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Molecular Diagnostics

Types of Molecular Diagnostics

As stated earlier, there are several types of molecular diagnostics: genetic tests, biomarker tests, and companion diagnostics. The terms “genetic tests” and “biomarker tests” are often used interchangeably, but we are presenting them here separately. You may find them in either category when researching this topic. Companion diagnostics are a separate category and will be discussed as such.


A few examples of successful molecular diagnostic genetic tests are:

Myriad Genetics: BRACAnalysis®
Assesses the risk of developing breast or ovarian cancer associated with inheriting mutations in the BRCA1 and BRCA2 genes by DNA sequencing

Genomic Health: Oncotype DX® Breast Cancer Assay
Predicts benefit of chemotherapy and risk of recurrence in estrogen-receptorpositive, HER2-neu negative breast cancer patients by assessing gene expression levels of 21 genes from tumor tissue.


For many tumor types, biomarkers represent an important shift in cancer care. These biologic indicators are increasingly being used to help physicians screen, diagnose, and monitor patients. Certain biomarkers may help in prognostic evaluation, assessment of treatment response, and monitoring for disease recurrence.4

Predictive vs. Prognostic Biomarkers

Following are several examples of biomarkers that may be categorized as “prognostic” or “predictive”:

Prognostic Biomarkers provides information about the patient’s overall cancer outcome, regardless of therapy, for example:

  • HER2-neu expression in breast cancer, cancer of the stomach, and cancer of the junction where the esophagus meets the stomach (gastrointestinal junction)
  • MSI (microsatellite instability) in colorectal cancer
  • NPM1 and FLT3 mutations in acute myeloid leukemia (AML)
  • Oncotype Dx® in breast cancer and colon cancer

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Predictive Biomarkers provide information about the effect of a treatment and may be predictive of response, resistance, or toxicity, for example:

  • Epidermal Growth Factor Receptor (EGFR) to determine whether a solid tumor (e.g., of the lung, colon, head or neck, pancreas, or breast) is positive for EGFR overexpression, guiding treatment
  • KRAS mutations in colon cancer
  • BRAF mutations in colon cancer and malignant melanoma
  • HER2-neu expression
  • CYP2D6 genetic variants that may be associated with decreased metabolism of the medication tamoxifen to its active form (endoxifen). (In women with estrogen-receptor-positive breast cancer, it has been suggested that reduced metabolism of tamoxifen may reduce its effectiveness in reducing the risk of recurrence. However, the clinical trial results to date have offered contradictory findings.)
  • UGT1A1, DPYD, TYMS testing for gene mutations that predict sensitivity to specific chemotherapy drugs

A predictive biomarker may or may not be a target for therapy.5

Emerging Biomarkers

In addition to well-established biomarkers--such as KRAS and EGFR in colorectal and lung cancer and HER-2-neu and ER/PR in breast cancer--many new biomarkers are being investigated in multiple tumor types. Some biomarker studies have started to show promising data, but validation of such markers will require multiple steps, possibly taking many years of research.

Example: Non-Small-Cell Lung Cancer (NSCLC) gene mutations


This image illustrates how far we have come in identifying mutations in Non-Small-Cell Lung Cancer (NSCLC).

Remember that NSCLC is just one of several lung cancer types. This image shows that there are many different gene mutations that may be associated with NSCLC, further complicating how best to treat a specific patient.

Although we have gained knowledge in recent years concerning KRAS and EGFR mutations in NSCLC, much remains to be learned about the other markers identified on this image.

Image from Pao et al, Nature Medicine 18,349–351 (2012)


As discussed above, the term '”molecular diagnostics” is a general one that includes all tests and methods used to identify disease or risk for disease by analyzing molecules, such as DNA, RNA, or proteins.

In contrast, “companion diagnostics” is a term used to describe a type of molecular diagnostic test that is developed by a drug company at the same time that their new drug is being developed. Patients will be tested with this molecular diagnostic before treatment to see if they will respond to the new drug. This approach promises to improve overall outcomes, while reducing less effective care and adverse events.

The use of a companion diagnostic is becoming more common in predicting drug effectiveness and optimal dosage. According to experts, this will eventually become the norm. "It's a new field, and it's growing," says Peter Tolias, executive director of the Institute of Genomic Medicine at the UMDNJ-New Jersey Medical School.

Although the use of companion diagnostics is a relatively new concept, as more biomarkers are being discovered and validated, it’s challenging the concept of “one size fits all” in drug development and promises to change the way drugs are discovered, developed, and marketed. It is hoped that the day will come when analysis of blood or tissue samples may determine whether cancer patients will respond to a specific drug.


In this illustration, “Responders” to the medication are depicted on the left and “non-responders” are shown on the right.

Image courtesy of Ventana Medical Systems    

In the last five years, most of the major pharmaceutical companies have established new programs for companion diagnostic products. "In the olden days, they never used to worry about who their drug was going to be functioning in, or who's going to have an adverse effect," Tolias says.

However, the tide has changed, and pharmaceutical companies are now increasingly focused on developing new agents that can target only cancer cells, and providing companion diagnostics to identify those patients who may benefit most, those who are unlikely to benefit, and/or those who at most risk for adverse effects.

This image depicts the process used by Industry to identify a biomarker and then to develop both a drug that targets the marker as well as a molecular diagnostic to test for the biomarker in patients.

Image courtesy of Asuragen



“Content Developed September 1, 2012”


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