Missed Opportunities
Global oncology guidelines and studies, including those from the ESMO Precision Medicine Working Group and JCO Global Oncology, show that biomarker testing results are typically returned in about 10-14 days in many regions, and may take several weeks in areas where samples must be shipped to specialized laboratories.
The natural inclination is to act immediately, especially in the face of the anxiety that accompanies a new diagnosis. People often believe that starting treatment right away gives the best chance of survival. This sense of urgency affects not just patients, but caregivers and healthcare providers too. However, acting without biomarker results can mean missing the chance for more effective, targeted therapies that are tailored to the biology of the tumor, or the opportunity to participate in a clinical trial. When it comes to colorectal cancer, waiting for the right information isn’t hesitation, it’s precision.
Troy's Story
Diagnosis
Troy Warshel started having abdominal pain and other gastrointestinal symptoms in October. With his wife Jodi by his side, Troy had a frustrating series of appointments and imaging tests, pursuing the possibilities of acid reflux or even a rare parasitic infection picked up in the Middle East during his military service. Troy was finally scheduled for a colonoscopy 2 months later. Having had a negative FIT screening test in the past, colorectal cancer was not in mind for Troy and Jodi, but the senior doctor in the recovery room told them, “We found a tumor”. They were unable to get the colonoscope past the mass. Because of the severity of the blockage, Troy had surgery ten days later, and stage III colorectal cancer was confirmed.
Chemotherapy
As Troy recovered from surgery, the couple dove into learning everything they could about his upcoming chemo, its side effects, and how to prevent them. Troy says, “I knew it was going to suck, I was kind of prepared for that.” Jodi researched icing protocols to prevent peripheral neuropathy from oxaliplatin and mouth rinses to prevent mouth sores from capecitabine. Troy began his first cycle, an oxaliplatin infusion and 2 weeks of capecitabine pills. “I felt so bad, I didn’t get out of bed for 9 days, it was brutal,” says Troy. Jodi adds that at first, “We thought “no pain, no gain”. That’s what chemo is. But I knew, something’s not right.”
Jodi was tireless in her efforts to find out why Troy was having such terrible symptoms. The night before his next infusion, just as she was about to put down her phone and go to bed, Jodi came across a comment in an online forum asking about DPD deficiency testing. She discovered the website of Advocates for Universal DPD/DPYD Testing and recognized Troy’s symptoms. “This is it! This is 100% - this is it.” She went on to read the devastating stories of patients with DPD deficiency who died from the toxicity of capecitabine and fluorouracil because they lacked the enzyme, DPD, that would break down those drugs in their bodies.
Advocacy
At Troy's appointment the next day, Jodi asked his team if he had been tested for DPD deficiency. She was told it wasn’t indicated, and that Troy’s lack of mouth sores did not line up with having DPD deficiency. Jodi was sure that the mouth rinses Troy had been using to prevent mouth sores were working, masking this important symptom of DPD deficiency-associated capecitabine toxicity. Jodi spoke up, suggesting that the severity of Troy's symptoms may also appear reduced due to his unusually high pain tolerance and excellent physical fitness, and asked that he have DPD testing anyway. The team agreed, the DPD deficiency test was ordered, and together they decided to give Troy another week of recovery between cycles, and to reduce his chemotherapy dose because of intolerable side effects.
A week later, Troy began his second cycle with the reduced dose. The following day, Troy received a call from his oncology team. His testing showed that he has intermediate DPD deficiency. His body has a reduced ability to break down capecitabine, leaving him with dangerous amounts of it in his system. Troy’s dose needed to be reduced even further to prevent a further severe toxic reaction. Troy notes, “I couldn’t advocate for myself. Without Jodi, I would have been dead, for sure. Not a doubt in my mind.”
Knowing Is Worth the Wait
Troy’s chemotherapy proceeded with a reduced dose of capecitabine, and he is now “NED”; he has no evidence of disease. But DPD testing was not the only biomarker testing Troy had, and his other results have also changed his care. Troy’s colorectal cancer has a mutation in the BRAF gene which means he has a higher risk of his cancer returning. Now that they have that information, Troy’s team has planned his follow-up care to include more frequent monitoring, including imaging scans, blood tests, and colonoscopies to look for any sign of the cancer recurring. Metastatic colorectal cancer patients who have Troy’s particular BRAF mutation, known as V600E, may be eligible for targeted therapy with a BRAF inhibitor drug. On their experience with biomarker testing, Jodi starts, “You’ve just got to ask the questions. Knowing your subset and knowing that every single cancer is different...” and Troy finishes, “Knowing your cancer is critical.”
Biomarkers Provide Vital Information
The results of biomarker testing provide you and your care team with critical information about you and your cancer that is used in making various treatment decisions. Colorectal cancers are not all the same; each cancer has characteristics that influence how it should be treated, and you and your healthcare team will make treatment decisions together.
Treatment Decisions
Targeted Therapy
What it is: Targeted therapy is cancer treatment that uses medications to target cancer cells directly and more precisely destroy cancer. Nearly half of the oncology drugs approved in the U.S. since 1998 are precision therapies that rely on biomarker testing. Targeted therapy can work in several ways.
- Blocking the cancer cells’ growth and survival mechanisms
- Blocking the development of the blood supply the tumor needs to survive
- Helping a patient’s immune system recognize and kill cancer cells
- Recognizing specific cancer cells and delivering an anti-cancer drug directly to them
Why it matters: All of these ways of targeting cancer cells depend on information about your cancer’s biomarkers. Biomarkers help your care team understand the specific type of colorectal cancer you have so they can match you with the most effective treatment. Tumors that have microsatellite instability, a biomarker also called MSI-High or dMMR, often respond well to immunotherapy. Biomarkers can also reveal whether your tumor is likely to respond to certain therapies or if alternative approaches may be needed. In colorectal cancer with BRAF V600E mutation, BRAF inhibitors can be combined with EGFR inhibitors and MEK inhibitors to reduce the likelihood of drug resistance. By identifying these unique characteristics early, your team can build a more personalized and effective treatment plan.
Avoiding Inappropriate Treatments
What it is: Decision-making about cancer treatment involves not only choosing the right treatments but also avoiding the wrong ones. There are treatments that may be ineffective against a particular colorectal cancer. And certain treatments may actually be especially harmful or dangerous in certain people.
Why it matters: Using a treatment that isn’t effective for your type of cancer can delay you from getting the care that could actually help. This lost time may allow the cancer to grow or become harder to treat. It also means you’re exposed to side effects from a therapy that isn’t providing real benefit. Your biomarkers can provide clues about which treatments won’t be effective. For example, EGFR inhibitors are not usually effective in patients with KRAS mutations, so they aren’t given.
Some biomarkers, like DPD/DPYD and UGT1A1, can also predict which treatments may be particularly harmful to you. Chemotherapy drugs usually have some negative side effects, but in some people, they are severe or even fatal. Drug metabolism is a process your body uses to break down medicine into forms that are easier for your body to use or get rid of. Enzymes are chemicals in the body that help this process. In people who have drug metabolism enzymes that are abnormal or absent, the severity of side effects can increase. Knowing about your drug metabolism enzymes through biomarker testing can help your doctor choose the right dose of medicine for you or even avoid certain drugs that would be dangerous to you.
Prognosis
What it is: Prognosis is the expected course of a disease. Some biomarkers can predict the outlook of your cancer, including how aggressive it will be. Biomarkers may also give information about the risk of the cancer returning after treatment. This helps your care team decide what follow-up care you may need. It can also give you a better understanding of what to expect during and after treatment.
Why it matters: Prognostic information can affect how your cancer is treated. It guides decisions about whether or not to use chemotherapy after surgery, a treatment called adjuvant chemotherapy. Some patients with stage II colorectal cancer may be cured by surgery alone, but in patients with an aggressive subtype of colorectal cancer, adjuvant chemotherapy is recommended to kill any remaining cancer cells and prevent recurrence.
Prognosis also impacts choices about how and when to check to make sure the cancer hasn’t come back after treatment. After colorectal cancer treatment, patients and their healthcare teams make decisions about this follow-up care, including imaging scans, blood tests, and colonoscopies. If a patient has a colorectal cancer with biomarker results that predict a higher risk of recurrence, follow-up care will involve more frequent testing to look for any signs of the cancer returning.
Surgery for the Future
What it is: There are times when a person who is at very high risk of cancer recurrence may have more extensive surgery for their colorectal cancer to lower the risk of their cancer coming back. There are also rare situations in which patients at very high risk of CRC may have surgery to prevent colorectal cancer before they ever get it, called prophylactic or preventive surgery. Biomarkers also play a role in determining the surgical approach to tumors that have spread outside the colon and rectum, called metastases.
Why it matters: The type of surgery a person has for colorectal cancer, or even for precancerous colorectal polyps, can be guided by biomarker testing results. Biomarker testing (including genetic testing) can reveal whether a patient has a hereditary cancer syndrome. Hereditary cancer syndromes are health conditions that are passed down in families through genes. People can be born with a change in their DNA that increases their risk of cancer. About 5% of colorectal cancers are due to a hereditary cancer syndrome.
The most common hereditary colorectal cancer syndrome is Lynch Syndrome. People with Lynch syndrome have a 40-80% lifetime risk of CRC, with women at the lower end of the range, and men at the higher end. Together with their healthcare teams, patients with colorectal cancer from Lynch Syndrome may decide to have more extensive surgical procedures, like having more of their colon removed and not just the segment affected by a tumor. This is because of the very high likelihood their cancer will come back. More extensive surgery can lower that risk.
Familial Adenomatous Polyposis and its subtypes cause about 1% of colorectal cancers, but the lifetime risk of CRC in people with untreated FAP is close to 100%. Therefore, people with Familial Adenomatous Polyposis often have total removal of their colon and rectum, even if they are diagnosed in the precancerous stage. If precancerous tumors are left untreated, they will become cancer. And because of FAP, these patients will continue to develop precancerous tumors. Removal of the organs that develop the tumors greatly reduces the risk of colorectal cancer.
Biomarkers can also be used in decision-making about surgery to remove tumors that have spread outside the colorectum, called metastases or metastatic tumors. Removal of metastases, or metastasectomy, may be made possible by targeted therapy, which is guided by biomarker testing. For example, tumors with microsatellite instability may shrink after a strong response to immunotherapy, making them resectable. In addition, a good response to targeted therapies in HER2 amplified tumors, tumors with NTRK fusion, or tumors with KRAS G12C mutation may make these metastases small removable. Other RAS mutations and BRAF V600E mutations often predict poor outcomes from aggressive surgery to remove liver metastases.
Clinical Trials
What it is: More than half of oncology clinical trials involve the use of biomarkers, and this number is on the rise. Around 55% of all oncology clinical trials in 2018 involved the use of biomarkers, as compared with about 15% in 2000.
Why it matters: In many of these trials, biomarkers are used for patient selection, either to include patients with certain biomarker testing results or to decide they are not a good candidate for the trial. In this case, biomarker testing serves as a matchmaker between patients and clinical trials.
An increasing number of clinical trials study patients with multiple tumor types that share a biomarker, for example, all solid tumors with NTRK fusion, which could include patients with colorectal cancer, lung cancer, or thyroid cancer. These are called basket trials, because patients with different diseases are considered as one “basket” of patients because they have the same biomarker. This is in contrast to trials that focus on one specific cancer, instead focusing on the shared biomarker. The only way to be matched with a trial like this is through biomarker testing.
Another type of clinical trial treats patients with a single cancer type, but patients are assigned to different treatments based on their distinct biomarkers. This is called an umbrella trial because it consists of smaller sub-trials under the umbrella of the larger trial. These designs greatly increase trial efficiency for targeted agents but depend on timely, accurate biomarker testing.
It’s important to have biomarker testing results before starting treatment, so that clinical trial matching can happen first. Many clinical trials require that patients be “treatment-naive” to participate. That means that patients who have started treatment already will be ineligible for those trials. Early biomarker testing and waiting for results gives patients the greatest chance to participate in a clinical trial.
Dan's Story
Routine Screening
Dan Shockley, a U.S. Navy veteran of three conflicts, had a routine colonoscopy for colorectal cancer screening at the then-recommended starting age of 50. That screening changed everything. Dan’s doctors discovered hundreds of polyps throughout his colon and rectum. They suspected that a hereditary syndrome may have caused these precancerous polyps, which if left untreated, would become colorectal cancer.
A Diagnosis
Dan’s immediate instinct was to rush towards treatment. He says, “I wanted to get the surgery, get it done as quick as possible.” His team recommended that he have genetic testing. Dan’s curious and positive nature, coupled with his military background, helped him wait for the facts and gather more information. “We have two choices. We can react or we can respond. My military background equipped me to respond by gathering information so I can make a logical decision.” Dan did not have cancer so there was no urgent testing order and turnaround times for testing were considerably longer in 2011, so he had several weeks to read credible resources and talk extensively with his gastroenterologist, genetic counselor, colorectal surgeon, and the chief of surgery. After germline genetic testing, Dan was diagnosed with attenuated Familial Adenomatous Polyposis, or aFAP.
Familial Adenomatous Polyposis and its subtype attenuated Familial Adenomatous Polyposis are inherited syndromes of high cancer risk. FAP and aFAP cause numerous abnormal growths, called adenomatous polyps, in the colon and rectum that will become colorectal cancer if left untreated. The timeline of polyp growth and cancer development is different in classic FAP and attenuated FAP. The average age of colorectal cancer is 39 years in patients with classic FAP. For attenuated FAP, the average age of colon cancer or rectal cancer development is 55. Dan’s polyps had been diagnosed just in time.
A Plan
Armed with this knowledge, Dan decided to undergo total proctocolectomy with permanent ileostomy. This means his entire colon and rectum were removed, and an opening in the abdominal wall, called a stoma, was created. Dan’s ileum (the last segment of the small intestine) was connected to this stoma to create an ileostomy which allows his small intestine to pass waste out of the body. A removable ostomy pouch is attached to the skin around the stoma to collect waste for disposal.
Knowing Is Worth the Wait
Since his preventive surgery more than 13 years ago, Dan has not developed colorectal cancer. Removing the precancerous polyps and the organs in which they would have continued to occur has prevented colorectal cancer for Dan.
Dan has taken the acronym of the condition that changed his life, AFAP, and turned it into his life’s motto, Always Forge Ahead with Purpose. Since his diagnosis and treatment, Dan has become a fierce advocate for others in similar situations. He is an ambassador for the hereditary colorectal cancer community, the rare disease community, and the ostomy community, and he speaks to bring awareness and support to men’s mental health. Dan continues to spread his message, “Stay positive, ask lots of questions, talk to your family, talk to your medical team, and research, try to obtain as much information as possible to prepare yourself.”
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