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

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.

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Gene Expression–Based Prediction of Neoadjuvant Chemotherapy Response in Early Breast Cancer: Results of the Prospective Multicenter EXPRESSION Trial

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-20-2662 ◽

2021 ◽

Vol 27 (8) ◽

pp. 2148-2158

Author(s):

Karolina Edlund ◽

Katrin Madjar ◽

Antje Lebrecht ◽

Bahriye Aktas ◽

Henryk Pilch ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Neoadjuvant Chemotherapy ◽

Early Breast Cancer ◽

Chemotherapy Response

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Association between the nucleosome footprint of plasma DNA and neoadjuvant chemotherapy response for breast cancer

npj Breast Cancer ◽

10.1038/s41523-021-00237-5 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Xu Yang ◽

Geng-Xi Cai ◽

Bo-Wei Han ◽

Zhi-Wei Guo ◽

Ying-Song Wu ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Neoadjuvant Chemotherapy ◽

Cancer Patients ◽

Cell Receptor ◽

Chemotherapy Response ◽

Breast Cancer Patients ◽

Plasma Dna ◽

Transcription Start Sites ◽

Response To Chemotherapy

AbstractGene expression signatures have been used to predict the outcome of chemotherapy for breast cancer. The nucleosome footprint of cell-free DNA (cfDNA) carries gene expression information of the original tissues and thus may be used to predict the response to chemotherapy. Here we carried out the nucleosome positioning on cfDNA from 85 breast cancer patients and 85 healthy individuals and two cancer cell lines T-47D and MDA-MB-231 using low-coverage whole-genome sequencing (LCWGS) method. The patients showed distinct nucleosome footprints at Transcription Start Sites (TSSs) compared with normal donors. In order to identify the footprints of cfDNA corresponding with the responses to neoadjuvant chemotherapy in patients, we mapped on nucleosome positions on cfDNA of patients with different responses: responders (pretreatment, n = 28; post-1 cycle, post-3/4 cycles, and post-8 cycles of treatment, n = 12) and nonresponders (pretreatment, n = 10; post-1 cycle, post-3/4 cycles, and post-8 cycles of treatment, n = 10). The coverage depth near TSSs in plasma cfDNA differed significantly between responders and nonresponders at pretreatment, and also after neoadjuvant chemotherapy treatment cycles. We identified 232 TSSs with differential footprints at pretreatment and 321 after treatment and found enrichment in Gene Ontology terms such as cell growth inhibition, tumor suppressor, necrotic cell death, acute inflammatory response, T cell receptor signaling pathway, and positive regulation of vascular endothelial growth factor production. These results suggest that cfDNA nucleosome footprints may be used to predict the efficacy of neoadjuvant chemotherapy for breast cancer patients and thus may provide help in decision making for individual patients.

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