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, Melvyn Ang, Conal AskinLouise Bamford, Ruth Boyd, Miriam Buckley, Jacqueline Clarke, Lynn Darragh, Elaine Davis, Jennifer Foreman, Rebecca Gallagher, Janine Gill, Michael Hanna, Naomi Hill, Gareth Irwin, Peter Mallon, Seamus McAleer, Joanne McAllister, Melanie Morris, Nicole Pierce, Sigi Refsum, Samantha Sloan, Sinead Treanor, Jacqueline James, Colin 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
Pages (from-to)247-258
Number of pages12
JournalBritish Journal of Cancer
Volume126
Issue number2
Early online date02 Nov 2021
DOIs
Publication statusPublished - 01 Feb 2022

Bibliographical note

Funding Information:
This work was supported by Almac Diagnostic Services and Cancer Research UK (C44582/A29302). Almac Diagnostic Services undertook microarray and RNA sequencing, but otherwise, the funders had no role in the collection, analysis and interpretation of the data.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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