J. Randolph (Randy) Hecht, MD, a professor of Clinical Medicine at the David Geffen School of Medicine of University of California, Los Angeles (UCLA), and the director of the UCLA Gastrointestinal Oncology Program, discusses the investigation of XL092 plus atezolizumab (Tecentriq) in patients with microsatellite stable (MSS)/microsatellite instability–low (MSI-L) metastatic colorectal cancer (mCRC).

The actively accruing phase 3 STELLAR-303 trial (NCT05425940) is investigating the combination of XL092 plus atezolizumab in patients with MSS/MSI-low mCRC who have progressed on or are intolerant to standard-of-care therapy options. XL092 is a TKI targeting MET, VEGF2, and the TAM kinases AXL and MER.

Patients with mCRC typically respond well to first-line therapy and can benefit from second-line therapy; however, patients have historically not done well with salvage therapy, Hecht says. Regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf) represent salvage therapy options, but these therapies only produce modest benefit. This has created an unmet need that must be addressed within the mCRC patient population, Hecht explains. 

Immunotherapy has not been an effective treatment option for most patients with mCRC, and investigators are aiming to find ways to make immunotherapy work in patients who do not have a genetic marker that makes them sensitive to this treatment, Hecht explains. A small fraction of patients with mCRC have microsatellite instability (MSI) or mismatch repair deficiency (dMMR), and, initially, those patients are sensitive to standard checkpoint inhibitors. However, for the vast majority of other patients with mCRC, these drugs do not work, Hecht says. There has been an effort to explore other approaches and combinations that make patients sensitive to checkpoint inhibition.

Inhibiting PD-1 or PD-L1 alone may not be sufficient enough to elicit an immune response. Therefore, investigators are exploring ways to inhibit other immunosuppressive mechanisms to get a response, and using a TKI in combination with a checkpoint inhibitor could represent one way to improve responses to immunotherapy in patients with mCRC, Hecht concludes.

Videos

J. Randolph (Randy) Hecht, MD, discusses the investigation of XL092 plus atezolizumab in patients with microsatellite stable/microsatellite instability–low metastatic colorectal cancer.

Dr. Hecht on the Investigation of XL092/Atezolizumab in MSS/MSI-L mCRC

J. Randolph (Randy) Hecht, MD, a professor of Clinical Medicine at the David Geffen School of Medicine of University of California, Los Angeles (UCLA), and the director of the UCLA Gastrointestinal Oncology Program, discusses the common symptoms of esophageal squamous cell carcinoma (ESCC).

The majority of patients with ESCC are diagnosed relatively late in their disease, and many patients do not have symptoms at the onset of the ESCC, Hecht explains. Patients who are diagnosed with ESCC tend to be smokers and drinkers, and when they begin to exhibit symptoms of ESCC, they could experience dysphasia or difficulty swallowing. However, patients may address these symptoms by changing their eating habits and how they chew their food, which prevents them from seeking medical care, Hecht notes. Additional symptoms associated with ESCC include unexplained weight loss, hiccups, vomiting with streaks of blood, and streaks of blood in mucus coughed up from the lungs.

Any patients who develop dysphasia or difficulty swallowing should seek immediate medical evaluation, Hecht emphasizes. Since patients do not seek early medical care, many patients with ESCC in the United Stated are diagnosed with locally advanced or metastatic disease when they are evaluated, Hecht continues.

ESCC is more common in other parts of the world compared with the United States and Western Europe, Hecht says. Among patients with esophageal cancer in the United States, ESCC comprises a minority of the population. In previous decades, ESCC did represent the majority of esophageal cancers in the Unites States; however, ESCC has been overtaken by esophageal adenocarcinoma, Hecht adds. According to the National Cancer Institute, esophageal adenocarcinoma accounts for approximately 80% of esophageal cancer diagnoses in the United States. Due to the increased rates of esophageal adenocarcinoma, ESCC did fall to the wayside regarding clinical trials, although more studies are now being conducted in this space.

J. Randolph (Randy) Hecht, MD, discusses the common symptoms of esophageal squamous cell carcinoma. 

Dr. Hecht on the Symptoms and Diagnosis of ESCC

: What advice do you have for providers caring for patients with metastatic colorectal cancer?

My advice for providers caring for patients with metastatic colorectal cancer is to really arm yourself with all the necessary and important information—not only about the patient, but also about the tumor characteristics and the molecular genomics—because they can make a difference in guiding care and in pushing the envelope and improving survival; and not only survival, but also the quality of life for many of these patients. We've made a lot of advances in MSI [microsatellite instability] and immunotherapy in patients with mismatch-repair deficiency. We now have several active targets including HER2, including 

 G12C, specifically. It is important to look at the fine print and look at the mutations, and consider all of the potential options. The more therapies that we can offer, the more clinical trials that we can offer our patients, the better our outcomes will be.

: That makes a lot of sense. If I were to add one thing here, I'd say to make sure to talk to your pathologist every now and then.

: If you have something that is bothering you about the way you're testing, and you feel like you want to add a specific IHC [immunohistochemistry] test or work with them to create a workflow so that all the molecular testing that is needed goes through. Because the surgical pathologists are the ones handling the tissue and preparing it and they can work with the lab to separate out cores or do whatever you need to make sure that tissue is handled most appropriately, and so that you have what you need when you need to test. If you're sending it out, or if you want to develop something in-house or whatever it is, maybe for assays. A lot of surgical pathologists have a lot of knowledge about precision medicine these days, so it's something to keep in mind.

: Absolutely, that's 100% right and we do it all the time. To that end, also, you shouldn't be practicing alone. This really is a multi-team approach, a multimodality approach in many ways for many patients, so it's important to do as exactly as you said, communicate with the pathologists, ask the surgeon a question if you think that surgery may be an option at least for the discussion to really try to offer our best treatment interventions for the patients.

: Are there any other ongoing trials and novel treatment combinations that you are looking forward to seeing the data coming out on?

: Yes, in the metastatic setting, the HER2 targeting will continue to evolve in moving to the first-line setting, which is really exciting. There will hopefully be progress in BRAF targeting as well in the first-line setting where we have approval for 

 V600E in combination, but hopefully moving that to the first-line as well will be positive. And then 

: I'm very hopeful. We have made some progress in 

G12C, which is a small percent of our patients. But there are active drugs and certainly, preclinical work investigating other 

 mutations which are very common in colorectal cancer and other GI [gastrointestinal] tumors as well as lung cancer that will continue to move the field forward in that area, and actually very much change things for us, because 

was always something that was just so prevalent. Fifty percent of our metastatic patients have 

 mutations, but we just had nothing to offer them, so that's incredibly exciting.

: The mutations up-front eventually emerge.

: That's another thing: they're tricky. They're not simple. But it's going to be a good target. It is already looking like that for 

 G12C, but I think that that's going to be another exciting one.

: I am definitely interested in seeing what comes out on that front.

: Thank you so much, Jackie, for a really interesting and fun conversation. And thank you to the audience. We hope you find this program informative.

Experts provide advice for providers treating patients with metastatic colorectal cancer and highlight exciting potential combination treatments on the horizon.

Advice for Providers Treating Metastatic Colorectal Cancer

: How will the potential approval of new therapy targeting HER2 [human epidermal growth factor receptor 2] impact the treatment landscaping further?

I think approval of new therapies targeting HER2 will be important in this landscape. I think mainly we always want efficacy, but we also want to minimize toxicity. Although fam-trastuzumab deruxtecan is an active agent, as I mentioned in HER2-amplified colorectal cancer, it did have quite a bit of serious adverse events—grade 3 or worse. The most common were hematologic and gastrointestinal, but there was also, I believe, about 9% of interstitial lung disease. So, it was not without toxicity. In terms of drugs, we look for efficacy but we look at toxicity as well, and there are certain combinations that are less toxic, which I think will be important to be approved. More efficacious combinations that are durable— not just in response rate—but that offer improvement in progression-free survival and improvement in overall survival, I think, will be key.

Dr Andrea Cercek reviews key clinical trials in HER2-amplified colorectal cancer treatment and considers how the approval of new therapies will impact the current treatment landscape.

Novel Therapies in HER2-Amplified Metastatic Colorectal Cancer

: What treatment options are available for this patient if and when they progress?

: After first-line therapy with FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] and bevacizumab, you would then initiate trastuzumab plus pertuzumab. That's our HER2 [human epidermal growth factor receptor 2]-targeted therapy in the second-line setting. Following that we still have the chemotherapy backbone of FOLFIRI [leucovorin, fluorouracil, irinotecan], which is an active combination and should be utilized after progression on HER2-targeted therapy. There are 2 other approved oral agents, regorafenib and TAS-102 [tipiracil hydrochloride], which can be used, but of course, we need to think about potential clinical trials as well. Clinical trials are always an important thing to keep in mind. Most likely for this patient, it would be after progression on FOLFIRI. For most trials, you need progression on 2 lines of cytotoxic chemotherapy, but not always. If the patient is a fit for a clinical trial, they should be considered, but those are kind of our standard options. Then, in terms of further HER2-targeted therapy, that's limited—but hopefully something that will continue to develop over time and will have better targets, but fam-trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-HER2 antibody and sort of this linker to a topoisomerase 1 inhibitor. It was studied in patients who were exposed to prior HER2 therapy and showed some promising responses even in those patients who were previously exposed to HER2 targeting because it just works by a different mechanism.I think that could then potentially be a target or a combination that's utilized for this patient as well.

Andrea Cercek, MD, explains the potential treatment options for metastatic colorectal cancer after disease progression.

Treatment Options after Disease Progression in Metastatic Colorectal Cancer

 Andrea, I have a case that I want to discuss with you. A 50-year-old man presented his primary care provider with bright-red blood per rectum and changes in bowel habits for 6 months. He was referred to a gastroenterologist for a colonoscopy, which unfortunately found an obstructing mass in the rectum of the sigmoid colon and was diagnosed as poorly differentiated adenocarcinoma. It’s stage IV.

In addition to the PET [positron emission tomography] CT scan showing FDG [fluorodeoxyglucose] avidity of the hypermetabolic sigmoid colon mass, there were liver metastases as well as retroperitoneal lymphadenopathy. Molecular testing was done on the tumor, and it showed a microsatellite stable tumor. It was RAS-BRAF wild type, and the HER2 [human epidermal growth factor receptor 2] IHC [immunohistochemistry] was 3+. The patient received FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] plus bevacizumab and then progressed and received trastuzumab plus pertuzumab.

Which factors affect treatment choice in the metastatic setting? How do you individualize therapy when looking at a patient like this?

 It’s always important to take a bunch of factors into consideration before starting therapy. We think about our patient characteristics, not necessarily the age of the patient but the physical fitness, or what we call performance status—how symptomatic they are from their disease. Are they weakened by it? Do they show signs and symptoms of the disease? This particular patient was 50 years old and just had red blood per rectum, with no other mention of significant effects of disease burden.

Then there are things like patient preference. What does the patient want? You always have to talk to the patient and discuss that this is an advanced disease and in multiple locations. Most likely the therapy is not curative. It’s very treatable, however, so we try to treat the disease as best as we can with the options we have available. Once we learn more about your particular tumor, we keep going. The further we go, the better our treatment options will be. That’s the general approach, but it’s always important to talk with patients about the reality of the situation. Some people may prefer to be more or less aggressive, and it’s a mutual decision. We always have to lay out all the treatment options.

Then [we look at] the biology of the tumor: tumor location, tumor characteristics, and the molecular characteristics. In this case, we look at the location. In colon cancer, location really makes a difference. We know a bit in terms of prognosis, but we don’t necessarily change treatment for that with backbone chemotherapy. Patients who have a left-sided descending colon and rectal tumors can benefit from anti-EGFR therapy if they’re RAS type, but right-sided tumors do not. That kind of backbone, that addition of a biologic to the chemotherapy backbone, matters with tumor location. The symptoms [are also important]. This patient had a rectal tumor, which is oftentimes painful and bleeding. We try to start therapy as quickly as possible in those instances.

Then we talk to our pathologist and ask for guidance in terms of the pathological findings in the tumor, not so much in metastatic disease. In terms of high-risk features and low-risk features, that matters a bit more in resected disease in stage II or III, but what are the characteristics? What are the molecular genomics? And in left-sided tumors, what is the HER2 status?

Can you tell me a little about this tumor? Can I use anti-EGFR therapy? It’s left-sided, and there are good data for left-sided tumors as first-line therapy with the addition of anti-EGFR therapy to the chemotherapy backbone. Can I do that in this case with HER2IHC 3+ or a RAS BRAF wild-type tumor?

 There have been some data out there. When we say HER2 IHC 3+, we’re telling you that it’s positive for HER2overexpression. On a scale with 0, 1, 2, and 3, for how HER2 protein is expressed, 0 means there’s no reactivity for the HER2antibody. There’s noHER2 expression: +1 staining is negative. It was seen only at a very high power. It’s very weak: +2 is equivocal, meaning we’ll reflect those cases to FISH [fluorescent in situ hybridization]. It’s often visible at 10X magnification. When we see 3+, it’s positive for HER2 overexpression, which correlates withHER2 amplification. When we have these tumors, when we bring that anti-EGFR, there have been some data that when there’s HER2 amplification, they don’t respond as well. Cause is definitely associated with primary resistance to anti-EGFR therapy. I caution the oncologists about looking at that and what options there are for someone who’s overexpressingHER2 on her tumor. It doesn’t have other mitogen-activated protein kinase pathway alterations.

 That’s why—very appropriately, in this case—this patient received FOLFOX [5-fluorouracil, leucovorin, oxaliplatin] plus bevacizumab because of the HER2 amplification, as opposed to the anti-EGFR therapy, which we typically think about in a left-sided rectal tumor. In this patient, would you encourage HER2 testing before starting first-line therapy? In this case, it was done perhaps in first-line therapy or maybe later, but they certainly had the information available for the second decision point of second-line therapy.

 It’s definitely something that’s important to know up front. You can plot this patient out because of this HER2positivity, so we’re going to skip the anti-EGFR and look at what else is available. One reason to have it up front is to have this knowledge available. Often these patients with metastatic colon cancer will respond for a period of time, and you’ll inevitably need this knowledge. Rather than go back and look for the tissue and test and do all this, it’s up front. It’s in the patient’s record. It’s there when it will be needed for stage IV disease. That’s the beauty of doing it up front. We can say that down the line, this isn’t the best option, or this is, or we can continue looking for which option is best because of the knowledge that you have up front.

 I agree completely. You just have a much better plan of attack if you know which strategies you can utilize at what time and with which combinations. Ideally, up front is best.

Dr Jaclyn Hechtman presents the profile of a patient with HER2+ metastatic colorectal cancer and has a conversation with Dr Andrea Cercek on how to personalize frontline therapy selection in each patient.

Individualizing Therapy in HER2+ Metastatic Colorectal Cancer

 How do you see the molecular testing landscape changing in the future?

 We’re going to see an increase in how much comprehensive genomic testing we’re doing: a lot more NGS [next-generation sequencing] in the future as we get these rare targets. Only a few colon cancers here and there are having NTRK fusions, and 3% to 5% are having HER2 implications. But then patients get drugs that are less toxic and that are effective, and they prolong their lives and improve the quality of their lives. We’re going to see an increase in these comprehensive tests. We’re also going to see a lot of increases in ctDNA [circulating tumor DNA] testing. In the earlier stages, we’re using it for MRD [minimal residual disease], but in the future we may start looking for targets in ctDNA. Possibly even in earlier stage I disease, depending on how patients with these biomarkers do, especially if they’re at high risk if they do MRD. Maybe we’ll see if DNA will start looking for these targets.

 It’s great that you brought up circulating tumor DNA or cell-free DNA and how we use it in general in oncology. Specifically in colorectal cancer, MRD is important because we want to know if there’s any residual microscopic disease that we can act on. It’s a challenge because we have this tool to detect the ctDNA, but we don’t always have the tools to act on it, or we rarely do. Only certain drugs work for microscopic colorectal cancer, so if a patient still has positive circulating tumor DNA or evidence of MRD, how do we act on that? That remains a huge challenge where this technology is important. As you said, we’re going to learn. We’re doing a lot of trials, so we’re going to learn, and our therapies will improve. Little by little, with some of these targeted interventions, we’ll probably make a difference and be able to eliminate that microscopic disease or that minimal residual disease that’s detected by ctDNA. At the moment, it’s great if it’s negative; everybody is happy. But if it’s positive, sometimes it’s challenging because we don’t have the tools to treat it better, so it will definitely be a very important tool in the treatment of metastatic colorectal cancer.

 As we do that, a lot of these ctDNA tests are custom for each patient and are using specific alterations in the tumor to detect MRD. But those tests often don’t tell you what was in the tumor. Once the technologies get better, we’ll be able to reliably say if this is a targetable alteration in the tumor, there is MRD, and how much of that target is circulating, and then track that as we go. Of course, not all of these patients are having something targetable, but as the number of targets increase, we can hope for more of that.

 How are you using ctDNA when you’re treating patients in your practice?

 We have several clinical trials that are monitoring ctDNA as a marker of minimal residual disease of response to therapy. I’m very excited to learn more about those results. Some cooperative group trials are asking these same questions: how ctDNA guides our adjuvant or postoperative therapy, and does it make a difference for our patients? I utilize it in that way in clinical trials.

In the absence of a clinical trial and routine practice, many patients come with ctDNA being done. I’m not against using it, but I refer to it often as a fancy CEA [carcino embryonic antigen]. We have CEA that we’ve been using for a long time. It’s reliable in some patients; it’s not reliable in others. If the CEA increases over time, but I don’t see any radiographic evidence of disease, I don’t have the tools to act on it, so I’d wait. That’s very similar to my approach with ctDNA, but it causes a bit more anxiety.

Sometimes it’s a bit of a challenge, although it will be a really important tool once we have better treatment options. In some people, it’s more reliable than in others. We’re learning on some of these trials that it’s dependent on the assay and that it’s not as easy to interpret. It’s not black and white. There’s sometimes background noise. Some assays are certainly much better than others. There’s still a lot of learning that we need to do about ctDNA, but it will definitely become part of our treatment algorithm for metastatic colorectal cancer in the future.

A look at how the molecular testing landscape in colorectal cancer is evolving.

The Future of Molecular Testing in Colorectal Cancer

When you request HER2 testing, how are you requesting it?

 At the moment, we’re doing it with next-generation sequencing [NGS], so I typically get all the information back in a few weeks. We’re not routinely doing immunohistochemistry, although that will be part of our standard soon for advanced disease. As a pathologist, what has been your experience at Memorial [Sloan-Kettering Cancer Center] and now in Miami [Cancer Institute]? Do you see differences? What’s the real-world feeling? We’re sometimes spoiled in academic institutions because we have all this testing readily available.

 I’ve been in 3 practice settings: academics, industry, and now a community hospital setting. It’s interesting. In academics, we often have disease-management teams. In these disease-management teams, you decide what’s going to be refraction. A student pathologist says this is what I see under the microscope; it’s cancer. Then the team— radiologists, pathologists, oncologists, and surgeons—decide together that all these patients are going to get testing up front. That’s 1 way to do it. We have our refraction testing and pick a certain assay up front at these multidisciplinary meetings. The good thing about these refraction-testing methods is that no patients fall through the cracks. I see this, and it’s automatically done. It’s not as if a patient might miss testing somehow because something slipped through the cracks. That’s 1 good thing about refraction testing.

Other times, when tissue is more scarce—this might happen for small biopsies or psychology samples—the oncologists request them, rather than the pathologist automatically doing it. Because oftentimes pathologists are a little scared of ordering a test that’s not necessary, and then there’s nothing anything left in the paraffin block to do further tests. That’s another way of doing it. In the industry, a lot of the time the pathologist can order these piecemeal tests, but oncologists often order the big NGS panels. In the community [setting], instead of having everything available within the same in-house laboratory, the pathology laboratories are often smaller and you have more send-out tests. Let’s say you want HER2 [human epidermal growth factor receptor 2]–IHC [immunohistochemistry]. If it’s a practice of just a few pathologists, oftentimes they’ll send out for HER2-IHC. Or they’ll have the oncologists request whichever method they prefer, whether it’s NGS or HER2-IHC with refracts to FISH [fluorescence in situ hybridization]. You’re right: depending on the practice setting, that determines how testing is ordered. It’s definitely not standardized within our health care system.

 It would be wonderful if it could be, but unfortunately not yet.

 What are some of the challenges and barriers to testing that you’ve seen for HER2?

 In HER2 specifically, interpreting IHC and FISH and what’s positive, what’s actionable, and what’s the degree of expression. As I mentioned, when we use next-generation sequencing, it’s the time from ordering the test to obtaining the results. We often have to get the pathology slides, which takes time, and then we run it through our lab and get those results. Sometimes it’s a challenge because you need to make a treatment decision rather quickly. For example, in second-line therapy where HER2-targeted therapy is approved, we may not have those results back. This is why I was stressing that the earlier the test can be ordered, the better it will be for our future decision-making.

As a whole, outside academic institutions, it’s dissemination of this information that HER2 is an important target, and that it should be tested like MSI [microsatellite instability] for potential therapies and therapeutic interventions. That’s a big challenge and an important 1 that we need to work on. Ideally, we would have a universal test that we could all rely on, but that’s not where our health care is with several companies having different assays and institutions utilizing in-house tests or outside tests. Those challenges will exist, so it’s more on our side to educate the providers to order the best tests that are relatively quick and can be utilized to help treat the patient.

Drs Hechtman and Cercek discuss how practice setting affects molecular testing options and the barriers patients face in receiving testing.

Challenges and Barriers to Colorectal Cancer Molecular Testing

Moving on to detecting HER2 [human epidermal growth factor receptor 2]. There’s still a lot for us to learn about with HER2 in colorectal cancer, and I’m so glad you’re here to help guide us through this in terms of how we can best detect HER2 amplification in colorectal cancer. Which tests should we use? Which patients should we screen?

 The tests that we use are dependent on a few things when we break them out. How quickly do we need the results? Oftentimes for colon cancer, we do have a good amount of time, so we have the sectioned specimen with decent tissue. When time is not of the essence, next-generation sequencing is available. That usually takes 2 to 3 weeks for these broader panels, and they can identify whether there’s an amplification of HER2. But if you have something like a lymph node or something that has a lot of other types of cells that aren’t cancer and your purity is low, the signal of how many HER2 copies you have will be drowned out by all these other cells. Or if we have a small clone of HER2amplification or a relatively small clone—and a lot of tumor cells that don’t have that—you might not be able to pick up the HER2 amplification when we’re doing next-generation sequencing because all the DNA is assessed together.

When we’re looking for IHC [immunohistochemistry], the difference is that each cell is individually visualized, so you can determine if this is clonal vs subclonal. Meaning that if the majority of tumor cells have HER2 amplification or if it’s a population of them, we don’t run into the problem of drowning out the HER2amplification signal with IHC. It’s also faster and cheaper, but it doesn’t tell you whether there’s a concomitant downstream mutation in 

, which are important when you’re deciding which therapy you’re going to use. [It doesn’t tell you] whether the patient is eligible for a HER2 inhibitor and which 1.

FISH [fluorescence in situ hybridization] is similar to IHC in that the tumor cells are directly visualized. But instead of reviewing it with a regular microscope, we use a fluorescence microscope. There are a few more steps to this exam, and rather than protein overexpression, which we see with IHC, when we do this refracts FISH testing for those equivocal cases, and you’re counting the number of signals of HER2. It’s normalized against another portion of the same chromosome CEP17. And you derive an average of how many HER2 copies based on an area of the tumor that you think has the highest HER2 population.

That’s really helpful. As a medical oncologist, what we know about HER2 in metastatic colorectal cancer is that it’s more likely to occur in left-sided tumors and the rectum, but it’s not exclusive to that location. I wouldn’t not do HER2 testing in a right-sided tumor; it would just be more likely to be amplified in left-sided tumors. It’s about 3% to 5% of all patients, so it’s not a small number considering how common colorectal cancer is.

As you mentioned, and it’s really important, it’s not mutually exclusive from 

 mutations. We do the IHC, and it helps us, but we still need to know the RAS status and the BRAF status because that changes the therapies we can offer. In many ways, it changes our approach to HER2 targeting. But there are also data showing that patients who have HER2-amplified tumors that are RAS wild-type, left-sided, still don’t benefit from anti-EGFR therapies. It should give us a little pause if we know that a tumor is left-sided but HER2 amplified to use anti-EGFR therapies. It gets a bit complicated, but it’s an important marker to pay attention to at this point in terms of different therapies that we can offer.

Andrea, at what point in the patients’ journey do you usually obtain HER2testing in these colon cancer specimens?

 That’s a great question. Historically, I try to get next-generation sequencing on all my patients with metastatic colorectal cancer when I meet them. Ideally, they’re newly diagnosed before starting first-line therapies, so I will usually know the HER2status a few weeks after meeting them. At the moment, our therapies that target HER2 are approved after the first progression on the first line. However, as is usually the case, we’ll be moving treatment into earlier lines of therapy—the earlier, the better. But at some point when the patient is on first-line chemotherapy, we should get that information.

Experts describe which patients should be screened for HER2 amplification in colorectal cancer and how best to detect it.

Detecting HER2 Amplification in Colorectal Cancer

In terms of technology, you mentioned Sanger sequencing initially, now we do next-generation sequencing. What do you use? Do you use next-generation sequencing, IHC [immunohistochemistry]? What are the best options for us in colorectal cancer?

: It’s dependent on multiple factors. It’s what’s available, and what your timeline is, sometimes a really fast answer is desired, and based on how much tissue you have, and the quality of tissue. Going down the list of some of these biomarkers, for 

 mutations, we are always doing sequencing. Whether it’s next-generation sequencing or Sanger sequencing, we’re sequencing the DNA to determine a point mutation status. For microsatellite instability [MSI], we extract the DNA. It’s a DNA-based test again, we can do it by next-generation sequencing, or we can do it with PCR [polymerase chain reaction]-based tests that are a little simpler. Sometimes instead of, or in addition to, microsatellite instability testing, we test for mismatch repair [MMR] deficiency, and those are IHC markers. There are 4, and this is commonly done. The sensitivity and specificity of MMR IHC is very good, but nothing’s perfect, and because of that, we sometimes do MSI status plus MMR IHC because it’s such an important biomarker to determine eligibility for new checkpoint inhibitors, as well as screening for Lynch syndrome in patients with colon cancer.

 gene fusions, we can do IHC as a screen, so we have an 

 IHC. But in a lot of the newer, more broad next-generation sequencing assays, we find the majority of 

 gene fusions, even if we’re looking at just the DNA, but the RNA ones are even more sensitive. So there are RNA next-generation sequencing assays for fusions. And then when we get to 

 amplification, it’s a little different. These can be detected by next-generation sequencing provided we have good enough tumor purity. But if a quick answer is desired, we have low tumor purity, or if we have very little tissue in total, like a small biopsy, then we have other methodologies. IHC is one methodology, and often when IHC is equivocal, meaning the staining is of moderate intensity, we reflex to fluorescent in situ hybridization [FISH]. IHC and FISH are these piecemeal assays that only detect 1 thing, but they’re faster, so each assay has its advantages and disadvantages.

: That’s the key point, in general, for community oncologists where you’re sitting in front of a patient with metastatic colorectal cancer, you want as many answers as possible with the test to determine the next steps in treatment. So next-generation sequencing really provides us with MSI information, 

 amplification. As you said, it’s not perfect. The issue with that is it takes some time to get those results. But something like mismatch repair deficiency to offer potentially immunotherapy for a patient who’s mismatch repair deficient, or for genetic screening for Lynch syndrome is a very quick turnaround, and can help guide first-line therapies. It’s as you said exactly, a little dependent on what we’re looking for and what the timing of things is. But certainly, the most comprehensive I would say is next-generation sequencing, which really should be done on all patients at some point, preferably at the beginning, at the time of diagnosis.

A pathologist explains how she chooses between a variety of molecular testing technology options in colorectal cancer.

Molecular Testing Options in Colorectal Cancer

 “My Treatment Approach: Targeting HER2 in Metastatic Colorectal Cancer

”I’m Andrea Cercek, section head of colorectal cancer and codirector of the center for young-onset colorectal and gastrointestinal cancers at Memorial Sloan Kettering [Cancer Center in New York]. Joining me today is my colleague, Dr Jaclyn Hechtman.

: Hi, it’s a pleasure being here. Thank you, Dr Cercek, for introducing me. I am a former Memorial Sloan Kettering Cancer Center pathologist. Now, I am the director of precision oncology diagnostics at Miami Cancer Institute. I am also an associate pathologist at Baptist Hospital here in Miami, Florida. It’s a pleasure seeing you again, Dr Cercek.

: It’s great to see you, we miss you. Let’s get started.

We’ll be discussing molecular testing in metastatic colorectal cancer. Jaclyn, can you provide us with a brief historical overview of molecular testing within colorectal cancer, and how this field has evolved and continues to evolve?

: Until the last maybe 8 years, molecular testing had been done by piecemeal methodology, namely Sanger sequencing. The first target in colon cancer to be a part of the precision oncology diagnostics portion of oncology was E

; we were testing for things that would confer primer resistance to EGFR inhibitors. That would be 

V600E mutations. In the very beginning, this was done by Sanger sequencing.

More recently it’s been done with next-generation sequencing. In the last few years, we’ve seen quite an explosion of different targets, and with these broader panels, where we were doing it piecemeal before, we can now test for multiple alterations at once. These other alterations include amplifications in 

, fusions, and also now extended testing for mutations in 

 rather than just doing 1 Sanger reaction, we’re looking at various enzymes within 

as well as signatures, so our next-generation sequencing panel can also assess the microsatellite instability [MSI] status. That is how things have evolved from piecemeal, simple molecular tests to larger comprehensive, broader next-generation sequencing assays.

: That’s a great overview of where we were, and how far we’ve come in under a decade, in the last 8 years, as you mentioned. We’ve really made progress in identifying targets of potential resistance to drugs that we have available, but then excitingly and importantly, also potential targets that we have drugs available for that could improve outcomes. MSI is certainly one of those. You mentioned the other key targets in colorectal cancer, namely 

 mutations for drugs we shouldn’t use like anti-EGFR inhibitors, and 

targeting combinations now. MSI-high obviously with immunotherapy or mismatch repair-deficient tumors, 

 gene fusions also we have a target for. Then importantly,

 amplification, which is a newer target in colorectal cancer but has certainly been around for a long time in other diseases like breast and gastric cancer.

 now is an active target as well, so it’s not just a negative marker in terms of telling us that we shouldn’t use anti-EGFRtherapy. We now have drugs that target 

G12C. That’s exciting too and sort of a recent development.

Jaclyn Hechtman, MD, provides an overview of the history of molecular testing in colorectal cancer and how testing has evolved.

Jaclyn Hechtman, MD

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