A new blood test, dubbed CancerSEEK, can identify eight common cancers ― ovary, liver, esophagus, pancreas, stomach, colorectal, lung, and breast cancer ― say researchers from the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland.
The new test measures circulating tumor DNA (ctDNA) from 16 genes as well as eight protein biomarkers, and then uses machine-based learning to analyze the data.
“The use of a combination of selected biomarkers for early detection has the potential to change the way we screen for cancer, and it is based on the same rationale for using combinations of drugs to treat cancers,” said Nickolas Papadopoulos, PhD, senior author and professor of oncology and pathology, in a statement.
In the future, the blood test could be used to detect cancers “early enough that they could be cured by surgery alone, but even cancers that are not curable by surgery alone will respond better to systemic therapies when there is less advanced disease,” said one of the corresponding authors, Anne Marie Lennon, MD, PhD, professor of medicine, surgery, and radiology and clinical director of gastroenterology. “Earlier detection provides many ways to improve outcomes for patients,” she added.
The new test is described in a report published online January 18 in Science.
It is still early days for the test. “To actually establish the clinical utility of CancerSEEK and to demonstrate that it can save lives, prospective studies of all incident cancer types in a large population will be required,” the researchers conclude.
Nevertheless, they believe that this study “lays the conceptual and practical foundation for a single, multi-analyte blood test for cancers of many types.”
The researchers also estimate that the cost of this single test will be less than $500. “This is very much an estimate of what we think it will likely cost if it was implemented as a widely used screening test,” Dr Lennon told Medscape Medical News.
If this does turn out to be the case, this blood test would be considerably less expensive and more convenient that current screening tests, such as colonoscopy and mammography.
Novel Approach: Looking at Both Mutations and Proteins
“A novelty of our classification method is that it combines the possibility of observing various DNA mutations together with the levels of several proteins in order to make the final call,” said co-corresponding author Cristian Tomasetti, PhD, associate professor of oncology and biostatistics, who developed the algorithm, in a release.
From initially looking at several hundred genes and 41 protein biomarkers that might detect cancers prior to metastasis, the Hopkins researchers settled on interrogating segments of 16 genes and analyzing levels of eight protein biomarkers.
The eight proteins are cancer antigen 125, carcinoembryonic antigen, cancer antigen 19-9, prolactin, hepatocyte growth factor, osteopontin, myeloperoxidase, and tissue inhibitor of metalloproteinases 1.
The first component of CancerSEEK determines mutations in ctDNA obtained from the blood sample. With purified DNA from plasma, the researchers amplified the sample with multiplex–polymerase chain reaction using a robust 61-amplicon panel that had the ability to detect rare mutations expected in plasma ctDNA.
The 61 primer pairs were designed to amplify 66 to 80 base-pair segments of the DNA in regions of interest from 16 genes. The amplified products were uniquely labeled with a DNA barcode and were matched to reference sequences present in the Catalog of Somatic Mutations in Cancer dataset or ones that were predicted to be inactivating mutations in tumor suppressor cells.
“Keeping the mutational panel small is essential to minimize false positive results to keep such tests affordable,” said Joshua Cohen, an MD-PhD student at the Johns Hopkins University School of Medicine, who is and the article’s first author.
The second component of CancerSEEK is determining levels of eight cancer protein biomarkers. According to the researchers, the reason for incorporating this component into the mix is because “early-stage tumors do not release detectable amounts of ctDNA, even when the most sensitive techniques are used to identify them.”
The eight proteins selected could be reproducibly evaluated through a single immunoassay platform.
Details of the Study
For the study, the researchers recruited 1005 patients with stage I to III cancers of the ovary, liver, esophagus, pancreas, stomach, colorectum, lung, or breast who had not yet undergone surgery. The median age of the patients at diagnosis was 64 years. The most common stage at presentation was stage II (49%); 20% of patients had stage I disease; and 31% of patients had stage III disease.
The study also included 812 healthy individuals (median age, 55 years) who had no history of cancer. These individuals served as a control population.
Patients were excluded if they had undergone prior neoadjuvant therapy, were determined to have stage IV disease after resection, or if their blood had been drawn while anesthesia was being administered.
Peripheral blood was collected from the cancer patients before they underwent surgical resection.
The CancerSEEK blood test was used to detect the presence of mutations in 2001 genomic positions of the 16 genes. Luminex bead-based immunoassays were performed using panels that determined the levels of 39 proteins, including the eight protein biomarkers.
A patient’s test result was classified as positive if the frequency of a mutation in one of the 16 genes or the levels in one of the eight proteins, or their combination, was significantly elevated with respect to the control population.
The algorithm then used machine-learning tools and statistical analyses to determine the median sensitivity and specificity through 10 iterations of 10-fold cross-validations.
“One of the most important attributes of a screening test is the ability to detect cancers at an early stage,” the researchers note.
The median sensitivity of CancerSEEK was 73% for stage II cancers, 78% for stage III cancers, and a low 43% for stage I cancers.
For stage I cancers, the highest sensitivity was for liver cancer (100%), and the lowest was for esophageal cancer (20%).
The median overall sensitivity — the ability to find cancer — was 70% for the eight common cancers, which account for more than 60% of cancer deaths in the United States. The sensitivities ranged from 98% for ovarian cancer to a low 33% for breast cancer.
For the cancers for which there are currently no screening tests available — ovary, liver, stomach, pancreas, and esophagus cancers — the sensitivities ranged from 69% to 98%.
The specificity of CancerSEEK was >99%, with a positive score found in only 7 of the 812 healthy individuals who acted as the control population.
Dr Lennon told Medscape Medical News that for the seven healthy individuals who tested positive, those results were presumed to be false positives. “However, it is feasible that they could have an undiagnosed cancer and were asymptomatic. Unfortunately, we don’t have any follow-up on them,” she said.
Determining Tissue of Origin
To determine the tissue of origin in patients with a positive CancerSEEK test, the researchers devised an algorithm that took into account the ctDNA, the level of any of the eight protein biomarkers as well as the 31 other proteins determined by the panels in the immunoassay, and the sex of the patient. For this analysis, esophageal and gastric cancer patients were grouped together, because endoscopy was the optimum follow-up in both cases.
Using this algorithm for 626 cancer patients who scored positive on CancerSEEK, and without using any other information, the researchers were able to localize the origin to two anatomic locations in a median of 83% of patients and to a single organ in a median of 63%.
“Given that driver gene mutations are usually not tissue-specific, the vast majority of the localization information was derived from protein markers,” the researchers write. The accuracy was highest for colorectal cancer (84%) and lowest for lung cancer (39%).
“Such multi-analyte tests would not be meant to replace other non-blood based screening tests, such as those for breast or colorectal cancers, but to provide additional information that could help identify those patients most likely to harbor a malignancy,” the researchers note.
Study Limitations
A key limitation of the study was that patients with known cancers were enrolled.
“Though none of our patients had clinically evident metastatic disease at the time of study entry, most individuals in a true screening setting would have less advanced disease and the sensitivity of detection is likely to be less than reported here,” the researchers acknowledge.
“Our vision is that the test would be used in asymptomatic individuals to screen for cancer, similar to what we’re currently doing with mammography or colonoscopy,” Dr Lennon told Medscape Medical News.
Another limitation of the study was that the multiple-fold cross-validation was not conducted on an independent set of cases for testing.
The original article contains a full listing of the investigators’ relevant financial relationships.
Science. Published online January 18, 2018.
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