SERUM TUMOUR MARKERS:

APPLICATIONS AND ABUSES

Leslie Charles Lai

Gleneagles Kuala Lumpur

Objectives

➢To know the usefulness of the more commonly requested

serum tumour markers.

➢To understand the limitations of serum tumour markers.

➢To know when tumour markers should or should not be

measured.

Misuse of serum tumour markers

➢Misconception that serum tumour markers can be used reliably to screen for and diagnose cancers.

➢Many laboratories in Malaysia include tumour markers in their wellness packages and executive screening profiles.

➢This practice is not evidence-based.

➢ Indiscriminate use of tumour markers results in unnecessary investigations, thus increasing healthcare costs, and may cause patients unnecessary worry.

WHAT ARE TUMOUR MARKERS?

Substances related to the presence or progress of a tumour.

IDEAL TUMOUR MARKER

➢Detectable only when malignancy is present

➢ Specific for the type and site of malignancy

➢Correlates with the amount of malignant tissue present

➢Responds rapidly to a change in tumour size

➢Cost-effective

At present no tumour marker fulfills all of these criteria.

Uses of Tumour Markers

➢ Screening }

➢Diagnosis } limited value

➢ Prognosis }

➢Monitoring response to therapy } valuable

➢Detection of recurrence } functions

Probably only hCG, as a marker for choriocarcinoma, is used for all of the above.

Prostate Specific Antigen (PSA)

➢ Prostate cancer is the most common cancer in men in many

Western countries.

➢ In the US, the lifetime risk of being diagnosed with prostate

cancer is approximately 11% but the lifetime risk of dying of

prostate cancer is only 2.5%.

➢ In autopsy studies of men who died of other causes, more than

20% of men aged 50 to 59 years and more than 33% of men

aged 70 to 79 years were found to have prostate cancer.

Prostate Specific Antigen (PSA)

➢The median age of death from prostate cancer is 80 years.

➢More than two-thirds of all men who die of prostate cancer are

older than 75 years.

➢Older men, African-American men, and men who have a

family history of prostate cancer have a greater risk of

developing prostate cancer.

Factors that alter serum PSA

➢ PSA levels increase with age due to a higher prevalence of benign prostatic hyperplasia in the elderly male population.

➢ Finasteride causes a 50% decrease in PSA levels.

➢Herbal products (Saw palmetto in its pure form and Permixon) do not decrease serum PSA levels significantly.

➢Acute prostatitis

Factors that alter serum PSA

➢ Following ejaculation

➢Lower urinary tract endoscopic manipulation

➢Transrectal and transperineal prostatic biopsy

➢ Prostatic massage

➢Bladder catheterisation

➢Cycling

Screening for prostate cancer

➢The goal of screening for prostate cancer is to identify high-

risk, localised prostate cancer that can be successfully treated

in order to prevent morbidity and mortality associated with

advanced or metastatic prostate cancer.

➢ In screening programmes, approximately 30% of Western men

who are asymptomatic with PSA levels >4 ng/ml have prostate

cancer.

➢With the additional finding of an abnormal DRE an incidental

PSA >4 ng/ml is associated with a cancer predictive value

close to 50%.

Screening for prostate cancer

➢Adequate evidence from randomised clinical trials shows that

PSA-based screening programmes in men aged 55 to 69 years

may prevent approximately 1.3 deaths from prostate cancer

over approximately 13 years per 1,000 men screened.

➢ Screening programmes may also prevent approximately 3

cases of metastatic prostate cancer per 1,000 men screened.

Screening for prostate cancer

➢There is inadequate evidence to assess whether the benefits of

screening for African-American men and men with a family

history of prostate cancer aged 55 to 69 years are different

from that for the average-risk population.

➢There is also inadequate evidence to assess whether there are

benefits to start screening in these high-risk groups before the

age of 55 years.

➢Adequate evidence from RCTs is consistent with no benefit of

PSA-based screening for prostate cancer on prostate cancer

mortality in men 70 years and older.

?Benefits of PSA-based Screening for

Prostate Cancer

➢The reduction in prostate cancer deaths from PSA screening

is very small.

➢A large US study (US Prostate, Lung, Colorectal, and

Ovarian cancer screening trial) showed no benefit from

screening.

?Benefits of PSA-based Screening for

Prostate Cancer

A large European study (European Randomised Study of

Screening for Prostate Cancer) found that

1 in 781 men, aged 55 to 69 years at enrolment,

avoids dying from prostate cancer after 13 years

because of screening.

?Benefits of PSA-based Screening for

Prostate Cancer

The Cluster Randomised Trial of PSA Testing for

Prostate Cancer (CAP) of a single invitation to PSA-

based screening in the UK among 415,357 men and a

median follow-up period of 10 years found no

significant difference in prostate cancer mortality

between the invited group and the control group.

Harm resulting from screening

➢Most prostate cancers found by PSA screening are

▪ slow growing

▪ not life threatening

▪ will not cause a man any harm during his lifetime

➢Almost all men with PSA-detected prostate cancer opt to

receive treatment.

Harm resulting from screening

➢ For every 1,000 men who are screened with the PSA test:

▪ 30 to 40 men will develop erectile dysfunction or urinary

incontinence due to surgical treatment

▪ 2 men will experience a serious cardiovascular event, such as a

heart attack, due to surgical treatment

▪ 1 man will develop a serious blood clot in his leg or lungs due

to surgical treatment

➢ For every 3,000 men who are screened with the PSA test:

▪ 1 man will die due to complications from surgical treatment

Current Recommendations on

Prostate Cancer Screening

Population-based prostate cancer screening is not recommended in the guidelines by:

American Academy of Family Physicians

American College of Physicians (ACP)

College of Pathologists, Academy of Medicine of Malaysia

European Group on Tumour Markers (EGTM)

National Cancer Institute (NCI)

National Academy of Clinical Biochemistry (NACB)

UK Cancer Screening Committee

US Preventive Services Task Force (USPSTF)

Current Recommendations on

Prostate Cancer Screening

Malaysian CPG on Utilisation of Serum Tumour Markers 2003 does not recommend population screening for prostate cancer (http://www.acadmed.org.my).

Clinical usefulness of tumour markers. Lai LC, Cheong SK, Goh

KL, Leong CF, Loh CS, Lopez JB, Nawawi H, Sivanesaratnam

V, Subramaniam R. Malaysian J Path 2003; 25(2): 83-105.

Recommendations of Malaysian CPG

➢ Population screening for prostate cancer among Malaysian

men is not recommended.

➢ PSA should be used in combination with DRE to enhance

early detection.

➢Age-specific PSA ranges, PSA velocity and PSA density are

not useful in the diagnosis of prostate cancer.

Recommendations of Malaysian CPG

➢ Free to total PSA ratio is helpful in detecting prostate cancer in patients with a serum PSA level of between 4 and 10 ng/ml.

➢ PSA is useful in monitoring response to treatment and in the early detection of recurrence.

Copyright ©1998 American Association for Clinical Chemistry

Gion, M. et al. Clin Chem 1998;44:2462-2470

Total PSA and percent free PSA (FT Ratio) in CaP and BPH

Limitations of serum PSA

as a tumour marker

➢Approximately a quarter of all newly diagnosed prostate cancers in the West present with normal serum PSA levels.

➢Two thirds of men with high serum PSA levels will be shown to have a non-cancerous pathology on ultrasound-guided biopsy.

USPSTF 2018 Recommendations for

PSA-based Screening for Prostate Cancer

➢ PSA-based screening for prostate cancer has both potential benefits and harm.

➢The USPSTF does not recommend screening for prostate cancer unless men express a preference for screening after being informed of and understanding the benefits and risks.

USPSTF 2018 Recommendations for

PSA-based Screening for Prostate Cancer

➢The net benefit of PSA-based screening for prostate cancer in men aged 55 to 69 years is small.

➢The potential benefits of PSA-based screening for prostate cancer in men 70 years and older do not outweigh the expected harm.

Alpha-foetoprotein (AFP)

Raised AFP levels are seen in

▪ Hepatocellular carcinoma in adults

▪ Hepatoblastoma in children

▪ Germ cell tumours

▪ Cancers, e.g., gastric, colorectal, biliary, pancreatic and lung

▪ Liver regeneration

▪ Hepatitis

▪ Chronic liver disease and cirrhosis

▪ Pregnancy

▪ Neural tube defects

NACB (2010) recommendations: Liver cancer

➢AFP may be used in conjunction with abdominal ultrasound

for early detection of hepatocellular carcinoma (HCC) in

patients with chronic hepatitis or cirrhosis associated with

hepatitis B or C virus infection.

➢AFP concentrations >200 g/L in cirrhotic patients with typical

hypervascular lesions >2 cm in size are consistent with HCC.

➢After a diagnosis of HCC, post-treatment monitoring with AFP

is recommended as an adjunct to imaging, especially in the

absence of measurable disease.

Genomic Biomarkers for Liver Cancer

In a nested study evaluating potential serum microRNA as

screening biomarkers of hepatocellular carcinoma, a

microRNA panel outperformed AFP in detecting early

preclinical HCC but sensitivity remained too low to be a

reliable screening tool.

Human Chorionic Gonadotrophin (hCG)

➢Elevated levels are found in germ cell tumours such as

choriocarcinoma (always), teratoma, seminoma and

dysgerminoma.

➢As about 50% of cases of choriocarcinoma follow a molar

pregnancy, hCG can be used to screen this high risk group of

patients.

NACB (2009) recommendations:

Testicular cancer

➢AFP, HCG, and lactate dehydrogenase (LDH) are

recommended for

▪ diagnosis/case finding

▪ staging

▪ prognosis determination

▪ recurrence detection

▪ therapy monitoring

➢AFP is also recommended for differential diagnosis of

non-seminomatous and seminomatous germ cell tumors.

Carcinoembryonic Antigen (CEA)

Levels are modestly elevated in numerous conditions:

▪ Colorectal cancer

▪ Hepatitis, cirrhosis, alcoholic liver disease

▪ Pancreatitis

▪ Inflammatory bowel disease

▪ Diverticulitis

▪ Renal failure

▪ Chronic obstructive pulmonary disease

▪ Breast, stomach and lung cancer

▪ Healthy individuals who smoke

▪ Poorly controlled diabetes

NACB (2009) recommendations:

Colorectal cancer

In colorectal cancer, CEA is recommended for

▪ Prognosis determination

▪ Post-operative surveillance

▪ Therapy monitoring in advanced disease

CA 19-9

Levels may be raised in:

▪ Pancreatic cancer

▪ Liver cancer

▪ Stomach cancer

▪ Colorectal cancer

▪ Acute and chronic pancreatitis

▪ Cholestasis, cirrhosis, acute cholangitis

▪ Cystic fibrosis

▪ Poorly controlled diabetes

Malaysian CPG Recommendations:

Pancreatic cancer (CA19-9)

➢Not useful for pancreatic cancer screening and diagnosis.

➢Very high levels may usually predict the presence of unresectabletumours.

➢Useful for monitoring response to treatment.

➢Useful in early detection of recurrence following pancreatectomy.

Screening for Breast Cancer in Average-Risk

Women: American College of Physicians 2019

➢ In average-risk women aged 40 to 49 years, clinicians should

discuss whether to screen for breast cancer with

mammography before age 50 years. Discussion should include

the potential benefits and harm and a woman's preferences.

➢The potential harm outweighs the benefits in most women

aged 40 to 49 years.

➢ In average-risk women aged 50 to 74 years, clinicians should

offer screening for breast cancer with biennial mammography.

Screening for Breast Cancer in Average-Risk

Women: American College of Physicians 2019

➢ In average-risk women aged 75 years or older or in women

with a life expectancy of 10 years or less, clinicians should

discontinue screening for breast cancer.

➢ In average-risk women of all ages, clinicians should not use

clinical breast examination to screen for breast cancer.

NACB (2009) recommendations:

Breast cancer

➢Estrogen and progesterone receptors are mandatory for

predicting response to hormone therapy.

➢Human epidermal growth factor receptor-2 (HER-2)

measurement is mandatory for predicting response to

trastuzumab (Herceptin).

➢Urokinase plasminogen activator/plasminogen activator

inhibitor 1 may be used for determining prognosis in lymph

node-negative patients.

CA 125

➢Elevated values occur in 82% of women with ovarian

cancer and may be raised in endometrial, colon, breast

and lung cancers.

➢May be elevated in benign conditions, e.g.,

endometriosis, liver cirrhosis and pancreatitis.

➢Elevated in 1% of healthy blood donors.

NACB recommendations: Ovarian cancer

CA 125 is recommended (with transvaginal ultrasound) for

▪ Early detection of ovarian cancer in women at high risk

for this disease

▪ Differential diagnosis of suspicious pelvic masses in

postmenopausal women

▪ Detection of recurrence

▪ Monitoring of therapy

▪ Determination of prognosis

Serum tumour markers: how to order and interpret them

(Clinical Review)

Sturgeon CM, Lai LC and Duffy MJ

BMJ 2009: 339: 852-58.

Useful Tips

➢Tumour marker results are rarely diagnostic and cannot replace

biopsy for establishing the primary diagnosis of cancer.

➢A raised tumour marker result does not necessarily indicate a

particular malignancy but may provide some indication of its

likelihood.

➢Results within normal limits do not exclude malignancy.

Useful Tips

➢Measurements of tumour markers are not recommended

for patients with vague symptoms when the population

likelihood of cancer is low.

➢The main clinical use of existing serum tumour markers

is in post-operative surveillance and in monitoring after

chemotherapy, endocrine therapy or radiotherapy.

Useful Tips

➢Tumour marker results are often method dependent –

patients should ideally be monitored using the same

method.

➢Tumour marker results should always be interpreted in

the context of all available information including clinical

findings, imaging investigations and other blood tests

(e.g. renal, liver function and haematological tests).

Recommendations as a result of the

ACB National Audit on

Tumour Marker Service Provision - May 2012

➢No single tumour marker is specific for malignancy.

➢ Serum tumour markers are rarely elevated in patients in early

malignancy.

➢Measurement of tumour markers are not recommended in patients

with vague symptoms when the likelihood of cancer is low.

Recommendations as a result of the

ACB National Audit on

Tumour Marker Service Provision - May 2012

➢Requesting multiple tumour markers in an attempt to identify the

primary cancer or the presence of secondaries is rarely of value.

➢Tumour markers should only be requested in situations where the

results can influence clinical practice with a consequent

favourable outcome for the patient and should only be used in

areas where there is sufficient expertise to interpret the results.

➢The main use of serum tumour markers is in monitoring of

diagnosed cancer patients.

Can Tumour Markers Help to

Personalise Chemotherapy?

➢ Perhaps the most exciting potential application of biomarkers is

their use to personalise cancer therapy.

➢ Personalised medicine with targeted biological/chemotherapy

based on biomarkers that reflect tumour biology is not yet possible.

➢However, the evolution of genomic profiles and protein signatures

combined with efforts to expand therapy for various cancers will

help inform treatment approaches in the future.

Case 1

14.11.12

➢ 75 year old lady complained of feeling extremely weak

and tired, poor appetite and weight loss.

➢Malignancy was suspected and female tumour markers

were requested.

Case 1

14.11.12 Female tumour marker panel

AFP 3.8 ng/ml (<8.1)

CA 125 358 U/ml (<35.0)

CA 19-9 2,396 U/ml (<50)

CEA 1,694 ng/ml (<5.0)

Case 1

14.11.12

AST 82 U/L (<35)

ALT 31 U/L (<45)

ALP 138 U/L (50-136)

Bilirubin 9.9 µmol/L (3.0 – 17.0)

Creatinine 91 μmol/L (53-88)

eGFR 56 ml/min/1.73 m2

Case 1

16.11.2012

CT Thorax

▪ 5.1 x 4.0 x 5.6 cm non-calcified soft tissue mass in superior

segment of right lower lung lobe posteriorly

▪ Numerous non-calcified nodules are seen scattered throughout

the rest of the lung bilaterally

▪ Multiple enlarged mediastinal lymph nodes

▪ Lytic destruction of T3, T4 and T5 vertebral bodies

▪ Expansile soft tissue destruction of the left 9th rib medially

Case 1

16.11.12

CT Abdomen and Pelvis

▪ Multiple solid lesions within the liver, the largest in segment 6

4.7 x 6.0 x 5.3 cm, in keeping with metastases

▪ Lytic lesions in L4 vertebral body anteriorly at least 1.2 cm

Patient passed away in February 2013.

The tumour marker panel did not identify the primary cancer

and did not influence outcome.

Case 2

65 year old lady presented to the gastroenterologist with weight

loss on 6.8.14.

CA 19-9 5,755 U/mL (<50)

CEA 294 µg/L (<5.0)

HbA1c 12.9 % (newly diagnosed diabetes)

Random plasma glucose 32.4 mmol/L

Urine ketones Negative

Case 2

7.8.14

➢Ultrasound abdomen and pelvis

▪ Mild fatty liver

▪ A tiny gallbladder polyp

▪ A small simple left renal cyst

➢Chest X-ray: Normal

➢Colonoscopy: Normal

Case 2

➢Referred to me for diabetes management and I saw her

on 7.8.14

➢Commenced on NovoMix insulin and metformin XR

6.8.14 15.8.14

CA 19-9 5,755 U/mL 4,321 U/mL (<50)

CEA 294 µg/L 72.6 µg/L (<5.0)

➢ Patient was lost to follow up.

CONCLUSIONS

➢ Few tumour markers are useful for screening and diagnosis

of tumours or in determining prognosis.

➢The main use of tumour markers is in monitoring response

to treatment and in the detection of recurrence.

Thank You