Development and Validation of a Tool Integrating the 21-Gene Recurrence Score and Clinical-Pathological Features to Individualize Prognosis and Prediction of Chemotherapy Benefit in Early Breast Cancer

Abstract

Purpose: The 21-gene recurrence score (RS) is prognostic for distant recurrence (DR) and predictive for chemotherapy benefit in early breast cancer, whereas clinical-pathological factors are only prognostic. Integration of genomic and clinical features offers the potential to guide adjuvant chemotherapy use with greater precision.

Methods: We developed a new tool (RSClin) that integrates RS with tumor grade, tumor size, and age using a patient-specific meta-analysis including 10,004 women with hormone receptor-positive, human epidermal growth factor receptor 2-negative, and node-negative breast cancer who received endocrine therapy alone in the B-14 (n = 577) and TAILORx (n = 4,854) trials or plus chemotherapy in TAILORx (n = 4,573). Cox models for RSClin were compared with RS alone and clinical-pathological features alone using likelihood ratio tests. RSClin estimates of DR used a baseline risk with TAILORx event rates to reflect current medical practice. A patient-specific estimator of absolute chemotherapy benefit was computed using individualized relative chemotherapy effect from the randomized TAILORx and B-20 trials. External validation of risk estimation was performed by comparing RSClin estimated risk and observed risk in 1,098 women in the Clalit registry.

Results: RSClin provides more prognostic information (likelihood ratio χ²) for DR than RS or clinical-pathological factors alone (both P < .001, likelihood ratio test). In external validation, the RSClin risk estimate was prognostic for DR risk in the Clalit registry (P < .001) and the estimated risk closely approximated the observed 10-year risk (Lin concordance 0.962). The absolute chemotherapy benefit estimate ranges from 0% to 15% as the RS ranges from 11 to 50 using RSClin in a 55-year-old woman with a 1.5-cm intermediate-grade tumor.

Conclusion: The RSClin tool integrates clinical-pathological and genomic risk to guide adjuvant chemotherapy in node-negative breast cancer and provides more individualized information than clinical-pathological or genomic data alone.

FIG 1.

The RSClin tool provides individualized prognosis estimates based on entry of patient information for the RS result, age, tumor size, and tumor grade. Example estimates (solid line) and 95% CIs (dotted lines) provided by the RSClin tool for 10-year distant recurrence risk for endocrine therapy alone with 21-gene expression assay ranging from 0 to 50 for a 55-year-old woman with a tumor size of 1.5 cm, a typical clinical scenario in which the 21-gene RS is commonly used in clinical practice. (A) Results for tumor grade 1; (B) results for tumor grade 2; (C) results for tumor grade 3. RS, recurrence score.

FIG 2.

The RSClin tool provides individualized estimates for chemotherapy benefit based on the entry of patient information for the RS result, age, tumor size, and tumor grade. Example estimates and 95% CIs provided by the RSClin tool for the absolute benefit of adjuvant chemotherapy for (A) tumor grade series, (B) tumor size series, and (C) patient age series. RS, recurrence score.

FIG 3.

Comparison between estimate of absolute chemotherapy benefit provided by the RSClin tool (using PSMA estimate of relative chemotherapy benefit derived from B-20 and TAILORx) with estimate of absolute chemotherapy benefit if relative chemotherapy benefit was held constant (assuming higher RS result was associated with higher recurrence risk, but not greater relative chemotherapy benefit). Examples provided include (A) a 55-year-old woman with a 1.5-cm intermediate-grade tumor (a typical low clinical risk patient) and (B) a 55-year-old woman with a 2.5-cm high-grade tumor (a typically high clinical risk patient). RS, recurrence score.

FIG 4.

External validation of RSClin: Risk estimates provided by the RSClin tool versus real-world patient outcomes in the Clalit Health Services cohort: Analysis of the 1,098 patients divided into 5 quintiles based on increasing risk as calculated by the RSClin tool. Bars represent 95% CIs. The Lin concordance correlation is 0.962.