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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.