Measurement of endocrine activity (SET2,3) related to prognosis and prediction of benefit from dose-dense (DD) chemotherapy in estrogen receptor-positive (ER+) cancer: CALGB 9741 (Alliance).
Authors: Metzger Otto , Ballman Karla V. , Campbell Jordan , Liu Minetta C. , Ligibel Jennifer A. , Chen Eveline , Du Lili , Symmans W. Fraser Fraser 
Published: June 2022

505

Background: We investigated the clinical utility of SET2,3, a novel biomarker designed to measure to endocrine sensitivity. SET2,3 measures nonproliferative 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). CALGB 9471 is a seminal phase III study that showed improved DFS and OS from 2-weekly dose-dense (DD) vs 3-weekly chemotherapy in ER-negative cancers. Risk of recurrence (ROR-PT) score (intrinsic subtype, proliferation score and tumor size) measured by Nanostring assay was reported to be prognostic in CALGB 9741, but did not predict benefit from DD chemotherapy. Methods: SET2,3 was performed using an aliquot of 200-300 ng RNA (residual from prior ROR-PT testing) from 682 ER+ tumor samples and tested using the QuantiGene Plex bead-based hybridization assay (ThermoFisher, Luminex). We report results for the primary and two secondary objectives of the NCI/CTEP-approved correlative science proposal CSC0154) to evaluate SET2,3 in CALGB 9741 for prognosis (primary endpoint: 95%CI for 5-year (yr) DFS > 75% for High SET2,3 using the predefined prognostic cutpoint 2.10), SET2,3 prognostic independence from ROR-PT, and prediction of outcome according to chemotherapy regimen. We used Cox models to estimate hazard ratios (HR) for prognosis and comparison with ROR-PT results (using c-indices) and for prediction according to chemotherapy schedule using an interaction term (prespecified significance level for interaction: p < 0.10). Results: The study met its primary endpoint with a 5-yr DFS of 85.6% (95%CI 81.3-90.2) in the High-SET subset (244/613, 40%). High-SET vs Low-SET was significantly associated with favorable outcomes at 5 yr (DFS 85.6% vs 69%, p <.0001; OS 95.3% vs 84.6%, p <.0001) and 10 yr (DFS 77.7% vs 58.2%, p <.0001; OS 86.9% vs 65.9%, p <.0001). PAM50 ROR-PT and SET classification were available for 596 tumors. In multivariate models for DFS and OS, SET2,3 remained an independent prognostic variable for DFS (SET high vs low HR = 0.46, 95% CI, 0.34 – 0.63, p < 0.0001; PAM50 ROR-PT high vs low HR = 1.22, 95% CI, 0.91 – 1.64, p = 0.18) and for OS (SET high vs low HR = 0.36, 95% CI, 0.25 – 0.53, p < 0.0001; PAM50 ROR-PT high vs low HR = 1.26, 95% CI, 0.91 – 1.75, p = 0.16). Similar observations were seen in models including SET and PAM50 ROR-PT as continuous variables. Lower SET2,3 values predicted improved outcomes from DD vs 3-weekly chemotherapy (interaction p=0.0998 for DFS, 0.042 for RFS and 0.027 for OS). This was unrelated to menopausal status and lower SET2,3 values favored DD concurrent treatments. Conclusions: SET2,3 index was strongly prognostic, independent of ROR-PT, and predicted survival benefit from DD chemotherapy in pre- and postmenopausal women with ER+ cancer. Clinical trial information: NCT00003088.