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
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 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.
