EARLY Cancer Detection with a Blood Test – Too Many False Positives!

Detecting cancer cells or cell fragments in blood to achieve early detection has long been a desired goal and an area of intensive research. “Liquid / fluid / blood biopsy” is already used with FDA approval to identify cancer-related gene mutations that may be targets for targeted drugs in patients who already have a cancer diagnosis. However, it has not yet matured enough for early detection in people without a cancer diagnosis and has not been approved for this use. Striking studies on the use of liquid biopsies in cancer were presented at the American Society of Clinical Oncology (ASCO) 2021 Annual Meeting.

New data on the blood test developed by the biotechnology company GRAIL, called Galleri, showed that it detected a cancer signal across a very broad range of cancer types and that more than half of the cancers detected were at an early stage, when they are often treatable.

The Galleri test was tested in the clinical trial called RATHFINDER; however, the results show more false positives than true positives, which could be a problem if it were applied to the entire population.

New results

Last month, Grail announced that the test’s first clinical launch in the United States was about to take place. The RATHFINDER trial enrolled 6662 people over the age of 50 who did not have active cancer but had various risk factors. Of this group, 6629 were evaluated.  

An interim analysis of the results was presented at the meeting by Dr. Tomasz M. Beer. Beer said that a cancer signal was detected in 92 of 6629 people (1.4%), and that diagnostic resolution for cancer had been achieved in 65 of these individuals as of March 2021; in other words, the test ultimately called these 65 people positive for cancer.

Among these 65 people, “true-positive” results were found for 29 patients, and their cancer diagnoses were confirmed. “False-positive” results were obtained for 36 people.

Beer said, “36 participants were classified as false-positive based on the initial diagnostic workup, and their final status will be defined after a full 12-month follow-up. Of the 63 patients called positive by the blood test, 90% had at least one imaging test. The median number of imaging tests was 1.26, and 88% of patients underwent minimally invasive procedures such as biopsy”.

There are more false positives than true positives

As the study’s discussant, Dr. Max Diehn, an associate professor of radiation oncology at Stanford University in California, emphasized that false positives outnumbered true positives and said, “there were a significant number of invasive procedures that could harm these false-positive individuals who did not have cancer”.

Diehn also pointed out that most true positives were not solid (organ) tumors but lymphoid malignancies (lymphomas) and that it was not known whether early detection of lymphoid malignancy had a clinical benefit: “Most of the tumors were lymphoid, and because we generally consider them systemic diseases at diagnosis, it is unclear whether discovering them earlier would provide a survival benefit.”

Detection rate

In his presentation, Beer said that in this interim analysis, the overall cancer detection rate was 1.4% and the overall positive predictive value (PPV) for cancer detection was 44.6%.

Note: Positive predictive value is the probability that subjects with a positive screening test actually have the disease. Negative predictive value is the probability that subjects with a negative screening test actually do not have the disease.

For participants with additional cancer risk factors (such as a smoking history, genetic predisposition or a cancer history more than 3 years earlier), PPV increased to 57.1%, but it fell to 30% for participants without these risks. However, Beer noted that the study was not designed for a statistical comparison between these two groups.

More than half of the newly detected cancers were at early stages, when cancer is generally easier to treat. Of participants newly diagnosed with cancer, 57% were found to have stage 1-3 cancer and 39% stage 1-2 cancer. Beer ended his presentation by emphasizing that participants would continue to be followed. “We will determine the incidence of cancer diagnoses in all participants within 12 months after the initial blood draw, during which the specificity and negative predictive value of the multicancer early detection test will be assessed.”

Beer also said in a press release: “The interim results of PATHFINDER show that a routine blood test can detect many different cancers even before symptoms appear, an approach with significant potential advantages. Most importantly, it can detect cancers for which there is no recommended screening test today, so two-thirds of cancers are not screened. These results are an important step toward expanding early detection to many more cancer types.”

Strengths and weaknesses of early cancer detection with liquid biopsy

Deihn noted that the study had both strengths and some limitations, and that some questions remained unanswered.

“The strengths of this study are that its large, prospective design demonstrates the feasibility of implementing a multicancer early detection test in real time. The time to diagnostic resolution was relatively short, and there was a significant subset of detected stage 1 and 2 solid tumors.”

Limitations include incomplete follow-up and the lack of sensitivity and specificity assessment. Deihn says that several key questions remain unanswered. “Could the cases without diagnostic resolution, which account for nearly a third of cases, be enriched for false positives? If so, would that lower the positive predictive value? We await the final results to assess this.”

Deihn also said it was not known whether a large number of patients with negative test results would develop cancer in the long term. “This is important for assessing the test’s sensitivity, especially for early-stage solid tumors.”

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