Tumour Marker Testing – a Cautious CONTENTS: Approach

A CASE-BASED SERIES ON PRACTICAL PATHOLOGY FOR GPs

SEPTEMBER 2020

Tumour marker testing – a cautious CONTENTS: approach

• PSA testing update • CA125 screening • When pre-test counselling is vital © The Royal College of Pathologists of Australasia • Guidance for asymptomatic patients Authors: 2

Dr Jared Millican Dr Stephen Li Dr Mark Wong MBBS MSc (Int Med) MBBS MSc MPH MBA MAACB AFRACMA BSc(Med) MBBS FRACP PhD AFCHSM CMgr FIML FRCPA FHKSCC Medical Oncology Clinical Trials Fellow, Director Core Pathology & Clinical Senior Staff Specialist in Medical Oncology, Westmead Hospital. Chemistry. ICPMR, NSW Health Westmead/Blacktown Public Hospitals. Pathology (West Sector) Westmead Visiting Medical Officer, Westmead Private, Hospital. Norwest Private and Macquarie University Hospitals. Honorary Clinical Associate Professor Macquarie University.

Common Sense Pathology is developed by the Royal College of Pathologists of Australasia and supported by Australian Doctor Group.

While the views expressed are those of the authors, modified by expert reviewers, they are not necessarily held by the College.

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This publication is supported by funding from the Australian Government Department of Health. Introduction 3

Earlier detection of cancer is associated with higher rates of overall survival1. This principle has driven the adoption of screening tests for cancer such as BreastScreen. The idea of blood tests for the detection of cancer is attractive, but most of these are hindered by poor sensitivity and specificity. This limits their use to monitoring of previously treated cancer.

Recent changes have occurred in the evidence and in indications for tumour marker testing.

In this issue of Common Sense Pathology, we examine four clinical scenarios and the current evidence for tumour marker screening for previously undiagnosed malignancy.

PSA testing

In Australia, prostate cancer was the second most commonly diagnosed malignancy in males in 2019 (after skin cancer) and the second highest cause of cancer death after lung cancer1. Prostate specific antigen (PSA) testing for the detection of prostate cancer is the subject of ongoing controversy. In 2016, guidelines supported by the National Health & Medical Research Council (NHMRC) were released to assist in decision-making in this vexed area2. These guidelines recommended that men aged 50-69 should be provided with information on the benefits and harms of PSA testing to assist in their decision on testing every two years2.

The consensus view

The consensus view was that PSA testing should not be offered to individuals under the age of 40 and over the age of 70. Men in these age-groups requesting a PSA test should be informed that the harms of testing may be greater than the benefits2. The NHMRC fact sheet PSA testing for prostate cancer in asymptomatic men … Information for health practitioners can be used to assist in this discussion. If a patient elects to undergo PSA monitoring, the PSA should be repeated every two years. Results greater than 3.0ng/mL (or the 95th percentile cut-off adjusted for age) warrant a repeat PSA one to three months later and a free-to-total PSA percentage test. Patients should be referred for consideration of biopsy if: • The repeat PSA is >5.5ng/mL or • If the PSA is >3.0ng/mL and the free-PSA percentage is <25%2.

When to perform digital rectal exams

Digital rectal examination (DRE) is not recommended routinely in asymptomatic patients. However, DRE is an important part of the clinical examination in any patient with symptoms or investigations suggestive of prostate pathology.

Does DRE affect PSA levels?

Several small studies have provided conflicting results but certainly, DRE does not cause a large change in PSA levels. In one randomised controlled trial of 143 patients, a median increase of 0.4ng/mL was observed while other smaller trials have found either a similar or insignificant change3–5. With this limited evidence, it is wise to avoid PSA testing after a recent DRE. As the half-life of PSA is two to three days, testing within three days of DRE may have a slightly high false-positive rate. 4 What else elevates the PSA reading?

Other factors that can elevate the PSA reading include advanced age, benign prostatic hypertrophy, prostatitis and prostate biopsies6. Finasteride and other 5-alpha reductase inhibitors can reduce PSA levels as does surgical or medical castration. Natural variation and different laboratory standards can cause variability of 20–25%6. This is why the testing method used by the laboratory is stated on the report. If a different laboratory assay is used, the potential variation should be taken into account, particularly when the PSA level is close to the cut-off for decision-making7.

Case in point – Joe aged 63

Joe reports weak urine stream and hesitancy. The reduction in flow volume means Joe is symptomatic and therefore a candidate for PSA testing. Advising Joe on the results of his test should take into account sensitivity and specificity (Figure 1).

Using a cut-off reading of 3.0ng/mL would minimise the effect of inter-assay variability. Had Joe been asymptomatic it would have been prudent to discuss the benefits and risks of PSA testing.

Figure 1: Sensitivity and specificity of common tumour markers and other screening tests

Sensitivity (%) Specificity (%)

PSA (cutoff of 3.0ng/mL)8 32.2 86.7

CA125 (cutoff of 35U/mL)9 78.7 77.9

Immunochemical FOBT10 53–100 93

AFP for Liver Cancer in Cirrhosis11 65 90

Screening Mammography12 75.6 94.9 When pre-test counselling is vital 5

For a screening test to be clinically useful, it should have high sensitivity, specificity and predictive value. Tumour markers, particularly in the early stage of cancers, have variable sensitivity and specificity. For this reason, pre-test counselling is vital, lest the patient receive either false reassurance or needless alarm13. A study of 68,436 patients given multi-modality cancer screening in the US-based Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer screening trial showed that 60.4% of men and 48.8% of women had at least one positive test. As a result, 28.5% and 22.5% respectively had an invasive investigation14. These results underline the caution with which we must approach tumour marker screening tests. Case in point – Joe aged 63 In ovarian cancer there is a significant difference in outcomes between Stage I-II disease where five-year survival exceeds 80% and Stage III-IV disease, where five-year survival is 15–30%15. This continues to drive research into ovarian cancer screening tests. In the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) trial of 200,000 women, there was a statistically insignificant 199 fewer deaths after 11 years in the screened group (148 v 347, p=0.1)16. However, for every 10,000 patients screened, 14 false-negative surgeries were performed. As the evidence stands, this is why the US Preventative Task Force and RACGP clinical guidelines on ovarian cancer screening do not recommend the use of CA125 in asymptomatic patients17,18.

Assessing the balance between risk and benefits

This exercise becomes more complex in patients with a family history of breast or ovarian cancer. The Australian Government provides access to the Familial Risk Assessment – Breast and Ovarian Cancer tool online to help assess the risk of breast or ovarian cancer based on family history risk factors and provide advice on further referrals. However, even in women at high risk of ovarian cancer, trans-vaginal ultrasound or CA125 are not recommended for screening purposes in a recent Cancer Australia position statement19. The recommended strategy for these patients is referral for genetic assessment and discussion of bilateral salpingo-oophorectomy.

Sensitivity (%) Specificity (%)

PSA (cutoff of 3.0ng/mL)8 32.2 86.7

CA125 (cutoff of 35U/mL)9 78.7 77.9

Immunochemical FOBT10 53–100 93

AFP for Liver Cancer in Cirrhosis11 65 90

Screening Mammography12 75.6 94.9 Case in point – Lorraine aged 40

Lorraine has a higher than average risk of ovarian cancer. Based on the current evidence, Lorraine should be advised about the risks and potential harm of CA125 screening. CA125 screening will not prevent the development of any cancer. Reduction in ovarian cancer mortality due to screening has not been proven to date; even in very large trials. An assessment of the family history of breast and ovarian cancer and use of the Familial Risk Assessment tool is best, with further referrals based on the results. Ovarian cancer in premenopausal 6 patients

Ovarian cancer in younger women is relatively uncommon. However, if an adnexal mass is found, CA125 is recommended to determine the Risk of Malignancy Index (see Figure 2). Note that the sensitivity and specificity of CA125 alone is affected by multiple other factors. In the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) Screening Trial20 elevated CA125 was associated with age, former smoking and prior hormone therapy while factors associated with lower levels were current smoking and obesity. Historically, a level of >200U/mL was sometimes used as a cut-off to improve specificity but this has not been rigorously evaluated. Inflammatory bowel disease has been associated with elevated CA125 levels. In a comparison of 131 patients, including 31 controls, both ulcerative colitis and Crohn’s disease were associated with elevated CA125 levels though the difference was only statistically significant for ulcerative colitis21.

Case in point – Veronica aged 37

Veronica presents with pelvic pain and an adnexal mass is identified on examination. At Veronica’s age, ovarian cancer is rare at only 2.79 cases/100,000 patients1. However, the finding of an adnexal mass will require some additional investigation. Cancer Australia recommendations utilise the Risk of Malignancy index22 for the evaluation of a pelvic mass. A score of >200 in a meta-analysis identified malignant masses with a sensitivity and specificity of 79.2% and 91.7% respectively Figure( 2)4.

The next step for Veronica is a difficult clinical question, and probably one best made by shared decision-making. Veronica is informed about the findings and has an opportunity to express her preferences. As she is premenopausal, she will not fall into the high-risk category on the Risk of Malignancy Index if her CA125 is also normal. However, if the sensitivity of the index is only 79.2%, then a proportion of malignancies will be missed and Veronica may not be comfortable with this approach. With unilateral lesions surgery would not necessarily preclude a future pregnancy, so a referral for a consideration of surgical exploration would be the best option.

Figure 2: Risk of Malignancy Index19,22

Criteria Scoring System Menopausal Status (A) Premenopausal 1 Postmenopausal 3 Ultrasound Features (B) Loculations Solid areas No features = 0 Bilateral lesions One feature = 1 Ascites >1 features = 3 Metastases } CA125 (C) Level (U/mL)

Risk of Malignancy Index A X B X C Living with Lynch syndrome 7

Lynch Syndrome (hereditary non-polyposis colorectal cancer) is an autosomal dominant genetic condition. It appears to be due to ineffective DNA mismatch repair and is associated with a higher risk than average of colorectal, endometrial, ovarian and pancreatic cancer in young adults. The risk of each cancer subtype varies depending on the exact mismatch repair defect that has been inherited.

Guidelines on risk management

Guidelines on risk management and a variety of other factsheets and patient information on cancer- related issues and treatment are available at www.eviq.org.au. This site is maintained by the Cancer Institute of NSW. Recommendations under these guidelines vary depending on the underlying inherited mutation.

Case in point: Eve aged 27

Eve is confirmed to have Lynch syndrome and is referred to a hereditary cancer service for guidance on risk management. Testing of relatives is also undertaken. Under the guidelines, there is no role for tumour marker testing for Eve. Instead, consideration should be given to risk-reducing salpingo-oophorectomy and hysterectomy once childbearing is complete. These factors inform Medicare reimbursement benefits.

Item 66650 allows for test reimbursement for a number of tumour markers: CA15.3, CA125, CA19.9, CASA, CEA, HCG, NSE, thyroglobulin, AFP and HCG. However, the reimbursement is only for the detection of hepatocellular carcinoma (AFP), gestational trophoblastic disease (HCG) and germ cell tumour (HCG, AFP). The other tumour markers such as CA125 and CEA are only reimbursed for the monitoring of known malignancy and not for detection or screening. PSA for the purpose of screening has separate item codes (66659 and 66660) reflecting the earlier recommendations. Criteria Scoring System Menopausal Status (A) Premenopausal 1 Postmenopausal 3 Ultrasound Features (B) Loculations Solid areas No features = 0 Bilateral lesions One feature = 1 Ascites >1 features = 3 Metastases CA125 (C) Level (U/mL)

Risk of Malignancy Index A X B X C 8

Tumour marker testing – a cautious approach

Key points for GPs

• For a screening test to be clinically • CA125 is not recommended for screening useful, it should have high sensitivity, of asymptomatic patients, even those at specificity and predictive value. higher-than-average risk.

• Tumour markers, particularly • PSA testing for men aged 50-69 is in the early stage of cancers, have available after a discussion of the risks variable sensitivity and specificity and and benefits. for this reason, pre-test counselling is vital. • If a patient elects to undergo PSA monitoring, the PSA should be repeated • Tumour markers such as CA125 every two years. typically demonstrate lower specificity than other screening tests such as mammography or FOBT.

References

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