Risk of recurrence and chemotherapy benefit for patients with node-negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with pathologic and clinical factors

Abstract

Purpose: The 21-gene breast cancer assay recurrence score (RS) is widely used for assessing recurrence risk and predicting chemotherapy benefit in patients with estrogen receptor (ER) -positive breast cancer. Pathologic and clinical factors such as tumor size, grade, and patient age also provide independent prognostic utility. We developed a formal integration of these measures and evaluated its prognostic and predictive value.

Patients and methods: From the National Surgical Adjuvant Breast and Bowel (NSABP) B-14 and translational research cohort of the Arimidex, Tamoxifen Alone or in Combination (TransATAC) studies, we included patients who received hormonal monotherapy, had ER-positive tumors, and RS and traditional clinicopathologic factors assessed (647 and 1,088, respectively). Individual patient risk assessments from separate Cox models were combined using meta-analysis to form an RS-pathology-clinical (RSPC) assessment of distant recurrence risk. Risk assessments by RS and RSPC were compared in node-negative (N0) patients. RSPC was compared with RS for predicting chemotherapy benefit in NSABP B-20.

Results: RSPC had significantly more prognostic value for distant recurrence than did RS (P < .001) and showed better separation of risk in the study population. RSPC classified fewer patients as intermediate risk (17.8% v 26.7%, P < .001) and more patients as lower risk (63.8% v 54.2%, P < .001) than did RS among 1,444 N0 ER-positive patients. In B-20, the interaction of RSPC with chemotherapy was not statistically significant (P = .10), in contrast to the previously reported significant interaction of RS with chemotherapy (P = .037).

Conclusion: RSPC refines the assessment of distant recurrence risk and reduces the number of patients classified as intermediate risk. Adding clinicopathologic measures did not seem to enhance the value of RS alone nor the individual biology RS identifies in predicting chemotherapy benefit.

Fig 1.

CONSORT diagram. ANA, anastrozole; ATAC, Arimidex, Tamoxifen Alone or in Combination study; ER, estrogen receptor; IBC, invasive breast cancer; NSABP B-14, National Surgical Adjuvant Breast and Bowel study B-14; RT-PCR, reverse transcription polymerase chain reaction; TAM, tamoxifen.

Fig 2.

Distribution of covariates in the 1,444 patients with N0, estrogen receptor–positive breast cancer. (A) Recurrence score (RS); (B) tumor grade; (C) tumor size; (D) age.

Fig 3.

(A) Proportion of patients with N0, estrogen receptor–positive breast cancer classified as low, intermediate, and high risk by recurrence score (RS) and RS-pathology-clinical assessment (RSPC), and (B) cross-classification of patients (N = 1,444). Cochran-Mantel-Haenszel (CMH) test compares RS with RSPC for the proportions of patients in the three risk classes. Average risk for each risk group is the meta-analysis weighted average estimate (with 95% CI) of the 10-year incidence of distant recurrence (DR). Average risks are not significantly different between RS and RSPC (P = .68, .27, .42 for low-, intermediate-, and high-risk groups, respectively, z-test); average risk significantly increases with increasing risk group (P < .001 for both RS and RSPC, z-test for trend).

Fig 4.

Example of recurrence score (RS) and RS-pathology-clinical (RSPC) risk assessments with 95% CIs for patients of age 50 years with specific tumor grades and sizes.