Lec 23 - Tumor Markers

What is cancer

Cells in the body grow uncontrollably and spread to other parts of the body

What are the impacts of cancer

- Uncontrolled cell division

- Escape from apoptosis (programmed cell death)

- Invasion of abnormal cells into other tissues

- Evasion from immune system

Causes of cancer

Genetic changes in that change cell function

- Inherited

- Exposure to carcinogens (infection, smoking, etc.)

- Random: errors in DNA that are not repaired during cell division

Cancer incidence by age

Increasing incidence with age

Carcinoma

Epithelial cell cancer

Sarcoam

Bonf/soft tissue cancer

Leukemia

Cancer of white blood cells

Lymphoma

Cancer of lymphocytes

Cancer incidence statistics

43% of canadians diagnosed with cancer, leading cause of death in Canada (24.7% of deaths)

Incidence and mortality trends of lung cancer

In males, lung cancer incidence and mortality is decreasing - shows public health programs are working.

In females, lung cancer is increasing and mortality is icnreasing

Why is breast cancer and prostate cancer incidence higher than mortality?

Screening programs catch cancers early, allowing for early treatment

What is a tumor marker

A substance present or produced by a tumor or by the host in response for the tumor

Where can tumor markers be found

Cells, tissues, or other body fluids - determines what type of testing can be done

5 year survival of prostate cancer, breast cancer, lung cancer

91%, 89%, 22%

What are some common tumor marker characteristics

- Increased or decreased production of a normal molecule

- Altered molecule

- Abnormal molecule

Types of molecules used for tumor markers

- Metabolites/small molecules

- Hormones

- Receptors

- Antibodies

- Proteins

- Oncofetal antigens

- Carbs

What is the idea tumor marker?

100% sensitivity and specificity - but this is never the case as there is overlap between healthy patients, and in benign diseases

What are the characteristics of an ideal tumor marker?

- High sensitivity

- High specificity

- Easily obtainable sample

- Conveniently measured

- Proportional to disease

- Impacts patient care

An ideal tumor marker has high sensitivity - what does this mean?

Detectable in patients with disease - not a lot of false negatives

An ideal tumor marker has high specificity - what does this mean?

Absent in the health population and in people with non-malignant conditions

An ideal tumor marker has an easily obtainable sample. What does this mean?

Present in biological matrix that is accessible (and acceptable) at concentration that reflects disease. Ideally blood or urine test. Not as obtainable is biopsies, thorocentesis

An ideal tumor marker is conveniently measured

Validated, simple, reproducible and inexpensive measurement procedure (assay)

What are some things to keep in mind for a conveniently measured tumor marker

- Automated analysis vs manual vs specialized skill set

- Standardized assay (reference ranges consistent)

- Inexpensive cost per test

- Tumor marker stability and storage

An ideal tumor marker has to be proportional to disease - what does this mean?

Tumor marker reflects disease burden, and changes with changes in disease

An ideal tumor marker has to impact patient care - what does this mean?

Improves patient outcomes/care

Tumor marker evaluation

- Sensitivity and specificity depend on reference intervals (cutoffs)

- Need to define population used to determine reference intervals

- Age --> reflect population that will have test

- Healthy --> comorbidities?

Reference individual hierarchy

1. A healthy population reflecting the age and gender of those with the cancer of interest

2. A healthy population reflecting the age and gender of the general population

3. A cohort of patients who have undergone total knee arthroplasty

Clinical applications of tumor markers

Screening

Diagnosis

Prognosis

Prediction of response

Monitoring response

Monitoring disease

Tumor marker screening

Identify treatable early stage, where early intervention is beneficial

Tumor marker diagnosis

Most are used as an aid - but could be cancer specific. Testing is done in symptomatic patients - cause for confirmatory testing if screen is positive

Tumor marker prognosis

Provide probability of outcome, disease progression, risk of relapse, aggressive disease

Tumor marker prediction of response

Identify if a specified treatment will have likely benefit to patient (treatment decisions). Becomes more useful as more targeted therapies exist

Tumor marker monitoring response

Determine if tumor is responding to treatment (continue to change treatment). Change/stop treatment if not effective or no response (consider side effects of treatment without benefit)

Tumor marker monitoring disease

Detect disease progression after treatment. Look for recurrence/relapse after treatment. Change in tumor based on clinical symptoms

Screening test for colorectal cancer

FIT - fecal immunochemical test

Role of fecal immunochemical test

Detects globin chain in the stool - blood in stool associated with malignant cell transformation within GI tract

Prognosis + Monitoring test for colorectal cancer

Carcinoembryonic antigen (CEA)

Carcinoembryonic antigen prognosis

Increased levels at initial diagnosis of colorectal cancer associated with poorer outcome

Carcinoembryonic antigen monotiring

Used for treatment testing and recurrence of colorectal cancer

Sensitivity of carcinoembryonic antigen

Not specific to colorectal cancer, also increased in other cancer and benign conditions

Tumor marker of pancreatic cancer

CA19-9

What is CA 19-9

Sialyated lewis blood group antigen. Elevated in GI cancers.

Clinical applications of CA 19-9

Prognosis, Predicting treatment response, monitoring treatment response, monotiring progression/recurrence

What else increases CA 19-9

Diabetes, Acute chronic pancreatitis, Jaundice, IBS, Liver Disease, Cholestasis

Screening marker for ovarian cancer

CA 125

What is the role of CA 125 as a tumor marker

Glycoprotein with unknown function - increased in 80% of patients with advanced epithelial ovarian cancer

Clinical signifcance of CA 125

- AId in diagnosis of pelvic masses BUT not screening

- Prognosis - persistent increase = poorer prognosis

- Monitoring - response to therapt, recurrence

What are non-cancer increases in CA-125

Menstruation, PID, Pregnancy, Liver disease, resoiratory disorders

Newer screening methods for ovarian cancer

Human epididymis 4, Inhibin A + B

Breast cancer screening

Biopy looking for Estrogen receptor, Progesterone receptor, HER2 receptor

Tumor markers for breast cancer

CA 15-3 and CA 27.29

Use of CA15-3 and CA 27.29

Post treatment monitoring (recurrence)

Genetic markers of breast cancer

BRCA1/BRCA2 - inherited breast cancer, displays risk for breast cancer

Tumor marker of prostate cancer

Prostate-specific antigen (PSA)

Role of Prostate specific antien

Enzyme that cleaves semenogelins to increase seme fluidity. Increased in prostate cancer and non-malignant conditions

Non-malignant increases of PSA

- Benign prostatic hyperplasia

- Digital rectal exam

- Ejaculation

PSA Screening use

Controversy - over diagnosis and overtreatment with associated morbidity and mortality. No differentiation between aggressive and indolent disease

PSA diagnostic use

If symptomatic, increased PSA increases likelihood of prostate cancer. Diagnostic accuracy is still poor.

Free PSA levels and prostate cancer

Risk of prostate cancer is inversely related to % free PSA

PSA prognosis use

Normograms to look at localized vs metastatic disease

Tumor marker of hepatocellular carcinoma

alphafetoprotein (AFP)

What is AFP

Oncofetal antigen produced by fetal liver in pregnancy, and increased in hepatocellular carcinoma

AFP screening use

Screen in high risk population - cirrhosis, chronic hep b/c infections, alcohol related, hemochromatosis.

Done alonside abdominal ultrasound

Early detection = improved clinical outcomes

AFP diagnostic use

Can diagnosed with liver lesions in cirrhosis

AFP prognosis

Higher concentrations = poorer prognosis of liver cancer

AFP use in post treatment monitoring

Monitor disease status during palliative care

tumor marker for multiple myeloma

Paraprotein