field notes - the journal of precision medicine · pediatric center for precision oncology at texas...
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FIELD NOTES
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Early this year, backed by a 3-year, $1.5-million grant from the Sohn Conference Foundation, Columbia
University Medical Center announced plans to provide genome sequencing to all children in New
York City diagnosed with high-risk cancers. The initiative is an outgrowth of Columbia’s Precision
in Pediatric Sequencing (PIPseq) program, launched in 2014—the first program nationally to
conduct sequencing in all of its pediatric cancer patients on diagnosis. “We now have the capability
and the financial backing to have a city-wide and regional impact,” said Andrew Kung, Columbia’s
chief of pediatric hematology, oncology, and stem cell transplantation and PIPseq’s director.
In any case, the rate of actionable alterations is
likely higher in adult cancers than pediatric
ones because adults have more mutations, said
Parsons – particularly in druggable regions
such as genes coding for protein kinases. More
targeted cancer therapies have been developed
for adults than for children. On the other
hand, the logistics of clinical sequencing are
currently more challenging in adult cancers,
said Kung, simply due to the volume of cases
that molecular tumor boards would have to
handle. Somehow that process will have to be
streamlined, he said.
But even when sequencing identifies an
actionable mutation, patients don’t always
get the matched drug, said Katherine Janeway,
senior physician in pediatric oncology at
Dana-Farber / Boston Children’s Cancer and
Blood Disorders Center. Sometimes, the drug
is only available through a clinical trial and the
patient is either ineligible or too ill – or even
too well – to enroll. For young children,
special formulations – not pills – may be
needed. “Clearly there are pieces of this that
we don’t yet understand,” she said.
Janeway spearheaded a multicenter trial of 100
patients, also published in January, that found a
30% rate of actionable alterations but found that
the percentage of cases in which sequencing has
some clinical implication was closer to 40%.
She is now leading a larger trial, of 825 children
across 12 institutions, that will examine whether
receiving a targeted therapy identified through
sequencing actually improves outcome. “That
hasn’t been demonstrated in this patient
population yet,” she said.
In Kung’s experience at Columbia, sequencing
helped clinical decision-making in some
two-thirds of cases – sometime by identifying
therapies unlikely to work. For example, it
steered Kung’s team away from two bone
marrow transplants. “I think as you look at
next generation sequencing as a diagnostic, the
value has to expand beyond the identification
of actionable alterations,” Kung said.
Columbia’s sequencing protocol involves
exome sequencing of tumor cells and normal
tissue as well as RNA sequencing of tumor
tissue; its lab can pinpoint not just mutations,
but also translocations and copy number
variations. “We’re finding that about half of
all our clinically impactful findings come from
RNA analysis,” he said. Some other programs
limit sequencing to selected gene panels,
which may be more palatable to payers,
Kung said. But they may not position the field
to gain as much as it can from sequencing.
“There’s no perfect platform,” he said. “In
the setting of limited resources and limited
coverage, we need the sweetspot between
affordability and sensitivity.
Clinical Conundrumsby Alla Katsnelson, Ph.D
Alla Katsnelson, Ph.D, is an independent science writer
and editor based in western Massachusetts.
S everal single-institution experiences
over the past few years have started
to show the value of sequencing
for specific cancer populations.
Now, efforts are efforts hearing up to try to
aggregate cancer sequencing data more broadly
and start its evaluate outcomes and impact
in the clinic. In the past several months,
several US medical centers have reported that
sequencing in pediatric cohorts with multiple
types of high risk cancers yielded about a 30-
45% rate of potentially relevant alterations,
including 10-20% of patients with mutations
in genes or pathways for which targeted drugs exist.
What exactly the cancer community means
by “actionable” is still somewhat up for
debate, said Will Parsons, Director of the
Pediatric Center for Precision Oncology at
Texas Children’s Cancer Center, which in
January published results of a pilot study
sequencing 150 children. Pathogenicity is
well-defined for germline mutations, but
much less so for ones in tumor cells. “A
mutation found in one type of cancer might
mean something different in another type
of cancer,” Parsons said. Efforts such as the
Clinical Genome Resource, a National
Institutes of Health-funded consortium,
are working on standardizing definitions of
actionability, “so at least everyone is speaking
the same language,” he added.