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Prior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker.
We performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence).
Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease–free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local–regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6).
Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.)
Building on a foundation of clinical and laboratory observations, translational research, broad collaborations, and global education, adjuvant therapy for early-stage breast cancer has been an effective public health intervention. Standardization and even a one-size-fits-all philosophy were supported by individual trials and the worldwide overviews that showed proportional reductions in risk with chemotherapy in particular. Because higher risk, identified anatomically on the basis of tumor size or the presence of ipsilateral axillary nodal metastases, was associated with greater absolute therapeutic benefit, many clinical groups set risk thresholds, defined as a tumor size of 1 cm in the greatest dimension or any involved nodes, to guide chemotherapy use.
However, we also began to recognize that we could take a different approach with both older (endocrine) and newer (anti–human epidermal growth factor receptor type 2 [HER2]) targeted treatments. Here we could be more biologically selective by using markers — which can be favorable or unfavorable prognostic factors — primarily for their predictive usefulness.2 Predictive biomarkers can identify tumors that are more likely to respond to specific targeted treatments, and they allow us to avoid ineffective options. The inability to select similarly for or against chemotherapy use, coupled with the toxic effects, costs, and inconvenience of chemotherapy, has been a growing source of concern.