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KSR Number: KSRL3347

Gene expression profiling for guiding adjuvant chemotherapy decisions in women with early breast cancer: an evidence-based and economic analysis

Risk of Bias Assessment

Overall summary: High risk of bias in the review

Bottom Line

Current evidence suggests that the Oncotype-DX test may reliably predict the risk of disease recurrence or death from any cause in women with newly diagnosed early stage (stage I–IIIa) invasive breast cancer. However, these conclusions should be interpreted with caution, since several methodological issues mean relevant studies may have been missed, and reviewer error and bias may be present. Further high quality studies are needed to formally validate the prognostic and predictive value of the Oncotype-DX test.

Risk of Bias Assessment

Overall summary High risk of bias in the review

High

Studies were restricted based on language (only English studies were included) and publication format (abstracts and poster presentations were excluded). Only a single reviewer was involved in study selection, and no information was provided regarding the number of authors involved in the data extraction or quality assessment process, meaning reviewer error and bias may be present. Insufficient study characteristics were provided. Quality assessment was not performed using an appropriate tool.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably no
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review High

Details of Review

Number of studies 26
Number of participants NR
Last search date 19th March 2010
Review type Prognostic/Predictive
Objective To determine the laboratory performance, prognostic value, and predictive value of the Oncotype-DX genetic test in women with newly diagnosed early stage (stage I–IIIa) invasive breast cancer that is oestrogen-receptor (ER)-positive or ER- and/or progesterone-receptor-positive.
Population Women with newly diagnosed early stage (stage I–IIIa) invasive breast cancer that is oestrogen-receptor (ER)-positive or ER- and/or progesterone-receptor-positive
Interventions Index test: Oncotype-DX testing
Comparator NA
Outcome Primary outcome: risk of 10 year distant recurrence of breast cancer

Secondary outcome: risk of 10 year death due to any cause.

Tertiary outcomes: risk of locoregional recurrence or disease-free survival (DFS).

Laboratory performance, prognostic value and/or predictive value of the Oncotype-DX test.
Study design Any observational trial, controlled clinical trial, randomised controlled trial (RCT), meta-analysis or systematic review
Reference standard NA
PP factor Gene expression profile across 21 genes measured by the Oncoytpe-DX test

Results

In terms of Oncotype-DX test reliability, three studies reported that the standard deviation in repeat measurements was generally less than or equal to 3.0 RS units, suggesting that the test was reliable (3 studies).

In terms of Oncotype-DX test failure rate, thirteen trials reported that the test could fail due to insufficient tumour sample in tissue block, insufficient RNA for RT-PCR, failure of RT-PCR and low signal of reference genes. For tests that were considered to have failed due to insufficient tumour sample in the tissue, block, a failure rate was reported to range from 2.7% to 44.9% (13 studies).

In terms of the prognostic value of Oncotype-DX in lymph node-negative patients, the risk of distant recurrence or all-cause mortality was reported to segregate into low, intermediate and high risk depending on a low, intermediate or high Oncotype-DX recurrence score (4 studies). In three out of four studies, this was a significant difference; in one out of four studies, no statistical results were reported.

In terms of the prognostic value of Oncotype-DX in lymph node-positive patients, the risk of distant recurrence or all-cause mortality was reported to segregate into low, intermediate and high risk depending on a low, intermediate or high Oncotype-DX recurrence score (2 studies). Both studies reported that this was a significant difference.

In terms of the predictive value of Oncotype-DX in lymph node-negative patients, a single study reported that only women in a high risk category based on Oncotype-DX recurrence score showed significant reductions in the risk of distant recurrence for chemotherapy vs. tamoxifen (risk ratio [RR] 0.26, 95% confidence interval [CI] 0.13 to 0.53; 1 study). Conversely, the risk of recurrence in the Oncotype-DX low risk group was reported to increase with chemotherapy (RR 1.31, 95% CI 0.46 to 3.78; 1 study). Similar results were reported for all-cause mortality.

In terms of the predictive value of Oncotype-DX in lymph node-positive patients, a single study reported a reduction in the risk of recurrence following chemotherapy in women in the Oncotype-DX high risk category (hazard ratio [HR] 0.59, 95% CI 0.35 to 1.01; 1 study). Similar results were reported to all-cause mortality.

Full Risk of Bias Assessment

The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were reported in the eligibility criteria based on the study characteristics. Studies were restricted based on language (only studies published in English were included) and publication format (abstracts and poster presentations were excluded).

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably no
Concerns regarding specification of study eligibility criteria High

MEDLINE (Ovid), 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) were searched for studies published from 1st January 2006 to 19th March 2010. As this review aimed to update a previous, relevant systematic review, which searched up to January 2007, databases were searched from 2006 to 2010; this was considered appropriate. The reference lists of the included studies and reviews on the topic were also examined for any additional relevant studies. The search terms and structure of the search strategy seemed appropriate to retrieve all eligible studies. The search was restricted to English language publications only; since this issue was already downgraded in ROBIS 1, this was not downgraded again here. A single reviewer was involved in study selection. Articles with unknown eligibility were reviewed with a second reviewer (a clinical epidemiologist) and then a group of clinical epidemiologists until consensus was achieved.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? No
2.5 Were efforts made to minimise error in selection of studies? Probably no
Concerns regarding methods used to identify and/or select studies High

No information was provided on the number of authors involved in data extraction. Insufficient study characteristics were provided, which impacted the interpretation of results. The methodological quality was assessed using GRADE; this was considered insufficient as a standalone assessment. No information was mentioned regarding the number of authors involved in the quality assessment.

3.1 Were efforts made to minimise error in data collection? No information
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? No
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably no
3.5 Were efforts made to minimise error in risk of bias assessment? No information
Concerns regarding methods used to collect data and appraise studies High

The synthesis appeared to include all relevant studies. A narrative synthesis was performed to summarise the findings. All pre-defined analyses appear to have been reported. Biases in the primary studies were taken into consideration while reporting the findings.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low

Abstract

UNLABELLED: 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? Research methods: Literature search: 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.