SET2,3 to inform on chemotherapy decisions in ER-positive breast cancer

The novel SET2,3 genomic test was prognostic for disease-free survival (DFS) and overall survival (OS) in patients with node-positive breast cancer, even after controlling for ROR-PT score. Moreover, in patients with ER-positive breast cancer, SET2,3 results could be utilised to decide which patients were most likely to benefit from dose-dense versus conventional chemotherapy.

The novel SET2,3 genomic test, which measures non-proliferative HR-related transcription, has been validated as a prognostic tool for DFS in patients with ER-positive breast cancer after neo-adjuvant therapy [1]. The ROR-PT and PAM50 intrinsic subtype tests could not predict which patients would benefit from dose-dependent chemotherapy in a previous study [2]. To this end, Dr Otto Metzger (Dana-Farber Cancer Institute, MA, USA) and colleagues aimed to assess the prognostic performance of SET2,3 in patients with ER-positive breast cancer in the phase 3 CALGB9741 trial (n=613; NCT000030880) [3].

A high SET2,3 score was associated with an improved 5-year DFS compared with patients with a low SET2,3 score (86% vs 73%; HR 0.47; 95% CI 0.35–0.64), causing the primary endpoint of this study to be met. Similar results were obtained for the 5-year OS rates (95% vs 85%; HR 0.38; 95% CI 0.27–0.54). Moreover, the prognostic value of SET2,3 was still significant (P<0.0001) after controlling for ROR-PT, showing that SET2,3 is adding independent prognostic value. Furthermore, a significant interaction effect was observed between SET2,3 score and the choice of chemotherapy on DFS (Pinteraction=0.098). In patients with lower SET2,3 scores, dose-dependent chemotherapy would be the preferential option, whereas those with higher SET2,3 scores seem to benefit more from conventional chemotherapy. The interaction effect was even stronger when the investigators looked at OS outcomes (Pinteraction=0.027) and remained significant after controlling for HER2 status.

“The future of SET2,3 may allow us to identify patients who would benefit from dense intense chemotherapy and/or adjuvant abemaciclib,” reasoned Prof. Erica Stringer-Reasor (University of Alabama at Birmingham, AL, USA), discussant of this trial. “However, validating this assay in future prospective and retrospective trials is warranted.”

1. Du L, et al. Ann Oncol. 2021;32(5):642–651.
2. Liu MC, et al. NPJ Breast Cancer. 2016;2:15023.
3. Metzger O, et al. 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). Abstract 505, ASCO 2022 Annual Meeting, 3–7 June, Chicago, IL, USA.

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Posted on 5 August 2022