Beyond PSA Testing for Prostate Cancer

Perspective Beyond PSA testing for prostate cancer

Better biomarkers are needed to ensure early and accurate detection and prognosis of prostate cancer

rostate cancer is now the most common cancer for patients with a Gleason score between 6 and 10 or diagnosed in men in Australia,1 and Australia has accurate prognosis. P one of the highest incidence rates of prostate There are two main clinical pathology objectives that need cancer in the world, with an estimated age-standardised to be met by biomarker technology. rate of 119.2 per 100 000 men.2 Before 1960, the primary diagnostic test for prostate cancer was the prostatic acid  Early, accurate detection of the cancer: PSA testing phosphatase test. This was eventually replaced in the fails to achieve this because of the large number of fi 1980s by the prostate-speci c antigen (PSA) test. false positives. A PSA reading > 4 ng/mL has a PSA, a glycoprotein enzyme encoded in humans by the positive predictive value of 30%, meaning that less KLK3 gene, was discovered by Flocks and colleagues in than one-third will have prostate cancer, and 3 if  4 ng/mL, a negative predictive value of 85%, 1960. Although a few small studies in the early 1980s 9,10 suggested that PSA might be useful in the diagnosis of meaning that 15% will have prostate cancer. Both prostate cancer,4 other studies found that its primary of these problems result in poor patient management benefit was for monitoring cancer progression and the and less than optimal outcomes. impact of treatment.5 As a result, in 1986 the United States  Early, accurate prognosis: although PSA testing has Food and Drug Administration (FDA) approved PSA been used to help predict disease progression, its testing for monitoring the progression of prostate cancer. lack of expression in many aggressive cancers leads However, in 1994, despite scant evidence for its accuracy to problems with reliability for early, accurate as a diagnostic test, the FDA succumbed to pressure from prognosis. biotechnology companies, clinicians and men’s lobby groups and approved the PSA test for screening; but only Clearly, PSA is not an optimal biomarker for accurate when combined with a digital rectal examination and prostate cancer diagnosis and prognosis, but it is the in men aged 50 years and older.6 current standard that clinicians are generally expected to use. Problems with PSA testing Clear identification of the core of the tumour is ideal, including its leading edges and invasive fronts, to The standard PSA total blood test has a sensitivity range achieve an accurate Gleason grade and prognosis. of 78e100%, with a specificity range of 6e66%.7 However, PSA immunochemistry does not currently Sensitivity may be improved by combining total PSA with enable reproducible, if any, visualisation of the cancer other isoforms; however, at the expense of specificity.8 in some tissue biopsies or prostatectomy samples. It Notably, in an attempt to avoid biopsy, measuring the therefore adds minimally to Gleason grading. The free PSA percentage for patients with total PSA levels in lack of effective biomarkers for visualising prostate the grey area of 4e10 ng/mL, although more accurate cancer and the reliance on standard haematoxylin than total PSA alone, still results in missed cancers. and eosin stains contributes to unreliable Gleason grading. Unfortunately, elevated serum PSA concentrations are not specific to prostate cancer, being also associated with PSA screening: evidence and controversies benign prostatic hyperplasia, prostatitis, other inflammatory conditions, recent sexual intercourse and Two large randomised studies designed to determine the even bicycle riding. Indeed, less than 50% of men who benefit of PSA screening yielded apparently conflicting have undergone a biopsy in response to a PSA reading results. In the US, the Prostate, Lung, Colorectal and > 4.0 ng/mL are diagnosed with prostate cancer.9 1 Ovarian Cancer Screening Trial, which randomised Doug Brooks Further, about 15% of men with a “negative” PSA reading 76 693 men aged 55e74 years between PSA screening 1 have prostate cancer. Ian N Olver with digital rectal examination and usual care, showed Adrian J Thus, PSA testing does not effectively meet any of the that up to 15 years median follow-up, the rate of death Esterman1,2 major requirements for pathological assessment, and PSA from prostate cancer was very low and did not differ is only useful as a biomarker for detection, prognosis and significantly between the two study groups.11 The 1 University of South 4 June 2018 Australia Cancer monitoring in patients who have cancers that secrete it in European Randomized Study of Screening for Prostate j Research Institute, high concentrations. The biology of PSA, including its Cancer randomised 182 160 men aged 50e74 years to PSA Adelaide, SA. fl 2 Australian Institute secretion during in ammatory reactions and its control of screening compared with a control group who were not of Tropical Health the fluidity of ejaculate, limits its use in defining prostate screened. The study showed a mortality advantage at 13 and Medicine, James e Cook University, cancer pathology. Moreover, PSA immunohistochemistry years of 21% in the 162 243 participants aged 55 69 12 MJA 208 (10) Cairns, QLD. does not provide a reliable system for detecting and years. However, a recent combined analysis of the two Doug.Brooks@ visualising prostate cancer in biopsy samples. These trials concluded that after accounting for differences in unisa.edu.au limitations result in missed cancer diagnoses, unnecessary implementation and settings, the trials provide 426 biopsies on patients, over-treatment with surgery, and compatible evidence that screening reduces prostate 13 doi: 10.5694/mja18.00324 inaccurate information on which to base a clinical decision cancer mortality. Perspective

Notably, a mortality benefit takes many years to become However, these approaches do not distinguish primary apparent, but the harms in a large group subject to pathology from secondary downstream biology; over-diagnosis and subsequent over-treatment can affect consequently, they rely on associations to provide an quality of life immediately. The two most prominent indicator of outcome. This has been a major limitation, as harms resulting from treatment for prostate cancer are investigators use their test cohorts to develop a set of impotence and incontinence. This is why the Australian biomarkers or an algorithm. The problem with this Government Standing Committee on Screening has approach is that secondary cohort testing often fails, as recommended against population-based PSA screening, the biomarker panel is specific to certain patients or and has suggested that better tests are needed.14 sample groups. We believe that prostate cancer biomarker development The search for alternative biomarkers should first recognise the critical cell biology and only then use the technology to develop the biomarkers, and A biomarker is any biological molecule found in blood, finally, test the biomarkers on independent highly other body fluids or tissues that can be objectively annotated cohorts of patient samples with accurate measured and evaluated as a sign of a normal or abnormal longitudinal information. The recent identification of biological process and a pathogenic condition or altered endosome biology in prostate cancer is a step disease. Unfortunately, this broad definition has towards such an alternative approach.19 Interestingly, contributed to many of the problems in biomarker PSA and many of the other biomarkers under current research, with attempts to fit biomarkers to a purpose investigation have direct biology associated with this rather than recognising that each biomarker has a place in pathway and, for example, like PSA, are secreted from the pathological process. Once we fully understand the endosomal organelles. Endosome control secretion is a biology of the disease, it should be easier to assign a logical first choice for biomarker investigation to identify biomarker to a particular functional role. This might then a candidate biomarker that is consistently secreted from meet the need for diagnosis, prognosis, predictive cancer cells and reliably detected in circulation. We are at biomarkers and surrogate biomarkers, instead of pushing a point where biomarker discovery needs to be linked PSA into different categories and trying to adapt it for to critical cancer cell biology, so that we can identify multiple purposes. We believe we are at the point of biomarkers that reflect the primary pathology, provide needing to return to the cell biology of the disease and optimal detection, enable visualisation of the develop biomarkers that accurately reflect different pathogenesis in biopsies, and facilitate early, accurate aspects of the pathogenesis. A recently commissioned prognosis. report provides a detailed review of the appropriate use 15 and implementation of cancer biomarkers. Conclusion In the search for new prostate cancer biomarkers, a number of technologies and approaches have been Current PSA-based diagnostic tests cannot accurately detect prostate cancer. After the cancer has been employed. These include proteomics, secretomics, fi lipidomics, metabolomics, detailed analysis of the cell identi ed, the histopathological grading is less than biology of the cancer, and systems biology. New reliable; and current pathology tests are not able to technologies together with the evaluation of combinations effectively distinguish between indolent and aggressive of existing biomarkers are providing some promising life-threatening cancer. These major problems with fi prostate cancer pathology testing result in poor patient avenues for the identi cation of effective prostate cancer — biomarkers. For example, prostate cancer antigen 3 and management the solution lies in the development and the TMPRSS2:ERG fusion transcript have been shown to appropriate validation of new prostate cancer have higher specificity, which could potentially reduce biomarkers. false-positive results.16 Other potential approaches Competing interests: Doug Brooks is developing cancer biomarkers for commerci- alisation with Envision Sciences Pty Ltd. combine markers — for example, the Stockholm-3 model combines protein biomarkers with genetic Provenance: Commissioned; externally peer reviewed. n polymorphisms and clinical characteristics — and have ª 2018 AMPCo Pty Ltd. Produced with Elsevier B.V. All rights reserved. been shown to outperform PSA in high risk disease.17 The use of circulating tumour cells is also being investigated.18 References are available online at www.mja.com.au. J 0 (10) 208 MJA j ue2018 June 4

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1 Australian Institute of Health and Welfare. Cancer in Australia 11 Pinsky PF, Porok PC, Yu K, et al. Extended mortality results for prostate 2017 (AIHW Cat. No. CAN 100; Cancer Series No. 101). Canberra: AIHW, 2017. cancer screening in the PLCO trial with a median 15 years follow-up. Cancer https://www.aihw.gov.au/reports/cancer/cancer-in-australia-2017/ 2017; 123: 592-599. contents/table-of-contents (viewed Mar 2018). 12 Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer 2 International Agency for Research on Cancer. GLOBOCAN 2012: estimated mortality: results of the European randomised study of screening for cancer incidence and mortality worldwide in 2012. http://globocan.iarc.fr prostate cancer (ERSPC) investigators. Lancet 2014; 384: 2072-2035. (viewed Mar 2018). 13 Tsodikov A, Gulati R, Heijnsdijk, et al. Reconciling the effects of screening on 3 Flocks RH, Urich VC, Patel CA, Opitz JM. Studies on the antigenic properties prostate cancer mortality in the ERSPC and PLCO Trials. Ann Intern Med of prostatic tissue. 1. J Urol 1960; 84: 134-143. 2017; 167: 449-455. 4 Wang MC, Papsidero LD, Kuriyama M, et al. Prostate antigen: a new 14 Australian Government Department of Health Standing Committee on potential marker for prostatic cancer. Prostate 1981; 2: 89-96. Screening. Prostate cancer screening. http://www.cancerscreening.gov.au/ 5 Kuriyama M, Wang MC, Lee CI, et al. Use of human prostate-specific antigen internet/screening/publishing.nsf/Content/prostate-cancer-screening? in monitoring prostate cancer. Cancer Res 1981; 41: 3874-3876. (viewed Apr 2018). 6 Medscape. PSA test is misused, unreliable, says the antigen’s discoverer. 15 Olver I, Brooks DA, Esterman A. Cancer biomarkers in Australia. Adelaide: Medscape Aug 08, 2014. https://www.medscape.com/viewarticle/828854 University of South Australia, 2017. http://www.unisa.edu.au/Global/Health/ (viewed March 2018). Research/Cancer%20Biomarkers%20in%20Australia%20Report.pdf (viewed Mar 2018). 7 Harvey P, Basuita A, Endersby D, et al. A systematic review of the diagnostic accuracy of prostate-specific antigen. BMC Urol 2009; 9: 14. 16 Pal RP, Kockelbergh RC, Pringle JH, et al. Immunocytochemical detection of ERG expression in exfoliated urinary cells identifies with high specificity 8 Roddam AW, Duffy MJ, Hamdy FC, et al. Use of prostate-specific antigen patients with prostate cancer. BJU Int 2016; 117: 686-696. (PSA) isoforms for the detection of prostate cancer in men with a PSA level of 2-10 ng/ml: systematic review and meta-analysis. Eur Urol 2005; 48: 17 Eklund M, Nordström T, Aly M, et al. The Stockholm-3 (STHLM3) model 386-399. can improve prostate cancer diagnostics in men aged 50-69 yr 9 Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer compared with current prostate cancer testing. Eur Urol Focus 2016; among men with a prostate-specific antigen level 4.0 ng per milliliter. doi: 10.1016/j.eurf.2016.10.009 [Epub ahead of print]. N Engl J Med 2004; 350: 2239-2246. 18 Hille C, Pantel K. Prostate cancer: circulating tumour cells in prostate cancer. 10 Catalona WJ, Richie JP, Goodman PJ, et al. Comparison of digital rectal Nat Rev Urol 2018; doi: 10.1038/nrurol.2018.25 [Epub ahead of print]. examination and serum prostate specific antigen in the early detection of 19 Johnson IRD, Parkinson-Lawrence EJ, Keegan H, et al. Endosomal gene prostate cancer: results of a multicentre clinical trial of 6,630 men. J Urol expression: an important new indicator for prostate cancer patient 1994; 151: 1283-1290. prognosis? Oncotarget 2015; 6: 37919-37929. - 4 June 2018 j MJA 208 (10)

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