One of the primary challenges in the treatment of patients with early-stage breast cancer is determining which patients will benefit from adjuvant chemotherapy. Traditionally, treatment decisions have been made based on a combination of tumor characteristics and patient and physician perspectives regarding risks and benefits. Recent technologic advances, including the development of gene-expression arrays, have led to the identification of molecular signatures that provide prognostic information in addition to the basic clinicopathologic features of individual tumors. While these new methods allow for more refined determination of prognosis for an individual patient, few data are available to support use of these new technologies in the clinic for treatment decision-making. At present, data from a single retrospective study are available to support the use of one assay, the 21-gene recurrence score, for decision-making regarding adjuvant chemotherapy. Large, multinational clinical trials are currently ongoing to evaluate the use of two of the multiparameter assays, although it will be many years before oncologists can apply the results of these trials in the clinic.
Technical and analytical advances have facilitated the application of high-throughput analysis to clinical specimens, a process that has been referred to as "molecular profiling." This term, as applied here, may refer to identifying various "markers," including genomic, proteomic, and epigenomic expression patterns, or a combination thereof. Technologic advances have led to the ability to measure thousands of genes by a variety of validated methods, and analytical models have been developed that facilitate analysis of the voluminous amount of data that are generated.
This technology has enabled "discovery-based research" to be conducted, in which large volumes of data are generated from clinical specimens and analyzed without a specific hypothesis, in contrast to the traditional scientific paradigm of "hypothesis-based research," in which a limited number of genes/proteins are investigated based upon a specific hypothesis and rationale. Discovery-based and hypothesis-based research are not mutually exclusive, however-profiling may also be used to test specific hypotheses that are based upon sound scientific rationale.
Promise and Pitfalls of Gene-Expression Profiling
Evaluation of the genomic expression patterns of clinical specimens that are linked to classical clinicopathologic, treatment, and outcome information has led to the development of several multigene markers that are nicely described in this review by Drs. Henry and Hayes, and which have also been reviewed elsewhere. The authors outline the potential promise and pitfalls of the clinical application of gene-expression profiling for localized-stage breast cancer, with emphasis on its potential for predicting chemotherapy benefit in patients with hormone receptor–positive disease.
The application of genomic profiling may lead to the following scenarios in patients with hormone receptor– positive disease who clearly benefit from hormonal therapy:
• "treatment sparing" in those with a favorable genomic profile who may be adequately treated with hormonal therapy but would have been offered chemotherapy because of unfavorable clinicopathologic features;
• "treatment selection" in those with an unfavorable genomic profile who may be offered chemotherapy in addition to hormonal therapy, but would have been offered hormonal therapy alone based upon favorable clinicopathologic features;
• "treatment direction" in those for whom the genomic profile (whether favorable or unfavorable) provides a clear treatment path despite equipoise about the most appropriate therapy recommendation based upon clinicopathologic features; and
• "treatment confirmation" in patients whose genomic profile (whether favorable or unfavorable) confirms the treatment recommended based upon clinicopathologic features.
Assessing Genomic Assays
Of course, it is possible that the genomic profile may not result in treatment selection, sparing, direction, or confirmation. Several small studies have suggested that one of the genomic assays, the 21-gene Oncotype DX assay (Genomic Health, Inc), may change treatment recommendations by physicians and decisions by patients approximately 25% of the time, and it also frequently confirms physician recommendations and patient decisions made based upon clinicopathologic features. One of the major objectives of the Trial Assigning Individualized Options for Treatment (TAILORx), which Drs. Henry and Hayes describe, is to refine the clinical utility of the 21-gene assay that is integrated into the trial. The trial was designed in a manner that incorporates what is already known about the utility of the marker, provides the potential to increase the proportion of patients for whom the test result provides a clear treatment path, and facilitates the opportunity to evaluate other markers in the future once the trial results are sufficiently mature.
To the credit of the cancer community and the patients it serves, the TAILORx trial has received enthusiastic support. The trial has been opened at more than 900 sites in the United States and Canada, and at several international sites. With an accrual rate of approximately 2,200 patients per year, it is projected to reach its accrual goal in 2009. The timely completion of this trial, and the Microarray for Node-Negative Disease May Avoid Chemotherapy Trial (MINDACT), will provide important information in the years to come about the utility of these assays, and others to be developed in the future.
-Joseph A. Sparano, MD
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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