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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

Keywords

  • Antineoplastic Agents
  • Breast Neoplasms
  • Chemotherapy, Adjuvant
  • Gene Expression Profiling
  • Neoplasm Staging
  • Prognosis
  • Treatment Outcome
  • Tumor Markers, Biological