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Introduction to
Cancer Biomarkers
Updated January 2016
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The Need for Precision Medicine
•  We need to better target patients for specific therapies and, more
importantly, identify which therapies should not be given to certain
patients
–  Prevent over-treatment of patients and sustain quality of life
–  Prevent the utilization of resources on therapeutic options with little
potential for outcome improvement
•  What we are looking for is “Precision Medicine”
–  Stratifying patients into treatable vs. non-treatable groups and having specific
therapeutic options for each patient subgroup
–  The key to stratifying patients is the development of biomarker tests
“Each pa(ent with cancer is different—biologically, clinically, economically, and socially—
and a one-­‐size-­‐fits-­‐all approach to trea(ng cancer is not op(mal. As oncologists, our focus has always been, and must remain, trea(ng the pa(ent, not the disease. We must each acquire the skills and make the commitment to do so in the op(mal way” — Dr. Richard Schilsky, ASCO President, 2008-­‐2009 Introduction to Cancer Biomarkers • January 2016
Slide 2
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What is a Biomarker?
•  Biomarkers can be used for diagnosis or for predicting
outcomes
Biomarker: A substance or measurement used as an indicator of a biologic
state. It is a characteristic that is objectively measured and evaluated as an
indicator of normal biologic processes, pathogenic processes, or pharmacologic
responses to a therapeutic intervention.
Type of Biomarker
Definition
Early Detection
(screening)
Enabling intervention at a potentially more curable stage than under
typical diagnostic conditions
Diagnostic
Disease-specific indicator used for validated diagnosis
Disease Monitoring
Assessing response during therapy with potential for adjusting
intervention (e.g. dose) on a personal basis
Risk Assessment
Leading to preventive interventions for those at sufficient risk
Prognostic
Allowing for more aggressive therapy for patients with poorer prognosis
Predictive
(efficacy or safety)
Providing guidance in choice of therapy
Introduction to Cancer Biomarkers • January 2016
Slide 3
Cancer Biomarkers
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Rapidly Changing Biomarker Landscape
Cancer Biomarker Publications, 1980 – 2013
18,000
16,000
14,000
12,000
10,000
8,000
AAGR: 10.53% 6,000
4,000
2,000
0
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
–  Mutations
–  Expression level
–  Copy number
–  Gene expression profiles
–  Imaging (physiologic /
biologic changes)
20,000
Number of Biomarker Publications
•  Over the past 35 years,
research has increased
our understanding of
biomarkers for cancer
•  Cancer biomarkers usually
fall into one of the
following groups:
Source: PubMed Search, Conducted September 2014, Epiphany Partners Inc.
Introduction to Cancer Biomarkers • January 2016
Slide 4
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Companion Diagnostics?
•  A companion diagnostic is a medical test that is considered “essential” for the safe
and effective use of a corresponding drug or biologic product
–  Identify patients who are most likely to benefit from a particular therapeutic product
–  Identify patients likely to be at increased risk for serious side effects as a result of treatment with a
particular therapeutic product
–  Monitor response to treatment with a particular therapeutic product for the purpose of adjusting
treatment to achieve improved safety or effectiveness
•  On July 31, 2014, the FDA issued “Guidance for Industry: In Vitro Companion
Diagnostic Devices”
–  This guidance is to help companies identify the need for companion diagnostics at an earlier stage in
the drug development process and to plan for co-development of the drug and companion diagnostic
test
–  The ultimate goal of the guidance is to stimulate early collaborations that will result in faster access
to promising new treatments for patients living with serious and life-threatening diseases
•  With the emerging understanding of the heterogeneity of tumor expression,
differential expression over time, and other confounding factors, how will the
regulatory and diagnostic markets adapt?
–  Is it “business as usual” or will there need to be new approaches in place (e.g., multiple biopsies as
done in prostate cancer, redefining “positivity” to account for heterogeneity, etc.)?
–  Will advances in second generation sequencing trump the biomarker market?
Introduction to Cancer Biomarkers • January 2016
Slide 5
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Prognostic versus Predictive
•  Prognostic biomarkers are associated with the likelihood of an
outcome independent of treatment
•  Predictive markers are associated with the results of a specific
therapy
Prognostic
•  Associated with the likelihood of an
outcome (e.g., survival, response, recurrence)
such that magnitude of association is independent
of treatment
•  Inform about an outcome independent of specific
treatment (ability of tumor to proliferate, invade,
and/or spread)
•  Example: HER2 is prognostic for recurrence in
node-negative breast cancer patients
Predictive
•  Associated with the results of a specific
therapy and are useful for selecting patients for
specific therapies
•  Imply some level of relative sensitivity or
resistance to specific treatments or agents
•  Examples:
•  HER2+ for Herceptin (trastuzumab):
Outcome with chemotherapy of 54% vs.
38%
•  ALK for Xalkori (crizotinib): Improved
outcomes for NSCLC patients with ALK+
mutations
Introduction to Cancer Biomarkers • January 2016
Slide 6
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Cancer Products and Biomarkers
•  Cancer biomarkers that serve as predictors or surrogates for
treatment outcomes can guide treatment selection
–  In some cases, a biomarker can be a requisite for deciding on a specific
treatment
Informa3onal Biomarker Only
Biomarker Recommended for Treatment U3liza3on
Biomarker Required for Treatment U3liza3on
c-­‐Kit expression Gleevec (GIST)
UGT1A1 allele variant Camptosar
HER2/neu over-­‐expression Hercep(n, Tykerb, PERJETA (BC)
Dele=on of chromosome 5q (5q del) Revlimid (MDS)
EGFR presence Erbitux, Vec(bix (CRC)
DPD deficiency 5-­‐FU, Xeloda
Non-­‐mutated Codon 12 or 13 kRAS Erbitux, Vec(bix (CRC)
EGFR presence Tarceva (NSCLC)
Philadelphia chromosome Sprycel, Marqibo (ALL)
Philadelphia chromosome Busulfan (CML)
ALK muta=on Xalkori (NSCLC)
PML/RAR gene fusion Vesanoid (APL)
V600E BRAF Muta=on Zelboraf (Melanoma)
UGT1A1 allele variant Tasigna
Introduction to Cancer Biomarkers • January 2016
Slide 7
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Established Cancer Biomarkers
Biomarker
Prognostic
BCRA-1 and BRCA-2
mutations
✔
c-kit mutations in GIST
EGFR mutations and high
gene copy number in nonsmall cell lung cancer
(NSCLC)
HER2/neu overexpression
(HER2+) in breast cancer
Hormone (estrogen,
progesterone) receptor
(HR) status in breast
cancer
Philadelphia-positive (Ph+)
status in leukemias
NOTE:
✔
(mutations
only)
✔
Predic
-tive
Comments
Impact
Prognostic for development of breast and
ovarian cancers
Minor: approximately 5–10% of breast cancers
and 10-15% of ovarian cancers
✔
Mutations are predictive for efficacy of
Gleevec/Glivec
Maximum: 95% of GIST patients are c-kit
positive
✔
Mutations (but not high copy number) are
prognostic for favorable survival; both markers
are predictive for efficacy of EGFR tyrosine
kinase inhibitors (Tarceva, Iressa); copy number
(but not mutations) appear to be predictive for
efficacy of EGFR monoclonal antibodies
(Erbitux,Vectibix)
Minor in Caucasian patients (10% mutation
rate); Moderate in Asian patients (30%
mutation rate).
✔
HER2(+) breast cancer has poor prognosis;
predictive for efficacy of Herceptin, Tykerb/
Tyverb, PERJETA
Moderate: approximately 25-30% of breast
cancer is HER2(+)
✔
Predictive for efficacy of hormone therapy,
such as tamoxifen, aromatase inhibitors
(Arimidex, Femara, Aromasin), or Faslodex.
Major: approximately 75% of breast cancer is
HR(+)
✔
Predictive for efficacy of Gleevec/Glivec
(CML and ALL), Tasigna (CML), and Sprycel
and Marqibo (ALL)
Maximum: Ph+ is seen in 95% of CML;
Moderate: 25–30% of adult ALL, and 2–10% of
pediatric ALL
(variable)
EGFR = epidermal growth factor receptor
Introduction to Cancer Biomarkers • January 2016
Slide 8
Cancer Biomarkers
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Established Cancer Biomarkers
Biomarker
Prognostic
Predic
-tive
Comments
Impact
Oncotype Dx (21-gene) and Mammaprint
(70-gene) GEPs provide prognostic risk of
recurrence. Oncotype Dx is also predictive
of the general efficacy of chemotherapy.
Moderate: estimate that 20% of Oncotype Dxtested patients could be spared chemotherapy
✔
Low levels are predictive for toxicity of
thiopurine drugs (mercaptopurine,
azathioprine, thioguanine)
Minor: approximately 10% of the population
has lower than normal TPMT levels
UGT1A1 homozygous
status of associated allele
✔
Predictive for toxicity (neutropenia) of
irinotecan therapy
Minor: ~10% of the North American
population have reduced enzyme UGT1A1
activity due to homozygous allele, requiring a
reduced starting dose of irinotecan
KRAS mutation in
colorectal cancer (CRC)
✔
Predictive of resistance to EGFR monoclonal
antibodies (Erbitux,Vectibix)
Moderate: Approximately 35% of CRC has the
KRAS mutation
Prognostic for recurrence (high levels
associated with high risk of recurrence);
predictive for tamoxifen (low levels have
better outcomes) and chemotherapy (high
levels respond to chemotherapy)
Major: High levels of uPA and PAI-1 have
equaled the prognostic value of lymph node
status (Note: while widely utilized in Europe,
relatively new to U.S.)
Low levels are predictive for the efficacy of
platinum-based chemotherapies in NSCLC
Moderate: Approximately 50 to 60% of NSCLC
have low expression of ERCC1
Low expression is associated with response
to gemcitabine
Moderate: Approximately 50 to 60% of NSCLC
have low expression of RRM1
Patients on tamoxifen with a CYP2D6 variant
have an increased recurrence risk
Minor: 7 to 10% of breast cancer patients on
tamoxifen are found to be slow metabolizers
Gene expression profiles
(GEPs) of breast cancer
✔
TPMT levels in acute
lymphocytic leukemia
✔
(Oncotype
Dx only)
uPA and PAI-1 levels in
breast cancer
✔
✔
ERCC1 levels in non-small
cell lung cancer (NSCLC)
✔
✔
✔
✔
✔
RRM1 levels in non-small
cell lung cancer (NSCLC)
CYP2D6 variants in breast
cancer patients
NOTE: CYP2D6 = Cytochrome P450 2D6; ERCC1 = excision repair cross complementation group 1; PAI-1 = plasminogen activator inhibitor 1; RRM1 = ribonucleotide
reductase M1; : TPMT = thiopurine methyltransferase; UGT1A1 = uridine diphosphate glucoronosyl transferase 1A1, uPA = urokinase-type plasminogen activator.
Introduction to Cancer Biomarkers • January 2016
Slide 9
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Established Cancer Biomarkers
Biomarker
ALK (anaplastic lymphoma
kinase) mutation
BRAF mutations (especially
V600E variant)
Prognostic
✔
✔
Predic
-tive
✔
✔
Comments
ALK mutations is an independent predictor
of survival with positive patients having
significantly better outcomes
Predictive for response with ALK-targeted
agents (crizotinib)
BRAF positive patients have a poor clinical
outcome and higher levels of recurrence
across multiple cancers (melanoma, thyroid,
colorectal, etc.)
Predictive for improved survival for BRAFtargeted agents (e.g., vemurafenib)
Introduction to Cancer Biomarkers • January 2016
Impact
Minor: approximately 5% of NSCLC patients
are ALK positive, mainly patients with
adenocarcinoma
Major: estimates of 60 to 80% of melanoma
patients have a BRAF mutation;V600E
mutations may account for 80 to 90% of
mutations (50 to 70% of patients)
Slide 10
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Biomarkers: Confounding Factors
•  The detection and/or utility of potential biomarkers can be influenced by disease,
age, or external factors
Demographic
Factors
•  Biological heterogeneity results in the different parts of the tumor expressing
different biomarkers
•  Aging, physiologic, and/or pathologic processes may change biomarker expression
(e.g., increased genetic instability as tumors progress)
•  Diet, drugs, or environment may impact the presence of biomarkers
•  Biomarkers can be regulated by other factors: e.g., cytogenetics, histology
Tumor-specific
Effects
•  Biomarkers can be regulated by other mutations: e.g., FLT3-ITD and NPM1 in
AML
•  Biomarkers may only apply to specific subsets or stages (e.g., KRAS in metastatic
CRC (clinical))
•  Biomarker expression may fluctuate over time and be impacted by therapy (e.g.,
breast cancer)
•  Testing technologies also confound the implication of biomarkers
Testing
Technologies
•  Currently, both IHC and FISH are used to test for HER2 expression levels in a
step fashion; however, some low IHC expressers may be high FISH expressers
•  Future implications of multiple testing requirements vs. sample availabtility (Single
test technologies vs. next generation genetic screening)
Source: Intratumor heterogeneity, NEJM, March 8, 2012
Introduction to Cancer Biomarkers • January 2016
Slide 11
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Biomarker Utilization Issues
Clinical Utility
Diagnostic Testing
Regulatory
Environment
Reimbursement
•  Few of the new biomarkers have been validated with respect to clinical
utility
•  We need to understand intratumor heterogeneity and “re-testing” as
patients progress
•  Currently, laboratory testing and molecular oncology segments are
effectively two separate industries
•  Current approval processes varies based on the type of test (FDA vs.
CMS)
•  Coverage decisions are difficult based on limited clinical data and poor
clinical trials
•  Lack of a standardized coding system raises questions regarding
appropriate payments and ability to track specific test utilizations
Introduction to Cancer Biomarkers • January 2016
Slide 12
Cancer Biomarkers
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Companion Diagnostics?
•  A companion diagnostic is a medical test that is considered “essential” for the safe
and effective use of a corresponding drug or biologic product
–  Identify patients who are most likely to benefit from a particular therapeutic product
–  Identify patients likely to be at increased risk for serious side effects as a result of treatment with a
particular therapeutic product
–  Monitor response to treatment with a particular therapeutic product for the purpose of adjusting
treatment to achieve improved safety or effectiveness
•  On July 31, 2014, the FDA issued “Guidance for Industry: In Vitro Companion
Diagnostic Devices”
–  This guidance is to help companies identify the need for companion diagnostics at an earlier stage in
the drug development process and to plan for co-development of the drug and companion diagnostic
test
–  The ultimate goal of the guidance is to stimulate early collaborations that will result in faster access
to promising new treatments for patients living with serious and life-threatening diseases
•  With the emerging understanding of the heterogeneity of tumor expression,
differential expression over time, and other confounding factors, how will the
regulatory and diagnostic markets adapt?
–  Is it “business as usual” or will there need to be new approaches in place (e.g., multiple biopsies as
done in prostate cancer, redefining “positivity” to account for heterogeneity, etc.)?
–  Will advances in second generation sequencing trump the biomarker market?
Introduction to Cancer Biomarkers • January 2016
Slide 13
Isn’t it Time You Had
an Epiphany?
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Main Number: +1-650-242-4626
Peter Davis
Derick Nguyen
[email protected]
[email protected]
(218) 305-4049
(650) 513-2722
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