Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer
Eileen E. Parkes, Kienan I. Savage, T F Lioe, Clinton Boyd, Sophia R. Halliday, Steven M. Walker, Keith Lowry, Laura A. Knight, Niamh E. Buckley, Andrena Grogan, Gemma E. Logan, Alison Clayton, Jane Hurwitz, Stephen Kirk, Jiamei Xu, Fatima Abdullahi Sidi, Matthew P. Humphries, Victoria Bingham, Neo-DDIR Investigators, Melvyn Ang, C Arl A. L Askin, Louise Bamford, Ruth Boyd, Miriam R.E. Buckley, Jacqueline Clarke, Lynn Darragh, E.Jack Davis, Jennifer Foreman, Rebecca Gallagher, Janine Gill, Michael G. Hanna, Naomi Hill, Gareth Irwin, Peter Mallon, Seamus McAleer, J McAllister, Melanie Morris, Nicole Pierce, Sigi Refsum, Samantha Sloan, S Treanor, Jaqueline A. James, Colin R. James, D. Paul Harkin, Richard D. Kennedy, Stuart McIntosh
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. TRIAL REGISTRATION: Not applicable (non-interventional study). CRUK Internal Database Number 14232.