Download Signaling Pathway Biomarkers in Gastrointestinal Malignancies

Signaling Pathway Biomarkers in
Gastrointestinal Malignancies
HGF
EGFR/EGFR
MET
HER2/EGFR
Gab1
RAS
Shp2
Shc
Grb2 SOS
PI3K/AKT
Pathway
RAF
MEK
ERK/
MAPK
PI3K/AKT
Pathway
Personalized Medicine May Help Guide
Treatment Planning
• In medical practice, clinicians typically prescribe medications according to general
information about what might be effective for patients based on product labeling;
this trial-and-error approach is in contrast to the goal of personalized medicine1
• From the FDA’s perspective, “personalized medicine promises to increase
benefits and reduce risks for patients by improving both the safety and
efficacy of medical products”
• For any individual patient, the actual safety and effectiveness of a treatment may
vary as a result of genetic and environmental factors, as well as the interaction of
these factors
• Advances in diagnostic tools used to measure or evaluate an indicator of a normal
biological process, pathogenic process, or response to a therapeutic intervention
may permit clinicians to individualize or personalize treatment for patients by
identifying those who may or may not benefit from a particular treatment plan 1,2
Before personalized medicine approach
After personalized medicine approach
or
Genotype
Normal gene
Mutated gene
The top panel illustrates an example in which patients get the same drug, regardless of genotype.
The lower panel illustrates a personalized medicine approach in which treatment selection is
based on specific patient genotype (eg, presence of mutated gene).1,3
Biomarkers in Gastrointestinal Malignancies
That May Have Clinical Utility
• Aberrant signal transduction due to a variety of mechanisms drives carcinogenesis
by promoting abnormal cell growth, proliferation, invasion, angiogenesis, and
disrupting apoptosis4
• Identification of particular molecules or biomarkers (proteins and genes) within
specific signaling pathways may provide information that may aid in cancer
detection, diagnosis, or may inform or guide treatment plans5
• A biomarker is a characteristic that can be scientifically measured and evaluated to
serve as an indicator of a normal or pathogenic biologic process and/or a
response to a specific treatment plan1
• Several biomarkers have been identified or are being investigated in various
gastrointestinal malignancies6–9
• HER2, EGFR, VEGFR, mTOR, MET, PDGFR, and IGFR are putative biomarkers in
esophagogastric adenocarcinoma; while FGF2, VEGF, EGFR, HER2, MET, PI3K,
phospho-Akt, and RAS/RAF are potential biomarkers in gastric cancer
HER2=human epidermal growth factor receptor 2; EGFR= epidermal growth factor receptor;
VEGFR=vascular endothelial growth factor receptor; mTOR=mammalian target of rapamycin;
MET=mesenchymal-epithelial transition factor receptor; PDGFR=platelet-derived growth factor
receptor; IGFR=insulin-like growth factor receptor; FGF2=fibroblast growth factor-basic; CA
19-9=carbohydrate antigen 19-9; MUC1=mucin 1; SMAD4=mothers against decapentaplegic
homolog 4; HENT1= human equilibrative nucleoside transporter 1
• In pancreatic cancer, CA 19-9, a prognostic serum biomarker indicates disease
recurrence after surgical resection; MUC1 and mesothelin expression are under
investigation as prognostic biomarkers that predict survival, and SMAD4 levels
have been reported to be associated with disease progression10
• The mutational status of BRAF, KRAS, NRAS, and PTEN/PI3KCA are under
investigation in mCRC11
• The presence of aberrations such as gene amplification or protein overexpression in
MET is a negative prognostic indicator in gastric cancer8,9,12
• Other biomarkers, such as c-Kit, a growth factor receptor present in gastrointestinal
stromal cell tumors (GIST), have been shown to be a predictive biomarker for
response to specific treatment plans13
HGF
EGFR/EGFR
HER2/EGFR
MET
Gab1
RAS
Shp2
Shc
Grb2
SOS
RAF
PI3K/AKT
Pathway
MEK
ERK/
MAPK
PI3K/AKT
Pathway
Biomarkers in Gastric Cancer
• Multiple molecular abnormalities have been identified in gastric carcinomas,
resulting in aberrant signaling that promote carcinogenesis7
• Aberrant activation of HER2 or MET stimulates downstream signaling through PI3K/AKT,
key proteins in the regulation of genes that affect cell survival and apoptosis, and
through the RAS/RAF pathway, which promotes cell growth and proliferation7,14
• HER2 is overexpressed in 12–22% of gastric cancers and in 20–30% of
esophageal adenocarcinomas6,14
• While evidence shows that HER2 may act as both a prognostic and predictive
biomarker for these malignancies, evidence indicates that HER2 is primarily a
predictive biomarker in gastric cancer15
• MET, is a receptor tyrosine kinase, whose ligand is hepatocyte growth factor (HGF)9,16
• In some malignancies, abnormal stimulation of MET promotes transformation,
tumor invasion, progression, metastases, and the epithelial-mesenchymal transition
that accompanies some tumors
• Aberrant signaling through MET can occur as a result of receptor overexpression,
upregulated production of HGF, or amplification of the MET gene16
• Mutations in the MET gene can lead to constitutive activation of the receptor
and promote proliferation and anti-apoptotic signaling17
• Cross-talk between MET and other receptors, including EGFR, HER2, and HER3,
can also lead to constitutive activation of the PI3K/AKT pathway7
• Overexpression of the MET protein and amplification of the MET gene has
been observed in 26-74% and 2-23% of gastric cancers, respectively17-25
• Investigators have examined the relationship between aberrant MET and
different characteristics of gastric carcinomas such as depth of tumor invasion,
lymph node metastasis, stage of disease, and poorer survival
• When MET protein expression was assessed by immunohistochemistry (IHC), 14% of
samples in one study showed no MET protein expression; immunoreactivity ranged from
weak to strong in tumor cells of the remaining tumors; normal gastric mucosa weakly
expressed MET protein26
• Aberrant MET can be identified in a majority of esophageal adenocarcinomas, many
colorectal adenocarcinomas, and high MET expression may be associated with
development of metastases and poorer outcomes13
• Other biomarkers under investigation in upper gastrointestinal malignancies
include VEGF, SMO, and mTOR, which have been studied in patients with
metastatic gastric cancer16
HGF
EGFR/EGFR
HER2/EGFR
MET
Gab1
RAS
Shp2
Shc
Grb2
SOS
RAF
PI3K/AKT
Pathway
MEK
ERK/
MAPK
PI3K/AKT
Pathway
Biomarkers in Pancreatic Cancer
• Pancreatic cancer is extremely aggressive, and it remains a leading cause of
cancer-related deaths worldwide27
• CA 19-9 has long been thought to inform behavior of pancreatic carcinomas
• Tumor suppressor genes that have been implicated in the pathogenesis of
pancreatic cancer include p53, p21, and SMAD4, and activating mutations in
oncogenes including KRAS and cyclin D—these mutations occur in up to 75%,
60%, 55%, 90%, and 82%, of pancreatic cancers respectively
• MUC1 and mesothelin expression, as measured by IHC, are prognostic biomarkers in
pancreatic cancer that predict survival9
• Furthermore, the molecular markers HENT1, ERCC1, and RRM1 may predict response
to a specific antimetabolite therapy
• Correlative analysis of blood based biomarkers from patients with advanced pancreatic
cancer identified statistically significant prognostic markers for overall survival, including
Ang2, CRP, ICAM-1, IGFBP-1, and TSP-2 28
• MUC1 is expressed in >60% of pancreatic adenocarcinomas.29-35 Studies have
shown that SMAD4 is inactivated in ≥30% of pancreatic ductal adenocarcinomas.
KRAS has been shown to be mutated in ~80% of pancreatic cancers.
• Mutations in KRAS are common in pancreatic cancers; these gain-of-function
mutations result in inappropriate stimulation through downstream signaling
cascades that ultimately promote tumor initiation, progression, proliferation,
and invasion36
• In addition, constitutively activated KRAS signaling contributes to up-regulation of
other molecules that promote expansion of the desmoplastic stroma characteristic of
pancreatic carcinoma
• Aberrant signaling through KRAS may also indirectly promote collagen
production and further promotes tumor invasion and progression
• Reactivation of downstream mediators in pancreatic cancer bypass the
EGFR pathway, allowing resistance to develop37
• Such resistance mechanisms include the PI3K/AKT and Hedgehog pathways
HGF
EGFR/EGFR
HER2/EGFR
MET
Gab1
RAS
Shp2
Shc
Grb2
SOS
RAF
PI3K/AKT
Pathway
MEK
ERK/
MAPK
PI3K/AKT
Pathway
Biomarkers in Colorectal Cancer
• Chromosomal instability, which involves DNA copy number variation, may provide
prognostic information in CRC10
• Recent studies indicate that microsatellite instability, DNA methylation and DNA copy
number may be helpful towards selection of an appropriate treatment plan
• Multiple signaling pathways have been implicated in the pathogenesis of mCRC38,39
• Aberrant signaling through the RAS/RAF pathway occurs as a consequence of
mutations in KRAS, NRAS, or BRAF in mCRC—these aberrations in genes and
proteins may impact treatment pans38,40
• Oncogenic mutations in phosphoinositide-3 kinase (PI3K) are present in 12–30% of
colorectal cancers42,43
Genetic mutations in chromosomal instability–positive
colorectal cancers41
Oncogenes
KRAS: Cell proliferation, survival, and transformation
CTNNB1: Regulation of Wnt pathway target genes that promote
tumor growth and invasion
PIK3CA: Cell proliferation and survival
Tumor suppressor genes
APC: Inhibition of Wingless/Wnt signaling; cytoskeletal regulation
TP53: Cell cycle arrest, apoptosis induction
SMAD4, SMAD2: Intracellular mediators of the TGF-β pathway
DCC: cell surface receptor for netrin-1
• Patients with mCRC having BRAF mutations have been shown to have
decreased survival as compared with patients with unmutated BRAF 38,40
• The prevalence of different mutations that affect the RAS/RAF pathway in mCRC
patients has been analyzed—overall, mutations in KRAS exon 2 have been observed in
~40% of mCRC44–46
• Other distinct mutations in KRAS, as well as mutations in NRAS, account for another
~10% of patients with mCRC
• Taken together, this indicates that mutations in NRAS and KRAS may affect up to
50% of patients with mCRC
• Mutations in BRAF affect 8–10% of all mCRC patients, and up to 15% of
mCRC patients with unmutated KRAS
HGF
EGFR/EGFR
HER2/EGFR
MET
Gab1
RAS
Shp2
Shc
Grb2
SOS
RAF
PI3K/AKT
Pathway
MEK
ERK/
MAPK
PI3K/AKT
Pathway
Evaluating Biomarkers With Companion Diagnostics
May Help Inform Treatment Plan Decisions
• Increased understanding of the key molecular pathways in carcinogenesis has
resulted in the identification of a variety of biomarkers1,12
• Development of diagnostic tests based on biomarkers may help stratify patients into
subpopulations that differ in their susceptibility to a different disease or their response
to a specific treatment plan; which may include diet, therapy, and exercise47
• A companion diagnostic (CDx) is an in vitro diagnostic (IVD) device or an imaging tool
that provides information that is essential for the safe and effective use of a
corresponding therapeutic product 2
• A CDx may identify the patients who are more likely to benefit or have increased
risk of serious adverse events from treatment with a particular therapeutic product
• Biomarker-based CDx must demonstrate both analytic and clinical validity to
achieve regulatory approval, and the robustness of the development process
must be ensured and documented 1,2
• Additional investigation must demonstrate the relevance and usefulness of CDx
Patient population
Diagnostic
negative
Diagnostic
positive
Identification of biomarkers and development of diagnostic tests may be used to determine
whether certain patients may differ in their responses to specific treatment plans1,2
• IVD, a reagent, instrument, or system intended for use in diagnosis of disease or other
conditions, including a determination of the state of health, in order to cure, mitigate, treat,
or prevent disease or its sequelae.1 Such products are intended for use in the collection,
preparation, and examination of specimens taken from the human body.
• Laboratory developed tests are designed, manufactured, and used by a single laboratory
• In contrast, IVD kits are generally developed by conventional manufacturers, submitted
for FDA review, and if cleared or approved, are sold to labs, hospitals, and/or physicians’
offices, where these kits are used to perform the tests
• Deeper sequencing and more extensive mutational analysis (eg, next generation sequencing
of multiple genes) is demonstrating the presence of biomarker mutations48
• The FDA recognizes that regulatory oversight of CDx to ensure that tests
“provide a reasonable assurance of safety and effectiveness, while also fostering
innovation and progress in personalized medicine”1
HGF
EGFR/EGFR
HER2/EGFR
MET
Gab1
RAS
Shp2
Shc
Grb2
SOS
RAF
PI3K/AKT
Pathway
MEK
ERK/
MAPK
PI3K/AKT
Pathway
Amgen is Committed to Advancing the Science of
Personalized Medicine
• New information is continuously emerging that refines our understanding of the
molecular pathways and biomarkers that drive the carcinogenic process3
• Research to evaluate biomarkers in gastrointestinal malignancies is ongoing
• CDx may play a role in predicting likelihood of response, patients unlikely to
respond, or individuals at greater risk of adverse effects to a given treatment plan
• Integrating biomarkers into routine clinical practice may aid in detection,
diagnosis, and treatment planning
• Amgen remains committed to the science of personalized medicine
and biomarkers
HGF
EGFR/EGFR
HER2/EGFR
MET
Gab1
RAS
Shp2
Shc
Grb2
SOS
RAF
PI3K/AKT
Pathway
MEK
ERK/
MAPK
PI3K/AKT
Pathway
Definitions
A biomarker is a characteristic that can be scientifically measured and evaluated to serve
as an indicator of a normal biologic process, a disease, or as a response to a therapeutic
intervention. Biomarkers are generally measured using either a diagnostic test, IVD test,
imaging diagnostic, or other objective measurement method.1
Prognostic markers provide information regarding the natural history of a disease; they are
useful in predicting probable clinical outcomes; prognostic enrichment strategies (those with
a greater likelihood of having a disease-related endpoint event or a substantial worsening in
condition) for example, could be selection of high-risk patients to include in a trial.1,38
Predictive biomarkers provide information regarding the likelihood of response to a particular
therapy or patients who may or may not benefit from certain treatments. Thus, a trial employing
a predictive enrichment strategy would include patients more likely to respond to a particular
intervention or treatment plan.38
A companion diagnostic (CDx) is an IVD device or an imaging tool that provides information
that is essential for the safe and effective use of a corresponding therapeutic product.1,2
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Notes
Notes
This booklet contains forward-looking statements that are based on Amgen’s current expectations and beliefs and are
subject to a number of risks, uncertainties, and assumptions that could cause actual results to differ materially from those
described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking
statements. Forward-looking statements involve significant risks and uncertainties, including those more fully described in
the Risk Factors found in the most recent Annual Report on Form 10-K and periodic reports on Form 10-Q and Form 8-K
filed by Amgen with the U.S. Securities and Exchange Commission, and actual results may vary materially. Except where
otherwise indicated, Amgen is providing this information as of May 15, 2014 and does not undertake any obligation to
update any forward-looking statements contained in this booklet as a result of new information, future events, or otherwise.
Provided as an educational resource. Do not copy or distribute.
©2014 Amgen Inc. All rights reserved. 79855-R1-V1