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Clinical Trial
. 2023 Sep;129(4):706-720.
doi: 10.1038/s41416-023-02310-1. Epub 2023 Jul 7.

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

Nalinie Joharatnam-Hogan #  1 , Duaa Hatem #  2 , Fay H Cafferty  1   3 , Giovanna Petrucci  2 , David A Cameron  4 , Alistair Ring  3   5 , Howard G Kynaston  6 , Duncan C Gilbert  1   7 , Richard H Wilson  8   9 , Richard A Hubner  10   11 , Daniel E B Swinson  12 , Siobhan Cleary  1 , Alex Robbins  1 , Mairead MacKenzie  13 , Martin W G Scott-Brown  14 , Sharmila Sothi  14 , Lesley K Dawson  15 , Lisa M Capaldi  16 , Mark Churn  16 , David Cunningham  5 , Vincent Khoo  3   5 , Anne C Armstrong  10 , Nicola L Ainsworth  17 , Gail Horan  17 , Duncan A Wheatley  18 , Russell Mullen  19 , Fiona J Lofts  20 , Axel Walther  21 , Rebecca A Herbertson  7 , John D Eaton  22 , Ann O'Callaghan  23 , Andrew Eichholz  24 , Mohammed M Kagzi  25 , Daniel M Patterson  26 , Krishna Narahari  27   28 , Jennifer Bradbury  29 , Zuzana Stokes  30 , Azhar J Rizvi  31 , Georgina A Walker  32 , Victoria L Kunene  33 , Narayanan Srihari  34 , Aleksandra Gentry-Maharaj  1 , Angela Meade  1 , Carlo Patrono  2 , Bianca Rocca  2 , Ruth E Langley  35
Affiliations
Clinical Trial

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

Nalinie Joharatnam-Hogan et al. Br J Cancer. 2023 Sep.

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.

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Conflict of interest statement

DC reports grants from MedImmune/ AstraZeneca, Clovis, Eli Lilly, 4SC, Bayer, Celgene, NIHR EME, Leap, Roche and ownership interest and advisory role to OVIBIO. VK reports honoraria for speakers’ bureaus, personal fees and non-financial support from Accuray, Astellas, Bayer, Boston Scientific, and Janssen. DW reports sponsorship from Roche, AstraZeneca, Novartis, Pfizer for ad boards and travel fees from Roche. AW reports consulting fees from GlaxoSmithKline, Clovis, MSD and conference attendance from GlaxoSmithKline. VK reports honorarium from Servier, Roche, Amgen and Clovis Oncology pharmaceutical companies for presentation, educational meeting support, and article write-up. AG-M is a co-investigator on studies exploring novel biomarkers in ovarian cancer, funded by Micronoma and iLoF, with the research funding awarded to UCL. CP reports personal fees from Acticor Biotech, Amgen, Bayer, Eli Lilly, Tremeau, and Zambon; institutional grants from AIFA (Italian Medicines Agency), Bayer, Cancer Research UK, and European Commission; he chairs the Scientific Advisory Board of the International Aspirin Foundation. BR reports speaker fees from Swedish Orphan Biovitrum AB, a grant for an investigator-initiated trial from Bayer AG and consulting fees from Aboca. RL reports grant funding for the Add-Aspirin trial and the AsCaP collaboration, and honorarium from the Aspirin Foundation supported by Bayer. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. U-TXM study.
Urine samples were collected at trial entry (off aspirin), after an 8-week run-in period of aspirin 100 mg daily for all participants and 3–6 months after random allocation to aspirin 100 mg, aspirin 300 mg or matched placebo daily.
Fig. 2
Fig. 2. Distribution of U-TXM at registration by tumour-specific cohort—breast (n = 260), colorectal (n = 192), gastro-oesophageal (n = 53), prostate (n = 211).
The dotted line represents the median value in healthy individuals [31].
Fig. 3
Fig. 3. U-TXM levels at the end of the run-in period after 8 weeks of aspirin 100 mg daily.
Panel a by tumour cohort and Panel b for the whole group.
Fig. 4
Fig. 4. U-TXM levels over time at 3 time points (baseline, end of run-in and 3–6 months after random allocation).
Panel a–c random allocation to aspirin 100 mg, 300 mg and matched placebo respectively.
See this image and copyright information in PMC

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