Shai Friedland, MD, discusses the novel multimodal FirstSight test, which showed promise in identifying colorectal cancer, as well as precancerous polyps and advanced adenomas.
Shai Friedland, MD
The novel multimodal FirstSightCRC test has shown promise in identifying colorectal cancer (CRC), as well as precancerous polyps and advanced adenomas, said Shai Friedland, MD, who added that results from the blood-based assay can inform whether a patient should undergo a colonoscopy.
“Now, multiple cancers can be detected in the blood, and we are getting better at doing that [in colon cancer],” said Friedland. “This is the first time we have convincingly shown that we can also detect precancers in the blood. We can use a relatively noninvasive blood test to intervene earlier, before a patient develops cancer.”
At the 2020 ASCO Virtual Scientific Program, Friedland presented the interim results of a study evaluating the test in 354 patients with no prior history of CRC and who were scheduled to undergo a colonoscopy. Prior to colonoscopy, patients’ blood was drawn and analyzed with the FirstSight assay.
The findings demonstrated a clear association between patients’ FirstSight Scores and polyp size, as well as the number of polyps. The test achieved 90% specificity and 100% sensitivity for detecting CRC, in addition to 75.5% sensitivity for detecting advanced adenomas. Overall, the test elicited a 79.7% sensitivity for detecting advanced adenomas and CRC.
The FirstSight assay evaluates 3 biomarkers: circulating gastrointestinal epithelial cells, validated somatic oncogene and tumor suppressor mutations, and methylation with Septin9 of cell-free tumor DNA (cfDNA). According to Friedland, this element is critical in predicting polyp size, number of polyps, as well as DNA mutation and methylation status.
In an interview with OncLive, Friedland, a professor of medicine (gastroenterology and hepatology) at Stanford University Medical Center, discussed the need to develop noninvasive testing methods to detect precancer and cancer, and the promise of the FirstSight assay in CRC.
OncLive: Could you discuss the rationale for conducting this study with the FirstSight blood-based assay?
Friedland: Colon cancer is the cause of a lot of morbidity and mortality in the United States and throughout the world. We have good tests for screening. When we intervene early on in colon cancer, or even before precancerous polyps [progress] to cancer, the outcomes are very good. If we catch [the cancer] late, the outcomes are poor. Colon cancer is an ideal target for screening because we have an effective early treatment and it is a common disease.
Many patients are screened with colonoscopy in the United States, which is an excellent test. Colonoscopy detects cancer and polyps very well and allows us to remove polyps at the same time.
The downside to colonoscopy is that it is invasive. Most people undergo sedation, [which means] they have to take the day off of work, and there is some risk associated with sedation. [Additionally], there is a very lengthy bowel preparation [with colonoscopy] that is extremely inconvenient.
We know there is a [portion] of the population that we cannot convince to undergo colonoscopy, so there is a real need [to develop] noninvasive screening tests. Currently, there are some good noninvasive screening tests that involve stool that look for either blood in the case of fecal immunochemical test (FIT) or a combination of blood and DNA mutations in the case of Cologuard®. FIT is inexpensive and [effective], but it is a stool test. There is another segment of the population that will never accept the stool test. You can order [the test] and reorder the test, but some patients never turn it in. Additionally, FIT is not very good at picking up adenomas, but it is good at identifying cancers.
Cologuard, which is a stool DNA and blood test, is also good at identifying cancers. [Although it is] better at picking up adenomas [than FIT], it is still not [optimal].
We are hoping to improve the convenience of screening by offering a blood test, which is something that everybody [has access to], and the detection of cancers and adenomas before they become cancerous.
What biomarkers does the test analyze?
This test uses 3 different factors to determine a risk score for who has polyps and cancer. Circulating epithelial cells are cells that come mainly from the colon and are shed into the bloodstream. We know that there are significantly more of them in patients who have a [higher cancer burden], but there are still very, very few of these cells. The key component of this is [to use] a very sensitive assay to detect circulating epithelial cells. The second component is DNA mutations that are associated with colon cancer. We check the blood for mutations in genes that are known to be involved in colon cancer. Number 2 is methylation, which is another component of the genetic changes that happen with colon cancer. Methylation, specifically of the SEPT9 gene, is available as a standalone blood test for colon cancer. However, it performs very poorly.
The assay we use incorporates all 3 of these elements, which is an important part of the study.
How does this blood-based assay compare with colonoscopy?
In this study, we used colonoscopy as the gold standard because it really is the best test that we have available. We need to know who has cancer, the stage of the cancer, who has polyps, how many polyps they have, and how big those polyps are. All of that information is picked up by the colonoscopy. If any cancer is detected, the patient gets a CT scan and staged.
All of the patients in this study underwent colonoscopy. However, right before their colonoscopy, they had their blood drawn. The blood was sent to the lab and analyzed without the knowledge of what the colonoscopy results were. Then we compared the results of the blood test and the results of the colonoscopy to determine how [good the blood-based test] is at detecting patients with polyps and patients with cancers.
In the study, you were able to track progression to potentially inform the colonoscopy interval. Could you elaborate on these findings?
Several groups of patients were enrolled in this study. Some patients are pure screening patients who have never had a colonoscopy before and never had any polyps. Some are patients who have had polyps in the past, but those polyps were removed. Now, we are asking if those patients have developed any new polyps or cancers.
It turns out that the test performs very well in both those groups with 1 minor exception. The exception is that some patients who have had very large polyps or advanced adenomas in the past remain positive even after removing those polyps. For example, if a patient had a very large polyp removed 3 years ago, their blood test may be positive because, somehow, the changes that occur in the colon are not all eliminated by removing the polyp.
With that exception, if you take either [pure] screening patients or patients who have had small polyps removed in the past, the test performs very well. It can help us figure out who would benefit from either their first colonoscopy or a follow-up colonoscopy. Follow-up colonoscopies are very common. In our hospital in Virginia, they account for more colonoscopies than colonoscopies on people who have never been screened before.
Overall, we think that we’re over utilizing colonoscopy in these patients. If a patient has had some small polyps in the past and they are on their second, third, or fourth colonoscopy, we don’t get as much “bang for our buck,” and the patient had to go through that [rigorous] preparation. This is an important group for us to target with this test to figure out whether they actually need another colonoscopy.
What are the next steps for this research? What questions remain unanswered?
It was important for us to convince everyone that this test not only detects cancers, but that it detects precancerous polyps. To do that, we wanted to do a detailed analysis. If a patient has more polyps, the test should give them a higher score. If the patient has bigger polyps, the test should give them a higher score. All those things came through in our abstract, and it has done a pretty convincing job [at showing] that we are detecting polyps.
The reason I say that is important is because the other tests that are coming [out] are based on DNA mutations and methylation tests in the blood. Those are pretty good at picking up cancer, but not so good at picking up polyps. So, we showed in our abstract that if you didn’t have the circulating endothelial cell component, [it was difficult] to identify polyps, the number of polyps, and the size of polyps. Again, you need all 3 of those components to make it work.
Now that we have shown that in this preliminary study, the next step is to have a big study that involves multiple centers and doesn’t include just 1 population. We need to show that it works for everybody out there in order to convince people that it could be adopted as a new screening method.
What is your take-home message regarding this research?
Compared with the follow-up tests for breast or pancreatic cancer, which are very invasive, the follow-up test in colon cancer is a colonoscopy. It is a test that most of us would like to avoid, but it is not the end of the world. That is where I think [this test] can make a big difference. It can bring more people to screening by offering them a simple blood test that can determine who needs a colonoscopy.
Friedland S, Watson D, Pan JY, et al. A sensitive and quantitative multimodal blood test for the detection of colorectal adenomas and cancer: correlation with size and number of polyps. J Clin Oncol. 2020;38(suppl 15):1555. doi:10.1200/JCO.2020.38.15_suppl.1555