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 - PubMed (original) (raw)

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

Norman Wolmark et al. J Clin Oncol. 2016.

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.

Trial registration: ClinicalTrials.gov NCT01420185.

© 2016 by American Society of Clinical Oncology.

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Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.

Fig 1.

CONSORT diagram. AC, doxorubicin plus cyclophosphamide; AC→P, doxorubicin plus cyclophosphamide followed by paclitaxel; ER, estrogen receptor; GHI, Genomic Health, Inc.; IBC, invasive breast cancer; NSABP, National Surgical Adjuvant Breast and Bowel Project; qPCR, quantitative polymerase chain reaction; RT-PCR, reverse transcriptase polymerase chain reaction; RTX, radiotherapy; TAM, tamoxifen.

Fig 2.

Fig 2.

Kaplan-Meier curves and estimates for distant recurrence risk in B-28 and B-14 by recurrence score risk groups and time period. Event counts are for those occurring within the time period shown. (A) Curves for B-28, 0 to 5 years; (B) curves for B-28, 5 to 10 years; (C) curves for B-14, 0 to 5 years; (D) curves for B-14, 5 to 15 years.

Fig 3.

Fig 3.

Kaplan-Meier curves and estimates for distant recurrence risk in B-28 by recurrence score risk groups, ESR1 expression level, and time period. (A) Curves for ESR1 ≤ 9.1, time 0 to 5 years; (B) curves for ESR1 ≤ 9.1, time 5 to 10 years; (C) curves for ESR1 > 9.1, time 0 to 5 years; (D) curves for ESR1 > 9.1, time 5 to 10 years.

Fig 4.

Fig 4.

Kaplan-Meier curves and estimates for distant recurrence risk over 5 to 15 years, by recurrence score risk groups, in high-_ESR1_–expressing patients in B-14.

Fig 5.

Fig 5.

Forest plots with Kaplan-Meier estimates and 95% CIs for the risk of distant recurrence after 5 years by recurrence score risk group in high-_ESR1_–expressing patients, in (A) B-28 (from 5 to 10 years) and (B) B-14 (from 5 to 15 years), within subgroups according to clinical and pathology characteristics. Int, intermediate; Mod, moderate

Fig A1.

Fig A1.

Scatter plots of recurrence score values by ESR1 expression level in NSABP B-28 and B-14. Reference lines for ESR1 expression are at the cut point for positivity by RT-PCR (6.5 CT) and at the cut point identified in B-28 (9.1 CT). (A) Plot for B-28; (B) Plot for B-14. ER, estrogen receptor.

Fig A2.

Fig A2.

Cox model hazard ratios (and 95% CIs) for the continuous recurrence score as a predictor of distant recurrence risk in NSABP B-28, in patients with high ESR1 expression, for a range of cut point values. The x-axis is the percentile of the ESR1 distribution in NSABP B-28, annotated with the ESR1 cut point value. ER, estrogen receptor.

Fig A3.

Fig A3.

Forest plot with Kaplan-Meier estimates and 95% CIs for distant recurrence risk by recurrence score risk group, by ESR1 expression level and time period, in NSABP B-28 patients. ER, estrogen receptor.

Fig A4.

Fig A4.

Kaplan-Meier curves and estimates for distant recurrence risk in NSABP B-14 by recurrence score risk groups, ESR1 expression level, and time period. (A) Curves for ESR1 ≤ 9.1, time 0-5 years; (B) Curves for ESR1 ≤ 9.1, time 5-15 years; (C) Curves for ESR1 > 9.1, time 0-5 years; (D) Curves for ESR1 > 9.1, time 5-15 years.

Fig A5.

Fig A5.

Forest plot with Kaplan-Meier estimates and 95% CIs for distant recurrence risk by recurrence score risk group, in high _ESR1_-expressing patients in NSABP B-14, by time period 0-5, 5-10, or 5-15 years.

Fig A6.

Fig A6.

Distant recurrence risk estimates over years 5-15, with 95% CIs, in NSABP B-14 high-_ESR1_-expressing patients, as a function of the recurrence score. The estimates are based on the quadratic model.

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