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bioRxiv · 10.64898/2026.09.10.750700

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

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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Abstract

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.

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Jordan, A., Anthonydhason, V., Baird, K., Maniati, E., Jones, J. L., Wall, I., Grigoriadis, A., Wang, J., AbdelFatah, T., Hodivala Dilke, K.. 2026-09-16. Mural β3-integrin signposts Stroma6, a gene signature predicting early relapse in low-risk and chemoresistant breast cancer. https://doi.org/10.64898/2026.09.10.750700

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