09 APRIL 2018
Physicians
struggle to identify which patients are likely to respond to a recently
approved therapy.
A landmark cancer drug approved last year
seemed to herald a long-anticipated change in the treatment of some tumours:
with medicines selected on the basis of molecular markers, rather than the
tissue in which the cancer first took root.
But clinicians and researchers are struggling
to put that theory into practice. Although the drug itself works well in a
variety of tumour types, some of the tests used to identify the molecular
markers, it turns out, do not.
On 15 April at the American Association for
Cancer Research annual meeting in Chicago, Illinois, researchers and
representatives from the US Food and Drug Administration (FDA) will discuss how
best to tackle the situation. “If you get a false negative result, you’re not
going to give that patient the therapy, which is terrible,” says Zsofia
Stadler, an oncologist at the Memorial Sloan Kettering Cancer Center in New
York City. “That’s why there’s such a debate.”
The drug in question, pembrolizumab
(Keytruda), works by firing up the body’s immune responses against
tumours. First approved by the FDA in 2014 to treat melanoma, it has since been
given the go-ahead to treat a handful of other cancers, including lung cancer .
But last year, researchers reported that
patients whose tumours had a disabled DNA-repair system also responded to the
drug, regardless of where the tumour originated1. Damaged DNA
can yield mutant proteins, which the immune system could target as potential
invaders. Scientists think this increases the chances that immune cells
unleashed by pembrolizumab will find and attack the tumour.
Mixed results
In May 2017, the FDA allowed pharmaceutical
giant Merck of Kenilworth, New Jersey, to market pembrolizumab to people with
advanced-stage cancer who had any solid tumour with that particular DNA-repair defect. “This is
absolutely a breakthrough approval,” says Razelle Kurzrock, an oncologist at
the University of California, San Diego. “We have seen some dramatic responses
in our patients.”
But the three kinds of tests commonly used to
look for the DNA damage that arises from that defect can produce conflicting
results, says Heather Hampel, a genetic counsellor at Ohio State University in
Columbus. One relies on PCR, a process that amplifies specific regions of the
genome; a second looks for certain proteins; and a third relies on DNA
sequencing. “Which is the best? Is any positive on any test sufficient?” Hampel
says. “Does that mean you should try them all? No one wants to miss a patient
who might benefit from pembrolizumab.”
And there are signs that some of the tests
might work better in certain tissues than others, says Shridar Ganesan, a
physician and cancer researcher at the Rutgers Cancer Institute of New Jersey
in New Brunswick. PCR assays, for example, look for changes in certain regions
of DNA called microsatellites. Particular microsatellites might be more prone
to damage in some tissues than others, he says.
Stadler notes that the degree to which the DNA
changes may also vary from tissue to tissue: colon cancers tend to accumulate
many mutations, whereas tumours in the adrenocortex generally have fewer. That
can lead to a false negative result in tissues with fewer mutations, she says.
Complicated future
Similar complications might arise for some
future tissue-agnostic drug approvals, particularly those based on DNA-repair
defects. This could include drugs called PARP inhibitors, which are currently
approved in the United States for breast and ovarian cancers caused by
mutations in either of two genes involved in DNA repair: BRCA1 or BRCA2.
Researchers are looking at whether PARP inhibitors might also work in any solid
tumour that carries similar DNA-repair defects, even if they aren’t caused
by BRCA1 or BRCA2 mutations. There are
multiple tests available to identify the patterns of DNA damage in such
tumours, says Hampel.
Evidence has also been building that the
overall number of mutations in a tumour could indicate how likely it is to
respond to immunotherapies such as pembrolizumab. Tests for this might also be
complex, notes Stadler.
Eventually, some of these issues will be
ironed out, says Michael Overman, an oncologist with the University of Texas MD
Anderson Cancer Center in Houston, as researchers gather data on which tests
work best in which cancers. But the FDA was wise to move forward with the
approval rather than wait for more evidence to sort out the issues with the
molecular marker tests, he says. “There are still a lot of open questions, but
the therapy works exceptionally well,” he says. “It was the right thing to do.”
Nature 556, 161-162 (2018)
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