Current Status of Prognostic Profiling in Breast Cancer: study
Mammostrat® (Applied Genomics, Inc.; Huntsville, AL) is a five-antibody panel. These antibodies were chosen from 140 novel and 23 commercially available antisera and were selected because of their ability to distinguish tumors with a high versus low risk for recurrence [39]. Cox proportional hazard and regression tree analyses were used to identify subpanels of antibodies that were able to predict the risk for recurrence in patients with ER-positive breast cancer. The resultant five-antibody panel was validated in two cohorts of patients, with the Cox model distinguishing ER-positive patients with poor outcomes from patients with good or moderate outcomes (HRs of 2.21 and 1.88 in cohort 1 and cohort 2, respectively). In a multivariate analysis, the risk for recurrence was independent of stage, grade, and lymph node status. However, this model was not useful for ER-negative patients. The five-antibody panel was subsequently validated in tamoxifen-treated LNN breast cancer patients from the NSABP B-14 and B-20 clinical trials, which indicated that the greatest clinical utility of the antibody panel may be in postmenopausal patients [40]. A separate study showed that both high- and low-risk patients benefited from adjuvant chemotherapy, but the absolute benefit for high-risk patients appeared greater [41].
CellSearchTM
CellSearchTM (Veridex, LLC; Warren, NJ) is not a genomic assay but a method to detect circulating tumor cells (CTCs) that are characterized by the lack of expression of CD45 cell surface antigen and by positive staining for epithelial cell adhesion molecule and cytokeratins 8, 18, and/or 19 [42]. These cells can be detected in the peripheral blood of some breast cancer patients [43]. It is believed that these cells are involved in the spread of metastases. Patients with metastatic breast cancer who had more than five CTCs at baseline and first follow-up had a worse prognosis than patients with fewer than five CTCs [44–46]. The CellSearchTM assay is now approved in the U.S. for risk stratification of patients with metastatic breast cancer based on the detection of CTCs in the peripheral blood. Changes in CTC count in response to therapy were also predictive of outcome. CTC-positive patients who became CTC negative after therapy had a significantly longer progression-free survival time (7.6 versus 2.1 months; p = .002) and overall survival time (14.6 versus 9.2 months; p = .006) than those with persistently elevated CTC counts [44]. A clinical trial is under way to examine the clinical utility of this test in switching treatment in patients who do not respond to initial treatment with a dropping CTC count.
EFFECT OF GENETIC CLASSIFICATION ON CLINICAL TRIAL DESIGN
Perhaps the most important contribution of genomic studies to breast cancer research has been the realization that breast cancer is not a single disease with heterogeneous ER or HER-2 expression, but a collection of molecularly distinct neoplastic diseases of the breast. To conduct clinical trials that include all the different molecular classes of breast cancer may be as na|fkve as combining all lymphomas into the same study. The existing and emerging diagnostic assays make it possible to molecularly stratify breast cancer patients for therapy and have important implications for clinical trial design. First and foremost, the incorporation of prospective tissue collection into future clinical trials is essential to maximize the information that can be gained from these studies [37, 38].
The incorporation of tissue collection into clinical trial design will allow prospective correlative studies to be performed and will also allow molecular stratification of patients for treatment arms [30]. Serial biopsies could make it possible to search for pharmacodynamic changes during therapy that may act as surrogate markers of response. This is important because novel agents may not cause rapid tumor regression and the use of validated molecular surrogate markers could also allow investigators to move away from the maximum-tolerated dose model of clinical trials and toward finding the biologically most relevant dose.
The integration of genetic profiling into clinical trial design necessitates that clinical trials become collaborative efforts among clinicians, scientists, pathologists, surgeons, and statisticians at the planning stages and during the trial [37, 38]. The inclusion of basic scientists will allow the clinical trial team to incorporate molecular hypotheses into the trial design at the earliest planning stages. Statisticians with special expertise in the analysis of high-dimensional datasets are also needed on the team, to ensure that the trial has adequate statistical power and that the conclusions are supported by the data. Without rigorous statistical scrutiny, it is very easy to generate misleading results from high-dimensional molecular datasets.
CONCLUSIONS
It is clear that genomic profiling has the potential to change the prognostication and treatment options for patients with breast cancer. Although a few genetic tests are already approved by the FDA and several others are commercially available, clinicians wonder if these tests are ready for practical application in the clinic. At this time, strong claims cannot be made about the clinical value of these assays and their potential superiority to standard clinicopathological parameters [37, 38]. However, several of these novel gene expression–based assays seem to augment existing prognostic tools. An important potential of microarray-based tests is that multiple predictions, including prognosis and sensitivity to various treatment modalities, may be generated from a single experiment. These assays would use information from different sets of genes measured from the same tissue for different predictions, which could substantially improve the cost-effectiveness of these emerging tests. In order to provide a truly personalized treatment recommendation, it is important to understand the risk for relapse and the probability of benefit from endocrine therapy and chemotherapy separately and to consider patient preferences in the light of these results.
Many of the currently available tests are based on retrospective studies performed on archival material, and thus, they do not provide the level I evidence that can only be gained from prospective, randomized, high-powered clinical trials [37, 38]. The MammaPrint® 70-gene set is currently being validated in the MINDACT clinical trial, which is being performed by the Breast International Group in conjunction with the European Organization for Research and Treatment of Cancer [35]. Likewise, oncotype DXTM is being evaluated in the TAILORx clinical trial, which is part of the National Cancer Institute’s Program for the Assessment of Clinical Tests. These trials should provide clinicians with definitive information regarding the clinical utility of these tests, and these studies will serve as models for future efforts addressing the clinical utility of gene-expression profiling. However, survival results from these studies will not be available for several years. It is also important to remember that some forms of clinical benefit from these novel tests may be more subtle than improvements in survival. It may be argued that additional information that helps patients and physicians feel more comfortable with a particular treatment recommendation has value on its own.
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