(Study type: Blood and/or tissue; the laboratory should be consulted regarding the appropriate specimen collection container; related body system: Circulatory/Hematopoietic, Digestive, Endocrine, Immune, Integumentary, Reproductive, Respiratory, and Urinary systems.) Care must be taken to use the same assay method if serial measurements are to be taken. Today’s approach to identifying and treating cancer has changed dramatically from the previous century’s approach. Numerous genetic sequence variations have associations with various types of cancer and are used to identify the potential for that cancer to be expressed in a given individual. Research has shown that cancer is not a distinctive disease with a specific cause and a single cure. In fact, the new wave of precision medicine is being driven by the discovery that cancer cells emerge as the product of a complex interplay among genetic, environmental, and individual lifestyle influences.

Traditional therapies such as surgery, chemotherapy, and radiation are still relevant, but molecular approaches are slowly gaining ground as more is learned about targeted therapy. The successful application of targeted therapy involves identifying the unique proteins produced by a growing tumor and developing a therapy that blocks further growth of the tumor. Targeted therapies attack only the malignant cells, as opposed to the traditional methods, which destroy both diseased and healthy tissue. The challenge for this new individualized approach to treating cancer is that research also shows that using the same therapy on the same type of cancer but in different individuals does not provide the same response.

Many years ago, before the terms personalized medicine and targeted therapy were coined, scientists in that time were aware that the cure given for one patient could be disastrous if administered to another patient with the same condition. This phenomenon is exemplified by the famous immunologist Karl Landsteiner, who discovered the major blood groups. As our understanding of how the body works at the cellular level expands, progress continues. Another emerging area of cancer treatment is immunotherapy. Drugs are being developed to target proteins associated with immune function that have been modified in the process of a cancer’s development, such that the immune system’s ability to recognize and destroy the malignant cells has been turned off.

Another developing area of knowledge regarding cancer pertains to gene changes that significantly increase the risk of developing specific types of cancer—that is, DNA sequence variations that run in a family. This is often called family cancer syndrome, inherited cancer syndrome, or genetic cancer syndrome. Specific cancers can occur within a family for a variety of reasons that are not genetic (e.g., sharing commonalities that increase the risk of developing cancer such as substance use disorders, environmental exposures, obesity, smoking, etc.). Additional information regarding how family cancer syndrome is identified and diagnosed can be obtained at https://www .cancer.org/cancer/risk-prevention/genetics/family-cancer-syndromes.html The most common examples of family cancer syndrome include:

• Hereditary breast and ovarian cancer (HBOC) syndrome
• Lynch syndrome (hereditary nonpolyposis colorectal cancer)

An interesting area of family cancer syndrome research involves emerging theories of family cancer inheritance. Ovarian cancer, caused by genetic sequence variations, is known to run in families and was previously believed to be passed on to future generations through female family members. It is now believed that increased risk for developing ovarian cancer can also come from male family members via transmission from a previously unknown X-linked gene sequence variation. The X-linked transmission theory is based on pedigree charts of related individuals with ovarian family cancer syndrome that cannot be explained by autosomal inheritance patterns alone (i.e., there were more total cases of ovarian cancer than cases of ovarian cancer attributable to a female relative). (Note: The BRAC genes associated with HBOC are located on autosomes; BRCA1 gene is on chromosome 17q12-21, and BRCA2 on chromosome 13q12-13.) This is where the X-linked transmission comes into play. Males carry one X and one Y sex chromosome; females carry two X sex chromosomes. This means females pass genes from their X chromosome to any of their offspring with a probability of 50%, or the chance of inheriting the gene with a sequence variation from one of two of their X chromosomes. Males pass genes from their X chromosome to all female offspring with a probability of 100% and never to male offspring with a probability of 0%. As with most scientific endeavors, more research is needed to refine our understanding of how genetics play a role in health and disease. A breakthrough in HBOC inheritance may inform the cause of other inherited cancer syndromes and ultimately lead to novel treatments and possibly prevention.

Alphabetical Listing for Commonly Requested Markers

• Alpha₁-Fetoprotein: A glycoprotein produced in the fetal liver, gastrointestinal tract, and yolk sac. It is also produced by a variety of tumors of the liver and reproductive organs.
• ALK sequence variation identification: Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer and the most common worldwide cause of death from cancer. A small percentage of NSCLC demonstrate changes in the ALK gene that make them more responsive to drug treatments than are NSCLC associated with other risk factors or genetic sequence variations.
• BCR-ABL sequence variation identification: Fluorescence in situ hybridization (FISH) is one method used to detect the BCR-ABL gene fusion associated with chronic myeloid leukemia (CML). FISH is more sensitive than cytogenetic testing for the Philadelphia chromosome (also associated with CML) and can also be performed on bone marrow samples. BCR-ABL testing is used to monitor response to therapy. The leukocyte alkaline phosphatase (LAP) score is not used in the current World Health Organization’s classification for chronic myeloproliferative neoplasms; a positive BCR/ABL-1 sequence variation is considered diagnostic for CML.
• BRAC 1 and BRAC 2 see studies titled “Biopsy, Breast” and “Genetic Testing”
• BRAF see study titled “Biopsy, Various (skin)”
• CA 125 or Muc16 is a glycoprotein member of the mucin family and is present in normal endometrial tissue. It appears in the blood when natural endometrial protective barriers are destroyed, as occurs in cancer or endometriosis. CA 125 is most useful in monitoring the progression or recurrence of known ovarian cancer. It is not useful as a screening test because elevations can occur with numerous other conditions, such as endometriosis, other diseases of the ovary, menstruation, pregnancy, and uterine fibroids. Persistently rising levels indicate a poor prognosis. Levels may also rise in pancreatic, liver, colon, breast, and lung cancers. Absence of detectable levels of CA 125 does not rule out the presence of a tumor.
• CA 15-3 is used to monitor patients for recurrence or metastasis of breast cancer.
• CA 19-9 is a carbohydrate antigen used in conjunction with other modalities to help diagnose and monitor therapy associated with gastrointestinal (GI), pancreatic, liver, and colorectal cancers.
• CA 27.29 is a glycoprotein product of the muc-1 gene. It is most useful as a serial monitor for response to therapy or recurrence of breast cancer.
• Carcinoembryonic antigen (CEA) is normally produced during fetal development and rapid multiplication of epithelial cells, especially those of the digestive system. A small amount of circulating CEA is detectable in the blood of healthy adults. The liver is the main site for metabolism of CEA. Because of the variability in CEA molecules, the test is not diagnostic for any specific disease and is not useful as a screening test for cancer. However, it is very useful for monitoring response to therapy in breast, liver, colon, and GI cancer. Serial monitoring is also a useful indicator of recurrence or metastasis in colon or liver cancer. CEA levels are higher in the blood of individuals who smoke than in those who do not smoke, so most laboratories will have a normal range for each group.
• EGFR testing may be used to identify the presence of mutated cell free DNA shed by the tumor into the blood, help determine which type of therapy will be useful, and determine how the cancer will respond to therapy; the test can identify resistance to targeted drugs. See study titled “Genetic Testing.”
• EPCAM, MLH1, MSH2, MSH6, PMS2: Genetic variants of these five genes are associated with Lynch syndrome (hereditary nonpolyposis colorectal cancer), an inherited disorder associated with increased risk of digestive, integumentary, reproductive, and urinary cancers, especially colon and rectal cancers. Identifying the presence of variants assists in diagnosis of Lynch syndrome and development of targeted therapy. Individualized findings include interpretive comments regarding the potential significance of test results. Positive findings may also provide a basis to recommend genetic counseling and associated predictive genetic testing for family members.
• Human chorionic gonadotropin (HCG) is a hormone secreted in large quantity by the placenta after conception; however, the test has also been established for use as a tumor marker. In the absence of a pregnancy, an elevated HCG level in blood or some body fluids (e.g., peritoneal fluid) may indicate the presence of a germ cell tumor such as testicular cancer in males and ovarian or molar (hydatidiform) cancer in females. Gestational trophoblastic disease (GTD) is a group of rare tumors, affecting females, that develop from cells that would normally become placental tissue during pregnancy. The most common types of GTD include hydatidiform mole (complete or partial), choriocarcinoma, placental-site trophoblastic tumor, and epithelioid trophoblastic tumor.
• Human epididymis protein 4 (HE4) is a protein marker associated with various types of cancer, including ovarian cancer. Significant or persistent elevations of HE4 may indicate the appearance, recurrence, or progression of epithelial ovarian cancer. A significant elevation would be an increase of greater than 25% over normal findings.
• HER-2–NEU see studies titled “Biopsy, Breast” and “Genetic Testing.”
• KRAS see studies titled “Biopsy, Breast,” “Colonoscopy,” and “Genetic Testing.”

Blood based markers for colon cancer

Laboratories are also developing cancer-specific liquid biopsy studies. Liquid biopsy is a term used to describe a test performed on blood or body fluid and is used to identify DNA from tumor cells, such as those associated with breast, colon, lung, and prostate cancers. A liquid biopsy is also known as a circulating tumor cell count or circulating tumor DNA. Currently there are two U.S. Food and Drug Administration (FDA)–approved blood tests for colorectal screening in people who are at average risk. The blood tests are not yet as sensitive or specific across all stages of colon cancer as imaging or stool based methods. Patients are encouraged to discuss with their health-care provider (HCP). the best test for their circumstances. Epigenomics’ Epi proColon® measures extracted specimens for sequence variations in the septin 9 gene in DNA shed by tumor cells into the blood. Presence of sequence variations is qualitatively identified using a polymerase chain reaction method. Guardant Health’s Shield®, approved by the FDA in July 2024, also qualitatively measures cell free DNA extractions for sequence variations in DNA shed by tumor cells that are associated with colorectal cancer. Shield® uses next-generation sequencing technology and a combination of proprietary bioinformatics algorithms. Current ACS and AGI guidelines do not recommend using these markers to screen patients.

A growing number of studies are used to identify cancer occurring at various sites in the body. Further detail for some of these tumor markers can be reviewed in the individual studies indicated in the table on the next page.