature or a high-risk microbiome that we can identify in healthy, young people, we’d be able to know who to target for earlier screening so that we can hopefully prevent the cancer from happening in these young people or catch the cancer at an earlier stage when it’s a lot more curable.

Because the microbiome has such an impact on our body’s immune system, as well, we’ll also be studying the effects of the microbiome at these different ages of diagnosis on different components of the immune system.

One very cool part of the grant is that we’ll be collecting stool samples from patients in their 20’s versus their 30’s versus over 50, as well as from healthy young people and actually transplanting and transferring these stool samples with their microbiome into mouse models of colon cancer.

We will see what impact each patient’s microbiome has on the development of colon cancers in these mouse models and study how exactly it is that it’s influencing the development of that cancer, and how it might be altering that mouse’s immune system to either lead to more aggressive growth or lead to less aggressive growth. 

Our hope is that we better understand the mechanism of how the microbiome might be interacting with the immune system to lead to colorectal cancer.

Through that, hopefully we can discover a signature or model target that we can then develop a new drug against that would either decrease the chances of this happening in young people or better treat colorectal cancer that has already developed in a young person.

How will you conduct the study

There are two parts to the study. The first is just collecting a lot of stool samples from a lot of different patients at young ages, across the whole spectrum of young age, also from a large number of people with older onset colorectal cancer, above the age of 50, and then from a young cohort of people without colorectal cancer. 

We want to analyze how the microbiome is different across these different ages and across cancer patients versus young, healthy patients.

The second part is to take a subset of these stool samples we’re collecting from these people and transplant them into mice to figure out what the mechanism and effect is on the immune system.

Has this study been done before

I don’t think so in terms of looking at young-onset colorectal cancer, specifically. It’s been done for other diseases to look at other variables and how the microbiome might be related to those variables.

As far as I know, this is the first study of its kind for young-onset colorectal cancer.

Who do you need as part of the study

We want to partner with as many patients as possible. Even though the rate of colorectal cancer happening in young people is rising, in terms of the overall colorectal cancer patient population,  it is still a small number.

If we’re going to be able to get answers as to what these risk factors are and what the underlying causes are, we’re going to need thousands and thousands of young patients to participate in research studies such as this.

We all need to work together, partner with each other to get this work done quickly.

Growing Focus on Targeted Therapies

Targeted therapies have really revolutionized the treatment of patients with metastatic colorectal cancer in recent years.

We used to not understand which mutations may predict for benefit or lack of benefit from certain drugs, but with the advent of cutting edge technologies that are available now to really sequence tumors and understand the genetic profile of tumors, we understand more and more which mutations have a role in prediction what treatments may help to benefit a patient.

Microsatellite Instability (MSI)

The most striking example is the patients who have microsatellite instability (MSI) high-colorectal cancer. Among metastatic patients, it’s really a tiny proportion of patients.

Way less than five-percent of all metastatic colorectal cancer patients have this MSI high type of colorectal cancer, but if they do, it predicts a remarkable response to immunotherapy drugs. 

These are patients who, if they respond, may have durable remissions lasting years, which is amazing for somebody with metastatic disease. So one of the biggest research priorities for us is to figure out for the other 95-percent of metastatic colorectal cancer patients, how can we get immunotherapy to work for them.

Here’s where the microbiome may actually have a role we’re just beginning to understand, as we were saying before, about how the microbiome interacts with the human’s immune system.

That could certainly be a factor in why 95-percent of colorectal cancers don’t respond to immunotherapy.

KRAS & NRAS

Other targets include KRAS and NRAS. KRAS is notoriously hard to target and develop drugs against. Approximately 50-percent of colorectal cancer patients do have mutation in either the KRAS or NRAS gene.

Where this knowledge has helped us in determining treatment recommendations for patients is if there is a KRAS or NRAS mutation in a patient’s tumor, then they are likely to not respond to drugs targeted the EGFR pathway.

VEGF

The other pathway that has been important for colorectal cancer is the VEGF pathway. These drugs that target the VEGF pathway we think work by targeting the mechanism by which tumors make blood vessels to feed themselves, so clearly trying to interfere with that may help to kill the cancer and perhaps help the patients not have progression of their cancer, and live longer.

Agents such as bevacizumab that are added to chemotherapy do seem to improve outcomes for patients with colorectal cancer.

HER2

We have a bunch of other targets, too, that have come on the scene. HER2, for example, has been a known target in breast cancer for a really long time. We’re now understanding that about five-percent of patients with colorectal cancer also have an overexpression of the HER2 gene. 

In those patients, it seems like drugs that target the HER2 pathway, similar to the ones used in breast cancer, may also be effective in these patients with colorectal cancer and overexpression of the HER2 gene.

A lot of those trials are still ongoing, but they’re being increasingly incorporated into the armamentarium of drugs that we have to treat these molecular subsets of colorectal cancer.

BRAF

Finally, the other gene that’s very important to know the status of for a patient with colorectal cancer is the BRAF gene, which is present in about 10- to 15-percent of all colorectal cancer patients. We now have new drug combinations that target the BRAF pathway, whereas patients previous to these discoveries didn’t have many treatment options.

So there have been so many advances in the last few years in regards to these targeted therapies. It’s very important that all colorectal cancer patients with metastatic disease make sure to get their tumor profiled so that these decisions can be made and more precision medicine approaches can be recommended.

Guidance to Cancer Patients and Caregivers

What’s your guidance to patients going to community hospitals who may have less access to research

It’s a great question. While it is true that more and more centers, whether academic or community, are in fact doing this and sending patients’ tumor samples off to be profiled and sequenced, we do know that there are still many, many patients out there whose tumors have not been profiled.

I do recommend that patients be informed in terms of the status of their key genes. One is whether or not they have microsatellite instability, the KRAS and NRAS, the BRAF and the HER2, those are the ones right now that have treatment implications.

It can really affect the types of treatments that are recommended that have knowledge of whether or not these molecular alterations are present in your tumor.

If it is not offered that the patient’s tumor sample is going to be sent off for sequencing, patients should definitely ask their oncologist about it. 

What are the basic questions patients should be asking their oncologists

It’s so important to be able to openly ask and talk to your oncologist about any question that may be on your mind. Even to ask, are there any questions I should be asking that I haven’t asked yet?

In general, the basic things to know are:

  • What kind of cancer do I have?
  • Where has it spread to if it has spread?
  • What stage is it?
  • What other tests do I need to be able to determine what stage it is or to help determine what type of treatment should be done?
  • Are there any other types of doctors I should see?
  • Is there a role for radiation, surgery, should I be meeting with those doctors?
  • What are the treatment options?
  • Often there are a few to choose from and so what are the data supporting each and which one would be recommended and why?

There are also clinical trials out there and a clinical trial is not for everyone, but it’s always good to know whether or not there is a clinical trial option out there that may improve your chances of having a good outcome or even if not, it just helps to advance the field of research and our understanding for future patients. 

Other things are what are the side effects of treatment? So if you have decided on treatment what are the likely side effects? It’s important patients get good teaching about what to expect and if there are side effects, how to manage them.

It’s very important to know who to call in case there’s a problem. There has to be a good communication plan with the treatment team.

Then there’s still so much more than just treating the cancer, there’s everything else. Especially for our young-onset colorectal cancer patients, there may be questions about impact on fertility.

There are effects on sexual health. There are concerns about nutrition, diet, and lifestyle. Then psycho-social support is so important to help a patient and their family get through this.

It really takes a village to help comprehensively care for a patient with cancer and all of those resources should be used so you can get the best treatment possible.

What are your thoughts on the advancements of medicine and research, and what it means for cancer patients

The future is bright. There have been such discoveries in cancer research that were before unimaginable.

The example I always give is the example of immunotherapy and how well it does work for the under five-percent of metastatic colorectal cancer patients where it currently works right now.

Even in someone with metastatic disease, there is now a chance perhaps of long-term remission and cure, whereas that wasn’t always something thought to be achievable with someone with stage four cancer.

The hope in science is limitless and it has resulted in discoveries that have changed the way patients are treated and that has more than doubled the survival of patients with colorectal cancer.

There are advances being made everyday. The longer you are around, and thriving on treatment, the more new advances will be made. Definitely talk with your oncologist about whether there are research opportunities you can participate in, whether they be clinical trials or studies of the microbiome where you can contribute your stool, or diet and lifestyle questionnaires.

There is still so much to be learned that will benefit you and will also benefit all the other future patients out there.


Thank you, Dr. Ng!
Several photos, including this one, supplied courtesy of Dana-Farber Cancer Institute. 

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