The Genomic Health multigene assay

The Genomic Health assay, a 21-gene prognostic profile, was put to the test in NSABP-B- 14, the Phase III comparison of adjuvant tamoxifen versus placebo in patients with nodenegative, ER-positive breast cancer. Analysis of the tamoxifen arm showed the assay to be a superior prognosticator when compared to the standard biomarkers and independent predictors. I believe the relative risk was three- or fourfold more powerful than the next factor, which was the patient’s age.

While the assay performed surprisingly well, it’s still a work in progress. It was validated in a select group of patients not representative of the entire target population, but work is being done to refine it. Some experts feel it’s premature to market the assay, but I believe it’s provocative enough to utilize in some individual cases. I believe its real value at this time is its potential contribution to clinical research. For example, patients for whom the assay suggests tamoxifen resistance could be randomly assigned to tamoxifen or an aromatase inhibitor.

Estrogen receptor status and tamoxifen efficacy in DCIS

NSABP-B-24 compared adjuvant tamoxifen to placebo in patients with DCIS. After four or five years of follow-up, the tamoxifen arm showed a 30 percent benefit, but we didn’t understand the relationship of this response rate to the tumor’s hormone receptor status. When the trial was initiated, assessing hormone receptors wasn’t required, but tumors were banked to conduct biological studies.

In a central laboratory, we later measured the estrogen and progesterone receptors by IHC on approximately 600 paraffin blocks distributed between the two arms of the study. The data convincingly showed that the benefit from tamoxifen was entirely restricted to the ER-positive cohort; no evidence of benefit was seen in the ER-negative cohort. We know that approximately 25 percent of DCIS cases are truly ER-negative.

Approximately two-thirds of the cases we analyzed had hormone receptors previously evaluated in their community hospitals and, using the central lab as the standard, the community error rate was approximately 30 percent — mostly false negatives. In the patients with ER-negative tumors, as defined by community labs, the relative risk for benefit from tamoxifen was approximately 0.5, which is biologically unbelievable.

Assessing the same patients in the central lab, the relative risk was 0.99, indicating no benefit, as we would expect. Clearly, the cohort of cases identified as ER-negative in the community was contaminated with false negatives. We can conclude from our data that tamoxifen does not reduce the recurrence rate in patients with ER-negative DCIS assessed in a reliable lab.

Effect of phenotype on benefit in the ATAC trial

The analysis of phenotypes and response to therapy using the ATAC data was fascinating. Anastrozole had an approximately 20 percent additional benefit over tamoxifen in the ER-/PR-positive and ER-negative, PR-positive subsets. In the ER-/PR-negative phenotype, the relative risk was close to one, but surprisingly in the ER-positive, PR-negative subset, the relative risk was 0.48.

We don’t know why the latter phenotype behaves so differently, but Dowsett and Osborne have formulated a hypothesis that involves contrasting the effect of tamoxifen versus anastrozole on the classical nuclear versus nonclassical membrane ER pathways. When the nuclear pathway is intact, estrogen activates the estrogen receptor, which induces the synthesis of the progesterone receptor; however, we can hypothesize that the pathway is not functioning in ER-positive, PR-negative tumors. If the membrane pathway is activated, it can lead to the activation of growth factor receptors and induce cell growth.

Tamoxifen is an antagonist in the nuclear pathway (hypothetically the nonfunctioning pathway in the ER-positive, PR-negative subset) and it’s an agonist in the membrane pathway, which may result in stimulating growth factors and tumor growth. On the other hand, aromatase inhibitors reduce estrogen levels to nearly zero and are antagonists on both pathways. This may explain the striking additional benefit for anastrozole seen in the ER-positive, PR-negative subset, which is the phenotype for 20 percent of breast cancer patients.

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Dr Allred is a Professor of Pathology at Baylor College of Medicine’s Breast Center in Houston, Texas.

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