EXAS Take, Parte Deux . . .
>>
PROBLEMS WITH CURRENT DETECTION METHODS FOR SCREENING
Fecal occult blood testing, flexible sigmoidoscopy and colonoscopy are the
three principal methods that have been used to detect colorectal cancer. Despite
the availability of these and other screening and diagnostic tests for more than
20 years, the rate of early detection of colorectal cancer remains low, with
only limited effect on mortality. In 1999, Medicare reimbursement records showed
that only 14% of Americans over age 65 were screened for colorectal cancer. We
believe that no screening strategy is commercially available today that allows
for the highly sensitive, early detection of colorectal cancer in a manner that
is acceptable to patients, medical practitioners and payors.
Medical practitioners characterize cancer-screening tests using three
principal parameters: sensitivity, specificity and compliance. Sensitivity
measures a test's ability to detect the presence of disease when the patient has
disease. Specificity measures a test's ability to correctly identify individuals
who are disease-free. A failure of specificity, commonly referred to as a false
positive, is the failure of a test to correctly identify an individual who is
disease-free. Compliance rates measure the percentage of patients for whom
screening is recommended that are screened at the recommended interval.
FECAL OCCULT BLOOD TESTING (FOBT). FOBT does not detect cancer directly but
rather detects the presence of blood in stool. Typically, a patient must
retrieve two small portions of stool from the toilet on each of three successive
days and smear each portion onto a small chemically impregnated card. The
patient must modify his or her diet to eliminate red meat and certain fruits and
vegetables and also eliminate the use of certain medications such as aspirin for
three days prior to the stool sample collection, as well as during the three
days of stool sample collection. If the FOBT results are positive, medical
practitioners refer the patient for colonoscopy for a definitive diagnosis.
Although FOBT is non-invasive, it has the following limitations:
- LOW SENSITIVITY. FOBT detects on average only 25%-30% of patients with
cancer in any stage and only approximately 12% of patients with
pre-cancerous adenomas greater than one centimeter.
- LOW RATE OF EARLY-STAGE DETECTION. FOBT is less effective in detecting
Dukes' A and B cancers, for which survival rates are higher and treatment
costs are less expensive, than in detecting Dukes' C and D cancers.
- LOW SPECIFICITY. Because blood can be present in the stool for many
reasons other than colorectal cancer, such as hemorrhoids or red meat in
the diet, FOBT has a reported false positive rate of approximately 7%,
based on Medicare claims data. We estimate that six to ten million FOBT
tests are completed each year. This means approximately 420,000-700,000
patients per year are unnecessarily referred for follow-up colonoscopies.
- LOW COMPLIANCE. Of the 74 million Americans age 50 and above who should be
annually screened, only 20 million receive FOBT cards annually and we
estimate only six to ten million of those complete the FOBT test. This
means less than 15% of those Americans who should be screened each year
complete an FOBT test. We believe this low compliance is a result of low
sensitivity at detecting early stages of cancer, the dietary restrictions
and unappealing nature of the process.
FLEXIBLE SIGMOIDOSCOPY. Flexible sigmoidoscopy is a procedure performed
without sedation, and after an often unpleasant bowel preparation, in which a
physician inserts a fiber-optic endoscope one to two feet into the colon to explore the lower third of the colon. If flexible
sigmoidoscopy results are positive, medical practitioners refer patients for
colonoscopy for further diagnosis.
Although flexible sigmoidoscopy is more sensitive and more specific than
FOBT, it has the following limitations:
- INVASIVE PROCEDURE. Before a flexible sigmoidoscopy procedure, a patient
must undergo a bowel preparation procedure to remove stool from the lower
third of the colon to make a visual examination possible. Since medical
practitioners perform flexible sigmoidoscopy without sedation, patients
feel varying degrees of pain and embarrassment.
- LOW SENSITIVITY. Flexible sigmoidoscopy at best can directly visualize no
more than half of all colorectal cancers and adenomas. The other half of
cancers are located in the upper two thirds of the colon, beyond the range
of the endoscope. A patient's inability to tolerate the procedure and
incomplete bowel preparation further limit sensitivity.
The above current screening methodologies are summarized below:
SENSITIVITY SPECIFICITY
METHOD PROCEDURE DESCRIPTION (APPROXIMATE) (APPROXIMATE)
---------------------- ------------------------------- ------------- -------------
FOBT - Detects presence of blood in 25%-30% 93%
stool
- Non-invasive
- Three days of retrieving
stool
FLEXIBLE SIGMOIDOSCOPY - Physician inserts endoscope 48% 95%
one
to two feet into colon
- Performed without sedation
- Unpleasant bowel preparation
COLONOSCOPY. Colonoscopy is a procedure that allows a physician to
visualize the entire length of the colon and, during the same procedure, remove
some cancerous and pre-cancerous lesions. A colonoscope is identical to a
flexible sigmoidoscope except that its insertion depth is approximately six feet
instead of one to two feet. Medical practitioners perform colonoscopy with the
patient under sedation after undergoing a thorough bowel preparation prior to
the procedure.
Although medical practitioners view colonoscopy as the definitive method for
diagnosis, we believe it is not a practical method for mass screening. The short
supply of skilled clinicians, the cost of the procedure and patient discomfort,
as well as a small risk of complications and death have limited the use of
colonoscopy as a screening test. If opinion leaders were to recommend
colonoscopy for screening of average-risk individuals, we estimate that it would
take more than a decade to perform a first round of screening on every one of
the recommended 74 million Americans age 50 and above.<<
So that's the present competition, and I have to agree, it ain't much. Here's a couple of abstracts on EXAS' approach:
>>Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel.
Gastroenterology 2000 Nov;119(5):1219-27 (ISSN: 0016-5085)
Ahlquist DA; Skoletsky JE; Boynton KA; Harrington JJ; Mahoney DW; Pierceall WE; Thibodeau SN; Shuber AP [Find other articles with these Authors]
Division of Gastroenterology and Hepatology, Department of Biostatistics, and Division of Molecular Genetics, Mayo Clinic, Rochester, Minnesota 55905, USA. ahlquist.david@mayo.edu.
BACKGROUND & AIMS: Assay of altered DNA exfoliated into stool represents an intriguing approach to screen for colorectal neoplasia, but multiple markers must be targeted because of genetic heterogeneity. We explored the feasibility of a stool assay panel of selected DNA alterations in discriminating subjects with colorectal neoplasia from those without. METHODS: Freezer-archived stools were analyzed in blinded fashion from 22 patients with colorectal cancer, 11 with adenomas > or =1 cm, and 28 with endoscopically normal colons. After isolation of human DNA from stool by sequence-specific hybrid capture, assay targets included point mutations at any of 15 sites on K-ras, p53, and APC genes; Bat-26, a microsatellite instability marker; and highly amplifiable DNA. RESULTS: Analyzable human DNA was recovered from all stools. Sensitivity was 91% (95% confidence interval, 71%-99%) for cancer and 82% (48%-98%) for adenomas > or =1 cm with a specificity of 93% (76%-99%). Excluding K-ras from the panel, sensitivities for cancer were unchanged but decreased slightly for adenomas to 73% (39%-94%), while specificity increased to 100% (88%-100%). CONCLUSIONS: Assay of altered DNA holds promise as a stool screening approach for colorectal neoplasia. Larger clinical investigations are indicated.<<
>>J Natl Cancer Inst 2001 Jun 6;93(11):858-65 Related Articles, Books, LinkOut
Detecting colorectal cancer in stool with the use of multiple genetic targets.
Dong SM, Traverso G, Johnson C, Geng L, Favis R, Boynton K, Hibi K, Goodman SN, D'Allessio M, Paty P, Hamilton SR, Sidransky D, Barany F, Levin B, Shuber A, Kinzler KW, Vogelstein B, Jen J.
Division of Head and Neck Cancer Research, Department of Otolaryngology-Head and Neck Surgery, The Johns Hopkins Medical School, The Johns Hopkins University, Baltimore, MD, USA.
BACKGROUND: Colorectal cancer cells are shed into the stool, providing a potential means for the early detection of the disease using noninvasive approaches. Our goal was to develop reliable, specific molecular genetic tests for the detection of colorectal cancer in stool samples. METHODS: Stool DNA was isolated from paired stools and primary tumor samples from 51 colorectal cancer patients. Three genetic targets-TP53, BAT26, and K-RAS-were used to detect tumor-associated mutations in the stool prior to or without regard to the molecular analyses of the paired tumors. TP53 gene mutations were detected with a mismatch-ligation assay that detects nine common p53 gene mutations. Deletions within the BAT26 locus were detected by a modified solid-phase minisequencing method. Mutations in codons 12 and 13 of K-RAS were detected with a digital polymerase chain reaction-based method. RESULTS: TP53 gene mutations were detected in the tumor DNA of 30 patients, all of whom had the identical TP53 mutation in their stools. Tumors from three patients contained a noninherited deletion at the BAT26 locus, and the same alterations were identified in these patients' stool specimens. Nineteen of 50 tumors tested had a K-RAS mutation; identical mutations were detected in the paired stool DNA samples from eight patients. In no case was a mutation found in stool that was not also present in the primary tumor. Thus, the three genetic markers together detected 36 (71%) of 51 patients (95% confidence interval [CI] = 56% to 83%) with colorectal cancer and 36 (92%) of 39 patients (95% CI = 79% to 98%) whose tumors had an alteration. CONCLUSION: We were able to detect the majority of colorectal cancers by analyzing stool DNA for just three genetic markers. Additional work is needed to determine the specificity of these genetic tests for detecting colorectal neoplasia in asymptomatic patients and to more precisely estimate the prevalence of the mutations and sensitivity of the assay.<<
From the S-1:
>>NAME ROLE IN DETECTION OUR SCIENTIFIC ADVANCE
------------------ ---------------------------------- ----------------------------------
MULTIPLE MUTATION - Each element of MuMu detects a - Sensitive and specific detection
DETECTION (MUMU) single mutation of a of single DNA mutations
cancer-related gene
DELETION - Detects short deletions and - Distinguishes between deletions
TECHNOLOGY insertions in the BAT-26 region and insertions resulting from
of a specific gene the testing itself, and those
associated with mismatch-repair
cancers
DNA INTEGRITY - Detects longer human DNA - Proprietary marker associated
ASSAY (DIA) fragments associated with with cancer that does not require
abnormality knowledge of which genes cause
cancer
ENUMERATED LOSS OF - Enumerates ratio of paternal DNA - Statistical method that applies
HETEROZYGOSITY as compared to maternal DNA at a a commonly used analytical
(E-LOH) given genomic site to identify technique to indicate a missing
chromosomal loss that is gene and does not require
characteristic of many cancers knowledge of which genes cause
cancer
MULTIPLE MUTATION. Multiple Mutation, or MuMu, identifies DNA mutations at
specific sites. We have selected 15 sites that are commonly mutated in the
colorectal cancer-related genes APC, P53 and K-RAS. We have designed our
proprietary MuMu method to allow simultaneous probing of different DNA sequences
and to allow analysis even though only a small amount of DNA in the sample is
derived from abnormal cells while the vast majority is derived from normal human
cells or bacteria.
DELETION TECHNOLOGY. Deletion Technology detects short deletions and
insertions in segments of DNA that are indications of defects in cellular
mechanisms for DNA repair. Approximately 15% of colorectal cancers, referred to
as mismatch-repair cancers, result from inactivation of the proteins that
normally repair errors in DNA after DNA replication. We have developed a
proprietary method for identifying this condition by detecting the presence of
short deletions and insertions in a DNA segment known as BAT-26. This altered
gene segment appears in virtually all colorectal cancers resulting from defects
in the mismatch repair mechanism.
DNA INTEGRITY ASSAY. DNA recovered from the stool of many cancer patients
contains a small but detectable population of DNA that is longer than DNA
recovered from individuals who are normal and have never had cancer or an
adenoma. Use of this proprietary detection method does not require knowledge of
which genes cause cancer. In addition to its utility for our colorectal cancer
tests, we believe that this discovery may lead us to the development of a marker
for other cancers, including lung, pancreas, gall bladder and bile duct cancers.
ENUMERATED LOSS OF HETEROZYGOSITY. In normal cells, the quantity of DNA
inherited from each parent is generally equal. This is not true for cells from
many different types of cancers, including virtually all non-mismatch repair
colorectal cancers. This condition, which is an imbalance of maternal and paternal chromosomal fragments, is called loss of heterozygosity, or LOH.
Prior to our development efforts, we believe that scientists were unable to
detect LOH in stool samples. We have developed proprietary methods for detecting
LOH in a highly heterogeneous DNA sample such as stool by enumerating the ratio
of fragments of DNA that are inherited from each parent at defined locations in
the genome. We call this detection method e-LOH. Use of this detection method
does not require knowledge of which genes cause cancer. We believe that our
novel e-LOH detection method may be broadly applicable to early cancer detection
from many body sites.<<
Now it seems the main competition in the future will be from technologies that measure this sort of thing in blood serum. Although sampling blood is more invasive than collecting stool samples, one has to figure some blood work will get done during the course of patient testing anyway, so I do not see this as a problem for this approach. It is more difficult, but it appears that all the markers -- APC, k-ras, p-53 -- can be measured in the blood. One mysterious little Pennsylvania company, OncoMedx, seems to be following this path, based on its own work and that of others (not sure if the changes at the BAT26 locus can be measured in serum):
>>Molecular detection of genetic alterations in the serum of colorectal cancer patients.
Hibi K, Robinson CR, Booker S, Wu L, Hamilton SR, Sidransky D, Jen J.
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA.
We have searched for the presence of genetic alterations in serum DNA obtained from 44 colorectal cancer patients. Microsatellite analysis using highly polymorphic markers revealed loss of heterozygosity and/or microsatellite instability in 35 of 44 (80%) primary tumors. No alterations were detected in the paired serum DNA. We next used an oligonucleotide-mediated mismatch ligation assay to detect tumor specific gene mutations in the serum. Among the 16 cases with a K-ras gene mutation in the tumor, the same mutation was detected in three paired serum samples. In the 10 cases with a p53 mutation in the tumor, the identical mutation was detected in seven corresponding serum samples. Comparison of the molecular analysis with clinical diagnosis of these patients revealed that none of the seven Dukes' stage B patients with a K-ras mutation in their tumors demonstrated a mutation in the serum. In contrast, five of seven stage B patients with a p53 mutation in the tumor demonstrated a mutation in the paired serum (P = 0.01, Fisher's exact test). Taken together, either a K-ras or p53 mutation was detected in the serum in 40% of the 25 patients (95% confidence interval, 21-61%), whose primary tumors contained a mutation and in 23% of the 44 patients (95% confidence interval, 12-38%) with colorectal cancer. The frequent detection of p53 mutation in the serum of patients with early stage tumors suggests a possible use of this approach for clinical prognosis and cancer monitoring of colorectal cancer patients.
PMID: 9537240 [PubMed - indexed for MEDLINE]
clincancerres.aacrjournals.org
Detection of APC and k-ras mutations in the serum of patients with colorectal cancer.
Lauschke H, Caspari R, Friedl W, Schwarz B, Mathiak M, Propping P, Hirner A.
Department of Surgery, University of Bonn, Germany.
Detection of tumor DNA in peripheral blood of patients with colorectal cancer (CRC) may allow early diagnosis of tumor disease and be of prognostic value. However, a reliable tumor marker detectable in the serum of patients with this disease is missing. Because k-ras and APC mutations occur frequently and at an early stage in CRCs, these mutations might also be detected in the serum of CRC patients and serve as tumor markers. Hence, tumor tissues of CRC patients were examined for the presence of mutations in the k-ras and APC genes. If a mutation was detected in the tumor, the serum of the patient was screened subsequently for the presence of this mutation. K-ray mutations were detected in 22 of 30 colorectal tumor tissues, but only in six patients was the mutation identified in their serum samples. Mutations of the APC gene were identified in 25 of 65 tumors: 20 of these 25 patients showed the respective mutation in their serum. Given their higher detection rate, APC mutations could be a more informative serum marker than k-ras in CRC patients.<<
EXAS will begin by marketing the colorectal test to clinical reference labs, then licensing the technology. It seems to me that tests of similar sensitivity and specificity are being developed for serum, and that they aren't that far behind. EXAS is still a ways from market with their big product, and their stock has been enjoying a good run on the back of the introduction of a product with a smaller niche:
>>MAYNARD, Mass., May 21, 2001 (BW HealthWire) -- EXACT Sciences Corporation (NASDAQ: EXAS chart, msgs) today announced the introduction of its PreGen-26(TM) test, the first application of its DNA-based, non-invasive colorectal cancer screening technology. The PreGen-26 test is specifically designed to detect colorectal cancer in people with known or suspected Hereditary Non-Polyposis Colorectal Cancer (HNPCC), an inherited predisposition for colorectal cancer.
An estimated 280,000 people are affected with HNPCC syndrome in the U.S., and those with HNPCC have an 80 percent lifetime risk of developing colorectal cancer. Due to this high risk, people with HNPCC should be screened frequently for the presence of colorectal cancer. Because the PreGen-26 test is conducted by analyzing DNA found in a stool sample, people with HNPCC syndrome and physicians who treat these patients now have a more convenient and non-invasive tool to help supplement currently available screening methods.
The PreGen-26 test detects colorectal cancer today in people with HNPCC by identifying microsatellite instability (MSI), which is present in more than 90 percent of HNPCC colorectal cancers. MSI occurs as a result of defects in the genes that normally proofread and then repair DNA after it is replicated, ultimately increasing the mutation rates and accelerating the progression of a benign tumor to a cancer. Unlike predispositional tests that indicate a person's lifetime risk of developing colorectal cancer associated with HNPCC, the PreGen-26 test detects the actual presence of colorectal cancer.<<
snip
So my take is that the competition is closer than they'd have us believe. A good short? Considering it's approaching resistance at its IPO price soon before lock-up expiration, and that I don't expect much news flow until later this year, I would say "yes." Sales from PreGen-26 will be negligible; it's away of getting the ales force some experience. Pending warning/rebuttal from more expert folks, I intend to start a position on the back of the rally I'm expecting soon. Somewhere in the 17 to 20 range, I'm guessing; I'll be looking for signs of blow-off.
Cheers, Tuck |
