Clinical Validity/Utility, Change in Practice Patterns, and Economic Implications of Risk Stratifiers to Predict Outcomes for Early-Stage Breast Cancer: A Systematic Review

Stanford University School of Medicine, Stanford, CA, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 07/2012; 104(14):1068-79. DOI: 10.1093/jnci/djs261
Source: PubMed


At least 14 stratifiers exist to assess recurrence risk, chemotherapy response, and overall survival (OS) in women with early-stage breast cancer (ESBC). These stratifiers have not been compared using a recently developed rigorous framework. We performed a systematic review of the literature on clinical validity/utility, change in clinical practice, and economic implications of ESBC stratifiers.
A systematic literature search was performed using PubMed, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Database of Systematic Reviews, and bibliographies of relevant studies. Data were extracted by two investigators and graded using a previously published framework. The Level-of-Evidence determination for each study was summarized, and the studies that provide evidence on change in clinical practice and economic implications are reported.
Fifty-six articles published original evidence addressing the 21-gene recurrence score (n = 31), 70-gene signature (n = 14), Adjuvant! Online (n = 12), 5-antibody immunohistochemistry panel (n = 3), 5-gene expression index (n = 1), and 14-gene signature (n = 1). The 21-gene recurrence score satisfied Level I evidence (the highest level of evidence among five levels) for estimating distant recurrence risk (DRR), OS, and response to adjuvant chemotherapy, and Level II for estimating local recurrence risk. The 5-antibody immunohistochemistry panel and 70-gene signature satisfied Level II evidence for estimating DRR and OS. Adjuvant! Online satisfied Level II evidence for estimating DRR, OS, and chemotherapy response. The 5-gene expression index satisfied Level III evidence for predicting DRR. The 14-gene signature satisfied Level III evidence for predicting DRR and OS. Ten studies reported changes in clinical practice patterns; seven studies reported economic implications.
The available evidence on the ability of stratifiers to predict risks of recurrence and response to chemotherapy in ESBC is growing. Level-of-Evidence determinations using the newer framework provide a solid scientific foundation for clinical recommendations.

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Available from: Hialy Riviera Gutierrez, Feb 24, 2014
    • "Several computational methods are available to integrate and analyse large datasets, with a range of statistical methods being used to identify a set of genes or gene expression signatures (biomarkers) that, potentially, enable discrimination of distinct molecular subgroups within a patient cohort, or that are associated with certain treatment responses [17– 21]. Such statistical classification of samples may clearly make sense when the susceptibility of a given patient to specific drugs is assessed, for example, for improving the treatment regime [22] [23] [24] [25]. However, whether the different gene signatures obtained by different statistical studies actually reflect the underlying biology of the disease in an individual patient is questionable [26] [27] [28]. "
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    ABSTRACT: The biological processes that keep us healthy or cause disease, as well as the mechanisms of action of possible drugs are inherently complex. In the face of this complexity, attempts at discovering new drugs to treat diseases have alternated between trial-and-error (typically on experimental systems) and grand simplification, usually based on much too little information. We now have the chance to combine these strategies through establishment of ‘virtual patient’ models, centred on a detailed molecular characterisation of thousands or even, in the future, millions of patients. In doing so, we lay the foundations for truly personalised therapy, as well as a far-reaching virtualisation of drug discovery and development in oncology and other areas of medicine.
    Drug Discovery Today Technologies 08/2015; 15:33-40. DOI:10.1016/j.ddtec.2015.07.002
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    • "The Oncotype DX 21-gene assay represents the first clinically validated multi-gene assay that can quantify the likelihood of breast cancer recurrence [8]. The recurrence score generated in this test has been consistently shown to directly impact decision-making in breast cancer management [25] [26]. Treatment decisions among medical oncologists for early breast cancer are variable even with the use of gene assays [27] [28]. "
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    ABSTRACT: Abstract Introduction The use of chemotherapy in node-negative, (O)Estrogen Receptor (ER)-positive breast cancer has changed significantly since the introduction of Oncotype DX to determine systemic recurrence risk based on tumour genomic signature. Aims This study aims to: 1.Document longitudinal changes in chemotherapy use, 2.Assess the impact of new evidence on local protocol. Methods A cohort study was undertaken, including consecutive patients with early node-negative, ER-positive breast cancer diagnosed between 2006 and May 2013, including a period of prospective clinical trial (Trial Assigning Individualised Options for Treatment (TAILORx)) recruitment. Data were collected regarding patient demographics, tumour clinico-pathological features, Oncotype DX use and recurrence score and chemotherapy use. All therapeutic decisions were made following multidisciplinary discussion, with adherence to guidelines and consideration of trial protocol and Oncotype DX recurrence scores. Results 479 consecutive patients were included in the study, of whom 241 (50%) underwent Oncotype DX testing, 97 as part of the TAILORx clinical trial. Oncotype DX testing began on a trial basis in 2007 and until October 2011, only patients enrolled on TAILORx availed of genomic profiling. From October 2011, Oncotype DX was used in all eligible patients as per National Cancer Control Programme (NCCP) guidelines. A total of 216 (45%) patients received chemotherapy. The use of chemotherapy changed in inverse proportion to the availability of the genomic assay. Of those patients in whom Oncotype DX was utilised, 138 (57%) were spared chemotherapy. Conclusion This study validates the use of molecular testing in the rationalisation of systemic therapy.
    European Journal of Cancer 09/2014; 50(16). DOI:10.1016/j.ejca.2014.08.002 · 5.42 Impact Factor
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    • "The highest LOE is level I, and a new designation of level Ib has now been defined, which uses archived tissue specimens from large, randomized, clinical studies with long-term outcomes that prospectively define the endpoints and analyses.13 A robust LOE category provides the evidence and a sound scientific foundation for clinical recommendations, guiding actual change in clinical practice.12 Studies that aim to determine clinical utility are designed differently than validation studies (level I evidence is not generated). "
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    ABSTRACT: The addition of adjuvant chemotherapy to hormonal therapy is recommended for patients with estrogen receptor-positive (ER+), node-positive (N+) early breast cancer (EBC). Some of these patients, however, are not likely to benefit from treatment and may, therefore, be overtreated while also incurring unnecessary treatment-related adverse events and health care costs. The 21-gene Recurrence Score assay has been clinically validated and recommended for use in patients with ER+, node-negative (N0) EBC to assess the 10-year risk of distant disease recurrence and predict the likelihood of response to adjuvant chemotherapy. A growing body of evidence from several large phase III clinical trials reports similar findings in patients with ER+, N+ EBC. A systematic review of published literature from key clinical trials that have used the 21-gene breast cancer assay in patients with ER+, N+ EBC was performed. The Recurrence Score has been shown to be an independent predictor of disease-free survival, overall survival, and distant recurrence-free interval in patients with ER+, N+ EBC. Outcomes from decision impact and health economics studies further indicate that the Recurrence Score affects physician treatment recommendations equally in patients with N+ or N0 disease. It also indicates that a reduction in Recurrence Score-directed chemotherapy is cost-effective. There is a large body of evidence to support the use of the 21-gene assay Recurrence Score in patients with N+ EBC. Use of this assay could help guide treatment decisions for patients who are most likely to receive benefit from chemotherapy.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    American Journal of Clinical Oncology 05/2014; 37(4). DOI:10.1097/COC.0000000000000086 · 3.06 Impact Factor
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