Listen to this podcast with advanced practice professionals providing an overview of the current biomarker testing landscape for patients with colorectal cancer, including their thoughts on overcoming key barriers to testing, education of patients and caregivers, and improving equity in the application of biomarker testing in patients with colorectal cancer.
Advanced practice providers discuss biomarker testing in patients with colorectal cancer. Listen in to learn from Ann Marie Siney, RN, MSN, ANP-BC, and Kathleen Boyle, DScPAS, PA-C, about familial cancer syndromes associated with colorectal cancer and key biomarker testing often used in patients with colorectal cancer, including their thoughts on overcoming key barriers to testing, education of patients and caregivers, and improving equity in the application of biomarker for all patients.
Presenters:
Ann Marie Siney, RN, MSN, ANP-BC
Division of Hematology/Oncology
UCLA Health
Santa Monica, California
Kathleen Boyle, DScPAS, PA-C
Gastrointestinal Cancer Center
Dana-Farber Cancer Institute
Boston, Massachusetts
Link to full program:
https://bit.ly/4spkxiC
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Hello and welcome to this Decera Clinical Education Oncology Podcast. I am your host, Jerfiz Constanzo. In today's episode, we are joined by Ann Marie Siney, who is a board certified adult nurse practitioner in the Division of Hematology Oncology at the UCLA Health in Santa Monica, California, and Kathleen Boyle, who is a physician assistant in the Gastrointestinal Cancer Center of the Dana-Farber Cancer Institute in Boston, Massachusetts.
Together, they will be discussing the role of advanced practice professionals, APPs, regarding biomarker testing and their application in patients with colorectal cancer. This episode is part of a larger educational program entitled The APP Guide to Actionable Biomarkers in Solid Tumors: Reducing Barriers, Promoting Confidence, and Leveraging Genetic Testing for Informed Treatment Decision Making.
For more information on Ann Marie and Kathleen, along with a link to the complete program, including downloadable resources, clinical commentaries, and educational podcasts for lung cancer and prostate cancer, please visit the notes for this episode. Now, let us hear what the experts have to say regarding the role of APPs in the application of biomarker testing in patients with colorectal cancer.
Ann Marie Siney (UCLA Health):
Ann Marie Siney. I work at UCLA Medical Center in GI oncology. I am happy to be here together with Kathleen covering this very important and, in the oncology world, very exciting topic today. Part of the reason for this is, as we know, colorectal cancer is the third most common cancer diagnosed in the US, and the second leading cause of cancer death among men and women in the United States. This is highly significant given that early-stage colon cancer is 90% curable and can often be 100% curable.
Unfortunately, that said, the incidence of colorectal cancer is growing, particularly in younger adults under the age of 55. And this, as you probably know, prompted the recent update in screening recommendations, with screening now recommended starting earlier at 45 for those who are at average risk for colorectal cancer. As we know, individuals with known inherited syndromes begin screening, however, at a much younger age. The most common ones in colorectal Lynch syndrome and familial adenomatous polyposis, FAP. The screening for these individuals start much earlier. For Lynch, it can begin as early as 20 to 25, and for those with FAP as early as 10 to 15 years old. Kathleen, given that colorectal cancer is being diagnosed at a younger age, how has this affected your practice?
Kathleen Boyle (Dana-Farber Cancer Center):
Thank you, Ann Marie, so delighted to be here to talk to you about this today. At Dana-Farber, we actually have a young onset colorectal cancer clinic that deals with individuals who are under the age of 50 who have been diagnosed with this disease either in the early stage or metastatic stage. I think you highlighted the importance of screening. The benefit of colonoscopy, as this is one of the cancers that actually does have a good screening method. There are also gene and blood stool testing kits that can be done to assess the risk of colon cancer for individuals, but it is important because the incidence of young folks is rising by 1% to 2% per year since the mid-1990s.
Advocating for our patients to get screened and also talking through the biomarkers that are present for our patients helps guide their treatment as well as potentially mitigate risk for their family members.
Ann Marie, in your clinic, I am sure people come in all the time asking and saying, "I was told I need genetic testing." How do you talk to your patients and clarify the difference between something like germline testing and somatic testing?
Ann Marie Siney:
Ok, that is a great question. As we know, the importance of biomarker testing has become much more significant in the last several years. You may have heard the term next generation sequencing. I am sure we all have who work in this field. It really has become a necessity in treating advanced metastatic colorectal cancer where you are targeting treatment to the individual genetic mutations identified. This is often called precision oncology or precision treatment.
Let us review quickly the difference between germline and hereditary biomarker testing versus somatic, which is tumor specific biomarker testing.
Germline, or hereditary biomarker testing, assesses for inherited genetic syndromes passed through family members. Most common one known probably around the world is BRCA, but the most common in colorectal cancer is Lynch syndrome, occurring in about 2% to 4% of all colorectal cancers. Lynch syndrome, or HNPCC, which is hereditary, nonpolyposis colorectal cancer occurs at a younger age, and it carries a 40% to 80% lifetime risk of developing colorectal cancer. So you see the importance of figuring out what inherited genetic mutations might be significant to a family.
FAP, familial adenomatous polyposis is a hereditary autosomal dominant genetic condition. That is caused by the APC gene. It accounts for less than 1% of all colorectal cancers, but it carries a 70% to 80% lifetime risk of developing colorectal cancer, depending on the variant you have. Very often prophylactic colectomy is recommended. Usually these families know there is a strong family history of cancer and they know that there is an inherited gene that is being passed down from family member to family member. These patients are usually being screened, which is better for their outcomes at a much earlier age.
Now, the difference with somatic biomarker testing is that you are looking for mutations specific to the tumor itself. This can be done on a liquid biopsy or a tissue biopsy. Liquid biopsy refers to a blood test. Most often it could also be saliva and urine, but in our arena we usually use a blood sample and it is analyzing circulating tumor DNA. These are circulating tumor cells that have been shed by the tumor into the blood. What is the benefit of that? The turnaround time is much faster, approximately a week. It does have limitations in that the amount of tumor DNA being shed into the blood may be low and too low to detect any mutations. Advanced disease and large tumor burden will likely shed more cells into the bloodstream, whereas early, small volume disease may be less reliable in that respect.
Tissue testing, on the other hand, requires a sample of tumor tissue and test for genetic mutations specific to the tumor. This is not entirely a new process. We have been testing for specific mutations by IHC, immunohistochemistry, for many years. For instance, KRAS status and HER2 status and mismatch repair, gene status. Most pathology departments will automatically perform initial testing by IHC for certain mutations once a diagnosis is made. Basically, the IHC testing is often done in just the general pathology department, and begins as soon as the diagnosis is made. So, it is helpful in early treatment decision making because it can identify MSI high disease, which is better treated than immunotherapy, but we will get into that a little further.
The NGS testing on tissue can take two to four weeks depending on how fast the tumor specimen is received. And when analyzing your NGS report, you may have noticed several reports indicating slightly different results. One may say no mutations, while another may show one or multiple mutations in the result. Testing, just to clarify, can be performed on DNA and RNA. Reason being that there may be different mutations on each.
Kathleen, can you provide us with more detail on the essential biomarkers to test for that guide, the treatment of colorectal cancer?
Kathleen Boyle:
Absolutely, Marie, thanks for that review. Germline testing, we are thinking about inheritable and familial transmitted patterns that increase risk for disease, and somatic mutations we are thinking about driver mutations or fusions that are one off and developed during the course of life that are non-hereditable.
All of our patients come in a variety of stages, and there are some things that we test specifically just in the curative setting and some things that we test in the metastatic setting. Ann Marie, where do you start conversations with your patients regarding biomarker testing when they present to your clinic?
Ann Marie Siney:
For early stage cancer patients, the quickest biomarker testing and the initial biomarker testing done is for HER2 and for MMR, which is MSI. As we all know, HER2 is well known and it is tested by IHC. We have been testing this for a very long time. This is not something that is new to our cancer arena. HER2 testing is very easily identified on IHC with a HER2 positive score. If the HER2 comes back as a three plus, however with HER2 being zero or one as a negative finding, anything that is HER2 2+ should be reflexed FISH.
Now for mismatch repair, or microsatellite instability, mismatch repair deficiency identifies error in the base pairs and that are not routinely corrected. This is what leads to microsatellite instability. MSI testing is done to examine the repeat size of the satellite of the select microsatellite markers. It is performed by PCR. MMR testing can be performed via IHC with that quick turnaround, and those who have a mutation in the MLH, MSH2, MSH6, or PMS2 should further be tested or indicates a positive Lynch syndrome.
There is a couple of caveats to that. When we are dealing with Lynch syndrome, to make sure that it is actually a true identification of Lynch syndrome, basically what you will find is that if then it is not Lynch syndrome.
Ann Marie Siney:
Kathleen, can you help us understand what else you might test for?
Kathleen Boyle:
We reviewed that all patients should have MSI or MMR testing and metastatic patients should have RAS, RAF, NTRK, POLE, and RET mutational testing. Some of the other things we test for which are not necessarily included in biomarker testing are DPYD and UGT1A1. Those really reflect enzymatic metabolization of some of the drugs that we utilize in therapy. While not a biomarker, patients may ask why did this gene get tested? Truly it is for tolerance and metabolization of drugs, and not necessarily a targeted biomarker like this conversation is focusing on.
We do have some survey data, as some oncology providers were surveyed to get an understanding about who orders this testing, how confident they feel ordering it. Let us dive into that. In a survey of 54 individuals, with the wide majority being nurse practitioners, nurses and research nurses and physician associates, we had about 80% of the 54 folks be within those APP designations or research nurse designations, with a few pharmacists and physicians. Ann Marie, it seems like there are a few barriers that people have regarding testing. Could you review what the survey data showed?
Ann Marie Siney:
Sure, absolutely. The barriers to testing usually have to deal with very often access to care, knowing the type of testing to do, and where we are sending it. Most commonly the barrier for testing that I find in my practice is that patients do not or are unable to afford it. This is a test that is covered by Medicare. This is very important. Everybody should know this. This test is covered by Medicare. However, there may be a copay with it. The important thing to know is that the majority, and I actually have not found a company that will actually charge the patient for the copay.
These companies are very, very good at telling and agreeing to not charging any copay. The billing department will often send them the bill. However, if they reach out to them and say, "I cannot afford this," then they will write it off. The most I have found any company to charge is $200. If the patient is telling you, "I cannot afford this," reach out to your rep. Give them their name. This is my patient who has a $1,200 copay.
Worse still, they are not a Medicare patient and their insurance just is not testing it. They are like, no, this we do not agree with this. Trust me, as we know, that definitely happens. The companies will not charge the patients. They want the data, and the data is important for guiding treatment, especially in the metastatic disease setting. That is the big take home message. We should be educating our patients about this testing, and we should be reaching out to our local reps and from there, advocating for our patients, getting the tests done.
The other issue that we may find is that there is insufficient tissue for analysis, which we will go into a little bit later, and the turnaround time. If you are doing the liquid biopsy, the turnaround time is very quickly. It is about a week, as we said earlier on. If you need to find the mutations on the actual tissue itself, that can take a little bit longer. It is good to get into the practice of, once the patient is diagnosed as a metastatic in the metastatic setting, it is automatic. You just reflex it. Like DPD deficient. If the patient is diagnosed with DPD deficient disease, it should be reflexed to automatically test. If the patient is diagnosed with colorectal cancer that is going to need infusional 5-FU, you automatically reflex it for testing for DPD deficiency. Same here. Once the patient is diagnosed with metastatic disease, it is automatic. It becomes that day you send the tissue, organize to send the tissue off to get tested. It may not help you immediately and you may not need it to because traditional chemotherapy may be the way to go, but it will help you down the line if they recur.
If you are unsure which test to order, then reach out to your rep also. They will tell you. Most commonly, the team itself is saying, "Let us do FoundationOne." You can always reach out to your reps and they will guide you and assist you and provide you with paperwork, and make the process as easy as possible.
Kathleen Boyle:
Absolutely. The data from the survey suggested that there is a bimodal spike of people in their confidence of discussing biomarker testing with their patient. We had a large number of folks who felt extremely confident, and also a large number of folks who felt not at all confident. Ann Marie and I have the luxury of working in a GI-focused oncology division, and acknowledge that not everyone has that ability, and keeping up with biomarkers can be difficult when you are seeing diseases of all natures. This data makes sense to reflect the mix of academic and community practices.
We also saw that there were some respondents who noted that they rarely or sometimes order KRAS or BRAF mutations, and we would reinforce that this is incredibly important for our metastatic patients to know KRAS and BRAF status, as this can guide therapeutic options and also extend prognosis for patients who might otherwise have quite limited lifespans from their metastatic disease. We also have some information about the biomarkers that are being tested in early colorectal cancer.
Now that we've reviewed a lot of the biomarkers, let us dive deep into the interpretation of these results and how we apply these to treatment decisions. Ann Marie, can you guide me through how you would manage patients with microsatellite instable disease, KRAS mutation, and RAF or MEK mutations?
Ann Marie Siney:
We have touched on this a little bit about MSI high disease. Patients with MSI high disease have a very different treatment approach to actually patients who have non-MSI or mismatch repair or MSI stable disease. MSI high disease is extremely responsive to immunotherapy. This has changed the paradigm and the way we treat MSI high disease in the last several years there. There is also still room for using chemotherapy, and what you may find though is that the chemotherapy like FOLFOX and CAPOX is being used in conjunction with immunotherapy.
Our standard immunotherapies are nivo, ipilimumab, pembro. You may also be using dostarlimab. There are several. Your practice and your institution may have preferences depending on who usually the pharmacy is working with to supply these medications. For neoadjuvant treatment, standard chemotherapy is very often required, but immunotherapy may be a good alternative choice. Elderly patients, patients who cannot tolerate the hardship of FOLFOX, FOLFIRI, or FOLFOXIRI, which is also utilized, these patients usually tolerate immunotherapy very well. As we know, immunotherapy does have significant side effects. You really do have to watch for those strange less than 1%, less than 2% side effects. It is not a benign treatment, but it is definitely for the majority of patients tolerated much better.
Let us talk a little bit about RAS and BRAF. KRAS and BRAF mutations, these also indicate which way we treat our patients. If a patient has an EGFR tumor basically more common on the left hand side. Left sided tumors are very often EGFR. Years ago we thought that everybody would respond well to cetuximab and to panitumumab, but then we found that not all patients were having good outcomes. To make a long story short, we then realized that if the patient was KRAS wild type, then, yes EGFR inhibitors were safe to use. If they were KRAS mutated, then these patients had worse outcomes. It is important to know which tumors, so more commonly left side.
Then what do we do with the right sided tumors? On the right sided tumors also, patients that are EGFR inhibited will not usually be treated with cetuximab or panitumumab, but they are susceptible to VEGF inhibitors. So, VEGF inhibitors can given for any type of metastatic colorectal cancer metastatic setting only. These patients it does not matter whether you are right sided or left sided, whether you are wild type or whether you are mutated.
Kathleen, what other biomarkers are you guys looking at these days?
Kathleen Boyle:
We are also looking at HER2, NTRK, POL, and RET. In terms of HER2 amplified tumors, if it is a HER2 amplified by IHC3+ or it is NGS amplified, as well as RAS wild type and BRAF wild type, we will consider trastuzumab and pertuzumab or tucatinib or lapatinib. If it is a HER2 amplified three plus with KRAS mutation or BRAF mutation, we are thinking trastuzumab deruxtecan. It is important to know what the HER2 status is, as HER2 amplification tends to have a worse prognosis with the wild type RAS and RAF, and similar to those of RAS mutations and better than those of BRAF mutants. Knowing where your biomarker positivity is helps guide your prognosis conversation.
We also will get NTRK fusion data. It is important to note that this is NTRK fusion, not amplification. NTRK fusions can be treated with entrectinib or larotrectinib or repotrectinib. For people who have POL pathogenic variants, this is a more favorable prognosis. It likely is secondary to immune responses that are stimulated by the precedence of numerous neoantigens produced because of some aberrant proofreading function. These patients actually get treated quite similarly to those who have MSI high status and respond well to immune checkpoint inhibitor therapy. For folks with RET fusions, we are talking about selpercatinib therapy.
If you are unsure and you do not have this biomarker testing back, then it is generally ok to start with the standard of care chemotherapy and then refine the plan accordingly. If you have someone with a high tumor burden who's highly symptomatic, get started on standard of care and refine after.
Ann Marie, do you ever consider rebiopsy and if so, when and what testing do you do if you are going to rebiopsy?
Ann Marie Siney:
Rebiopsy can be a difficult issue. You have to explain to the patient we really do not have enough tissue because tissue can be basically expired or shall we say, it is depleted from previous testing, or perhaps the tissue sample was small and the tissue sample prep, for example, after neoadjuvant treatment, there may only be a tiny small amount of active tumor left if any. This can make testing very difficult because there has to be a minimum number of cells to actually be able to test for mutations reliably.
We will often say to the patient, you have a liver lesion there, it is easily accessible. CT guided biopsies, sometimes ultrasound guided biopsy can access that, and it will just give us much more information on how we treat your tumor in the future, and you will likely have better outcomes. The only caveat to that is if there are no mutations then the patient has gone through this extra testing, but at least you know and that standard chemotherapy second line, third-line, fourth-line is the way to go.
This most often occurs obviously in the metastatic setting. We will have patients who come to us for clinical trial, and their tumor has been exhausted by previous testing or it is it is unavailable, or it is taking too long to get it from another facility. These are all reasons to actually read to retest and rebiopsy the patient. When we do that, we are looking for specific mutations like KRAS, BRAF, HER2, NRAS, NTRK, PIK3CA, RET. Because these are the type of tumors that will actually have an actual treatment.
The treatments are listed right there in the NCCN guidelines if you want to find them. For that specific mutation, this is the treatment. It also helps to lead us in the clinical trial setting because, for instance, KRAS is a common biomarker. KRAS G12C occurs for about less than 5% of colorectal cancer patients, but it does have an actual oral treatment that you can use for it.
Now the most common KRAS mutation in colorectal cancer is G12D, but we do not have an FDA approved specific treatment for that just yet. This is why further testing is going on so that we can identify potential treatments through clinical trial to see if these biomarkers will have a treatment in the future. That is probably a future discussion.
Ann Marie Siney:
Kathleen, when you are interpreting your NGS report and you see multiple or even one or two mutations, whether it be BRAF or EGFR or RET, where can you find information and how do you treat those specific mutations?
Kathleen Boyle:
I look primarily at the NCCN guidelines. There is a portion under colorectal cancer which has to do with molecular profiling, which outlines the drugs that we currently have standard of care for biomarkers that are tested via NGS. This is not a comprehensive list of all clinical trials or all prospective biomarkers of importance, but it has the standard of care biomarkers including HER2, KRAS, BRAF, and NTRK. Another place to look is the ASCO guidelines. They are one sheet quick summaries for each different type of disease. There is also the College of American Pathologists NGS worksheets. That is an effort to standardize some of this molecular profiling data, but all of these have ways to quickly cross match the biomarker and its associated therapies.
Ann Marie, in the survey, there was a question about PARP inhibition for BRCA mutations. That is not something in my clinic that we are managing. Can you comment on that?
Ann Marie Siney:
Yes. The use of PARP inhibitors in colorectal cancer is not FDA approved. It is known that in other GI cancers, and in particularly BRCA mutated cancers like pancreatic cancer, these patients do respond to PARP inhibitors, and they are FDA approved for that indication. For colorectal cancer, they are not. Now, whether they will be later at some point down the line remains to be seen. At this point, it is not routinely used in colorectal cancer.
Kathleen, that said, the question about biomarkers for novel or recently available targeted therapies segues right into that. You are at a research institute, are there novel therapies that you guys are investigating right now?
Kathleen Boyle:
Absolutely. I think you teed that up perfectly with the PARP inhibition. That is an off label use that is being utilized in other GI cancers, but not colon cancer, specifically. At our institution, we have a variety of KRAS trials. We have a pan-KRAS trial, a KRAS G12D mutational trial, a KRAS G12C, and a KRAS G12S mutational trial. We also have some investigative trials into bispecific antibody drug conjugates, as well as a WRN helicase inhibitor for MSI high tumors.
This NGS testing will give all of the biomarkers. It is up to us to think about what biomarkers we have seen in the data that suggests emerging evidence, and either refer to a center that has the clinical trial available, or speak with our internal teams about a specific patient's reporting and how we might be able to find a strategy that targets their mutational burden.
Ann Marie, there is also some questioning on this survey about how to communicate and educate your team, how to collaborate well, when talking about NGS testing. Can you talk about how you apply this knowledge to your multidisciplinary conversations?
Ann Marie Siney:
Yes. Because it is so common in our clinic right now and how we treat our patients, it is basically a team approach. The important thing, I think, for everybody to know is that patients are savvy and patients will ask questions. We need to be able to have answers and we need to be able to find answers. I think most of us as NPS and APPs basically have very good relationship with our medical oncologist. This is definitely a team approach. We do not survive with just one team member. That is why we have tumor board. We get everybody's input and we need to be able to reach out to these people.
A lot of the time emailing your pathologist and just say, "Hey, can you add HER2 testing? I did not see it on the initial report," because sometimes they will not do it, is adequate. Or can you test for EGFR on this new tumor or this new biopsy that we did? The genetic counsellors come into importance because we need patients who have the genetic inherited syndromes to meet with the geneticist. The oncology surgeons, the radiology team, it all depends on what approach you are taking to the patient's care. Multidisciplinary team meetings are a great way for everybody to communicate and to be educated. Also I find that finding references from ASCO, from your APP sources, the ONS are excellent sources for educating yourself, and your team and your patients actually.
Kathleen, where do you think we go with the mitigating health inequality regarding testing. That was a question also on the survey.
Kathleen Boyle:
A few things can be done to decrease health inequality. One, we are working as a team and during initial consults with oncologists, there is so much happening. Sometimes this biomarker testing can slip awareness. That is where we just need to work as a team to make sure that patients are getting initial NGS and rebiopsied as needed. Being proactive in monitoring their biomarker status.
Cost is also a major concern for providers. Making sure that they know that patients will not bear the financial burden. And as you mentioned, there is legislation in states requiring that there is insurance coverage of this testing. That does not necessarily mean there is adequate copays. It is important to have your local rep because many of these companies do not balance bill patients, and they generally do not charge a copayment greater than $100 or $200.
So, making sure we are working as a team, making sure no patients are slipping through the cracks, and making sure that we are giving patients a financially feasible way to access biomarker driven care that could truly improve their prognosis and outcomes is incredibly important.
When we are thinking about the different types of biomarkers needed for evaluation of colorectal cancer, there are some things that all patients should have tested, and some that only patients in the metastatic setting should have tested. All patients should have MSI, also known as MMR testing, which is a mismatch repair deficiency, which corresponds with how the DNA repairs errors within its transcription process or does not do so. This is important when considering the possible susceptibility to immunotherapy as a treatment, and also can be important on whether you refer someone to the genetic counselling team for germline evaluation of Lynch, as patients with Lynch syndrome very often have microsatellite instability.
For patients in the metastatic disease, it is important to have RAS, RAF, HER2, NTRK, POL, and RET mutational information. RET HER2 can be obtained via IHC. RAS and RAF testing can happen via next generation sequencing, while NTRK fusions can be detected on IHC, FISH, and DNA and RNA based NGS. POL pathogenic mutations variants are identified on PCR, and RET fusions can be found on IHC, FISH, PCR, DNA, or RNA-based NGS.
One thing that we are leaving out of this conversation that is important for other disease sites is PD-L1. Clinically, the bottom line for PD-L1 testing is that it is not needed in colorectal cancer treatment planning outside of a clinical trial, and is not recommended by NCCN guidelines. Current evidence and guidelines support MSI and MMR testing, and checking for hypermutated states like POL1, as well as actionable predictors of checkpoint inhibitor benefit. PD-L1 expression in colorectal cancer remains investigational and not validated for standard of care selection.
Jerfiz Constanzo:
Thank you, Kathleen and Ann Marie. Thanks to you, the listeners for joining us. As a reminder to view the full program, The APP Guide to Actionable Biomarkers in Solid Tumors: Reducing Barriers, Promoting Confidence, and Leveraging Genetic Testing for Informed Treatment Decision Making, and to access online content associated with this discussion, please click the link in the show notes. Thanks for listening.