Mural β3-integrin signposts Stroma6, a gene signature predicting early relapse in low-risk and chemoresistant breast cancer

The Oncotype DX (ODX) assay guides adjuvant chemotherapy in ER+/HER2- breast cancer but overlooks drivers from the tumour stroma, leaving some low-risk and chemotherapy-spared patients vulnerable to rapid relapse. Here, we show that perivascular mural {beta}3-integrin protein expression predicts early (3-year) relapse in ODX low-risk patients (HR = 15.80, P = 0.010), from which we derived a translatable 6-gene stromal signature, termed Stroma6. High Stroma6 expression predicted early recurrence in the ODX low-risk discovery cohort, with zero early relapses in the low-expression group. External validation in the METABRIC dataset confirmed that Stroma6 independently predicts rapid recurrence in ODX low-risk patients (HR = 11.68, P = 0.002). Furthermore, Stroma6 utility extends to clinical chemoresistance, independently predicting early events in a pan-subtype cohort with residual disease following neoadjuvant chemotherapy (HR = 2.29, P = 0.003). Ultimately, Stroma6 is a robust prognostic signature identifying patients at high risk of early recurrence across diverse clinical contexts.

Jordan, A., Anthonydhason, V., Baird, K., Maniati, E., Jones, J. L., Wall, I., Grigoriadis, A., Wang, J., AbdelFatah, T., Hodivala Dilke, K.

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