Page 175 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

154 PART II Diagnostic Procedures for the Cancer Patient

RNA seq the history of cancer medicine, treatments have been administered
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As does a microarray, RNA seq measures global gene expression. in a patient-specific and personalized manner. Even in the modern
era, the use of molecular data to guide the therapy of specific indi-
In microarrays the amount of mRNA from an individual gene is
VetBooks.ir measured by the cumulative fluorescence contributed by all cop- viduals with cancer is not entirely novel. The use of specific immu-
nohistochemical or cytogenetic markers to guide the diagnosis
ies of the mRNA transcribed from a given gene (see Fig. 8.5).
RNA seq, however, uses massively parallel sequencing, also known and prognosis has been a critical and routine practice in pathol-
as Next Gen sequencing, to sequence every mRNA in a sample. ogy laboratories for many decades. Furthermore, in some cancers
The sequence allows for identification of the gene from which it molecular markers have been used to guide treatment selection.
was derived. Because all mRNAs are sequenced, this methodol- For example, in human breast cancer a long-standing practice has
ogy allows the investigator to count the number of individual been to define the expression of hormone receptors as a means to
mRNAs. Genes that are highly expressed will have high numbers deliver specific therapeutics that alter downstream signaling path-
of mRNAs. ways. C-kit mutation status has been used in veterinary medi-
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Although RNA seq experiments involve a great deal more cine to direct therapy for mast cell tumors, 2,55 but conflicting data
bioinformatic complexity, they also can provide information not in the literature raise questions about this approach, and more
obtainable using microarrays. This includes the ability to identify investigation is needed. 16
potential mutations in coding regions because sequence informa- Although genomic data is expected to affect patient outcomes
tion is being obtained, and the ability to identify some fusion dramatically, genomic data has been slow to enter the clinic. One
genes that create fusion transcripts. of the first pilot studies incorporating molecular profiling to guide
therapy in advanced cancers was published in 2010. This study
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Personalized Medicine in Cancer faced considerable challenges, but the researchers found that 27%
of 68 patients treated according to molecular profiling recom-
Foundations of Precision Medicine: the Genetic mendations (i.e., PMED) experienced a longer progression-free
Basis of Cancer survival than during the most recent treatment on which they had
progressed. Although it is perhaps intuitively beneficial to incor-
Cancer is a genetic disease that arises as a consequence of the step- porate precise target identification into patient treatment, this
wise accumulation of disruptive mutations in genes that regulate approach still faces significant hurdles, and it remains to be proven
cell life and death. Clonal expansion of cell populations bearing through prospective trials that treatment based on PMED out-
cancer gene mutations fuels the formation of malignant tumors. performs a physician’s choice of treatment. Now, multiple clinical
This genetic model of cancer emerged in the latter 20th century trials incorporating genomics-guided therapy selection are under-
as a product of advances in genetics, evolution, and cancer medi- way to test this very hypothesis. In one such trial, the Stand Up To
cine. Through this mutational process, cancers acquire specific key Cancer and Melanoma Research Alliance Dream Team Clinical
properties, including self-sufficient growth signaling, resistance to Trial, molecularly guided therapy in non-V600E mutant BRAF
growth inhibitory signaling, invasion and metastasis, unlimited metastatic melanoma is being assessed. This is now an ongoing
replication potential, angiogenic signaling, immune modulation, randomized clinical trial.
DNA instability, metabolic dysregulation, and immune evasion. 53 Returning clinically relevant and actionable information based
The genetic model and its downstream phenotypes have since on genomic analysis within a window that enables effective treat-
been validated in many cancer types and provide a framework ment selection is a substantial challenge. Notable hurdles include
for our growing genomic understanding of cancer. The concept those associated with tumor biopsy; sample preservation and
of personalized or precision medicine stems from the previously transport; nucleic acid extraction and quality control; genomic
described genomic underpinning of cancer and its nascent and sequencing infrastructure and platform; data analysis and integra-
emerging complexity. Indeed, truly personalized and genomic tion; generation of digestible genomic reports for physicians, vet-
medicine now seeks to define the genomic drivers of a particular erinarians, and scientists alike; and performance of tumor board
patient’s cancer and match these alterations to specific therapeu- reviews to provide a treatment recommendation. Additional
tics. PMED is ushering in a new era in cancer therapy in which hurdles involve the implementation of precision medicine in the
clinical and translational value are applied to advances in the clinic.
genomic analysis of cancer. The discoveries and tools described In the broadest sense, the clinician seeking a PMED approach
previously have provided new opportunities to tailor cancer ther- for a patient must first ask what data would be most helpful.
apy to the individual molecular characteristics of a specific cancer, “I need new treatment options.” In the setting of a rare tumor or
in a specific patient, to guide diagnosis, prognosis, and treatment a patient with unusual tumor biology, new ideas for therapy may
selection. In many cases these genetic alterations can be matched be needed. In this setting an optimal PMED platform will identify
to specific therapeutic agents as a means to uniquely improve specific drivers of this patient’s cancer biology and propose new
outcomes for patients. Tumor samples and matched germline treatments. For such a clinical question, an optimal PMED plat-
samples (from peripheral blood or cheek swabs) may be collected, form likely will include an analysis of mutations in cancer-associ-
preserved, and then analyzed for genetic alterations in a core set of ated genes, with drug matching to target the presumed aberrant
cancer genes, which ultimately are matched to an individualized mutational targets of the individual cancer. The validation of the
therapeutic prescription. value of this approach has been difficult using conventional clini-
cal trial designs and may demand novel perspectives on evidence
How Precision Medicine Differs from the Current for clinical validation. Because many solid tumors are clinical
problems as a result of metastatic progression (e.g., canine osteo-
Practice of Oncology sarcoma), the optimal PMED platform will derive a list of “shed”
The use of patient-specific information as a means to deliver mutational targets from circulating biofluids (i.e., so-called liquid
PMED is not new to the treatment of cancer patients. Through biopsy) alone or in combination with tumor analysis.