CRC is one of the most common cancers worldwide, with approximately 1.36 million cases per year worldwide. Prognosis is highly dependent upon the stage at which the cancer is detected, highlighting the need for improved CRC screening program participation. According to the American Cancer Society the five-year survival rate for patients who have their cancer detected in the localized stage is 90%, compared to just 14% when there are distant metastases.
Therefore, there have been significant efforts to establish screening protocols to identify disease early. The US Preventative Services Task Force (UPSTF) provides guidance on a series of testing strategies for adults between ages 50 and 75:
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an annual fecal occult blood test (FOBT) or fecal immunochemical test (FIT);
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a FIT-DNA test (ie the Cologuard test from Exact Sciences) every three years or less;
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flexible sigmoidoscopy every five years, or every 10 years when combined with yearly FIT;
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CT colonography every five years; and
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colonoscopy every 10 years.
Similarly in Europe there are multiple national initiatives to screen the at-risk population, for instance a FIT test distributed to at-risk individuals once every two years, as in Scotland. The problem with these strategies is that compliance for fecal testing is low (in the range of 13-60% depending on the study), and colonoscopy, while highly accurate, is invasive and requires sedation. Combined, the CRC screening market is approximately 235 million people in the US and Europe.
Overview of CRC screening technologies
There are a number of different technologies currently being used or in development for the detection of colorectal cancer and they fall into three categories: invasive, fecal and blood.
Exhibit 2: CRC screening test data comparison
|
Company |
Type |
Cost |
CRC sensitivity |
AP sensitivity |
Specificity |
Colonoscopy |
Various |
Invasive |
$1,200 |
95% |
95% |
95% |
Sigmoidoscopy |
Various |
Invasive |
$600 |
50% |
50% |
92% |
FIT |
Various |
Fecal |
$23 |
74% |
24% |
96% |
gFOBT |
Various |
Fecal |
$5 |
40-70% |
12-24% |
93-98% |
Cologuard |
Exact Sciences |
Fecal |
$428 |
92% |
42% |
87% |
Epi proColon |
Epigenomics |
Blood |
$339 |
68-72% |
22% |
81% |
Nu.Q™ |
VolitionRx |
Blood |
$100 or less |
74-91% |
31%* |
90% |
Colox |
Novigenix |
Blood |
$300 |
78% |
52% |
92% |
Source: FDA, Exact Sciences, World Gastroenterology Organization, Agency for Healthcare Research and Quality, Imperiale et al., Multitarget Stool DNA Testing for Colorectal-Cancer Screening, N. Eng. J. Med. 370, 1287-1297, CMS. Notes: AP=adenomatous polyps. *Improved to 62% with a specificity of 90% with alternate panel, although CRC accuracy on this panel undisclosed.
The guaiac-based FOBT (gFOBT) is a relatively cheap (~$5) test in which stool samples are collected and analyzed for blood. A limitation of the test is that it typically involves collection of up to three different fecal samples on three different days, negatively affecting compliance. In addition, it does not discern between human and not-human blood so an ingestion of meat prior to the test could have a negative impact on results. Antioxidants such as vitamin C may interfere with the chemistry of the test, leading to false negatives. There are a variety of different versions of the test but sensitivity is in the 40-70% range and specificity is 93-98% according to the Agency for Healthcare Research and Quality (AHRQ). Sensitivity for precancerous lesions was pretty low, generally between 12% and 24% depending on the specific test.
The FIT was developed specifically to target human hemoglobin and therefore not be thrown off due to dietary sources. It is more expensive than gFOBT, but at ~$23 is still relatively inexpensive. FIT is considered to be more sensitive than gFOBT with a sensitivity 73.8% and specificity of 96.4%. However, it has limited ability to detect advanced precancerous lesions with a sensitivity of just 23.8%. Like the FOBT, the FIT involves the collection of up to three different fecal samples on three different days.
Cologuard is a test marketed by Exact Sciences that combines a molecular assay, consisting of two DNA methylation markers (NDRG4 and BMP3), seven DNA mutation markers (all related to KRAS) and a DNA normalization marker (Beta Actin), with a FIT test. Unlike the other fecal tests, it only requires one stool sample. In addition, due to the molecular assay component, the test is an order of magnitude more expensive than the standard FIT test. In Q317, average revenue per test was $428 across all providers ($512 from CMS and in the $300 range for private payers). It is also significantly more sensitive than a FIT test with 92.3% sensitivity but is less specific with 86.6% specificity, leading to a greater number of false positives than FIT. Cologuard also has a greater ability to detect advanced precancerous lesions with a sensitivity of 42.4%.
The gold standard for CRC diagnosis is the colonoscopy as it is highly accurate with few false positives or negatives. It is an invasive procedure that requires preparation and anesthesia. The colonoscope is a four-foot long tube the thickness of a finger that is inserted into the rectum. In order to prepare for the procedure a patient is often required to either drink a very large volume of a special cleansing solution or only ingest clear liquids for several days. Large doses of laxatives and enemas are also used. The adverse event rate is relatively high with a hospitalization rate for serious complications of one in 200, usually bleeding, colonic perforation or a negative reaction to anesthesia. This high rate of complications from this diagnostic test is one reason why the FDA is concerned with approving screening methods with high false positive rates as those false positives would be followed up by colonoscopies with their inherent risks. The colonoscopy is also the most expensive of the screening methods for CRC with a cost of $1,200 per procedure according to CMS.
Flexible sigmoidoscopy is an invasive screening method that involves the doctor inserting a 60cm sigmoidoscope into the rectum and permits a thorough examination of the distal portion of the colon but not the proximal portion, which limits its ultimate effectiveness (41% of CRC originates in the proximal colon) and is a major reason why fewer than a percent of eligible individuals get one, according to the CDC. Like a colonoscopy, it requires preparation including a clear liquid diet, laxatives to clean the colon as well as an enema though typically the preparation is less intense than with a colonoscopy. It is, however, a relatively safe procedure with only one in 5,000 screening subjects being hospitalized for a gastrointestinal complication (eg colonic perforation or serious bleeding). The cost of the procedure is also much less than a colonoscopy, around $600, according to figures from CMS.
Epi proColon is a blood test based on detecting aberrantly methylated DNA of the Septin9 gene. As it is based on just one marker, it is not very accurate, with a significant number of false positives and false negatives. In analyzing its pivotal trial data, the FDA commented that the test yields 37.7 false positives per every true positive compared to 5.4 false positives per every true positive for FIT. Although only approved by the FDA in 2016, Quest, the diagnostics giant, had been selling its version of the Septin9 test, dubbed ColoVantage, since 2009 via a CLIA-waiver (which does not require an FDA approval if certain conditions are met) and sales have been minimal.
Novigenix is developing Colox as a blood-based diagnostic for CRC that examines the activation of immune cells for a profile indicative of cancer. The test measures the expression levels of 29 genes in peripheral blood mononuclear cells. Colox demonstrated a 78.1% sensitivity and 92.2% specificity for CRC in a 782-person clinical trial. Additionally, Colox was able to detect adenomatous polyps (AP) that were greater than 1cm in size with a sensitivity of 52.3% with 92.2% specificity, an improvement over most current technologies. Colox is currently on the market in Switzerland, and the company is developing the next generation Colox Plus targeting EU launch in 2019 and entering US clinical trials in 2019.