In February 2010, the Medical Advisory Secretariat (MAS) began work on 
evidence-based reviews of published literature surrounding three pharmacogenomic 
tests. This project came about when Cancer Care Ontario (CCO) asked MAS to 
provide evidence-based analyses on the effectiveness and cost-effectiveness of 
three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based 
analyses have been prepared for each of these technologies. These have been 
completed in conjunction with internal and external stakeholders, including a 
Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup 
committees were developed for each disease area. For each technology, an 
economic analysis was also completed by the Toronto Health Economics and 
Technology Assessment Collaborative (THETA) and is summarized within the 
reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: 
www.health.gov.on.ca/mas or at 
www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION 
PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST 
CANCER: An Evidence-Based and Economic AnalysisEpidermal Growth Factor Receptor 
Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine 
Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung 
Cancer: An Evidence-Based and Ecopnomic AnalysisK-RAS testing in Treatment 
Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic 
Analysis
OBJECTIVE: To review and synthesize the available evidence regarding the 
laboratory performance, prognostic value, and predictive value of Oncotype-DX 
for the target population.
CLINICAL NEED: CONDITION AND TARGET POPULATION The target population of this 
review is women with newly diagnosed early stage (stage I-IIIa) invasive breast 
cancer that is estrogen-receptor (ER) positive and/or progesterone-receptor (PR) 
positive. Much of this review, however, is relevant for women with early stage 
(I and II) invasive breast cancer that is specifically ER positive, lymph node 
(LN) negative and human epidermal growth factor receptor 2 (HER-2/neu) negative. 
This refined population represents an estimated incident population of 3,315 new 
breast cancers in Ontario (according to 2007 data). Currently it is estimated 
that only 15% of these women will develop a distant metastasis at 10 years; 
however, a far great proportion currently receive adjuvant chemotherapy, 
suggesting that more women are being treated with chemotherapy than can benefit. 
There is therefore a need to develop better prognostic and predictive tools to 
improve the selection of women that may benefit from adjuvant chemotherapy. 
TECHNOLOGY OF CONCERN: The Oncotype-DX Breast Cancer Assay (Genomic Health, 
Redwood City, CA) quantifies gene expression for 21 genes in breast cancer 
tissue by performing reverse transcription polymerase chain reaction (RT-PCR) on 
formalin-fixed paraffin-embedded (FFPE) tumour blocks that are obtained during 
initial surgery (lumpectomy, mastectomy, or core biopsy) of women with early 
breast cancer that is newly diagnosed. The panel of 21 genes include genes 
associated with tumour proliferation and invasion, as well as other genes 
related to HER-2/neu expression, ER expression, and progesterone receptor (PR) 
expression.
RESEARCH QUESTIONS: What is the laboratory performance of Oncotype-DX?How 
reliable is Oncotype-DX (i.e., how repeatable and reproducible is 
Oncotype-DX)?How often does Oncotype-DX fail to give a useable result?What is 
the prognostic value of Oncotype-DX?Is Oncotype-DX recurrence score associated 
with the risk of distant recurrence or death due to any cause in women with 
early breast cancer receiving tamoxifen?What is the predictive value of 
Oncotype-DX?Does Oncoytpe-DX recurrence score predict significant benefit in 
terms of improvements in 10-year distant recurrence or death due to any cause 
for women receiving tamoxifen plus chemotherapy in comparison to women receiving 
tamoxifen alone?How does Oncotype-DX compare to other known predictors of risk 
such as Adjuvant! Online?How does Oncotype-DX impact patient quality of life and 
clinical/patient decision-making?
SEARCH STRATEGY: A literature search was performed on March 19(th), 2010 using 
OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the 
Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane 
Library, and the International Agency for Health Technology Assessment (INAHTA) 
for studies published from January 1(st), 2006 to March 19(th), 2010. A starting 
search date of January 1(st), 2006 was because a comprehensive systematic review 
of Oncotype-DX was identified in preliminary literature searching. This 
systematic review, by Marchionni et al. (2008), included literature up to 
January 1(st), 2007. All studies identified in the review by Marchionni et al. 
as well as those identified in updated literature searching were used to form 
the evidentiary base of this review. The quality of the overall body of evidence 
was identified as high, moderate, low or very low according to GRADE 
methodology.
INCLUSION CRITERIA: Any observational trial, controlled clinical trial, 
randomized controlled trial (RCT), meta-analysis or systematic review that 
reported on the laboratory performance, prognostic value and/or predictive value 
of Oncotype-DX testing, or other outcome relevant to the Key Questions, specific 
to the target population was included.
EXCLUSION CRITERIA: Studies that did not report original data or original data 
analysis,Studies published in a language other than English,Studies reported 
only in abstract or as poster presentations (such publications were not sought 
nor included in this review since the MAS does not generally consider evidence 
that is not subject to peer review nor does the MAS consider evidence that lacks 
detailed description of methodology).
OUTCOMES OF INTEREST: Outcomes of interest varied depending on the Key Question. 
For the Key Questions of prognostic and predictive value (Key Questions #2 and 
#3), the prospectively defined primary outcome was risk of 10-year distant 
recurrence. The prospectively defined secondary outcome was 10-year death due to 
any cause (i.e., overall survival). All additional outcomes such as risk of 
locoregional recurrence or disease-free survival (DFS) were not prospectively 
determined for this review but were reported as presented in included trials; 
these outcomes are referenced as tertiary outcomes in this review. Outcomes for 
other Key Questions (i.e., Key Questions #1, #4 and #5) were not prospectively 
defined due to the variability in endpoints relevant for these questions.
SUMMARY OF FINDINGS: A total of 26 studies were included. Of these 26 studies, 
only five studies were relevant to the primary questions of this review (Key 
Questions #2 and #3). The following conclusions were drawn from the entire body 
of evidence: There is a lack of external validation to support the reliability 
of Oncotype-DX; however, the current available evidence derived from internal 
industry validation studies suggests that Oncotype-DX is reliable (i.e., 
Oncotype-DX is repeatable and reproducible).Current available evidence suggests 
a moderate failure rate of Oncotype-DX testing; however, the failure rate 
observed across clinical trials included in this review is likely inflated; the 
current Ontario experience suggests an acceptably lower rate of test failure.In 
women with newly diagnosed early breast cancer (stage I-II) that is 
estrogen-receptor positive and/or progesterone-receptor positive and lymph-node 
negative:There is low quality evidence that Oncotype-DX has prognostic value in 
women who are being treated with adjuvant tamoxifen or anastrozole (the latter 
for postmenopausal women only),There is very low quality evidence that 
Oncotype-DX can predict which women will benefit from adjuvant CMF/MF 
chemotherapy in women being treated with adjuvant tamoxifen.In postmenopausal 
women with newly diagnosed early breast cancer that is estrogen-receptor 
positive and/or progesterone-receptor positive and lymph-node positive:There is 
low quality evidence that Oncotype-DX has limited prognostic value in women who 
are being treated with adjuvant tamoxifen or anastrozole,There is very low 
quality evidence that Oncotype-DX has limited predictive value for predicting 
which women will benefit from adjuvant CAF chemotherapy in women who are being 
treated with adjuvant tamoxifen.There are methodological and statistical 
limitations that affect both the generalizability of the current available 
evidence, as well as the magnitude and statistical strength of the observed 
effect sizes; in particular:Of the major predictive trials, Oncotype-DX scores 
were only produced for a small subset of women (<40% of the original randomized 
population) potentially disabling the effects of treatment randomization and 
opening the possibility of selection bias;Data is not specific to 
HER-2/neu-negative women;There were limitations with multivariate statistical 
analyses.Additional trials of observational design may provide further 
validation of the prognostic and predictive value of Oncotype-DX; however, it is 
unlikely that prospective or randomized data will become available in the near 
future due to ethical, time and resource considerations.There is currently 
insufficient evidence investigating how Oncoytpe-DX compares to other known 
prognostic estimators of risk, such as Adjuvant! Online, and there is 
insufficient evidence investigating how Oncotype-DX would impact 
clinician/patient decision-making in a setting generalizable to Ontario.