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Educational Supplement: Appendix
Factors
Used To Select Adjuvant TherapyOverview
Gary
M. Clark , Ph.D.
The terms prognostic
factors and predictive factors have been used
in many different contexts. Some factors may be patient-specific
(for example, race, age, socioeconomic, environmental); others may
be disease-specific (for example, biomarkers measured on tumor specimens,
serum, bone marrow, etc.). These factors have several potential
clinical uses, including identifying patients at high risk for a
specific disease or for diagnosing that disease, estimating prognosis
for patients diagnosed with a specific disease who receive no therapy
or standard therapy, predicting response to a particular therapy,
monitoring response to therapy during a treatment course, or identifying
targets of opportunity for new therapies.
For this presentation,
I will focus on prognostic biomarkers that might be used to estimate
prognosis for patients diagnosed with a specific disease who receive
no therapy or standard therapy, and on predictive biomarkers for
predicting response to a particular therapy. Evaluation of prognostic
biomarkers requires a single group of patients, preferably untreated.
Evaluation of predictive biomarkers requires two groups of patients,
preferably randomized to treatment or no treatment. Evidence of
predictability is obtained by computing a statistical test for an
interaction between treatment and biomarker status.
The clinical
endpoints for evaluating prognostic or predictive biomarkers may
be overall survival, disease-specific survival, disease-free survival,
progression-free survival, event-free survival, tumor response as
determined by tumor shrinkage, or modulation of another biomarker.
Efficacy may be expressed as absolute benefit or relative benefit.
Relative benefit for a survival endpoint is often expressed as the
relative risk (risk of dying in the experimental group divided by
the risk of dying in the control group), or the relative odds ratio
(odds of surviving vs. dying in the experimental group divided by
the odds of surviving vs. dying in the control group). The hazard
ratio obtained from statistical regression models is often used
to approximate the relative risk.
Only recently
have criteria been proposed for determining the clinical utility
of biomarkers. The American Society of Clinical Oncology (ASCO Expert
Panel, 1996) used very conservative criteria to develop practice
guidelines for using biomarkers. Partly in response to the lack
of consensus about these criteria, a tumor marker utility grading
system (TMUGS) was developed to differentiate levels of evidence
among published studies (Hayes, Bast, Desch, et al., 1996). The
College of American Pathologists used a modification of this system
to develop its consensus statements about prognostic factors in
breast, colon, and prostate cancer (Fitzgibbons, Page, Weaver, et
al., 1999).
Study designs
to evaluate biomarkers for different clinical uses vary with respect
to the types of subjects and/or tissues to be studied, the endpoints
that need to be measured, and the number of subjects and/or tissues
that need to be accrued. However, the basic methodological principles
for good study designs are common to all clinical uses (Altman,
Lyman, 1998). All study designs should be based on clearly stated
hypotheses. Assays should be reproducible and should be performed
without knowledge of the clinical data and patient outcome. Results
for individual factors should be analyzed using multivariate techniques
that incorporate standard biomarkers that are already in clinical
use. All results should be validated in subsequent studies before
they are incorporated into clinical practice.
Very few new
prognostic or predictive factors have been validated and endorsed
for clinical use during the past several years. Part of the reason
is a lack of adherence to proposed guidelines for the design, conduct,
analysis, and reporting of results from prognostic factor studies.
It is time to translate the principles of good study design and
analysis that have been developed for clinical trials to the evaluation
of new biomarkers.
References
Altman DG, Lyman
GH. Methodological challenges in the evaluation of prognostic factors
in breast cancer. Breast Cancer Res Treat 1998;52:289-303. Abstract.
American Society
of Clinical Oncology (ASCO) Expert Panel. Clinical practice guidelines
for the use of tumor markers in breast and colorectal cancer: report
of the American Society of Clinical Oncology Expert Panel. J Clin
Oncol 1996;14:2843-77. Abstract.
Fitzgibbons
PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic
factors in breast cancer: College of American Pathologists Consensus
Statement 1999. Arch Pathol Lab Med 2000;124:966-78. Abstract.
Hayes DF, Bast
RC, Desch CE, Fritsche H Jr, Kemeny NE, Jessup JM, et al. Tumor
marker utility grading system: a framework to evaluate clinical
utility of tumor markers. J Natl Cancer Inst 1996;88:1456-66. Abstract.
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