NcXHF

CARROLL, RAETZ, AND MEYER
most are treated with surgical excision, but 50% of cases also
show an ALK rearrangement, most commonly with TPM3
and TPM4. Finally, the majority of familial neuroblastomas
and, as described above, 8% to 10% of sporadic cases have
ALK activating point mutations. Another 2% to 3% of sporadic
cases have ALK amplifıcation. Early phase clinical trial
experience with the ALK inhibitor crizotinib (originally designed
as an MEK inhibitor) shows a remarkable response in
patients with refractory ALCL (eight of nine patients) and
IMT (three of seven patients), but less activity in ALKactivated
neuroblastoma (one of 11 patients). 22 These encouraging
results, in part, led to the development of the
currently open Children’s Oncology Group (COG)
ANHL12P1 randomized phase II trial for newly diagnosed
ALCL using brentuximab vedotin or crizotinib in combination
with chemotherapy.
Successful introduction of imatinib into conventional chemotherapy
for Ph ALL has had a profound effect on survival,
and this success has been followed by the investigation
of the second-generation tyrosine kinase inhibitor, dasatinib
in combination with chemotherapy. 1,23-25 Most children can
now be successfully cured without the use of stem cell transplantation.
Perhaps even more importantly from a population
base effect standpoint, approximately 10% of children
with standard-risk ALL and 27% of young adults with ALL
have “Philadelphia-like” (Ph-like) ALL that share a gene expression
profıle like Ph ALL but lack the BCR-ABL1 fusion
protein. These cases often share IKZF1 deletions, CRLF overexpression,
and have a poor prognosis. Recent large-scale sequencing
efforts have documented that the overwhelming
majority (91%) of samples from patients with Ph-like disease
carry kinase-activating alterations. 26 In particular, 12.6% of a
recent series of such patients had fusions that would respond
to ABL1 inhibitors such as imatinib (e.g., ABL1, ABL2,
CSF1R, and PDGFRB fusions) and more than one-half
had JAK-STAT pathway lesions such as CRLF2 rearrangements
with and without JAK2 mutations and other JAK-
STAT alterations. In vivo and in vitro models have confırmed
response to ABL1 inhibitors and JAK1/2 inhibitors, respectively.
26-28 There have now been numerous anecdotal reports
of patients with ABL1 class fusions showing dramatic
responses to tyrosine kinase inhibitors. 29,30 As a result, COG
plans to open a prospective trial comparing the outcome of
patients with ABL1 fusion treated with a combination of dasatinib
and chemotherapy with a historic control of recently
treated patients (chemotherapy alone).
These two trials for ALK-positive ALCL and Ph-like ALL
(as well as the previous two COG studies for Ph ALL) illustrate
the rapid integration of new agents for newly diagnosed
patients in a nonrandomized fashion. Preclinical data indicate
that the targets are essential for tumorigenesis and early
experience (some anecdotal for Ph-like ALL) shows spectacular
clinical effıcacy. Given the strong biologic rationale and
preclinical data for certain targeted agents a randomized trial
may not always be feasible, and in this case the two trials differ
remarkably in technical approaches. Simple ALK staining
indicates ALK activity, whereas, expression profıling is being
used to detect Ph-like ALL followed by a stepwise targeted
approach to identify cases appropriate for treatment with tyrosine
kinase inhibitors.
TUMOR HETEROGENEITY AND EVOLUTION
In addition to the relative dearth of effective targeted agents,
one of the biggest barriers to effective implementation of
clinical sequencing in oncology is tumor heterogeneity. 31 Indeed
many home grown sequencing efforts have not accounted
for this property of cancer populations. In contrast
to most adult cancers, pediatric tumors appear to have less
genomic instability with the possible exception of osteosarcoma.
Thus, endogenous sources of ongoing mutational frequency
throughout tumor evolution may be less of an issue in
childhood cancer; although, exogenous sources of genome
instability through cytotoxic therapy remains a possibility.
There is no doubt, however, that multiple subclones exist
within a given tumor and subclones may be geographically
distinct so that a single biopsy may not capture the full mutational
spectrum of a given tumor. In addition, human tumors
have been shown to follow a branched chain model in
which certain mutations, which are typically acquired early,
are truncal drivers, whereas, as others appear to drive subclones
(branch drivers). Targeting truncal drivers may provide
more clinical benefıt. Last, there is evidence to suggest
that clones may compete with one another so that targeting
one may lead to emergence of the competitor. Conversely,
clones may exist in a symbiotic relationship so that targeting
one may have a collateral effect on regression of another. All
these potential confounding evolutionary features of cancer
progression require consideration when designing sequencebased
therapeutic interventions.
Acute leukemia provides a convenient model to study tumor
evolution considering the feasibility of serial tumor sampling.
However, the use of cell-free DNA in the circulation is
proving to be a potential option of monitoring solid tumors
where access is challenging. As mentioned above, studies
have generally showed a complex, nonlinear evolutionary
history during which mutations may be acquired independently.
32 Examination of diagnosis and relapse pairs frequently
reveals outgrowth of a minor subclone that can be
backtracked to diagnosis (Fig. 1). These small subclones may
not be detected by conventional NGS approaches. These
studies have shown enrichment of genetic alterations (e.g.,
deletions of IKZF1, MSH6, EBF1, BTG1, and TBL1XR1, and
mutations of NT5C2 and RAS pathway mutations) that account
for resistance to conventional chemotherapy. 17-19,33,34
Thus, the outgrowth of these clones is profoundly shaped by
the selective forces of the chemotherapy applied. Earlier detection
and/or monitoring for emergence of subclones may
allow preemptive alteration of conventional agents and/or
targeted therapy to prevent overt relapse.
Although targeted therapy has had a profound effect on
disease regression for adult tumors like advanced BRAFmutant
melanoma and ALK fusion non-small cell lung cancer,
the benefıcial response is short lived with emergence of
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