Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.

Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

Tumor Markers
A broad spectrum of molecules, with widely varying characteristics, produced or induced by the
tumor cell and which reflects its growth and/or activity and allow the presence, development or
therapeutic response of a malignant tumor to be known.
Tumor markers are not specific to cancer. They can be found in benign diseases and normal
physiologic bodies.
The specificity of tumor markers is not their presence in malignant tumors but the concentration at
which they are detected there. Majority of TMs are synthesized and released also by normal cells,
thus normal values are established. So it is very important to know the normal values of tumor
markers.
Damage to tissues which produce tumor markers, caused either by non-malignant disease or by a
side effect of the treatment, will cause false positives, an increase in serum levels even in the
absence of cancer. Tumor markers have very low sensitivity and specificity. So there are false
positives that is why they are just part of the diagnosis of cancers.
A well differentiated tumor (resembles the cells from which it comes) can synthesize tumor markers.
The ability to synthesize disappears with undifferentiated tumors.
The histological grade or tumor differentiation is associated in the synthesis of a particular tumor
marker. The more undifferentiated the cancer is, the chances of it producing tumor markers is low.
The greater the number of tumor size, the greater will be the concentration of the TM. The more
advanced the disease is, the bigger the cancer burden is, and the higher the tumor marker.
The greater the locoregional or distant invasion, the greater the ease of access to the circulation,
where higher TM concentrations are detected
Changes in biliary and urinary function will produce false elevations of serum concentrations of
those TMs which are eliminated by these routes. That is why, false positives are present in patients
with liver disease or patients with chronic renal failure.
Characteristics of an ideal tumor marker:

Highly specific
Highly sensitive
Levels correlate with tumor burden
Short half life
Simple and cheap
Easily obtainable specimen

IN REALITY AN IDEAL TUMOR MARKER DOES NOT EXIST

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

Clinical Uses of Tumor markers:

Screening
Diagnosis
Prognosis
Prediction of treatment response
Response Assessment
Prediction of recurrence

Tumor markers and their site of origin:

CA 15-3 Breasts
AFP Liver
CA 19-9 Pancreas
B-HCG Testes
CA 12-5 Ovaries
CEA Colorectal
Calcitonin Thyroid
PSA Prostate
Classifications of Tumor Markers
The classification of TMs is not easy and the various systems which have been proposed, grouping them
according to their origin, physiologic and chemical characteristics, functions, etcetera are of more academic
than real interest as the majority of TMs can be classified in more than one group. Thus, it is more practical
to group them according to their clinical usefulness, sensitivity and specificity.
1) TMs of high sensitivity and high specificity
2) TMs of variable specificity and sensitivity
3) TMs with variable sensitivity and low specificity
TMs of high sensitivity and high specificity
These are the TMs which, despite the fact that they can be detected in various normal situations, in
abnormal situations or in the case of large increases, always indicate the existence of a malignant tumor
Example: Beta-HCG
Normally present in pregnant women but increases in males and non-pregnant women or in whom no
technical procedures have been carried out are indicative of a malignant tumor.
TMs of variable specificity and sensitivity
TMs with a low sensitivity and specificity in the initial stages, with serum levels indistinguishable from those
found in benign conditions. In advanced stages, serum concentrations can confirm a malignant tumor.
Examples: CEA, AFP, PSA, CA 125, CA 15-3, CA 19-9

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

TMs with variable sensitivity and low specificity

Sensitivity is dependent on the stage. Even in advanced stages, specificity is still low.
These markers are mostly used for monitoring and prognostication.
E.g LDH

TMs of high sensitivity and high specificity

Beta subunit of human chorionic gonadotropin (B-HCG)
Normal value: <2-5 IU/L
Glycoprotein hormone synthesized by the syncytiotrophoblastic cells of the placenta.
Its function is to maintain both the secretion of progesterone and the function of corpus luteum
during pregnancy. Thus, it is increased in pregnant women.
The detection of B-HCG in non-pregnant women should lead to the suspicion of a malignant tumor.
Increases is described in 24% of patients with SLE. Renal failure can also cause an increase.
Normally baseline B-HCG is done in those diagnosed with seminoma or non-seminoma testicular
cancers or yolk sac tumors of the ovaries.
TM: trophoblastic tumors, germ cell ovarian, testicular cancer

TMs of variable specificity and sensitivity

Alpha- Fetoprotein (AFP)
Normal value in most labs: 10-20 ug/L
A glycoprotein amino acid similar to albumin.
AFP synthesis starts early in the fetus (yolk sac to the liver)
High in pregnancy
High in neonates
Its function involves the transport of different substances such as steroid hormones, zinc, copper,
bilirubin.

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

False positives: benign, acute or chronic liver disease (liver cirrhosis), infectious liver disease
(hepatitis), toxic liver disease.
Increases in benign diseases are usually moderate (<100 ng/ml)
>400 ug/L is diagnostic in high risk patients
In patients with liver cirrhosis, cutoff is >500
TM: hepatocellular CA, testicular tumors, endodermal sinus neoplasms

Carcinoembryonic antigen (CEA)

Normal value: < 5ng/ml
High molecular weight glycoprotein
Function is unknown
It can be increased in liver cirrhosis, renal failure, COPD, pneumonia, TB, GI disorders, pancreatitis,
hyperthyroidism but increases in liver cirrhosis and renal failure are moderate, usually less than
25ng/ml.
It is a very good tumor marker for colorectal cancer. Most patients with colon cancer may not have
an increased CEA but it is helpful in monitoring and surveillance for possible recurrence.
Has low sensitivity, thus is not useful for general Colorectal Cancer screening
In CRC: it is routinely recommended in surveillance program after cancer has been confirmed
60% of cancer is missed due to low sensitivity
This is just used to have a baseline to know if after surgery or chemotherapy, patient will be
monitored. If CEA is increasing, there may be recurrence. But this is not used for screening.
TM: Colon, lung, breast, neck tumors
Carbohydrate antigen (CA 125)
Normal value: <35 U/ml
Glycoprotein derived from fallopian tubes, endocervix, and upper vagina and mesothelial cells
Increased in liver cirrhosis, renal failure, effusions, ascites, fluid retention, gynecologic diseases
(<350-600 U/ml). This poses a problem for ovarian cancers because most patients present with
ascites so an increase in CA 125 <600 is not a good indication of cancer but specificity is 90% when
value reaches 900 U/ml.
With 90% specificity, it cannot be used for diagnosis but should do other confirmatory tests
It is used as a marker for monitoring of epithelial ovarian cancer response to treatment and
recurrence.
It is not approved nor recommended for screening.
Screening with CA 125 is controversial in patients who are BRCA1/2 carriers who have not
undergone RRSO (no data showing survival benefit)
Normal value also depends on menopausal status and race. It is higher in premenopausal women
and Caucasian race
TM: ovarian carcinoma, endometrial carcinoma or pulmonary cancers

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

Human epididymis protein 4 (HE-4)

Normal value: < 100-150 pmol/L
It is used in conjunction with CA 125 for patients who are diagnosed or suspected to have ovarian
cancer
Present in female genital tract, the epididymis, vas deferens of male genital tract
Overexpressed in ovarian carcinoma (serous and endometrioid)
False positives: renal failure
It is recommended for monitoring for recurrence and for response to therapy.
Carbohydrate antigen (CA 19-9)
Normal value: < 37 U/ml
Is made up principally of carbohydrates
Naturally occurring in the G.I. tract of fetuses and neonates
False positives: renal failure, liver disease, jaundice and pancreatitis
This will pose a problem because most patients with pancreatic cancer present with jaundice
Specificity for pancreatic cancer is 98% when levels go up to equal or more than 1,000 U/ml
If presented with a jaundiced patient with abdominal pain and a pancreatic mass with a ca 19-9 of
2000, even without a histopath diagnosis, you can suspect that this patient has pancreatic cancer.
It is mainly used for surveillance following surgery or treatment
TM: pancreatic carcinoma, mucinous adenocarcinomas of the ovary, bronchopulmonary tumors
Prostate specific antigen (PSA)
Normal value: <4 ng/ml
It is a glandular kallikrein enzyme
It is synthesized in the prostate and secreted in the seminal fluid where it has a liquefying function
associated with its enzyme activity
False positive: prostatitis, BPH, UTI, procedures involving prostate
Androgenic treatments for BPH can cause decrease in PSA levels---- false negatives
It can be used for screening and surveillance/monitoring
According to the ASCO (American Society of Clinical Oncology) and the NCCN (National Comprehensive
Cancer Network) guidelines for screening of prostate cancer, PSA along with rectal exam and
ultrasound of the prostate can be used for screening.
TM: prostate cancer
Thyroglobulin (TG)
High molecular weight glycoprotein which is a predominant protein in the thyroid
Synthesis is specific to thyrocyte
Increases are detected in the third trimester of pregnancy, Graves disease, subacute thyroiditis,
toxic adenoma, infiltration of thyroid by other tumors, smoking
Anaplastic kind of thyroid cancer will not produce TG

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

The main use of TG is after surgery and is related to changes in the concentration with the presence
of residual tumor mass
For monitoring of recurrence of thyroid cancer
s/p thyroid lobectomy: <10 ng/ml
s/p total thyroidectomy: < 2 ng/ml
TM: differentiated thyroid cancer ------papillary, medullary

Ca 153
Normal value: < 30 U/L
Elevated INFREQUENTLY in early breast cancer
It is used for surveillance (detect recurrence)
No longer common used nowadays in the advent of new ancillary procedures
For advanced or recurrent breast cancers
TM: Breast cancer
Calcitonin
Normal value: <10 ng/L
Amino acid polypeptide
Increased in autoimmune thyroid diseases, renal failure, hypercalcemia, sepsis
TM: medullary thyroid cancer

TMs with variable sensitivity and low specificity

LDH

Non specific tumor marker

If this is high in testicular carcinoma and lymphoma, then the prognosis is worse because it reflects
overall tumor burden, tumor growth rate, and cellular proliferation.
Most of these TMs cannot be used to diagnose.
Gold standard for the diagnosis of cancer is still histopath diagnosis.
TM: testicular carcinoma, lymphoma

Strategies for improving the use of tumor markers

4 criteria that can help in differentiating and correctly evaluating results:
1) Serum TM levels
2) Exclusion of benign pathology
3) Sequential study of TMs
4) Technical interference
Serum TM levels
- serum levels of the majority of TMs which are observed in the absence of a tumor are usually moderate
- Examples:

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

If you have a patient with a PSA of 4.5ng/ml or 5ng/ml. The normal value of PSA is 4ng/ml. You
should first rule out a benign pathology like BPH before telling your patient that he has cancer.
A patient with a pancreatic mass and a CA 19-9 > 2000U/ml may be suspected of having cancer.
Exclusion of a benign pathology
- When the TM is increased, the existence of a benign disorder has to be ruled out
- Example: increased PSA in prostatitis or BPH
Sequential study of TMs
- An isolated finding of high levels of any TM is of limited value
- For example, if you are trying to monitor a patient with colorectal cancer who already had surgery or
treatment, a one-time high CEA level would not tell you that you have a recurrence. Usually, we request a
repeat CEA after a month or two.
- When there are doubts regarding the result, two or three sequential measurements should be carried out
at intervals of more than its plasma half-life (15-20 days).
Technical interference
- The fact that the results for a TM obtained by commercial methods are not always similar to one another
should also be taken into consideration, as this can cause considerable discrepancies
- Use same laboratory for repeat
Conclusions:
1. The majority of TMs have insufficient sensitivity and specificity to be used for the early detection of
cancer.
2. Challenges with tumor markers include lack of sensitivity/specificity, tissue accessibility and test
validity/reliability.
3. Joint assessment of clinical and laboratory data and a wide knowledge of the tumor markers are
essential for their correct use and maximum efficacy

Molecular oncology
Biomarkers
Biological molecules (genes or gene products) found in blood, body fluids or tissues that signal presence of
disease.
Examples:
Myocardial infarction - troponin, creatine kinase
Kidney disease - creatinine, cystatin C
CML Philadelphia chromosome
Biomarkers are used in
1) measuring the progress of disease
2) evaluating the most effective therapeutic regimens for a particular cancer
-It can help us predict its response to chemo or targeted therapy

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

3) establishing long term susceptibility to cancer or its recurrence

ER and PR
ER and PR are both members of the nuclear hormone receptor superfamily that includes the
androgen and retinoid receptors.
In metastatic breast cancer, 30-40% of ER and PR positive patients will have an objective response
which may last for several years.
So ER and PR can help us prognosticate. A positive ER and PR in patients with breast cancer has a
better prognosis because negative ER and PR tumors are unlikely to respond to endocrine therapy
or hormonal treatment such as Tamoxifen and aromatase inhibitors, and will benefit more from
chemotherapy.
Routinely measured for evaluation of breast cancer due to high predictive value
Her 2 neu
The most widely studied oncoprotein
Also known as erb 2 neu
Located on chromosome 17 which encodes a transmembrane protein of the EGFR family
Overexpressed in 15-30% of mammary carcinomas
Specific for breast cancer
Use as a diagnostic aide, prognostic and predictive factor for the treatment response
In all patients who are diagnosed with breast cancer, ER and PR, and her 2 neu are always checked.
If a patient is her 2 positive and has an aggressive tumor, then there is a poor prognosis.
EGFR in NSCLC (Epidermal Growth Factor Receptor in Nonsmall Cell Lung Cancer)
Initially used with the advent of targeted therapies like anti-EGFR tyrosine kinase inhibitors (Erlotinib
and Gefitinib) in NSCLC
If a patient is diagnosed with lung cancer, we check if EGFR positive. If there is positive EGFR
mutation, then the patient is a good candidate for the oral targeted treatment.
Based on studies showing abundance of EGFR in most NSCLC
Problem: not all tumors responded to anti-EGFR treatment
EGFR mutation became more predictive of response to anti-EGFR treatment
o Better survival seen in NSCLC patients with EGFR mutation
EGFR mutation noted to be higher in adenocarcinomas, especially among non- or light smokers of
Asian origin
There has been a study which involved the Philippines wherein they noted that most people with
EGFR mutation are of Asian descent, patients with adenocarcinoma, and those who are
nonsmokers.
Brca 1 and brca 2
Responsible for 85% of hereditary breast cancer and ovarian cancer
Common in women of Ashkenazi Jewish ancestry
Over all prevalence is 1 in 300 (BRCA1) and 1 in 800 (BRCA2)

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

Mutations in BRCA confer with a lifetime risk of 45-84% for breast cancer and 11-62% for ovarian
cancer
That is why individuals with mutation in their brca1 and brca2, should undergo genetic counseling
and should be referred for possible risk reduction surgeries like prophylactic bilateral mastectomy
and risk reduction salpingoophorectomy.
Genetic counseling is important prior to genetic testing

3 possible outcomes:
- positive
- variant of uncertain significance
- negative
High risk patients
- early onset breast cancer (<50 years old)
- triple negative breast cancer (ER PR her 2)
- 2 breast primaries in a single individual
- 1 close blood relatives with breast cancer < 50 years old
- 2 close relative with breast cancer at any age
- population at risk
- male breast cancer
RAS (K-RAS and N- RAS)
RAS proteins are critical mediators of cellular proliferation signals.
Mutations in KRAS and NRAS are found mostly in tumors (codon 12, 13, and 61).
RAS mutation in colorectal cancer predicts non response to anti EGFR antibody (Cetuximab) therapy.

Conclusions:
1. The clinical use of cancer molecular biomarkers must be done judiciously while research is still being
conducted to search for better biomarkers.
2. The paradigm shift towards personalized and individualized medicine relies heavily on the increased
use of diagnostic biomarkers and classifiers to improve diagnosis, management and treatment of
cancer.

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

Open forum
Question 1
What is the tumor marker used by Angelina Jolie that made her remove her breasts?
The biomarkers Brca1 and brca2. These are biomarkers that tells us that mutations in brca1 and
brca2 gives you a very high risk for cancer. Mutations in Brca 1 confer 86% lifetime risk of having
breast cancer. So it is almost sure.
So it is justified that Angelina Jolie had bilateral mastectomy?
Yes, because according to studies, once you undergo risk reduction surgeries, the risk goes down to
almost equal to non high risk patients or those without brca1 or brca 2 mutations.
Where can we have that Brca1, Brca2 testing?
I dont think it is available in the Philippines but there are laboratories which send out to US or
Singapore but the price range is between 1,000-4,000 USD. But I dont think it is applicable yet in
the Philippine setting because Filipinos are conservative when it comes to prophylactic mastectomy
or salpingoophorectomy. These patients are very young, in their child-bearing age so most of these
patients before they undergo testing should have at least genetic counseling.
Question 2
I heard of dogs being able to smell cancers. Can you comment on that?
This is the first time I heard that news. Well, an advanced breast cancer, even humans can smell
that. Most of advanced head and neck cancers and breast cancers can present with a fungating mass which
can be very foul-smelling.
(from the audience) In 2006, in the early cancer therapies published, a diagnostic accuracy in canine scent
detection in early and late cancers but there are no chemical compounds identified. But allegedly, there is
0.98 specificity for dogs to determine breath specimens that are specific for lung and breast cancers. But this
was not followed-up.
Question 3
Can a lack of sexual activity contribute to prostate cancer?
There have been some talks about that but it is not yet well established. We dont know yet the
cause of any cancers except for smoking. But I dont think so. I dont think there are studies
pertaining to that yet.
Question 4
What is the relationship on the CA level between polycystic ovarian diseases?
CA 125 is usually high in patients with even benign ovarian pathology like ovarian cyst, endometrial
cyst. But it should be less than 900. There is no specific value for polycystic or endometrial cancer. If

Clinical value of tumor markers

Maria Karen Luisa A. Villanueva- Timbol, M.D.
Medical Oncology
Manila Doctors Hospital

June 19, 2015

Internal Medicine 12th Post-graduate Course
Diamond Hotel

<900, any suspicious mass requires histopath diagnosis. Tumor markers could only support that but
it cannot confirm any cancer.
Question 5
Is there a specific PSA level that would differentiate BPH from prostate cancer?
According to studies, none. Although there are cut-offs. For PSA of 4-10, the chances of it being
caused by a cancer is low. If it is more than 10, or more than 20, then maybe it is prostate cancer.
Usually BPH can present with a high PSA but it is usually less than 10. However, I have a patient who
was diagnosed with prostate cancer. He has full-blown prostate cancer but his PSA is only 10. Again,
we do not really rely on tumor markers to diagnose.
Question 6
Is calcitonin more reliable than thyroglobulin for thyroid cancer?
Thyroglobulin is used more for monitoring and is used for more differentiated types of cancers like
papillary thyroid Ca and follicular thyroid Ca. Calcitonin is more specific for medullary thyroid cancer.
But most of these tumor markers are used more for monitoring.
Question 7
At the primary care level, which of the markers besides PSA can be requested?
Actually, you can request any of the tumor markers as long as it is indicated. For PSA, it is part of
screening so you can request it for high risk patients and those 50 years old and above. For example,
in a patient who presents with ascites, abdominal pain, and a suspicious mass in the ovary, then you
can request for CA 125. Just dont request for tumor marker packs. I see that a lot. Sometimes a
patient comes with all tumor markers. Sometimes there is a male patient with CA125 and CA153.
Tumor markers are not really cheap. We should be considering the suspect, what primary we are
dealing with, and just order 1 or 2 tumor markers.

Important points:
1. We should be prudent in requesting for tumor markers because they are not cheap.
2. Most of the tumor markers are used for monitoring and surveillance hence, not meant for
screening.