Gene-expression assays: New tools to individualize treatment of early-stage breast cancer
The clinical and economic data for the two currently available gene-expression assays are reviewed.
Two gene-expression assays, used to determine the risk of breast cancer recurrence in patients with stage I or II node-negative breast cancer, are currently available. Oncotype DX is an assay performed on RNA extracted from paraffin-embedded tumor tissue. It analyzes the expression of 21 genes: 16 cancer-related genes and 5 reference genes. The results are used to calculate a recurrence score to identify the likelihood of cancer recurrence in patients treated with tamoxifen. The results of two studies evaluating the ability of Oncotype DX to predict the risk of breast cancer recurrence suggest that patients with ER-positive, node-negative breast cancer and a low recurrence score may need only adjuvant treatment with tamoxifen, while intermediate- and high-risk patients may require additional treatment with adjuvant chemotherapy. MammaPrint, an oligonucleotide microassay performed on fresh-frozen tumor samples, analyzes the expression of 70 genes. Studies have found that MammaPrint allows young patients (<61 years) with early-stage breast cancer to be categorized as having a high or low risk of distant metastasis. High-risk patients may then be managed with more aggressive therapy.
Two gene-expression assays, Oncotype DX and MammaPrint, have been developed to determine the risk of breast cancer recurrence in patients with stage I or II node-negative breast cancer. In the future, these tests may be useful in determining the need for systemic adjuvant therapy in such patients.
Available from: Susan J Done
- "The gene profiles used to develop CMTC were derived from a commercially available whole-genome microarray platform that has become more affordable than currently available multigene assays, such as MammaPrint (70GS; Agendia Inc, Irvine, CA, USA) and Oncotype DX (Genomic Health, Redwood City, CA, USA), which report only a limited number of genes [24,45] at a high cost [19,50]. Furthermore, the clinical application of CMTC may be extended to other commercial genome-wide microarray platforms, as we have demonstrated the reproducibility of CMTC classification in the validation cohort derived independently from different DNA microarray platforms. "
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ABSTRACT: When making treatment decisions, oncologists often stratify breast cancer (BC) into a low-risk group (low-grade estrogen receptor-positive (ER+)), an intermediate-risk group (high-grade ER+) and a high-risk group that includes Her2+ and triple-negative (TN) tumors (ER-/PR-/Her2-). None of the currently available gene signatures correlates to this clinical classification. In this study, we aimed to develop a test that is practical for oncologists and offers both molecular characterization of BC and improved prediction of prognosis and treatment response.
We investigated the molecular basis of such clinical practice by grouping Her2+ and TN BC together during clustering analyses of the genome-wide gene expression profiles of our training cohort, mostly derived from fine-needle aspiration biopsies (FNABs) of 149 consecutive evaluable BC. The analyses consistently divided these tumors into a three-cluster pattern, similarly to clinical risk stratification groups, that was reproducible in published microarray databases (n = 2,487) annotated with clinical outcomes. The clinicopathological parameters of each of these three molecular groups were also similar to clinical classification.
The low-risk group had good outcomes and benefited from endocrine therapy. Both the intermediate- and high-risk groups had poor outcomes, and their BC was resistant to endocrine therapy. The latter group demonstrated the highest rate of complete pathological response to neoadjuvant chemotherapy; the highest activities in Myc, E2F1, Ras, β-catenin and IFN-γ pathways; and poor prognosis predicted by 14 independent prognostic signatures. On the basis of multivariate analysis, we found that this new gene signature, termed the "ClinicoMolecular Triad Classification" (CMTC), predicted recurrence and treatment response better than all pathological parameters and other prognostic signatures.
CMTC correlates well with current clinical classifications of BC and has the potential to be easily integrated into routine clinical practice. Using FNABs, CMTC can be determined at the time of diagnostic needle biopsies for tumors of all sizes. On the basis of using public databases as the validation cohort in our analyses, CMTC appeared to enable accurate treatment guidance, could be made available in preoperative settings and was applicable to all BC types independently of tumor size and receptor and nodal status. The unique oncogenic signaling pathway pattern of each CMTC group may provide guidance in the development of new treatment strategies. Further validation of CMTC requires prospective, randomized, controlled trials.
Breast cancer research: BCR 09/2011; 13(5):R92. DOI:10.1186/bcr3017 · 5.49 Impact Factor
Annals of Oncology 05/2008; 19(4):822-4. DOI:10.1093/annonc/mdn043 · 7.04 Impact Factor
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ABSTRACT: The authors contend that the crisis facing the U.S. health care system is in large part a consequence of that system's disease-oriented, reactive, and sporadic approach to care, and they suggest that a prospective approach to health care, which emphasizes personalized medicine and strategic health planning, would be a more rational way to prevent disease and maximize health. During recent years, personalized, predictive, preventive, and participatory medicine--that is, prospective care--has been receiving increasing attention as a solution to the U.S. health care crisis. Advocacy has been mainly from industry, government, large employers, and private insurers. However, academic medicine, as a whole, has not played a leading role in this movement. The authors believe that academic medicine has the opportunity and responsibility to play a far greater role in the conception and development of better models to deliver health care. In doing so, it could lead the transformation of today's dysfunctional system of medical care to that of a prospective approach that emphasizes personalization, prediction, prevention, and patient participation. Absent contributing to improving how care is delivered, academic medicine's leadership in our nation's health will be bypassed.
Academic medicine: journal of the Association of American Medical Colleges 09/2008; 83(8):707-14. DOI:10.1097/ACM.0b013e31817ec800 · 2.93 Impact Factor
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