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 Askin; Louise 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

doi:10.1038/s41416-021-01599-0

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 language	English
Pages (from-to)	247-258
Number of pages	12
Journal	British Journal of Cancer
Volume	126
Issue number	2
Early online date	02 Nov 2021
DOIs	https://doi.org/10.1038/s41416-021-01599-0
Publication status	Published - 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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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 6.77 MBLicence: CC BY

Temporal analysis of clinico-pathological variables and biomarkers in cancer
Halliday, S. (Author), Blayney, J. (Supervisor) & Kennedy, R. (Supervisor), Dec 2019
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Parkes, E. E., Savage, K. I., Lioe, T., Boyd, C., Halliday, S., Walker, S. M., Lowry, K., Knight, L., Buckley, N. E., Grogan, A., Logan, G. E., Clayton, A., Hurwitz, J., Kirk, S. J., Xu, J., Sidi, F. A., Humphries, M. P., Bingham, V., Ang, M., ... McIntosh, S. A. (2022). Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer. British Journal of Cancer, 126(2), 247-258. https://doi.org/10.1038/s41416-021-01599-0

@article{ddcf60aeb53840b385341226cc8804ab,

title = "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.",

author = "Parkes, {Eileen E.} and Savage, {Kienan I.} and Tong Lioe and Clinton Boyd and Sophia Halliday and Walker, {Steven M.} and Keith Lowry and Laura Knight and Buckley, {Niamh E.} and Andrena Grogan and Logan, {Gemma E.} and Alison Clayton and Jane Hurwitz and Kirk, {Stephen J.} and Jiamei Xu and Sidi, {Fatima Abdullahi} and Humphries, {Matthew P.} and Victoria Bingham and Melvyn Ang and Conal Askin and Louise Bamford and Ruth Boyd and Miriam Buckley and Jacqueline Clarke and Lynn Darragh and Elaine Davis and Jennifer Foreman and Rebecca Gallagher and Janine Gill and Michael Hanna and Naomi Hill and Gareth Irwin and Peter Mallon and Seamus McAleer and Joanne McAllister and Melanie Morris and Nicole Pierce and Sigi Refsum and Samantha Sloan and Sinead Treanor and Jacqueline James and James, {Colin R.} and {Paul Harkin}, D. and Kennedy, {Richard D.} and McIntosh, {Stuart A.}",

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: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = feb,

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doi = "10.1038/s41416-021-01599-0",

language = "English",

volume = "126",

pages = "247--258",

journal = "British Journal of Cancer",

issn = "0007-0920",

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Parkes, EE, Savage, KI, Lioe, T, Boyd, C, Halliday, S, Walker, SM, Lowry, K, Knight, L, Buckley, NE, Grogan, A, Logan, GE, Clayton, A, Hurwitz, J, Kirk, SJ, Xu, J, Sidi, FA, Humphries, MP , Bingham, V, Ang, M, Askin, C, Bamford, L, Boyd, R, Buckley, M, Clarke, J, Darragh, L, Davis, E, Foreman, J, Gallagher, R, Gill, J, Hanna, M, Hill, N, Irwin, G, Mallon, P, McAleer, S, McAllister, J, Morris, M, Pierce, N, Refsum, S, Sloan, S, Treanor, S, James, J, James, CR, Paul Harkin, D, Kennedy, RD & McIntosh, SA 2022, 'Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer', British Journal of Cancer, vol. 126, no. 2, pp. 247-258. https://doi.org/10.1038/s41416-021-01599-0

TY - JOUR

T1 - Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer

AU - Parkes, Eileen E.

AU - Savage, Kienan I.

AU - Lioe, Tong

AU - Boyd, Clinton

AU - Halliday, Sophia

AU - Walker, Steven M.

AU - Lowry, Keith

AU - Knight, Laura

AU - Buckley, Niamh E.

AU - Grogan, Andrena

AU - Logan, Gemma E.

AU - Clayton, Alison

AU - Hurwitz, Jane

AU - Kirk, Stephen J.

AU - Xu, Jiamei

AU - Sidi, Fatima Abdullahi

AU - Humphries, Matthew P.

AU - Bingham, Victoria

AU - Ang, Melvyn

AU - Askin, Conal

AU - Bamford, Louise

AU - Boyd, Ruth

AU - Buckley, Miriam

AU - Clarke, Jacqueline

AU - Darragh, Lynn

AU - Davis, Elaine

AU - Foreman, Jennifer

AU - Gallagher, Rebecca

AU - Gill, Janine

AU - Hanna, Michael

AU - Hill, Naomi

AU - Irwin, Gareth

AU - Mallon, Peter

AU - McAleer, Seamus

AU - McAllister, Joanne

AU - Morris, Melanie

AU - Pierce, Nicole

AU - Refsum, Sigi

AU - Sloan, Samantha

AU - Treanor, Sinead

AU - James, Jacqueline

AU - James, Colin R.

AU - Paul Harkin, D.

AU - Kennedy, Richard D.

AU - McIntosh, Stuart A.

N1 - 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).

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-021-01599-0

DO - 10.1038/s41416-021-01599-0

M3 - Article

C2 - 34728791

SN - 0007-0920

VL - 126

SP - 247

EP - 258

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 2

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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Student theses

Temporal analysis of clinico-pathological variables and biomarkers in cancer

Cite this