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BIOMARKERS
COMPARATIVE EFFECTIVENESS
SHARED DECISION MAKING
TREATMENT
PRINCIPLES ON THE PATHWAY TO TREATMENT:
Online Report from ASCO 2010
EDUCATIONAL PLANNING COMMITTEE
OVERVIEW OF EDUCATIONAL NEED
Edith P. Mitchell, MD, FACP
The method of making treatment decisions in oncology is
Clinical Professor of Medicine and Medical Oncology
evolving from a paternalistic model in which physicians make
Program Leader in Gastrointestinal Oncology
decisions based on consensus guidelines and evidence-based
Thomas Jefferson University
data to a shared model in which patients participate in choosing
Philadelphia, Pennsylvania
their own treatment. This new model requires a change in the
Christine M. O’Leary, PharmD, BCPS
Director, Clinical Services
Institute for Continuing Healthcare Education
Adjunct Pharmacy Practice Faculty
University of the Sciences in Philadelphia
Philadelphia, Pennsylvania
way information is shared and treatment decisions are made.
Integrating shared decision making into practice requires the
healthcare professional to properly prepare patients for
informed decision making, address his or her own biases, and
anticipate patient values. Healthcare providers need to learn how
to most effectively integrate patients into the shared
decision-making process.
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O N L I N E
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TARGET AUDIENCE
The target audience for this educational
initiative includes U.S.-based oncologists.
It is also appropriate for other healthcare
providers involved in the care of cancer
patients.
LEARNING OBJECTIVES
Upon completion of this activity, the
participant should be able to:
•Assess the evidence on available
biomarkers for cancer treatment and
incorporate a biomarker screening
evaluation into patient treatment
plans
•Assess the evidence on the value of
shared decision making on overall
outcomes in cancer patients
•Integrate comparative effectiveness
research into individual treatment
EDUCATIONAL
PLANNING COMMITTEE
Edith Mitchell, MD, has disclosed the
following relevant financial relationships
that have occurred within the past 12
months: Amgen/A, SB; DiagnoCure,
Response Genetics, Inc./C; Bristol-Myers
Squibb, Genentech, Inc., Merck & Co.,
Inc./SB.
Relationships are abbreviated as follows:
A, Advisor/review panel member; C,
Consultant; G, Grant/research support
recipient; E, Educational committee; H,
Honoraria; PE, Promotional event talks;
S, Stock shareholder; SB, Speakers’
Bureau; O, Other.
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PRODUCT DISCLOSURE
This educational activity will include
off-label discussion of the following:
chemotherapeutic agents.
CONTENT FREELANCER
ENERAL DISCLOSURE
G
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Elizabeth Friedenwald (Medical Writer)
has disclosed that she has not had any
relevant financial relationships specific
to the subject matter of this activity that
have occurred within the past 12 months.
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or services related to the content of this
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best available evidence.
Christine M. O’Leary, PharmD, BCPS,
has disclosed no relevant financial
relationships specific to the subject
matter of this activity that have occurred
within the past 12 months.
plans
DISCLOSURE
The educational content of this activity
has been peer reviewed and validated
to ensure that it is a fair and balanced
representation of the topic, based on the
Johanna Bendell, MD, has disclosed
that she has no relevant financial
relationships that have occurred within
the past 12 months.
CTIVITY DEVELOPMENT AND
A
MANAGEMENT TEAM
Cathy Pagano, CCMEP; Scott Kober,
CCMEP; Karen J. Thomas, CCMEP;
Sandra Davidson; April Reynolds, MS,
ELS; Tina Chiu, MEd; Melissa M. Schepacarter, CMP; and Courtney Cohen are
employees of the Institute for Continuing
Healthcare Education and are collectively
responsible for the planning, development, management, and evaluation of
this CME activity. These individuals have
disclosed that they have had no relevant
financial relationships specific to the
subject matter of this activity that have
occurred within the past 12 months.
Shunda R. Irons-Brown, PhD, MBA,
also an employee of the Institute, has
disclosed the following relationships:
Merck & Co., Inc./S; Bristol-Myers Squibb,
GlaxoSmithKline/O.
P A T H W A Y
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T R E A T M E N T
COMMERCIAL SUPPORT
Supported by an educational grant from
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mentioned herein.
The information is provided for general
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is not meant to substitute for the
independent medical judgment of a
healthcare professional relative to
diagnostic and treatment options of a
specific patient’s medical condition. In
no event will the Institute for Continuing
Healthcare Education be responsible for
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this activity.
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Copyright 2010, Institute for Continuing
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All rights reserved. No part of this
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INTRODUCTION
BIOMARKERS
Oncology is a dynamic field of medicine that is constantly
The technological advances in medicine in the last decade have
integrating new technologies and ideas in classifying tumors
been numerous and dramatic. One of the most significant has
and tumor subtypes based on histopathologic characteristics.
been the development of technology that allows scientists to
The evolving role of biomarkers is changing diagnostic and
peer deeply into molecules and unravel the human genome.
treatment patterns through a deeper understanding of the
This improved understanding of the human genome has allowed
mechanisms of tumorigenesis and factors related to growth,
for the development of novel therapies and has become an
progression, and development of metastases. The concept
integral part of cancer management, with applications including
of comparative effectiveness research is designed to impact
patient stratification, drug regimen selection, toxicity avoidance,
treatment and healthcare decisions by providing evidence
therapeutic monitoring, as well as detection of predisposition
such as potential effectiveness, benefits, and possible
to disease processes. These applications have resulted in more
toxicities of different treatment options. Resulting outcomes
personalized approaches to treatment for patients. As
lead to optimizing patient care — as evidenced by changing
technology is becoming more efficient and accurate (though not
prescribing patterns and potential cost savings — by encouraging
always affordable), correlation with survival and other outcomes
more rigorous evaluation of treatment efficacy and safety. Shared
has led to the widespread adoption of some tests by healthcare
decision making is changing the way healthcare providers and
providers. For example, in 2002, the detection of 1 million base
patients communicate with each other because of the broad
pairs in a person’s genome required years of work and cost more
availability of information.
than $500,000, whereas in 2010, the same project would take
What information do providers need to know to incorporate
these principles into practice? This monograph will describe
some of the important factors that impact these diverse topics,
with a focus on improving care for patients with cancer.
a few hours and cost a few hundred dollars. It is expected that
the ability to sequence a person’s full genome will soon cost less
than $1000 [Feero 2010].
T he general availability of information
about molecular pathology and genomics of
Definition: Biomarkers are characteristics that can be
a patient’s disease has led to fundamental
objectively measured and used as indicators of biologic
processes, both normal and pathogenic, or as predictors
of pharmacologic responses to a therapeutic intervention
[Biomarkers 2001].
changes in treatment and prognosis. In
particular, the field of oncology is directly
benefiting from the discovery and exploitation
of biomarkers. Biomarkers provide
molecular information about cancers that
can be prognostic or predictive, which
allows for more targeted and effective treatment for individual
patients. The information provided by biomarkers is creating
a new paradigm of individualized treatments for patients with
cancer; however, this technology is in its infancy, and only a few
biomarkers, such as human epidermal growth factor receptors
2 (HER2) in breast cancer and carcinoembryonic antigen (CEA)
in colorectal cancer, have been shown through rigorous testing to
be clinically relevant. Many more biomarkers are being evaluated
and, undoubtedly, many more have yet to be discovered. This
monograph will discuss just a few.
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Review of Selected Biomarkers in Selected Cancers:
Triple-Negative Breast, Colorectal, Pancreatic, and Non-small Cell Lung
TRIPLE-NEGATIVE BREAST CANCER | In the last 20 years,
for only a small proportion of breast cancer diagnoses (<20%)
mortality due to breast cancer has declined substantially, in
but have an increased risk of recurrence and death compared to
part because of the effective use of adjuvant medical therapy
other breast cancers [Dent 2007, Anders 2008]. It should also
[EBCTCG 2005]. However, in addition to discovering new thera-
be noted that the majority of patients who have the BRCA1 gene
pies, identifying cancers that are more likely to respond well
mutation develop triple-negative breast cancer [Anders 2008]. A
to a particular therapy may improve patient selectivity (but not
recent review of 284 women with triple-negative invasive breast
necessarily outcomes) [Dowsett 2008]. A number of biomarkers
cancer showed that 10.6% had BRCA1 mutations. Of these 30
are well established in determining the prognosis and effective
patients, none had a family history of breast or ovarian cancer,
management of breast cancer, including the status of estrogen
and the mean age of onset was 40.2 years [Fostira 2010].
receptors (ERs), progesterone receptors (PRs), and HER2. In fact,
Because of the lack of expression of ER, PR, and HER in triple-
these biomarkers have become a fundamental part of defining
negative breast cancer, there is a lack of effectiveness with many
the disease; new breast cancer treatments have been developed
of the standard targeted therapies. Although triple-negative
based on the presence or absence of these markers as well as
breast cancer has low expression of ER, PR, and HER2, it has
on the use of cDNA microarrays to determine molecular pheno-
high expression of CK5, CK14, caveolin-1, CAIX, p63, and epider-
type [Anders 2008, Dowsett 2008, Sotiriou 2009].
mal growth factor receptor (EGFR, HER1). It is important to note
In addition, a number of subtypes of breast cancer are more
that “triple negative” and “basal-like” are not synonymous terms.
aggressive and difficult to treat. Genomic analyses of breast
“Basal-like” describes the molecular phenotype of the tumor us-
cancer phenotypes have subclassified breast cancers into 4
ing cDNA microarrays; “triple negative” is a term based on clinical
important categories, each with different clinical behavior. These
assays of ER, PR, and HER2. While most triple-negative tumors
include the luminal A (ER-positive and/or PR-positive, HER2-neg-
are in fact basal-like, up to 30% are not. Similarly, up to 40% of
ative), luminal B (ER-positive and/or PR-positive, HER2-positive),
basal-like tumors are not triple negative, but rather ER-, PR-, or
HER2-positive (ER-negative and PR-negative), and basal-like (ER-
HER2-positive [Anders 2008].
negative, PR-negative, HER2-negative, CK5/6-positive, and/or
Data presented at the ASCO 2010 Annual Meeting on
HER1-positive) phenotypes, which, in this order, have increasingly
serveral potential biomarkers that are under investigation
aggressive behaviors and worse prognoses. Triple-negative breast
in triple-negative breast cancer are shown in Table 1.
cancers, the majority of which are considered basal-like, account
TABLE 1
DATA ON BIOMARKERS FOR TRIPLE-NEGATIVE BREAST CANCER PRESENTED AT ASCO 2010
POTENTIAL
BIOMARKER
Inactivation
of BRCA1 by
promoter
methylation
PTEN, EGFR,
KRAS, PIK3CA
as markers of
response to
cetuximab
AUTHOR
RESULT
DESCRIPTION
Grushko 2010
Predictive of potential response to
a common targeted therapy such
as PARP inhibitors
198 cancers analyzed for methylation of the BRAC1 promoter and expression
of ER, PR, HER2, EGFR, and CK5/6. Of 191 tumors, 28% were triple negative,
and 43% of these had BRCA1 methylation. Of 74 tumors, 19% were basal-like,
and 48% of these had BRCA1 methylation.
Khambata-Ford
2010
PTEN positivity associated with
improved PFS in triple-negative
patients. None of the biomarkers
were associated with cetuximab
benefit.
Retrospective review of phase II trial in 154 patients in which only TN patients
showed an improved response rate in an irinotecan/carboplatin + cetuximab
arm vs. a cetuximab arm alone (49% vs. 38%). In this study, tissue samples
were available for 124 cases. KRAS mutations were found in 5%, PIK3CA
mutations in 17% of all cases and 17% of TN cases, and ER positivity in 18%.
EGFR positivity was 47%, and PTEN positivity was 48%. Only PTEN positivity
in patients treated with cetuximab was associated with improved PFS.
PARP, poly (ADP-ribose) polymerase; PFS, progression-free survival; TN, triple negative
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COLORECTAL CANCER | Colorectal cancer (CRC) continues
CRC is reflected in practice guidelines. For example, in the 2011
to be a leading cause of cancer morbidity and mortality, with an
National Comprehensive Cancer Network (NCCN) Guidelines™
estimated incidence of 142,570 cases in 2010. It is the cause
for colon cancer [Engstrom 2011], determination of tumor KRAS
of mortality in 9% of patients, or 51,370 persons, with cancer
gene status is recommended for all metastatic stage IV disease
each year [ACS 2010]. Although an increase in screening with
and before consideration of cetuximab or panitumimab therapy.
colonoscopy and stool tests has contributed to a substantial
In addition, although data are inconsistent, an optional screen-
decrease in incidence, the lifetime risk of developing CRC is still
ing for BRAF V600E mutation might be considered. This year at
5.5% [Compton 2008].
ASCO, results were presented from many trials that investigated
the importance of biomarkers in predicting response to therapies.
The improved understanding of the molecular underpinnings of
Some of the key information is shown in Table 2.
CRC has contributed to the development of a model of CRC as
a multi-step accumulation of genetic and epigenetic alterations,
PANCREATIC CANCER | Cancer of the pancreas is a devastat-
and several such pathways have been identified. Up to 85%
ing disease that has a 5-year survival of only 6%. In 2010, an
of CRCs are associated with some type of genetic abnormal-
estimated 43,140 new cases will be diagnosed and 36,800 per-
ity that may be caused by mutations of a number of different
sons will die of pancreatic cancer. The low survival rate is partially
genes, including KRAS, BRAF, and TP53 as well as translocation
due to the disease being diagnosed most often in later stages, as
of chromosome 18q [Compton 2008, Smits 2008]. Between
well as few effective treatments. Surgery is only possible in less
15%-20% of CRCs have defects in repair genes (eg, hMLH1,
than 20% of patients. Chemotherapy and radiation therapy are
hMSH2, hPMS1, hPMS2, and hMSH6), which leads to ineffective
also options, and the combination of gemcitabine with erlotinib is
mismatch repair pathways or microsatellite instability [Compton
considered standard of care for advanced disease [ACS 2010].
2008, Smits 2008]. The importance of genetic abnormalities in
TABLE 2
INVESTIGATIONS OF BIOMARKERS IN COLORECTAL CANCER PRESENTED AT ASCO 2010
POTENTIAL
BIOMARKER
BRAF and
KRAS predictive
of cetuximab
efficacy
KRAS, NRAS,
and BRAF in
patients with
advanced CRC
being treated
with first-line
EGFR
KRAS and
BRAF predictive
of efficacy of
cetuximab +
chemotherapy
AUTHOR
RESULT
DESCRIPTION
Van Cutsem
2010
KRAS was predictive of treatment
outcome in patients with mCRC
who are receiving first-line
cetuximab + FOLFIRI. However,
BRAF mutation status did not
appear to be predictive.
In the phase III CRYSTAL trial, 1198 patients were enrolled and 1063 were
evaluated for KRAS and BRAF mutational status. For the 666 patients with
KRAS wild-type tumors, all efficacy endpoints were significantly improved with
cetuximab + FOLFIRI compared to FOLFIRI alone. The BRAF wild-type was found
in 625 of 566 patients, while KRAS wild-type and mutation was found in 59.
BRAF mutation was associated with poor prognosis in both treatment arms.
Maughan 2010
Although this trial had negative
outcomes, KRAS wild-type tumors
may benefit from cetuximab with
oxaliplatin.
In the COIN trial of 1630 patients, 80% of patients were genotyped and 43%
had KRAS mutations, 4% NRAS mutations, and 8% BRAF mutations. In this
trial, the addition of cetuximab to oxaliplatin did not result in a change in OS
or PFS. For patients who had KRAS wild-type, there was no change in OS or
PFS, but there was an increased response rate.
KRAS wild-type tumors are
associated with improvement
in response and duration in
patients given cetuximab therapy
compared to those who received
cetuximab alone.
In the CRYSTAL and OPUS studies, 1063 and 315 tissue samples, respectively,
were evaluated for KRAS mutations. Samples that were KRAS wild-type were
then evaluated for BRAF, and it was found that 625/666 in the CRYSTAL study
were BRAF/KRAS wild-type vs. 175/179 in the OPUS study. KRAS wild-type
tumors were associated with a significant improvement in OR, PFS, or OS in
patients given cetuximab therapy compared to those who received cetuximab
alone. Best outcomes were seen in patients who had both KRAS and BRAF
wild-type tumors; however, BRAF mutation status did not appear to be predictive
of cetuximab efficacy in combination with chemotherapy.
Bokemeyer 2010
mCRC, metastatic colorectal cancer; OR, overall response; OS, overall survival
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Improvements in the treatment of pancreatic cancer have been
autonomy. However, when the clinical perspective is the guiding
only incremental. Biomarkers are being widely investigated to
rationale, CER should help guide healthcare providers and
improve prognosis and appropriate treatment. Some potential
patients to choose treatments centered on evidenced-based
biomarkers for pancreatic cancer are shown in Table 3.
data of the highest quality [Mushlin 2010, Weinstein 2009,
Lyman 2010].
NON-SMALL CELL LUNG CANCER | Lung cancer is the leading cause of death by cancer in men and women. In 2010, an
Patients will likely benefit from the development of well-
estimated 222,520 new cases will be diagnosed and 157,300
designed studies that are integral to the comparative efficacy
people will die, which is equivalent to about 28% of all deaths by
initiative [Garber 2009]. As an important part of the evolving
cancer. Non-small cell lung (NSCLC) cancer accounts for 85% of
concept of personalized medicine, information on biomarkers
all cases. Despite improvements in treatment, 5-year survival for
is expected to improve both treatment effectiveness and safety
NSCLC is only 17% [ACS 2010].
by identifying the optimal population. In addition, targeted use
of treatments will hopefully help control healthcare costs by
For localized cases, surgery is possible, but lung cancer is
reducing the use of inappropriate or ineffective therapies.
diagnosed in later stages when adjuvant chemotherapy may
However, biomarkers will need to be co-developed along with
be beneficial. The standard of care for stage II and IIIa cancer
potential targeted therapies, which will present special
is cisplatin-based chemotherapy. However, responses are
challenges. Certainly, any trials for targeted therapies should
modest, and new treatments continue to be investigated.
archive tissue samples for potential future research. Other
Potential biomarkers that can optimize therapy are being
recommendations that have been proposed are shown in Table 6.
identified (see Table 4).
SHARED DECISION MAKING
COMPARATIVE EFFECTIVENESS
The trend in oncology is toward personalizing medicine with
As biomarkers are integrated into the treatment plan for patients
preventive measures and treatments that are tailored to an
with cancer, an ongoing challenge is evaluating their effective-
individual patient’s circumstances, both environmental and
ness. As with any emerging technology, rigorous evaluation is
genomic. However, changing patient expectations complicate
necessary to evaluate the clinical and cost effectiveness of
the integration of these new technologies, such as biomarkers,
biomarkers in improving treatments and patient outcomes.
into the treatment continuum for patients with cancer. Treatment
In 2009, the U.S. government authorized the expenditure of
decisions in oncology are evolving from a paternalistic model,
$1.1 billion to conduct research comparing “clinical outcomes,
in which physicians make unilateral decisions for patients based
effectiveness, and appropriateness of items, services, and
on consensus guidelines and evidence-based data, to a shared
procedures that are used to prevent, diagnose, or treat diseases,
model in which patients participate in choosing their own
disorders, and other health conditions” [Weinstein 2009].
treatment. This new model, called shared decision making (SDM),
Clinicians and patients will benefit from a system that offers
acknowledges the growing belief that patients have a right to
comprehensive and unbiased information about new therapies
autonomy and self-determination as well as the realization that
and how they compare to existing standards of care.
physicians are often not able to independently determine a
The fundamental model of comparative effectiveness research
patient’s values and beliefs about their care [Pieterse 2008].
(CER) is comprised of the well-designed and well-conducted
The majority of patients want and expect to be included in
prospective, randomized clinical trial and carefully performed
decisions about their healthcare because they believe that they
meta-analyses of these trials. However, many treatments cannot
are responsible for their own well-being [Stacey 2008]. In fact,
be evaluated using these strategies or have yet to be rigorously
recent studies in women with breast cancer show that active
studied. Other research approaches can be used instead,
patient involvement is associated with greater satisfaction with
such as cohort, population, and modeling studies; additional
care, including improvement in quality of life, physical and social
approaches have also been proposed (see Table 5).
functioning, as well as fewer reported side effects [Stacey 2008].
Ultimately, it is hoped that CER will improve health outcomes
The vast majority of patients and physicians believe in SDM.
by helping to identify the most effective and appropriate therapies
A recent study showed that, in the oncology setting, most
for patients while potentially minimizing exposure to ineffective
physicians (95%) and most patients (96%) prefer SDM. In fact,
interventions. The challenge for proponents of CER is the
the growing acceptance of SDM by the healthcare community
perception that it might lead to limited or loss of physician
is illustrated by its integration into recent consensus guidelines.
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TABLE 3 | BIOMARKERS FOR PANCREATIC CANCER
POTENTIAL
BIOMARKER
AUTHOR
RESULT
DESCRIPTION
Farrell 2008
Predictive marker of gemcitabine
therapy
In a prospective trial of 538 patients who were randomized to either gemcitabine
or 5-flourouracil, immunohistochemistry was performed on tissue to determine
hENT1 status. In the gemcitabine arm, hENT1 expression was associated with
OS and disease-free survival but was not in the 5-fluorourocil arm [Farrell 2008].
hENT
Tan 2010
Although this trial had negative
outcomes, KRAS wild-type tumors
may respond to cetuximab with
oxaliplatin
Prognostic for improved OS and PFS
RRM1—
determinant of
gemcitabine
resistance
Tan 2010
Shows trend toward being
predictive of response to
gemcitabine
Same study as above; showed trend in improved benefit for patients treated with
gemcitabine
RRM1
Tan 2010
Not prognostic
No prognostic value seen
Not predictive
After an observation that up to 82% of cases of metastatic pancreatic cancer
overexpressed HER2, a trial was initiated to evaluate the safety and efficacy
of trastuzumab followed by capecitabine in this patient population. After
207 patients had their disease evaluated for HER2 status, it was determined
that only 11% had HER2 overexpression. In addition, response rates were not
improved in the 17 patients treated. Based on this study, anti-HER2 therapy
does not appear to be beneficial.
hENT—
transports
gemcitabine into
cells
HER2 overexpression
— predictive of
response to antiHER2 therapy
Geissler 2010
hENT, human equilibrative nucleoside transported protein; RRM1, ribonucleoside reductase subunit M1
TABLE 4 | INVESTIGATIONS OF BIOMARKERS FOR NSCLC PRESENTED AT ASCO 2010
POTENTIAL
BIOMARKER
AUTHOR
RESULT
DESCRIPTION
ALK for treatment with antiALK therapies
Bang 2010
ALK was associated with high
response and a good safety profile
in patients treated with crizotinib
In this trial, 82 patients who were ALK-positive were treated with an ALK
inhibitor. ORR was 57%, DCR at 8 weeks was 87%, and probable PFS at
6 months was 72%. It should be noted that the mean age of this population
was 51 years, and 76% were nonsmokers.
Hensing 2010
PTEN loss was associated with
decreased PFS and OS with treatment with EGFR tyrosine kinase
inhibitors
In this study of 115 patients, 84 had tumors that were PTEN-positive. In patients
with loss of PTEN expression compared to those who were PTEN-positive, median PFS was lower (2.0 vs. 2.9 months) and OS was decreased (4.04 vs. 8.51
months, P=0.057). A multivariate analysis — which also included clinical factors
such as smoking, histology, and gender — using the Cox proportional hazards
model showed that PTEN was the only factor associated with improved survival
(P=0.046).
Johnson 2010
EGFR positivity (increased gene
copy and mutation status)
may be predictive for patients
being treated with vandetinib +
docetaxel; KRAS mutation showed
no predictivity
In a study of 1391 patients with stage IIIb/IV NSCLC who were treated with
vandetinib ± docetaxel, 570 archival tumor samples were analyzed for EGFR
and KRAS status. High EGFR protein expression shown with IHC (≥1% tumor
cells stained) was seen in 88% of patients, of whom 35% were FISH+ and 14%
were EGFR MT (exons 18-21). In this study, 13% were KRAS MT (exons 12-13).
Consistent trends in improved PFS, OS, and ORR were seen in patients with
EGFR (FISH+ or MT). However, no differences were seen in treatment types or
KRAS mutation status.
Herbst 2010
In patients treated with sorafenib,
KRAS mutation was associated
with an improved DCR, and EGFR
mutation was associated with a
decreased DCR
A phase II trial in 105 patients with lung cancer being treated with sorafenib,
erlotinib, vandetinab, and erlotinib plus bexarotene. Patients were analyzed for
DCR at 8 weeks. In this study 61% (11/18) of patients with a KRAS mutation
treated with sorafenib showed a DCR compared to 31% (4/13) of those treated
with erlotinib. By contrast, patients with an EGFR mutation had a significantly
lower response of 23% (3/13) than those with no mutation 64% (3/13)
(P=0.012).
Loss of PTEN
expression in
patients treated
with EGFR
tyrosine kinase
inhibitors
EGFR and KRAS
predict response
to vandetinib (an
EGFR inhibitor) +
docetaxel
EGFR, KRAS,
and BRAF
predict response
to sorafenib, a
small molecule
kinase inhibitor
DCR, disease control rate; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MT mutation; ORR, overall response rate
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In the 2010 update of guidelines on the early detection of
TABLE 5
POTENTIAL SOURCES OF COMPARATIVE
EFFECTIVENESS RESEARCH
prostate cancer developed by the American Cancer Society, SDM
has been incorporated into the process “[w]hen the evidence is
1. Randomized controlled trials (RCTs)
not clear that the benefits of screening outweigh the risks, an
2. Systematic reviews of and meta-analyses of RCTs
individual’s values and preferences must be factored into the
screening decision” [Wolf 2010].
3. Other comparative clinical trials
The definition of SDM is not consistent across studies [Pieterse
4. Population studies, including registries and administrative and claims data
2008], although the essential elements (as defined by a number
5. Prognostic and predictive association studies
of models) include presenting options and discussing patients’
6. Quality of life studies, including patient-reported outcomes
values (see Table 7) [White 2007, Charles 1999, Charles 1999a].
One study of 60 patients with rectal cancer showed that whereas
7. Clinical decision models, including cost-effectiveness and cost-utility analyses
physicians viewed patient participation in treatment choice as
TABLE 6
RECOMMENDATIONS FOR THE CO-DEVELOPMENT
OF TARGETED THERAPIES AND PREDICTIVE
BIOMARKERS [Lyman 2010]
reaching an agreement, 23% of patients felt that participation
could be solely defined as the physician providing information. In
this study, 81% of patients believed that not all patients would be
able to participate in choosing treatments and 74% believed that
1. Source studies should be well-designed, large, randomized trials with
appropriate control groups and clinically relevant endpoints of efficacy
and safety.
physicians would not be able to “weigh the pros and cons of treatment” for their patients.
2. Biomarkers should be based on a biologically plausible rationale, with
good test performance and reproducibility.
Implementing SDM in clinical practice will be challenging. Many
patients are not health literate, which is defined as the “capacity
3. Biomarker results should be available on a majority of subjects with a
detailed accounting of the reasons for unavailable samples or results.
to obtain, process, and understand basic health information and
services needed to make appropriate health decision” [Kutner
4. Biomarker subgroups and planned analysis should be prespecified.
2003]. The results of a national survey of American adults, which
5. Source studies should have adequate power to establish with confidence
any differential treatment effect in subgroups based on the biomarker.
is shown in Figure 1, showed that only 12% were considered pro-
6. Biomarker measurement should be blinded to the treatment group
assignment and study outcomes.
and 14% were below basic [Kutner 2006].
ficient in health literacy, 53% were intermediate, 22% were basic,
A further challenge is that patients’ perceptions of risk are
7. Appropriate adjustment for multiple testing should be reported.
complicated because they are affected by nonquantifiable issues,
such as personal motivations, social and community influences,
8. Formal testing of any drug/biomarker interaction should be conducted.
and emotional reactions [Klein 2007]. In addition, the presentation of multiple options can lead to “decisional conflict,” which
9. When possible, results should be adjusted for all known
prognostic/predictive factors.
can cause patients to change their minds, delay making a decision, regret a previous decision, and even blame a physician for
10. Consistent findings related to the biomarker should be observed in at
least two large trials.
a bad outcome [Stacey 2008]. A recent study reported that 66%
of women with early-stage breast cancer had trouble deciding
TABLE 7
ELEMENTS OF SHARED DECISION MAKING
[White 2007, Charles 1999, Charles 1999a]
between treatment choices (eg, mastectomy or lumpectomy with
radiation therapy). In another study, only 30% of patients with
advanced NSCLC felt certain about a choice between chemother-
• Discussing the nature of the decision
(What is the clinical issue being addressed?)
apy or best supportive therapy. The key factors related to these
• Describing treatment alternatives
decisional conflicts included feeling uninformed and unsupported
• Discussing the pros and cons of the choices
as well as being uncertain about their personal values [Stacey
• Discussing uncertainty; assessing family understanding
2008].
• Eliciting patient values and preferences
• Discussing the family’s role in decision making
As previously mentioned, the majority of physicians believe in
• Assessing the need for input from others
SDM; however, studies have shown that their treatment decisions
• Exploring the context of the decision and eliciting the family’s opinion
about the treatment decision
are often influenced by their own values and professional experience [Baldauf 2009]. A survey of more than 1,000 physicians
showed that 93% of urologists chose radical prostatectomy as the
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preferred treatment for men with moderately differentiated, clini-
Additionally, providing well-designed decision aids can facilitate
cally localized prostate cancer, while 72% of radiation oncologists
SDM. Decision aids provide patients with information about
believed that surgery and external beam radiation therapy were
treatment options and risks and benefits, as well as tools to help
equivalent or more appropriate treatment options. In other words,
clarify personal values. They may also provide more detailed
physicians chose the treatments that they were personally more
information about a disease condition [IPDAS 2010, Stacey
familiar with and would be in charge of delivering or performing
2008]. Currently, more than 500 decision aids are available or in
[Fowler 2000]. Based on their understanding of their patients,
development [IPDAS 2010]. In order to improve the reliability of
physicians may try to guess what a patient prefers, although stud-
these instruments, a group of interested professionals founded
ies have shown that they are poor at predicting an informed pa-
the International Patient Decision Aid Standards (IPDAS) Collabo-
tient’s treatment choice [Brothers 2004, Stalmeier 2007]. These
ration, which has developed standards to improve the quality of
studies confirm that it is important for physicians to be willing to
all decision aids [IPDAS 2010]. Familiarizing oncologists with the
discuss patient preferences and not make blind assumptions.
availability and applicability of these tools may greatly improve
the shared decision-making process with their patients.
Patient participation in treatment choices is becoming increasingly standard in oncology. Studies show that most patients would
CONCLUSION
prefer to share decision-making responsibilities about their overall health, and this process has been shown to favorably impact
Oncology treatments are complex and require weighing
a number of factors, including quality of life. Many healthcare
potential risks against potential benefits. Innovation in oncology
providers already use SDM in their practices, although some may
will continue to produce new technologies and treatments. Of
not be using it appropriately, and others still prefer a traditional,
the multitude of factors oncology practitioners must take into
paternalistic approach. To increase adoption of SDM, health-
consideration, the principles of shared decision making,
care providers would benefit from education and training about
comparative effectiveness, and utilization of biomarkers to
studies backing its use in oncology, as well as the most effective
methods and materials available to appropriately implement it for
all patients.
optimize treatment have been identified as critical elements
to incorporate into standards of practice. To implement these
principles, the oncologist must remain up to date on the most
recent evidence on tumor types and be informed about new
advances and involve their patients in therapeutic decision
making, with the ultimate goal of improved health outcomes
in the oncology patient population.
FIGURE 1 | HEALTH LITERACY IN AMERICAN ADULTS
14
ADULTS (%)
80
60
40
20
PERCENT BELOW BASIC
BELOW BASIC
BASIC
22
0
53
20
40
12
60
80
100
PERCENT BASIC AND ABOVE
INTERMEDIATE
O N L I N E
PROFICIENT
R E P O R T
F R O M
A S C O
2 0 1 0
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9
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