Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer

Eileen E Parkes, Kienan I Savage, Tong Lioe, Clinton Boyd, Sophia Halliday, Steven M Walker, Keith Lowry, Laura Knight, Niamh E Buckley, Andrena Grogan, Gemma E Logan, Alison Clayton, Jane Hurwitz, Stephen J Kirk, Jiamei Xu, Fatima Abdullahi Sidi, Matthew P Humphries, Victoria Bingham, Neo-DDIR Investigators, Jaqueline A JamesColin R James, D Paul Harkin, Richard D Kennedy, Stuart A McIntosh

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Abstract

BACKGROUND: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer.

METHODS: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures.

RESULTS: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression.

CONCLUSIONS: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming.


Original languageEnglish
JournalBritish Journal of Cancer
Early online date02 Nov 2021
DOIs
Publication statusEarly online date - 02 Nov 2021

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© 2021. The Author(s).

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