Page 141 - Read Online

Page 2 of 17 Li et al. J Cancer Metastasis Treat 2020;6:14 I http://dx.doi.org/10.20517/2394-4722.2020.27

INTRODUCTION
The past two decades have witnessed a significant paradigm shift in cancer treatment practices based on
increased understanding of oncogenic process. Molecular alterations in specific targets, usually kinases,
can result in constitutive activation of the targets and their downstream signaling activities, leading to
unchecked cellular proliferation, resistance to cell death, promotion of angiogenesis, and evasion of
[1]
immune surveillance, all of which are hallmarks of cancer . Matching a patient‘s cancer with a therapeutic
agent designed to specifically address the underlying molecular alteration has become the cornerstone
[2]
of precision oncology . Alongside the rapid advancement in cancer biology, the technical revolution of
molecular diagnostic platforms, particularly high-throughput next generation sequencing (NGS), has
made comprehensive profiling of tumor tissue and liquid biopsy samples feasible and affordable, not only
for scientific interrogation of cancer genome, transcriptome, and epigenome for target discovery and
[3,4]
mechanistic characterization, but also for patient selection and stratification in the clinical setting .
Several large-scale cancer sequencing efforts involving thousands of patient samples have not only
confirmed relatively frequent molecular alterations such as mutations in Kirsten rat sarcoma gene (KRas),
tumor protein p53 (TP53), and epithelial growth factor receptor (EGFR), but also revealed, in many cases
for the first time, low- and ultra-low frequency mutations that otherwise had been difficult to detect
without high-throughput deep sequencing in large number of samples. For instance, in a study by Armenia
and colleagues , whole exome sequencing data from 1,013 cases of prostate cancer (680 primary and 333
[5]
metastatic tumors) and matched germline were assembled and uniformly analyzed. The study identified a
total of 97 potential oncogenic genes, about 70 of which had not been previously implicated in the disease.
The majority of these newly identified mutated genes were found in less than 5% of the 1,013 cases. In
statistical terms, this is known as a “long-tail” distribution; in other words, some genes are mutated in
comparatively many cases, but many genes with oncogenic mutations are only found in few cases. This
“long tail” distribution also suggests that additional discovery of rarely mutated oncogenic drivers is likely
to continue along with the dramatic increase in the number of tumors sequenced. A similar “long tail”
distribution has also been observed in other tumor types, such as lung adenocarcinoma , head and neck ,
[7]
[6]
[8]
and breast . Arguably, this “long tail” phenomenon exists in most, if not all, tumors. Interestingly, some
of the same “long tail” genes are found across many distinct tumor types, suggesting common underlying
mechanism of tumorigenesis [9,10] .

The United States Food and Drug Administration (FDA) and other regulatory agencies generally approve
anti-cancer drugs on the basis of efficacy and safety data obtained from clinical trials with patients of
a particular tumor type. An example of this “one target, one tumor type” is the FDA’s 2001 landmark
approval of imatinib, a kinase inhibitor of Abelson tyrosine kinase (c-ABL), for the use in treating BCR-
ABL positive, chronic myeloid leukemia (CML), which heralded a new era in approval of drugs for single
indications with characteristic gene alterations . A decade later, crizotinib, a small molecule tyrosine
[11]
kinase inhibitor (TKI) of mesenchymal-epithelial transition factor (c-MET), anaplastic lymphoma kinase
(ALK), c-ros oncogene 1 (ROS1), and recepteur d’Origine Nantais (RON), received accelerated approval
for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with
EML4-ALK fusion. The approval was based on two single-arm trials demonstrating objective response rates
[12]
(ORRs) of 50% and 61% and median response durations of 42 and 48 weeks .

Even with the life-changing success of the “one target, one tumor type” approach, it is important to
remember that cancer is a complex disease. On the one hand, tumors that originate from the same tissue or
organ can be segmented into multiple subtypes, each of which can be defined by differentiating molecular,
pathological, and etiological features [13-15] . On the other hand, some distinct and seemingly unrelated
tumors of different histology can be traced back to a common dominant genetic defect that can be
exploited for therapeutic intervention by the same targeted agent, regardless of the histological tumor type