Articles www.thelancet.com/oncology Vol 11 January 2010 55 Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial Kathy S Albain, William E Barlow, Steven Shak, Gabriel N Hortobagyi, Robert B Livingston, I-Tien Yeh, Peter Ravdin, Roberto Bugarini, Frederick L Baehner, Nancy E Davidson, George W Sledge, Eric P Winer, Clifford Hudis, James N Ingle, Edith A Perez, Kathleen I Pritchard, Lois Shepherd, Julie R Gralow, Carl Yoshizawa, D Craig Allred, C Kent Osborne, Daniel F Hayes, for The Breast Cancer Intergroup of North America Summary Background The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen- receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. Methods The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. Findings There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0·006; hazard ratio [HR] 2·64, 95% CI 1·33–5·27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0·97; HR 1·02, 0·54–1·93), but an improvement in disease-free survival for those with a high recurrence score (score ≥31; log-rank p=0·033; HR 0·59, 0·35–1·01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0·029), with no additional prediction beyond 5 years (p=0·58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer- specific survival. Interpretation The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. Funding National Cancer Institute and Genomic Health. Introduction Multigene tumour assays report useful prognostic information for women with axillary node-negative breast cancer. 1–4 Of these, the 21-gene recurrence score assay provides a prognosis for patients with oestrogen- receptor-positive disease treated with tamoxifen alone. 1 In one study, the recurrence score also predicted chemotherapy benefit from standard chemotherapy. 5 Patients with a high recurrence score seemed to benefit greatly from the addition of chemotherapy to tamoxifen, whereas those with a low recurrence score did not. Recent studies have shown the value of the recurrence score when used with the standard pathology report, 6–8 which improved physician and patient decision making in lymph-node-negative scenarios. Use of the recurrence score as a prognostic and predictive tool in oestrogen- receptor-positive, lymph-node-negative breast cancer was recommended by the American Society of Clinical Oncology. 9 There have been no assessments of the value of the recurrence score in patients with oestrogen- receptor-positive disease and involved axillary nodes in studies that contain a tamoxifen-alone control group. These patients are routinely treated with chemotherapy and endocrine adjuvant therapy. 10 However, exploratory data suggest that those with higher concentrations of tumour oestrogen receptors might not derive benefit from chemotherapy, even if they are at high risk of recurrence because of positive nodes. 11–13 Some studies have shown less benefit of chemotherapy when the Lancet Oncol 2010; 11: 55–65 Published Online December 10, 2009 DOI:10.1016/S1470- 2045(09)70314-6 See Reflection and Reaction page 6 See Lancet 2009; 374: 2029–30 See Lancet 2009; 374: 2055–63 Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, IL, USA (Prof K S Albain MD); Southwest Oncology Group Statistical Center, Seattle, WA, USA (Prof W E Barlow PhD); Genomic Health, Redwood City, CA, USA (S Shak MD, R Bugarini DStat, F L Baehner MD, C Yoshizawa PhD); University of Texas MD Anderson Cancer Center, Houston, TX, USA (Prof G N Hortobagyi MD); University of Arizona Cancer Center, Tucson, AZ, USA (Prof R B Livingston MD); University of Texas Health Science Center at San Antonio, San Antonio, TX, USA (Prof I-T Yeh MD, Prof P Ravdin MD); University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA (Prof N E Davidson MD); Indiana University Medical Center, Indianapolis, IN, USA (Prof G W Sledge MD); Dana-Farber Cancer Institute, Boston, MA, USA (Prof E P Winer MD); Memorial Sloan-Kettering Cancer Center, New York, NY, USA (Prof C Hudis MD); Mayo Clinic, Rochester, MN, USA (Prof J N Ingle MD); Mayo Clinic, Jacksonville, FL, USA (Prof E A Perez MD); Sunnybrook Cancer Center, University of Toronto, Toronto, ON, Canada (Prof K I Pritchard MD); National Cancer Institute of Canada