The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.

Background: The use of molecular tools for prognosis and prediction of CT benefit in EBC has increased the complexity of decision making. The 21-gene RS (Oncotype DX) is included in the ASCO (2007) and NCCN guidelines (2006) for prognosis (risk of distant recurrence [DR]) and prediction of CT benefit in N0, ER+ EBC. In 2015, the NCCN added that the RS assay could be considered for select patients with 1-3 N+, ER+ EBC. Recently the ASCO BC biomarker/guideline group (J Clin Oncol 2016) advised that the “clinician should not use the 21-gene RS to guide decisions” and called the evidence quality “intermediate” and the recommendation “moderate” based on review of 2 N+ studies. It also advised no change in N+ clinical practice until the prospective SWOG S1007 study (RxPONDER) matures in several years. These discordant recommendations have led to major confusion among physicians, pts and payers. To address this controversy we herein report a comprehensive analysis of the body of evidence regarding the clinical utility of the RS in N+, ER+ EBC. Methods: All published studies involving N+, ER+ EBC with RS data were analyzed by type of study design and category of trial (validation, supportive, decision impact, cost-effectiveness, and prospective outcomes). Results: 30 studies provided clinical evidence supporting the value and utility of the RS in N+, ER+ pts. 7 studies employed a prospective-retrospective design or were prospective outcomes with clinical utility in >8000 N+ pts (Table). 23 additional studies assessed the impact of RS on CT decisions or cost-effectiveness. Study in N+/ER+Type of studyNEndpoints/resultsSWOG S8814 (Lancet Oncol 2010)Pro-retro36710-year DFS and BCSS: RS predicts risk of DFS event, BC death, and CT benefit (none to slightly worse if very low risk RS and 1-3 N+)TransATAC (JCO 2010)Pro-retro3069-year DR: RS predicts risk of DR in pts treated with ET without CTECOG E2197 (JCO 2008)Pro-retro2325-year DR: RS predicts DR risk in CT+ET treated ptsNSABP B-28 (ASCO-BCS 2012)Pro-retro106510-year DRFI: RS predicts DR risk in CT+ET treated ptsPACS-01 (ASCO 2014)Pro-retro5305-year DRFI/DFS: RS predicts DR risk in CT+ET treated ptsSEER (npj BC 2016)Prospective outcomes46915-year BCSM: RS predicts BCSM; pts with RS <18 (Nmi, 1-3 N+) had 1.0% BCSMWSG PlanB (JCO 2016)Prospective outcomes1198 (1088 N1-3/110 N0)3-year DFS: 98.4% in high risk N0/N+ ER+, RS <12 group and 97.5% in RS 12-25 group (5-year DFS 94.0% in both RS groups)BCSM: BC-specific mortality; BCSS: BC-specific survival; DFS: disease free survival; DR: distant recurrence; DRFI: distant recurrence free interval; ET: endocrine therapy; Nmi: micrometastases; pro-retro: prospective-retrospective. Conclusions: The 21-gene RS has now been studied in >10,000 N+, ER+ EBC pts across 30 studies worldwide, including 2 prospective outcomes studies in >5000 pts, confirming that the RS consistently identifies low risk 1-3 N+ pts in whom CT can effectively and safely be avoided. This evidence suggests that ER+ pts with few N+ and low RS should have a discussion of the pros and cons of adjuvant CT until the results of RxPONDER provide a definitive answer in several years. Citation Format: Mamounas E, Goldstein L, Penault-Llorca F, Roche H, Gluz O, Harbeck N, Nitz U, O'Shaughnessy J, Albain K. Chemotherapy (CT) decision in patients (pts) with node-positive (N+), ER+, early breast cancer (EBC) in the wake of new ASCO guideline – A different take on the evidence for the 21-gene recurrence score (RS) assay [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-02.