21-Gene Recurrence Score and Locoregional Recurrence in Node-Positive/ER-Positive Breast Cancer Treated With Chemo-Endocrine Therapy

Abstract

Background: The 21-gene recurrence score (RS) predicts risk of locoregional recurrence (LRR) in node-negative, estrogen receptor (ER)-positive breast cancer. We evaluated the association between RS and LRR in node-positive, ER-positive patients treated with adjuvant chemotherapy plus tamoxifen in National Surgical Adjuvant Breast and Bowel Project B-28.

Methods: B-28 compared doxorubicin/cyclophosphamide (AC X 4) with AC X 4 followed by paclitaxel X 4. Tamoxifen was given to patients age 50 years or older and those younger than age 50 years with ER-positive and/or progesterone receptor-positive tumors. Lumpectomy patients received breast radiotherapy. Mastectomy patients received no radiotherapy. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Cumulative incidence functions and subdistribution hazard regression models were used for LRR to account for competing risks including distant recurrence, second primary cancers, and death from other causes. Median follow-up was 11.2 years. All statistical tests were one-sided.

Results: There were 80 LRRs (7.5%) as first events (68% local/32% regional). RS was low: 36.2%; intermediate: 34.2%; and high: 29.6%. RS was a statistically significant predictor of LRR in univariate analyses (10-year cumulative incidence of LRR = 3.3%, 7.2%, and 12.2% for low, intermediate, and high RS, respectively, P < .001). In multivariable regression analysis, RS remained an independent predictor of LRR (hazard ratio [HR] = 2.59, 95% confidence interval [CI] = 1.28 to 5.26, for a 50-point difference, P = .008) along with pathologic nodal status (HR = 1.91, 95% CI = 1.20 to 3.03, for four or more vs one to three positive nodes, P = .006) and tumor size (HR = 1.28, 95% CI = 1.05 to 1.55, for a 1 cm difference, P = .02).

Conclusions: RS statistically significantly predicts risk of LRR in node-positive, ER-positive breast cancer patients after adjuvant chemotherapy plus tamoxifen. These findings can help in the selection of appropriate candidates for comprehensive radiotherapy.

Figure 1.

CONSORT diagram. AC = doxorubicin/cyclophosphamide; ER = estrogen receptor; GHI = Genomic Health, Inc.; NSABP = National Surgical Adjuvant Breast and Bowel Project; qPCR = quantitative polymerase chain reaction; P = paclitaxel; RT = radiotherapy.

Figure 2.

Comparison of the 10-year cumulative incidence of locoregional recurrence between 1065 estrogen receptor (ER)–positive, B-28 patients who were included in the present study and 999 ER-positive, B-28 patients who were excluded. Gray’s k-sample test was used, and all P values were one-sided (10-year cumulative incidence of LRR = 7.3%, 95% confidence interval [CI] = 5.8% to 9.0%, vs 6.2%, 95% CI = 4.8% to 7.9%, P = .50 on graph). ER = estrogen receptor; LRR = locoregional recurrence.

Figure 3.

Cumulative incidence of locoregional recurrence by recurrence score status. Gray’s k-sample test was used, and all P values were one-sided (10-year cumulative incidence of LRR for low, intermediate, and high recurrence score, respectively = 3.3%, 95% confidence interval [CI] = 1.8% to 5.4%; 7.2%, 95% CI = 4.8% to 10.2%; and 12.2%, 95% CI = 8.8%, 16.1% on graph). LRR = locoregional recurrence; RS = recurrence score.

Figure 4.

Cumulative incidence of locoregional recurrence by recurrence score (RS) and nodal status. A) Patients with one to three positive nodes (n = 722). Ten-year cumulative incidence of locoregional recurrence (LRR) was 3.2% (95% CI = 1.5% to 5.9%), 5.1% (95% CI = 2.8% to 8.4%), and 7.9% (95% CI = 4.7% to 12.1%) for low, intermediate, and high RS, respectively (P = .12). B) Patients with four or more positive nodes (n = 343). Ten-year cumulative incidence of LRR was 3.5% (95% CI = 1.1% to 8.0%), 11.6% (95% CI = 6.5% to 18.4%), and 20.3% (95% CI = 13.2% to 28.3%) for low, intermediate, and high RS, respectively (P = .001). Gray’s k-sample test was used, and all P values were one-sided. LRR = locoregional recurrence; RS = recurrence score.