Rebecca Kern

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the Cologuard DNA stool test, a first-line diagnostic test to screen for the detection of colorectal cancer in patients over age 50 years at average risk of colorectal cancer.

In a March 27 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee voted across the board 10-0 that the noninvasive Cologuard test, manufactured by Exact Sciences, demonstrated a reasonable assurance of safety and effectiveness and that the test’s benefits outweighed its risks.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin. According to the test’s proposed indications for use, a positive result for colorectal cancer should be followed by colonoscopy. Cologuard is not intended to replace colonoscopy. The sponsor is recommending that the test be repeated every 3 years, in addition to current clinical colorectal screening recommendations.

The firm’s multicenter, prospective pivotal study enrolled 12,776 patients in the United States and Canada to assess Cologuard as a screening test for the detection of markers associated with the presence of colorectal cancer or advanced adenomas.

Cologuard met the primary study objectives for the pivotal study – demonstrating sensitivity of 92.3% – meeting the trial’s objective of 65% – and a specificity of 86.6% – meeting the trial’s objective of 85%.

The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

Cologuard met its secondary outcome as well. Its sensitivity was greater than FIT for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced adenomas (42.4% vs. 23.8%, respectively.) These findings were reported last week in the New England Journal of Medicine (2014 [doi:10.1056/NEJMoa1311194]).

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

Panelists seemed impressed with the sensitivity and specificity data for the Cologuard test.

"The sensitivity data are shown to be superior to FIT for colorectal cancer and for advanced dysplasia, and indicate that this would be useful and appropriate as a screening test," said panelist Dr. Karen E. Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The only caveat I would make is although there is an increased sensitivity for advanced adenoma as well, because the sensitivity is 42%, clearly that wouldn’t be sufficient to recommend not having a colonoscopy," she added.

Several panelists also commented on the potential for the test to completely alter the practice of colorectal screening.

"I think just having a sense of the past 20 years of being in early detection, this is one of the biggest improvements in early detection that I’ve seen," said panelist Dr. Steven Skates, associate professor of medicine at Massachusetts General Hospital, Boston.

The panel chair, Dr. Ronald M. Przygodzki, acting director of the Biomedical Laboratory Research & Development at the U.S. Department of Veterans Affairs, also commented, "I typically refrain from commentary, but this is a phenomenal study in particular for one reason. ... You are looking at the large polyps that you would not otherwise find, and now you have a greater potential to actually cure."

FDA even noted in its prepanel summary documents that, "Screening guidelines may change if the [premarket approval application] for Cologuard is approved."

FDA and the sponsor have designed a post-approval study to collect longitudinal performance data to adequately ensure safety and effectiveness. The panel recommended a one- or two-arm study comparing the performance of the test outcomes from initial screening and screening at 3 years, to outcomes from screening at initial screening, year 1, year 2, and year 3.

FDA also noted the uniqueness of Exact Sciences’ approach to the study, in engaging both FDA and the Centers for Medicare & Medicaid Services early on.

"The sponsor, with the help of FDA and CMS, designed the study. So the fact that the sponsor was willing to go the extra step and have joint review from FDA and CMS is really telling," said Alberto Gutierrez, Ph.D., director of FDA’s Office of In Vitro Diagnostics and Radiological Health.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the Cologuard DNA stool test, a first-line diagnostic test to screen for the detection of colorectal cancer in patients over age 50 years at average risk of colorectal cancer.

In a March 27 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee voted across the board 10-0 that the noninvasive Cologuard test, manufactured by Exact Sciences, demonstrated a reasonable assurance of safety and effectiveness and that the test’s benefits outweighed its risks.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin. According to the test’s proposed indications for use, a positive result for colorectal cancer should be followed by colonoscopy. Cologuard is not intended to replace colonoscopy. The sponsor is recommending that the test be repeated every 3 years, in addition to current clinical colorectal screening recommendations.

The firm’s multicenter, prospective pivotal study enrolled 12,776 patients in the United States and Canada to assess Cologuard as a screening test for the detection of markers associated with the presence of colorectal cancer or advanced adenomas.

Cologuard met the primary study objectives for the pivotal study – demonstrating sensitivity of 92.3% – meeting the trial’s objective of 65% – and a specificity of 86.6% – meeting the trial’s objective of 85%.

The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

Cologuard met its secondary outcome as well. Its sensitivity was greater than FIT for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced adenomas (42.4% vs. 23.8%, respectively.) These findings were reported last week in the New England Journal of Medicine (2014 [doi:10.1056/NEJMoa1311194]).

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

Panelists seemed impressed with the sensitivity and specificity data for the Cologuard test.

"The sensitivity data are shown to be superior to FIT for colorectal cancer and for advanced dysplasia, and indicate that this would be useful and appropriate as a screening test," said panelist Dr. Karen E. Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The only caveat I would make is although there is an increased sensitivity for advanced adenoma as well, because the sensitivity is 42%, clearly that wouldn’t be sufficient to recommend not having a colonoscopy," she added.

Several panelists also commented on the potential for the test to completely alter the practice of colorectal screening.

"I think just having a sense of the past 20 years of being in early detection, this is one of the biggest improvements in early detection that I’ve seen," said panelist Dr. Steven Skates, associate professor of medicine at Massachusetts General Hospital, Boston.

The panel chair, Dr. Ronald M. Przygodzki, acting director of the Biomedical Laboratory Research & Development at the U.S. Department of Veterans Affairs, also commented, "I typically refrain from commentary, but this is a phenomenal study in particular for one reason. ... You are looking at the large polyps that you would not otherwise find, and now you have a greater potential to actually cure."

FDA even noted in its prepanel summary documents that, "Screening guidelines may change if the [premarket approval application] for Cologuard is approved."

FDA and the sponsor have designed a post-approval study to collect longitudinal performance data to adequately ensure safety and effectiveness. The panel recommended a one- or two-arm study comparing the performance of the test outcomes from initial screening and screening at 3 years, to outcomes from screening at initial screening, year 1, year 2, and year 3.

FDA also noted the uniqueness of Exact Sciences’ approach to the study, in engaging both FDA and the Centers for Medicare & Medicaid Services early on.

"The sponsor, with the help of FDA and CMS, designed the study. So the fact that the sponsor was willing to go the extra step and have joint review from FDA and CMS is really telling," said Alberto Gutierrez, Ph.D., director of FDA’s Office of In Vitro Diagnostics and Radiological Health.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel unanimously supported the approval of the Cologuard DNA stool test, a first-line diagnostic test to screen for the detection of colorectal cancer in patients over age 50 years at average risk of colorectal cancer.

In a March 27 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee voted across the board 10-0 that the noninvasive Cologuard test, manufactured by Exact Sciences, demonstrated a reasonable assurance of safety and effectiveness and that the test’s benefits outweighed its risks.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin. According to the test’s proposed indications for use, a positive result for colorectal cancer should be followed by colonoscopy. Cologuard is not intended to replace colonoscopy. The sponsor is recommending that the test be repeated every 3 years, in addition to current clinical colorectal screening recommendations.

The firm’s multicenter, prospective pivotal study enrolled 12,776 patients in the United States and Canada to assess Cologuard as a screening test for the detection of markers associated with the presence of colorectal cancer or advanced adenomas.

Cologuard met the primary study objectives for the pivotal study – demonstrating sensitivity of 92.3% – meeting the trial’s objective of 65% – and a specificity of 86.6% – meeting the trial’s objective of 85%.

The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

Cologuard met its secondary outcome as well. Its sensitivity was greater than FIT for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced adenomas (42.4% vs. 23.8%, respectively.) These findings were reported last week in the New England Journal of Medicine (2014 [doi:10.1056/NEJMoa1311194]).

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

Panelists seemed impressed with the sensitivity and specificity data for the Cologuard test.

"The sensitivity data are shown to be superior to FIT for colorectal cancer and for advanced dysplasia, and indicate that this would be useful and appropriate as a screening test," said panelist Dr. Karen E. Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The only caveat I would make is although there is an increased sensitivity for advanced adenoma as well, because the sensitivity is 42%, clearly that wouldn’t be sufficient to recommend not having a colonoscopy," she added.

Several panelists also commented on the potential for the test to completely alter the practice of colorectal screening.

"I think just having a sense of the past 20 years of being in early detection, this is one of the biggest improvements in early detection that I’ve seen," said panelist Dr. Steven Skates, associate professor of medicine at Massachusetts General Hospital, Boston.

The panel chair, Dr. Ronald M. Przygodzki, acting director of the Biomedical Laboratory Research & Development at the U.S. Department of Veterans Affairs, also commented, "I typically refrain from commentary, but this is a phenomenal study in particular for one reason. ... You are looking at the large polyps that you would not otherwise find, and now you have a greater potential to actually cure."

FDA even noted in its prepanel summary documents that, "Screening guidelines may change if the [premarket approval application] for Cologuard is approved."

FDA and the sponsor have designed a post-approval study to collect longitudinal performance data to adequately ensure safety and effectiveness. The panel recommended a one- or two-arm study comparing the performance of the test outcomes from initial screening and screening at 3 years, to outcomes from screening at initial screening, year 1, year 2, and year 3.

FDA also noted the uniqueness of Exact Sciences’ approach to the study, in engaging both FDA and the Centers for Medicare & Medicaid Services early on.

"The sponsor, with the help of FDA and CMS, designed the study. So the fact that the sponsor was willing to go the extra step and have joint review from FDA and CMS is really telling," said Alberto Gutierrez, Ph.D., director of FDA’s Office of In Vitro Diagnostics and Radiological Health.

GAITHERSBURG, MD. – The Food and Drug Administration advisory panel deemed the first-of-a-kind blood test to screen for colorectal cancer safe but not effective.*

At a March 26 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee* voted 9-0 with one abstention that the Epi proColon test, an in vitro diagnostic blood test manufactured by Epigenetics Inc., is safe to screen for colorectal cancer in patients with an average risk for the disease. Patients with a positive test would then be referred for diagnostic colonoscopy.

The panel was split in its view of the test’s effectiveness, however, voting 5-6 (the panel chair voted to break a 5-5 tie) that there was not a reasonable assurance of effectiveness for its proposed indications.

But it voted 5-4 (one abstention) that the benefits of the Epi proColon test outweighed its risks.

Epigenomics submitted its premarket approval application for the Epi proColon test last January for the detection of methylated Septim9 DNA in plasma derived from patient whole blood specimens. It currently has CE mark approval, and a first-generation version has been sold in Europe and the Middle East since 2009.

Two clinical studies were conducted to assess the clinical performance of Epi proColon. The pivotal clinical study was a prospective, multicenter trial comparing the test to colonoscopy using 6,857 samples collected in a previous noninferiority study. A supplemental clinical study was conducted comparing the performance of the Epi proColon test and a commercially available fecal immunochemical test (FIT) to colonoscopy.

In the pivotal trial, the Epi proColon test demonstrated a sensitivity of 68%, meeting the trial’s sensitivity target of 65%, but the test’s specificity of 80% did not meet the specificity target of 85%. The false-positive rate in the study was 21% higher than expected, indicating that more individuals than expected would be recommended to do a follow-up diagnostic procedure, such as a colonoscopy, which will be negative, the FDA said in its panel summary documents.

Some panelists questioned the sensitivity of the test, saying it was too low for a screening test, which should ideally have a sensitivity of 80%-90%. They also expressed concerns about the high false-positive rate.

"A sensitivity of about 70%, such that 30 out of every 100 people screened would be falsely negative, just seems too low as a screening test," said panelist Dr. Karen Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The sponsor indicated that those individuals would still be recommended to have colonoscopy. So colonoscopy would still be recommended for individuals who test positive for this test and for individuals who test negative for this test, so it’s unclear to me what really is the clinical utility of this test then."

In the supplemental study, Epi proColon demonstrated noninferiority to the FIT for sensitivity but not for specificity, indicating that Epi proColon test exhibited a higher rate of false-positive results, compared with the FIT.

The pivotal trial also found that the false-positive rate increased with age and in African American subjects. Although panelists generally felt it unnecessary for the sponsor to include this information in additional labeling or warnings, several said that the false-positivity rates should somehow be conveyed to physicians and patients.

The panel supported the inclusion of the following warning statements in labeling with the test: not intended to replace colorectal cancer screening by colonoscopy; positive results are not confirmatory evidence for the presence of colorectal cancer; and negative results do not guarantee absence of cancer.

The sponsor and the FDA are working on a postapproval study for the test, with a possible study design of three annual test cycles and two additional years of study.

*Correction, 3/27/2014: An earlier version of this story did not make it clear that an advisory panel to the FDA made this recommendation.

GAITHERSBURG, MD. – The Food and Drug Administration advisory panel deemed the first-of-a-kind blood test to screen for colorectal cancer safe but not effective.*

At a March 26 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee* voted 9-0 with one abstention that the Epi proColon test, an in vitro diagnostic blood test manufactured by Epigenetics Inc., is safe to screen for colorectal cancer in patients with an average risk for the disease. Patients with a positive test would then be referred for diagnostic colonoscopy.

The panel was split in its view of the test’s effectiveness, however, voting 5-6 (the panel chair voted to break a 5-5 tie) that there was not a reasonable assurance of effectiveness for its proposed indications.

But it voted 5-4 (one abstention) that the benefits of the Epi proColon test outweighed its risks.

Epigenomics submitted its premarket approval application for the Epi proColon test last January for the detection of methylated Septim9 DNA in plasma derived from patient whole blood specimens. It currently has CE mark approval, and a first-generation version has been sold in Europe and the Middle East since 2009.

Two clinical studies were conducted to assess the clinical performance of Epi proColon. The pivotal clinical study was a prospective, multicenter trial comparing the test to colonoscopy using 6,857 samples collected in a previous noninferiority study. A supplemental clinical study was conducted comparing the performance of the Epi proColon test and a commercially available fecal immunochemical test (FIT) to colonoscopy.

In the pivotal trial, the Epi proColon test demonstrated a sensitivity of 68%, meeting the trial’s sensitivity target of 65%, but the test’s specificity of 80% did not meet the specificity target of 85%. The false-positive rate in the study was 21% higher than expected, indicating that more individuals than expected would be recommended to do a follow-up diagnostic procedure, such as a colonoscopy, which will be negative, the FDA said in its panel summary documents.

Some panelists questioned the sensitivity of the test, saying it was too low for a screening test, which should ideally have a sensitivity of 80%-90%. They also expressed concerns about the high false-positive rate.

"A sensitivity of about 70%, such that 30 out of every 100 people screened would be falsely negative, just seems too low as a screening test," said panelist Dr. Karen Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The sponsor indicated that those individuals would still be recommended to have colonoscopy. So colonoscopy would still be recommended for individuals who test positive for this test and for individuals who test negative for this test, so it’s unclear to me what really is the clinical utility of this test then."

In the supplemental study, Epi proColon demonstrated noninferiority to the FIT for sensitivity but not for specificity, indicating that Epi proColon test exhibited a higher rate of false-positive results, compared with the FIT.

The pivotal trial also found that the false-positive rate increased with age and in African American subjects. Although panelists generally felt it unnecessary for the sponsor to include this information in additional labeling or warnings, several said that the false-positivity rates should somehow be conveyed to physicians and patients.

The panel supported the inclusion of the following warning statements in labeling with the test: not intended to replace colorectal cancer screening by colonoscopy; positive results are not confirmatory evidence for the presence of colorectal cancer; and negative results do not guarantee absence of cancer.

The sponsor and the FDA are working on a postapproval study for the test, with a possible study design of three annual test cycles and two additional years of study.

*Correction, 3/27/2014: An earlier version of this story did not make it clear that an advisory panel to the FDA made this recommendation.

GAITHERSBURG, MD. – The Food and Drug Administration advisory panel deemed the first-of-a-kind blood test to screen for colorectal cancer safe but not effective.*

At a March 26 meeting, the FDA Molecular and Clinical Genetics Panel of the Medical Devices advisory committee* voted 9-0 with one abstention that the Epi proColon test, an in vitro diagnostic blood test manufactured by Epigenetics Inc., is safe to screen for colorectal cancer in patients with an average risk for the disease. Patients with a positive test would then be referred for diagnostic colonoscopy.

The panel was split in its view of the test’s effectiveness, however, voting 5-6 (the panel chair voted to break a 5-5 tie) that there was not a reasonable assurance of effectiveness for its proposed indications.

But it voted 5-4 (one abstention) that the benefits of the Epi proColon test outweighed its risks.

Epigenomics submitted its premarket approval application for the Epi proColon test last January for the detection of methylated Septim9 DNA in plasma derived from patient whole blood specimens. It currently has CE mark approval, and a first-generation version has been sold in Europe and the Middle East since 2009.

Two clinical studies were conducted to assess the clinical performance of Epi proColon. The pivotal clinical study was a prospective, multicenter trial comparing the test to colonoscopy using 6,857 samples collected in a previous noninferiority study. A supplemental clinical study was conducted comparing the performance of the Epi proColon test and a commercially available fecal immunochemical test (FIT) to colonoscopy.

In the pivotal trial, the Epi proColon test demonstrated a sensitivity of 68%, meeting the trial’s sensitivity target of 65%, but the test’s specificity of 80% did not meet the specificity target of 85%. The false-positive rate in the study was 21% higher than expected, indicating that more individuals than expected would be recommended to do a follow-up diagnostic procedure, such as a colonoscopy, which will be negative, the FDA said in its panel summary documents.

Some panelists questioned the sensitivity of the test, saying it was too low for a screening test, which should ideally have a sensitivity of 80%-90%. They also expressed concerns about the high false-positive rate.

"A sensitivity of about 70%, such that 30 out of every 100 people screened would be falsely negative, just seems too low as a screening test," said panelist Dr. Karen Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

"The sponsor indicated that those individuals would still be recommended to have colonoscopy. So colonoscopy would still be recommended for individuals who test positive for this test and for individuals who test negative for this test, so it’s unclear to me what really is the clinical utility of this test then."

In the supplemental study, Epi proColon demonstrated noninferiority to the FIT for sensitivity but not for specificity, indicating that Epi proColon test exhibited a higher rate of false-positive results, compared with the FIT.

The pivotal trial also found that the false-positive rate increased with age and in African American subjects. Although panelists generally felt it unnecessary for the sponsor to include this information in additional labeling or warnings, several said that the false-positivity rates should somehow be conveyed to physicians and patients.

The panel supported the inclusion of the following warning statements in labeling with the test: not intended to replace colorectal cancer screening by colonoscopy; positive results are not confirmatory evidence for the presence of colorectal cancer; and negative results do not guarantee absence of cancer.

The sponsor and the FDA are working on a postapproval study for the test, with a possible study design of three annual test cycles and two additional years of study.

*Correction, 3/27/2014: An earlier version of this story did not make it clear that an advisory panel to the FDA made this recommendation.

A noninvasive, multitarget stool DNA test detected significantly more cancer than did a fecal immunochemical test in people at average risk for colorectal cancer, but had greater false positive results, according to a report published March 19 in the New England Journal of Medicine.

The study’s primary outcome was the ability of the DNA test to detect colorectal cancer. The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin.

The study investigators enrolled 12,776 asymptomatic persons aged 50-84 years who were scheduled to undergo a colonoscopy screening; of those participants, 9,989 could be fully evaluated. The study took place in 90 sites in the United States and Canada from June 2011 to November 2012, led by Dr. Thomas F. Imperiale from Indiana University, Indianapolis, and his associates.

The DNA test’s sensitivity was greater than FIT was for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced precancerous lesions (42.4% vs. 23.8%, respectively), the investigators reported (N. Engl. J. Med. 2014 March 19 [doi:10.1056/NEJMoa1311194]). The difference could be from the DNA marker and algorithm components of the test, they noted, because both the DNA and FIT tests use almost identical hemoglobin immunoassay components.

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

However, FIT was more specific for the detection of both colorectal cancer and advanced precancerous lesions, by absolute differences of 6.6%-8.3%, the authors noted.

"A noninvasive test with a high single-application sensitivity for curable-stage cancer may provide an option for persons who prefer noninvasive testing," the investigators concluded. However, "questions about testing intervals and tailoring require further consideration."

Exact Sciences funded the study. Dr. Imperiale reported receiving grant support from Exact Sciences.

A noninvasive, multitarget stool DNA test detected significantly more cancer than did a fecal immunochemical test in people at average risk for colorectal cancer, but had greater false positive results, according to a report published March 19 in the New England Journal of Medicine.

The study’s primary outcome was the ability of the DNA test to detect colorectal cancer. The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin.

The study investigators enrolled 12,776 asymptomatic persons aged 50-84 years who were scheduled to undergo a colonoscopy screening; of those participants, 9,989 could be fully evaluated. The study took place in 90 sites in the United States and Canada from June 2011 to November 2012, led by Dr. Thomas F. Imperiale from Indiana University, Indianapolis, and his associates.

The DNA test’s sensitivity was greater than FIT was for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced precancerous lesions (42.4% vs. 23.8%, respectively), the investigators reported (N. Engl. J. Med. 2014 March 19 [doi:10.1056/NEJMoa1311194]). The difference could be from the DNA marker and algorithm components of the test, they noted, because both the DNA and FIT tests use almost identical hemoglobin immunoassay components.

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

However, FIT was more specific for the detection of both colorectal cancer and advanced precancerous lesions, by absolute differences of 6.6%-8.3%, the authors noted.

"A noninvasive test with a high single-application sensitivity for curable-stage cancer may provide an option for persons who prefer noninvasive testing," the investigators concluded. However, "questions about testing intervals and tailoring require further consideration."

Exact Sciences funded the study. Dr. Imperiale reported receiving grant support from Exact Sciences.

A noninvasive, multitarget stool DNA test detected significantly more cancer than did a fecal immunochemical test in people at average risk for colorectal cancer, but had greater false positive results, according to a report published March 19 in the New England Journal of Medicine.

The study’s primary outcome was the ability of the DNA test to detect colorectal cancer. The secondary outcome was the DNA test’s ability to detect advanced precancerous lesions, including advanced adenomas and sessile serrated polyps measuring 1 cm or more in diameter, compared with the performance of a commercially available fecal immunochemical test (FIT) for human hemoglobin.

The multitarget stool DNA test includes molecular assays for aberrantly methylated BMP3 and NDRG4 promoter regions, KRAS mutations, and beta-actin (a reference gene for human DNA quantity), as well as an immunochemical assay for human hemoglobin.

The study investigators enrolled 12,776 asymptomatic persons aged 50-84 years who were scheduled to undergo a colonoscopy screening; of those participants, 9,989 could be fully evaluated. The study took place in 90 sites in the United States and Canada from June 2011 to November 2012, led by Dr. Thomas F. Imperiale from Indiana University, Indianapolis, and his associates.

The DNA test’s sensitivity was greater than FIT was for the detection of colorectal cancer (92.3% vs. 73.8%, respectively) and for advanced precancerous lesions (42.4% vs. 23.8%, respectively), the investigators reported (N. Engl. J. Med. 2014 March 19 [doi:10.1056/NEJMoa1311194]). The difference could be from the DNA marker and algorithm components of the test, they noted, because both the DNA and FIT tests use almost identical hemoglobin immunoassay components.

The DNA test’s sensitivity for the detection of advanced precancerous lesions was approximately half that for the detection of colorectal cancer. DNA testing was more sensitive than was FIT for the detection of lesions with high-grade dysplasia (69.2% vs. 46.2%; P = .004) and sessile serrated polyps 1 cm or larger (42.4% vs. 5.1%; P less than .001), and for the detection of advanced precancerous lesions within the size ranges observed, the investigators reported.

However, FIT was more specific for the detection of both colorectal cancer and advanced precancerous lesions, by absolute differences of 6.6%-8.3%, the authors noted.

"A noninvasive test with a high single-application sensitivity for curable-stage cancer may provide an option for persons who prefer noninvasive testing," the investigators concluded. However, "questions about testing intervals and tailoring require further consideration."

Exact Sciences funded the study. Dr. Imperiale reported receiving grant support from Exact Sciences.