Illumina has created a
splash by announcing the formation of a new company, GRAIL, to develop a ‘pan-cancer screening test’ using
patient blood samples. The aim will be to use Illumina's sequencing firepower and
expertise to develop tests to analyse circulating nucleic acids – DNA and
possibly also RNA – in the blood, with the goal of detecting circulating tumour
(ct) DNA in otherwise asymptomatic patients.
The basic premise seems reasonable – cancers detected early
in their development are less likely to have metastasised and are therefore
easier to treat successfully. However, there are many technical challenges that
will have to be managed and important questions surrounding the clinical
validity and utility of tests. In addition, concerns that screening could lead
to over-diagnosis and over-treatment should be addressed.
There is currently little (if any) evidence that measuring
ctDNA in blood can diagnose asymptomatic patients. One company in the United
Genomics, began marketing a test in September last year as a ‘cancer
stethoscope’ for those patients determined to be at high risk of developing
cancer (for example, smoking or family history). They received an untitled letter from the US Food and Drug
Administration (FDA) for their efforts, effectively
a warning that although they would not be subject to official action by
the FDA, they should change their marketing approach, given the lack of
evidence that these tests are clinically relevant.
Clinical utility and
Among the questions that the GRAIL researchers will have to
contend with are:
- Is the ctDNA test an accurate reflection of clinical reality? What
does the presence of ctDNA in the blood represent, particularly in an
asymptomatic patient? Does it represent a tumour that could cause the
patient harm, or a slow growing malignancy that is unlikely to need
treatment? What if the presence of ctDNA cannot be explained given the
- Threshold, sensitivity and specificity of tests. How much earlier
can ctDNA tests detect a cancer compared with conventional methods? How
much of a clinical advantage will this confer to the patient? Current
ctDNA tests/assays have been developed for use in patients whose cancers
have already been diagnosed using other methods. The tests need to be
specific enough to determine the driver mutations in the cancer as well as
its tissue of origin, complicated by the fact that certain genes are
implicated in more than one cancer e.g.
KRAS mutations are found in some pancreatic and colon cancers, less
commonly in other cancers. Understanding this information will require that
extensive data on the genetics of cancers are freely available.
- Are other technologies sensitive enough to confirm a ctDNA
diagnosis? Tumours diagnosed via ctDNA tests in asymptomatic patients
are likely to be small if discovered early. It is likely that some of
these tumours will be hard to detect (or undetectable) using currently
available scanning technologies, making clinical follow up difficult in
- Potential burden on the health system. There is a danger that
over-diagnosis and over-treatment could lead to a burden on the health
system, through spending money on costly further investigations and
interventions, to the psychological impact on patients. A balance will
need to be reached between managing the benefits of early diagnosis and
treatment versus the risks of over-treatment.
- What will the effect be on survival rates? There is still much
debate about the benefits of screening for different forms of cancer. For
example, while screening for breast cancer using mammography detects some
cancers at an earlier stage, many studies have demonstrated only a modest
decline in rates of advanced cancers. For example, extensive
clinical trials will be required to determine if patients whose cancers
are diagnosed earlier using this technology have better survival outcomes
than patients who are diagnosed via conventional methods.
- Cost. For this type of technology to be used in NHS cancer
services, extensive cost-benefit analyses will be required to determine if
this approach saves money in the long run. Developing tests that work is
one thing, developing cheap tests that work is quite another.
The bottom line
In short, this is going to take a
lot of work to take the tests to clinical practice, particularly validating
techniques in thousands of patients, including clinical follow up. However,
although the challenges are extensive, they are not insurmountable. It will be
interesting to see how the expertise and clout of Illumina and GRAIL rise to
the challenge – if they can deliver, the changes to the way cancer is diagnosed
and managed will be profound.