HC18: Biomarkers for early detection of cancer

Biomarkers

Cancer can be diagnosed based on:

• Physical examination
• Blood tests
• CT-scans
• Biopsies to obtain tumor tissue

A biomarker refers to a measurable indicator of some biological state or condition. Humans shed particles into the bloodstream or environment as evidence of their presence in a particular location:

• Small parts of cells
  • Microparticles
  • Exosomes
• Proteins
• Unique chemicals
• DNA and RNA

Biomarkers are measured and evaluated to examine:

• Normal biological processes
• Pathogenic processes
• Pharmacologic responses to a treatment
  • Therapeutic intervention

An ideal tumor marker for diagnosis:

• Should have great sensitivity, specificity and accuracy in reflecting the total disease burden
• Should be prognostic of the outcome
• Should be predictive of tumor recurrence
• Should be predictive of effectiveness of anti-cancer treatments

Samples for biomarker detection are:

• Blood, urine or other body fluids
• Tissues

Tumor cells and products circulate in blood and are easily detectable. However, tissue forms the issue. There is a limited access to tissue:

• Archival tissue is not obtained at the time of clinical decision
• Accessible metastatic tissue may not be representative

Circulating tumor cells

Because tissue access is limited, there is an increased interest in circulating tumor cells (CTCs). CTCs shed by primary and metastatic tumors can be used as “liquid biopsies”, providing real-time information about the patient’s current disease state. Molecular profiling in CTCs can be used for patient selection to stratify for targeted therapy or serve as well-defined treatment targets.

Clinical applications

Potential clinical applications of CTCs are:

• Blood testing using CTCs may aid in cancer diagnosis
• May serve as prognostic and predictive biomarkers
  • Changes in CTC counts could indicate sensitivity or resistance to anti-cancer therapy monitoring
• CTC enumeration may estimate tumor burden and tumor invasiveness
• Investigational platform to eludicate tumor biology
  • Whole genome/transcriptome sequencing

Microparticles:

CTCs are not whole tumor cells → they are circulating biomarkers. CTCs are very rare in the blood of cancer patients, ranging from 1 to over 1000 in 10 ml blood samples, which usually contain 50-100 billion red and white blood cells.

Microparticles from a tumor are released into the bloodstream. Microparticles are:

• CTCs
• Genomic DNA
• miRNA
• Microvesicles (MV)
• Microparticles (MP)

Clinical uses

Clinical uses of biomarkers are:

• Screening
• Making a diagnosis
• Marker of prognosis
• Monitoring of treatment efficacy
• Detection of recurrence of the disease

Screening:

A biomarker for screening must be:

• Highly specific (for a single type of cancer) → minimize false positive and negative
• Able to clearly reflect the early stage of disease
• Easily detectable without complicated medical procedures
• Cost effective

Monitoring of treatment efficacy:

A biomarker for monitoring treatment efficacy must:

• Correlate with tumor size/volume
  • The actual number of tumor cells in the body → tumor load
• Short in half-life circulation
• Be highly specific and sensitive for a single type of cancer

The ideal tumormarker has the following characteristics:

• Early detection
• Organ- and tumorspecificity
• Correlation with tumor stage and mass
• Prognostic information
• Sensitivity and specificity of 100%

The ideal tumormarker does not exist yet. All current tumormarkers are physiological components of plasma, and therefore not tumor specific.

A value within the reference interval (normal range) does not indicate a normal value for an individual patient. The sensitivity and specificity aren’t 100%. Current biomarkers are not only specific for cancer, but can also indicate benign conditions.

There are predicative and prognostic markers:

• Predictive → only patients who are marker positive show the treatment effect → says something about the response to treatment
• Prognostic → independent of the treatment, patients with a high value have a bad prognosis and patients with a low outcome have a better prognosis → says something about the prognosis

Top 8 biomarkers

Tumor markers often have more than 1 purpose and may be associated with more than 1 type of cancer. High tumor marker levels in blood can be a sign of cancer. Along with other tests, tumor marker tests can help doctors in their daily work. Some patients do not have elevated tumor marker levels, even if the type of cancer they have usually makes tumor markers.

The top 8 plasma tumor markers are:

• CA 15.3
  • Malignancy: breast cancer
  • Incidence: 12.000
• CEA
  • Malignancy: colorectal cancer
  • Incidence: 10.000
• PSA
  • Malignancy: prostate cancer
  • Incidence: 12.000
• CA 19-9
  • Malignancy: pancreas cancer
  • Incidence: 1.700
• CA125
  • Malignancy: ovarium cancer
  • Incidence: 1.100
• AFP
  • Malignancy: liver/testis cancer
  • Incidence: 300/600
• hCG
  • Malignancy: testis cancer
  • Incidence: 600
• Thyroglobulin
  • Malignancy: thyroid cancer
  • Incidence: 400

CEA:

CEA is present in blood in >10 ng/ml. It is stands for carcinoembryonic antigen, which is produced during fetal development. After birth, the production of CEA stops and is undetectable.

CEA is elevated in:

• Smokers
• Elderly
• Benign diseases
  • Liver cirrhosis
  • Emphysema
  • Rectal polyps

• Colorectal cancers
  • But also breast and lung cancers
  • Declines after tumor removal
• Recurrence of cancer after cancer treatment
• Not useful for screening for colon cancer

AFP:

AFP is present in blood in >10 ng/ml. It is stands for alpha fetoprotein, which is found in the fetus.

AFP is a tumor marker in:

• Liver cancer: hepatocellular carcinoma
• Testicular cancer: germ cell tumors
  • AFP is used for classifying and staging together with HCG
    • Nonseminomas: both AFP and HCG are elevated in 90% of cases
    • Seminomas: AFP isn’t elevated and HCG is elevated in 30% of cases

The AFP level is not directly related to tumor size, but is elevated in:

• Pregnancy
• Liver disease
  • Viral hepatitis
  • Cirrhosis
  • Gastro-intestinal tumors

CA19-9:

CA19-9 is present in the blood in >37 U/ml. It stands for carbohydrate antigen 19-9, which is present in the fetus in the epithelium of the fetal stomach. It is primarily used as a marker for pancreatic cancer. High levels also exist in conditions such as:

• Non-malignant liver disease
• Other disorders of the gastrointestinal tract

HCG:

HCG is present in the blood in >10 mIU/ml. It stands for Human Chorionic Gonadotropin-beta, which is normally produced by the placenta during pregnancy → it is an indicator of pregnancy. The protein can be detected in serum or urine. HCG is elevated in the majority of testicular cancer patients. Elevations may be observed in case of pregnancy and use of marijuana. Levels of HCG are useful in monitoring the effectiveness of treatment.

PSA:

PSA stands for prostate specific antigen. It is a protein which is normally made in the prostate gland in ductal cells that make some of the semen. PSA helps to keep the semen liquid. It is a glycoprotein → a serine protease. It is the most tested biomarker.

Detection of PSA allows early diagnosis of prostate cancer. Diagnosis of PSA for prostate cancer is mostly done in serum samples. Large screening trials have shown that PSA nearly doubles the rate of detection. Based on these data, PSA testing was approved by the US FDA for the screening and early detection of prostate cancer.

PSA is also found in the cytoplasm of benign prostate cells. An elevated blood PSA level in the normal range (<3 μg/L) or a slightly elevated PSA level above the normal range may be a result of:

• Benign prostate hypertrophy (BPH)
  • The prostate becomes bigger as men age
• Prostate cancer
• Both
  • Prostate cancer often is present in BPH, as most older men also have BPH

CA-125:

CA-125, a product of the MUC16 gene, is a mucin made by certain cells in the body which include those of the:

• Uterine tubes
• Uterus
• Cervix
• Lining of the abdominal and chest cavities

CA125 is a transmembrane glycoprotein which has very short cytoplasmic domain and a very long extracellular domain. The cellular function of the protein is still unknown. The protein exists in the cells of normal and cancerous tissues of ovaria.

CA125 is associated with progression of ovarian cancer and a few other cancer types. The CA125 level can be over 10 folds higher in ovarian cancer patients compared to the level in normal people.

Testicular cancer

Testicular cancer is the most common type of cancer in men between 15 and 35 years of age. If 1 tumor arises in 1 testis, the other testis has an increased risk. Children with undescended testes have a much higher chance of developing testis cancer at later age. The cure rates are very high:

• Stage I/II: 100%
• Stage III: 98%
• Stage IV: 80%

Testicular cancer is characterized by many germ cell tumors:

• 36% seminoma: HCG + LDH
• 64% non-seminoma: AFP + HCG

Biomarkers for testicular cancer are AFP and HCG, which are extremely useful for:

• Diagnosis
• Monitoring of treatment effect
  • A combination of normal levels of tumormarkers and CT-scans show that a patient has been cured
• Follow up to early detect recurrences

Cisplatinum:

Cisplatinum was introduced in the 1970s as a cure for young males with metastatic testicular cancer. It is used in combination with chemotherapy.