Thromboxane Biosynthesis in 	Cancer Patients and its Inhibition by Aspirin: A Sub-Study of the Add-Aspirin Trial

Nalinie  Joharatnam-Hogan; Fay H. Cafferty; Giovanna Petrucci; David A Cameron; Alistair Ring; Howard G. Kynaston; Duncan C. Gilbert; Richard H. Wilson; Richard A. Hubner; Daniel E. B Swinson; Siobhan Cleary; Alex Robbins; Mairead MacKenzie; Martin W.G. Scott-Brown; Sharmila Sothi; Lesley Dawson; Lisa M. Capaldi; Mark Churn; David Cunningham; Vincent Khoo; Anne C. Armstrong; Nicola L. Ainsworth; Gail Horan; Duncan A. Wheatley; Russell Mullen; Fiona J. Loftus; Axel Walther; Rebecca A. Herbertson; John D. Eaton; Ann O'Callaghan; Andrew Eichholz; Mohammed Mubashir Kagzi; Daniel M. Patterson; Krishna Narahari; Jennifer Bradbury; Zuzana Stokes; Azhar J. Rizvi; Georgina A. Walker; Victoria L. Kunene; Narayanan Srihari; Aleksandra Gentry-Maharaj; Angela Meade; Carlo Patrono; Bianca Rocca; Ruth E. Langley

Thromboxane Biosynthesis in Cancer Patients and its Inhibition by Aspirin: A Sub-Study of the Add-Aspirin Trial

Nalinie Joharatnam-Hogan, Fay H. Cafferty, Giovanna Petrucci, David A Cameron, Alistair Ring, Howard G. Kynaston, Duncan C. Gilbert, Richard H. Wilson, Richard A. Hubner, Daniel E. B Swinson, Siobhan Cleary, Alex Robbins, Mairead MacKenzie, Martin W.G. Scott-Brown, Sharmila Sothi, Lesley Dawson, Lisa M. Capaldi, Mark Churn, David Cunningham, Vincent KhooAnne C. Armstrong, Nicola L. Ainsworth, Gail Horan, Duncan A. Wheatley, Russell Mullen, Fiona J. Loftus, Axel Walther, Rebecca A. Herbertson, John D. Eaton, Ann O'Callaghan, Andrew Eichholz, Mohammed Mubashir Kagzi, Daniel M. Patterson, Krishna Narahari, Jennifer Bradbury, Zuzana Stokes, Azhar J. Rizvi, Georgina A. Walker, Victoria L. Kunene, Narayanan Srihari, Aleksandra Gentry-Maharaj, Angela Meade, Carlo Patrono, Bianca Rocca, Ruth E. Langley^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Background
Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases.

Methods
Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values.

Results
In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg.

Conclusions
Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

Original language	English
Journal	British Journal of Cancer
Publication status	Published - 7 Jul 2023

Keywords / Materials (for Non-textual outputs)

Aspririn
adjuvant therapy
thromboxane biosynthesis
PLATELET ACTIVATION
cancer
metastases

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s41416-023-02310-1
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Joharatnam-Hogan, N., H. Cafferty, F., Petrucci, G., Cameron, D. A., Ring, A., G. Kynaston, H., C. Gilbert, D., H. Wilson, R., A. Hubner, R., E. B Swinson, D., Cleary, S., Robbins, A., MacKenzie, M., W.G. Scott-Brown, M., Sothi, S., Dawson, L., M. Capaldi, L., Churn, M., Cunningham, D., ... E. Langley, R. (2023). Thromboxane Biosynthesis in Cancer Patients and its Inhibition by Aspirin: A Sub-Study of the Add-Aspirin Trial. British Journal of Cancer.

@article{9175e281480c418086134ebb11bbf6f6,

title = "Thromboxane Biosynthesis in Cancer Patients and its Inhibition by Aspirin: A Sub-Study of the Add-Aspirin Trial",

abstract = "BackgroundPre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases.MethodsUrinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values.ResultsIn total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg.ConclusionsPersistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.",

keywords = "Aspririn, adjuvant therapy, thromboxane biosynthesis, PLATELET ACTIVATION, cancer, metastases",

author = "Nalinie Joharatnam-Hogan and {H. Cafferty}, Fay and Giovanna Petrucci and Cameron, {David A} and Alistair Ring and {G. Kynaston}, Howard and {C. Gilbert}, Duncan and {H. Wilson}, Richard and {A. Hubner}, Richard and {E. B Swinson}, Daniel and Siobhan Cleary and Alex Robbins and Mairead MacKenzie and {W.G. Scott-Brown}, Martin and Sharmila Sothi and Lesley Dawson and {M. Capaldi}, Lisa and Mark Churn and David Cunningham and Vincent Khoo and {C. Armstrong}, Anne and {L. Ainsworth}, Nicola and Gail Horan and {A. Wheatley}, Duncan and Russell Mullen and {J. Loftus}, Fiona and Axel Walther and {A. Herbertson}, Rebecca and {D. Eaton}, John and Ann O'Callaghan and Andrew Eichholz and {Mubashir Kagzi}, Mohammed and {M. Patterson}, Daniel and Krishna Narahari and Jennifer Bradbury and Zuzana Stokes and {J. Rizvi}, Azhar and {A. Walker}, Georgina and {L. Kunene}, Victoria and Narayanan Srihari and Aleksandra Gentry-Maharaj and Angela Meade and Carlo Patrono and Bianca Rocca and {E. Langley}, Ruth",

note = "Funding Information: This work was specifically supported by CRUK (C471/A19252) and the AsCaP collaboration (C569/A24991). The main trial is supported by grants from Cancer Research UK (C471/A15015), the National Institute for Health Research Health Technology Assessment Programme (12/01/38) and the MRC (MC_UU_00004/02 and MC_UU_12023/28). Bayer Pharmaceuticals AG provided aspirin and placebo, free of charge. The role of the funder: The sponsor had no role in the design, analysis or decision to publish. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = jul,

day = "7",

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

}

Joharatnam-Hogan, N, H. Cafferty, F, Petrucci, G, Cameron, DA, Ring, A, G. Kynaston, H, C. Gilbert, D, H. Wilson, R, A. Hubner, R, E. B Swinson, D, Cleary, S, Robbins, A, MacKenzie, M, W.G. Scott-Brown, M, Sothi, S, Dawson, L, M. Capaldi, L, Churn, M, Cunningham, D, Khoo, V, C. Armstrong, A, L. Ainsworth, N, Horan, G, A. Wheatley, D, Mullen, R, J. Loftus, F, Walther, A, A. Herbertson, R, D. Eaton, J, O'Callaghan, A, Eichholz, A, Mubashir Kagzi, M, M. Patterson, D, Narahari, K, Bradbury, J, Stokes, Z, J. Rizvi, A, A. Walker, G, L. Kunene, V, Srihari, N, Gentry-Maharaj, A, Meade, A, Patrono, C, Rocca, B & E. Langley, R 2023, 'Thromboxane Biosynthesis in Cancer Patients and its Inhibition by Aspirin: A Sub-Study of the Add-Aspirin Trial', British Journal of Cancer.

TY - JOUR

T1 - Thromboxane Biosynthesis in Cancer Patients and its Inhibition by Aspirin: A Sub-Study of the Add-Aspirin Trial

AU - Joharatnam-Hogan, Nalinie

AU - H. Cafferty, Fay

AU - Petrucci, Giovanna

AU - Cameron, David A

AU - Ring, Alistair

AU - G. Kynaston, Howard

AU - C. Gilbert, Duncan

AU - H. Wilson, Richard

AU - A. Hubner, Richard

AU - E. B Swinson, Daniel

AU - Cleary, Siobhan

AU - Robbins, Alex

AU - MacKenzie, Mairead

AU - W.G. Scott-Brown, Martin

AU - Sothi, Sharmila

AU - Dawson, Lesley

AU - M. Capaldi, Lisa

AU - Churn, Mark

AU - Cunningham, David

AU - Khoo, Vincent

AU - C. Armstrong, Anne

AU - L. Ainsworth, Nicola

AU - Horan, Gail

AU - A. Wheatley, Duncan

AU - Mullen, Russell

AU - J. Loftus, Fiona

AU - Walther, Axel

AU - A. Herbertson, Rebecca

AU - D. Eaton, John

AU - O'Callaghan, Ann

AU - Eichholz, Andrew

AU - Mubashir Kagzi, Mohammed

AU - M. Patterson, Daniel

AU - Narahari, Krishna

AU - Bradbury, Jennifer

AU - Stokes, Zuzana

AU - J. Rizvi, Azhar

AU - A. Walker, Georgina

AU - L. Kunene, Victoria

AU - Srihari, Narayanan

AU - Gentry-Maharaj, Aleksandra

AU - Meade, Angela

AU - Patrono, Carlo

AU - Rocca, Bianca

AU - E. Langley, Ruth

N1 - Funding Information: This work was specifically supported by CRUK (C471/A19252) and the AsCaP collaboration (C569/A24991). The main trial is supported by grants from Cancer Research UK (C471/A15015), the National Institute for Health Research Health Technology Assessment Programme (12/01/38) and the MRC (MC_UU_00004/02 and MC_UU_12023/28). Bayer Pharmaceuticals AG provided aspirin and placebo, free of charge. The role of the funder: The sponsor had no role in the design, analysis or decision to publish. Publisher Copyright: © 2023, The Author(s).

PY - 2023/7/7

Y1 - 2023/7/7

N2 - BackgroundPre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases.MethodsUrinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values.ResultsIn total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg.ConclusionsPersistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

AB - BackgroundPre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases.MethodsUrinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values.ResultsIn total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77–82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg.ConclusionsPersistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

KW - Aspririn

KW - adjuvant therapy

KW - thromboxane biosynthesis

KW - PLATELET ACTIVATION

KW - cancer

KW - metastases

M3 - Article

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

Thromboxane Biosynthesis in Cancer Patients and its Inhibition by Aspirin: A Sub-Study of the Add-Aspirin Trial

Abstract

Keywords / Materials (for Non-textual outputs)

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