Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor–Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Project B-28 and B-14

Abstract

Purpose We determined the utility of the 21-Gene Recurrence Score (RS) in predicting late (> 5 years) distant recurrence (LDR) in stage I and II breast cancer within high and low-ESR1–expressing groups. Patients and Methods RS was assessed in chemotherapy/tamoxifen-treated, estrogen receptor (ER) –positive, node-positive National Surgical Adjuvant Breast and Bowel Project B-28 patients and tamoxifen-treated, ER-positive, node-negative B-14 patients. The association of the RS with risk of distant recurrence (DR) 0 to 5 years and those at risk > 5 years was assessed. An ESR1 expression cut point was optimized in B-28 and tested in B-14. Results Median follow-up was 11.2 years for B-28 and 13.9 years for B-14. Of 1,065 B-28 patients, 36% had low (< 18), 34% intermediate (18 to 30), and 30% high (≥ 31) RS. Of 668 B-14 patients, 51% had low, 22% intermediate, and 27% high RS. Median ESR1 expression by reverse transcriptase polymerase chain reaction was: B-28, 9.7 normalized expression cycle threshold units (CT) and B-14, 10.7 CT. In B-28, RS was associated with DR 0 to 5 years (log-rank P < .001) and > 5 to 10 years (log-rank P = .02) regardless of ESR1 expression. An ESR1 expression cut point of 9.1 CT was identified in B-28. It was validated in B-14 patients for whom the RS was associated with DR in years 5 to 15: 6.8% (95% CI, 4.4% to 10.6%) versus 11.2% (95% CI, 6.2% to 19.9%) versus 16.4% (95% CI, 10.2% to 25.7%) for RS < 18, RS 18 to 30, and RS ≥ 31, respectively (log-rank P = .01). Conclusion For LDR, RS is strongly prognostic in patients with higher quantitative ESR1. Risk of LDR is relatively low for patients with low RS. These results suggest the value of extended tamoxifen therapy merits evaluation in patients with intermediate and high RS with higher ESR1 expression at initial diagnosis.

21-Gene Recurrence Score Assay Predicts Benefit of Post-Mastectomy Radiotherapy in T1-2 N1 Breast Cancer

“…The 21-gene recurrence score (RS) assay (Genomic Health) is calculated on the basis of the RNA expression levels of 21 genes and has been validated in T1-2 N1 breast cancer to be prognostic of LRR, disease-free survival, and overall survival (OS; refs. [6][7][8][9][10]. Other gene profiling assays have demonstrated similar correlations (11)(12)(13).…”

“…The 21-gene RS assay has been validated as an independent prognosticator of LRR, distant recurrence, and OS in women with node-positive ER-positive breast cancer (6)(7)(8)(9)(10). Furthermore, RS has been shown to predict benefit to adjuvant systemic chemotherapy for women with node-negative cancer, and is endorsed by the ASCO 2016 Focused Guideline Update to be used in decision making regarding systemic treatment (34)(35)(36).…”

“…Potentially confounding this hypothesis, the 21-gene RS is also strongly prognostic for distant recurrence, a competing risk to LRR (8,9). Women with a higher RS are more likely to harbor occult systemic disease and therefore potentially less likely to derive a survival benefit from locoregional treatment.…”

Identifying Biomarkers to Select Patients with Early Breast Cancer Suitable for Extended Adjuvant Endocrine Therapy

“…These results strongly suggest that the Oncotype RS is not a solid candidate for the prediction of late distant recurrence in women with ER-positive disease. However, more recently, the Oncotype RS was evaluated in patients from the NSABP B-28 and B-14 trials for the prediction of late distant recurrence within low and high ESR1 levels [16]. The study found that Oncotype RS is strongly prognostic for late distant recurrence in women with a high ESR1 level (cut-off 9.1) and that extended tamoxifen therapy is warranted in those with high expression of ESR1 and intermediate/high risk patients.…”

Gene Expression Analyses in Early Breast Carcinoma — Quo Vadis?

“…In an analysis of 665 ER + node-negative patients in the TransATAC study, Oncotype DX ® was not found to have any significant effect on the prediction of late metastases more than 5 years after successful surgery [13]. By contrast, a prognostic influence of Oncotype DX ® on late distant metastases was demonstrated, depending on the gene expression of the estrogen receptor (ESR1) [14].…”