Abstract PD9-06: Evaluation of the predicted sensitivity to endocrine therapy (SET2,3 index) and the 21-gene Breast Recurrence Score® assay in node-positive postmenopausal breast cancer: Results from an analysis in the SWOG S8814 trial
Authors: Speers Corey W. , Symmans W. Fraser , Barlow William E. , Trevarton Alex , The Stephanie , Du Lili , Rae James M. , Shak Steven , Baehner Frederick L. , Sharma Priyanka , Pusztai Lajos , Hortobagyi Gabriel N. , Hayes Daneil F , Albain Kathy S. , Godwin Andrew , Thompson Alastair 
Published: March 2022

Abstract
Background. SWOG trial S8814 randomized postmenopausal patients with pathologic lymph node-positive (N+) breast cancer that was hormone receptor-positive to receive adjuvant anthracycline-based chemotherapy (cyclophosphamide, doxorubicin, fluorouracil) followed by tamoxifen endocrine therapy for 5 years (CAF-T), versus tamoxifen alone (TAM). The 21-gene Breast Recurrence Score® assay was prognostic in S8814 and predicted chemotherapy benefit in patients with higher Recurrence Score® (RS) (Albain et al, Lancet Oncol 2009). Other prognostic signatures have yet to be evaluated in this cohort. The sensitivity to endocrine therapy index (SET2,3) measures non-proliferative hormone receptor-related transcription (SETER/PR) adjusted for a baseline prognosis index derived from tumor size, nodes involved and a 4-gene molecular subtype (RNA4) (Du et al, Ann Oncol 2021). SET2,3 has been shown to provide prognostic information independent from neoadjuvant chemotherapy response. We sought to evaluate the predictive and prognostic value of SET2,3 in SWOG 8814. Methods. Independently, the SET2,3 index and cut point were calibrated from their diagnostic platform to the whole transcriptome RNA sequencing (RNAseq) platform in 85 sample pairs. Expression of the 31 transcripts used for SET2,3 were provided from RNAseq data of 283 tumors in S8814 (all previously tested for RS). Blinded calculated results of SET2,3 were then merged with outcome data. The planned analysis tested whether SET2,3 (continuous index, dichotomized high/low) provided additional prognostic information to RS (overall and in pts. with RS≤25) by treatment arm, and whether low SET2,3 was associated with chemo benefit. Cox proportional hazards models of disease-free survival (DFS) included SET2,3; RS; treatment arm; and (where relevant) interaction term and reported hazard ratios (HR) and 95% confidence intervals (95%CI). Results. There were 106 events over median follow-up of 9.1 years in 283 patients. 175 patients had RS ≤25, 108 had RS &gt;25. Distribution of the SET2,3 low was similar in both RS high (51%) and low groups (47%), reflecting minimal correlation between the two. As proportional hazards assumptions were met during the first 5 years only the analysis was restricted to 5 years. Adjusting for treatment arm, high SET2,3 category was highly prognostic in this randomized trial (HR 0.27, 95% CI 0.15-0.49, p&lt;0.0001). High SET2,3 was not predictive of chemotherapy response (interaction p=0.83). In multivariable Cox models (Table), continuous RS and SET2,3 were independently prognostic in the overall population for each treatment arm (p≤0.01), whereas only SET2,3 was prognostic for patients with RS≤25 (N=175, p&lt;0.001). In patients with RS≤25, continuous SET2,3 was prognostic within the CAF-T arm (HR 0.34, p=0.006) with similar results in the TAM alone arm (HR 0.38, p=0.062). Conclusions. SET2,3 added independent prognostic information to RS results in the S8814 trial for patients with N+ disease treated with tamoxifen, though it was not predictive of benefit from adjuvant chemotherapy. When RS result ≤25, SET2,3 remained independently prognostic. Hence, SET2,3 provided independent information complementary to RS, possibly because it incorporates tumor size and number of positive nodes. SET2,3 warrants further evaluation in patients with N+ breast cancer.
Table: Multivariable Cox models in the overall population and subset with RS≤25 by treatment arm.CohortTreatment ArmContinuous Recurrence ScoreContinuous SET2,3HR (95%CI) per 10 unitsp-valueHR (95%CI)per 1 unitp-valueAll RS(N=283)CAF-TAM(N=166)1.21 (1.04-1.40)0.0120.48 (0.31-0.76)0.002TAM(N=117)1.44 (1.18-1.76)&lt; 0.0010.48 (0.27-0.88)0.017RS≤25 (N=175)CAF-TAM(N=99)1.43 (0.58-3.49)0.440.34 (0.15-0.73)0.006TAM(N=76)1.66 (0.46-5.93)0.440.38 (0.14-1.05)0.062
Citation Format: Corey W. Speers, W. Fraser Symmans, William E. Barlow, Alex Trevarton, Stephanie The, Lili Du, James M. Rae, Steven Shak, Frederick L. Baehner, Priyanka Sharma, Lajos Pusztai, Gabriel N. Hortobagyi, Daneil F Hayes, Kathy S. Albain, Andrew Godwin, Alastair Thompson. Evaluation of the predicted sensitivity to endocrine therapy (SET2,3 index) and the 21-gene Breast Recurrence Score® assay in node-positive postmenopausal breast cancer: Results from an analysis in the SWOG S8814 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-06.