January 18, 2018

expert reaction to paper on potential non-invasive blood test for multiple types of cancer

A new study, published in Science, describes a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA.

Dr Mangesh Thorat, Deputy Director (Clinical) of the Barts Clinical Trials Unit, Centre for Cancer Prevention, Queen Mary University of London (QMUL), said:

“This looks promising but with several caveats and a significant amount of further research is needed before we can even contemplate how this might play out in screening settings. This is only a case-control study, and therefore needs further evaluation in large cohorts more representative of general population where such screening might be introduced.

“The sensitivity of the test in stage I cancer is quite low, about 40%, and even with stage I and II combined it appears to be around 60%. So the test will still miss a large proportion of cancers at the stage where we want to diagnose them. The proportion of common cancers (breast, lung, colorectal) detected is again not as high as other, rarer cancers. This may mean that a screening programme has to test a very large number of individuals to detect one cancer.

“This test looks to have a high specificity (although this needs to be tested further in a large population cohort) which could lower the likelihood of false positives, a key potential issue with screening aside from cost and uptake. However we won’t know the extent of over-diagnosis until a lot more data becomes available, but the nature of this test again suggests a potential to keep this issue to a minimum.

“The new issues it might throw up though are: it looks like it does a good job of predicting the cancer site, but in about a quarter of cases it may not be able to do so. Lot of imaging may be required to further diagnose the cancer, and we may still fail to identify the site, which creates an issue of what to tell these otherwise healthy individuals.”

Prof. Nicholas Turner, Professor of Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said:

“This paper is a step along the way to a possible blood test to screen for cancer, and the data presented is convincing from a technical perspective on the blood test. Potentially we can use a blood test like this to screen for undiagnosed cancers in asymptomatic people, and identify cancers at a point where they are more curable.

“However, the study does not support use of the blood test outside research studies, as it has not shown yet whether the blood test has the characteristics required for population screening, nor whether the blood test will improve outcome. There was a 1% “false positive” rate with the blood test. Although it is unknown if these were really false positives, perhaps those people had undiagnosed cancer, a false positive rate of 1% could be quite a concern for population screening. There could be a lot of people who are told they have cancer, who may not have it. We can only learn about how much this is, or is not, a problem through larger studies. Much larger studies will also be needed to address whether using these blood tests can help improve survival rates.

“We need larger population studies to assess blood tests like this, and it is important that we wait for the results of these studies before people consider having the tests.”

Prof. Paul Pharoah, Professor of Cancer Epidemiology, University of Cambridge, said:

“There has been a lot of interest in using so called liquid biopsies as a relatively non-invasive way to detect cancer.  The DNA from cancer cells is mutated and this mutated DNA can get into the blood stream (circulating tumour DNA, ctDNA) and be detected by sequencing the DNA in blood.  There have been many studies demonstrating that this can detect cancers at the time of diagnosis or can be used to detect cancer relapses.  However, there is a question about whether or not such a test will be able to detect cancer before it becomes symptomatic (i.e. at an early stage) and therefore be useful as a cancer screening test.

“The use of protein biomarkers for detecting cancer has been around for many years. While there are many that have proven useful in the diagnosis of symptomatic cancer, none have been shown to be useful for detecting cancer in people without symptoms (i.e as a screening test), with perhaps the exception of PSA for detecting prostate cancer.

“This group has developed a test that has combined ctDNA analysis with an analysis of protein biomarkers as a method to detect cancers. The authors used this new, combination test on blood samples from just over 1,000 clinically diagnosed patients with one of eight cancers – ovary, liver, stomach, pancreas, oesophagus, colorectal, lung, or breast  – and found that the cancer was successfully identified in about 70% of cases with false positive tests in 1% of individuals without cancer (specificity of 99%).

“This is a reasonable sensitivity and specificity, but there are some major caveats. Firstly, 80% of the cancer evaluated were stage 2 or stage 3 cancers (fairly advanced).  Demonstrating that a test can detect advanced cancers does not mean that the test will be useful in detecting early stage symptomatic cancer, much less pre-symptomatic cancer.  The sensitivity for the stage 1 cancers in the study was only 40%.

“Second, the study is somewhat unclear about how the relevant cut-offs for the test were identified in order to determine a positive and negative test.  It seems that the results from some of the cases and controls evaluated in this study were used for that purpose.  If so, the results are bound to overestimate the effectiveness of the test and an independent validation data set would be needed to demonstrate the real test performance.

“Third, the contribution of the protein biomarker component of the test to the sensitivity and specificity is not described.  Given that these protein biomarkers have not, in general, proved useful for early detection, if their contribution to the performance of this test is substantial, it would question the likely utility of the test in clinical practice.

“Before seeing the results of this test I regarded liquid biopsy as a potentially useful approach for the early detection of cancer.  Having seen these results I still regard liquid biopsy as a potentially useful approach for the early detection of cancer.  In other words, I do not think that this new test has really moved the field of early detection very far forward – it remains a promising, but yet to be proven technology.”

* ‘Detection and localization of surgically resectable cancers with a multi-analyte blood test’ by Cohen et al. published in Science on Thursday 18 January.

Declared interests

Prof. Nicholas Turner: No conflicts of interest.

Prof. Paul Pharoah: No conflicts of interest.