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Independent validation of a pre-specified four-kallikrein marker model for prediction of adverse pathology and biochemical recurrence

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Abstract

Background

Accurate markers for prostate cancer (PC) risk stratification could aid decision-making for initial management strategies. The 4Kscore has an undefined role in predicting outcomes after radical prostatectomy (RP).

Methods

We included 1476 patients with 4Kscore measured prior to RP at two institutions. The 4Kscore was assessed for prediction of adverse pathology at RP and biochemical recurrence (BCR) relative to a clinical model. We pre-specified that all analyses would be assessed in biopsy Grade Group 1 (GG1) or 2 (GG2) PC patients, separately.

Results

The 4Kscore increased discrimination for adverse pathology in all patients (delta area under the receiver operative curve (AUC) 0.009, 95% confidence interval (CI) 0.002, 0.016; clinical model AUC 0.767), driven by GG1 (delta AUC 0.040, 95% CI 0.006, 0.073) rather than GG2 patients (delta AUC 0.005, 95% CI −0.012, 0.021). Adding 4Kscore improved prediction of BCR in all patients (delta C-index 0.014, 95% CI 0.007, 0.021; preop-BCR nomogram C-index 0.738), again with larger changes in GG1 than in GG2.

Conclusions

This study validates prior investigations on the use of 4Kscore in men with biopsy-confirmed PC. Men with GG1 PC and a high 4Kscore may benefit from additional testing to guide treatment selection. Further research is warranted regarding the value of the 4Kscore in men with biopsy GG2 PC.

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Data availability

The data sets analysed for this study will be made available to researchers on reasonable request to the corresponding author.

Code availability

Code can be made available by making a request to the corresponding author.

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Acknowledgements

We thank Jesper Boulund Kristensen, Derya Pero Øztoprak, Mette Korsgaard Emdal and Helene Holm for excellent technical assistance and we also thank Mona Hassan Al-Battat for assistance with the kallikrein marker measurements. The Danish Cancer Biobank is acknowledged for providing patient samples and guidelines for handling and storage.

Funding

This work was supported in part by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center [P30 CA008748], a SPORE grant in Prostate Cancer to Dr. H Scher [P50 CA092629], the Sidney Kimmel Center for Prostate and Urologic Cancers, David H Koch through the Prostate Cancer Foundation. This work was also supported in part by the Swedish Cancer Society (Cancerfonden 20 1354 PjF) and General Hospital in Malmö Foundation for Combating Cancer. Furthermore, this work was supported in part by grants from the Velux Foundation (no. 11307) and The Danish Cancer Society (R99-A6338-14-S25).

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Author notes

  1. These authors contributed equally: Karina D. Sørensen, Hans Lilja.

Authors and Affiliations

  1. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

    Martin Rasmussen, Jacob Fredsøe & Karina D. Sørensen

  2. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Martin Rasmussen, Jacob Fredsøe, Michael Borre & Karina D. Sørensen

  3. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Amy L. Tin & Andrew J. Vickers

  4. Department of Pathology, Aarhus University Hospital, Aarhus, Denmark

    Benedicte Ulhøi

  5. Department of Urology, Aarhus University Hospital, Aarhus, Denmark

    Michael Borre

  6. Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, NY, USA

    James Eastham, Behfar Ehdaie, Bertrand Guillonneau, Vincent Laudone, Peter T. Scardino & Karim Touijer

  7. Uro-Oncology Department, Charité University Hospital, Berlin, Germany

    Bertrand Guillonneau

  8. Departments of Laboratory Medicine, Surgery, and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Hans Lilja

  9. Department of Translational Medicine, Lund University, Malmö, Sweden

    Hans Lilja

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  1. Martin Rasmussen
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Contributions

MR drafted and revised the manuscript. JF drafted and revised the manuscript. ALT analysed and interpreted the data, carried out the statistical analysis, drafted and revised the manuscript. AJV conceived and designed the idea, analysed and interpreted the data and revised the manuscript. BU conceived the idea and revised the manuscript. MB conceived the idea and revised the manuscript. JE conceived the idea and revised the manuscript. BE conceived the idea and revised the manuscript. BG conceived the idea and revised the manuscript. VL conceived the idea and revised the manuscript. PTS conceived the idea and revised the manuscript. KT conceived the idea and revised the manuscript. KDS conceived and designed the idea, interpreted the data, revised and approved the final version of the manuscript, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. HL conceived and designed the idea, interpreted the data, revised and approved the final version of the manuscript, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Hans Lilja.

Ethics declarations

Competing interests

HL holds patents on assays for intact PSA. AJV and HL are named on a patent for a statistical method to detect prostate cancer (the 4KScore test) that has been commercialised by OPKO Health. AJV and HL receive royalties from sales of the test. HL has stock and AJV has stock options in OPKO Health. KDS and JF are co-inventors on issued patents for epigenetic and microRNA biomarkers for prostate cancer, owned by Aarhus University and licensed to Qiagen.

Ethics approval and consent to participate

Ethical approval was obtained from the MSKCC IRB and The Central Denmark Region Committees on Health Research Ethics. Consent was received from all participants. The study was performed in accordance with the Declaration of Helsinki.

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Rasmussen, M., Fredsøe, J., Tin, A.L. et al. Independent validation of a pre-specified four-kallikrein marker model for prediction of adverse pathology and biochemical recurrence. Br J Cancer 126, 1004–1009 (2022). https://doi.org/10.1038/s41416-021-01661-x

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