Biomarker testing is important because it can give your healthcare team the information they need to decide if adding a targeted therapy to your chemotherapy treatments may work for you.
As the presence of certain biomarkers can indicate poor response to certain therapies or disease progression, biomarker testing should be discussed with your healthcare team as an ongoing part of your treatment plan.
Testing for specific biomarkers depends on a number of factors, including your age at diagnosis, stage of cancer, and overall health.
Personalising (or tailoring) medical treatment according to your biomarkers helps to:
- avoid potential adverse effects from ineffective treatments
- avoid delay in seeking alternative treatments which may be effective.
For people with bowel cancer that is not curable by surgery, treatment aims to prolong survival and improve quality of life.
The main histologic subtype of bowel cancer is adenocarcinoma.
Bowel cancers arise through a series of mutations that occur over the space of many years, and results in the evolution of normal tissue to adenoma (polyp) to carcinoma (cancer) to metastasis.
Bowel cancer most frequently harbour alterations in TP53, APC, KRAS, PIK3CA, and SMAD4.
In the past two decades, there has been increasing recognition that some mutations may be prognostic or predictive markers for specific therapies available in bowel cancer.
BRAF, KRAS, and NRAS are the most frequent predictive biomarkers for bowel cancer treatment.
Knowledge of the genetic mutations associated with different cancer types is increasing rapidly and is already influencing treatment choices.
The My Cancer Genome website is a database of information on genes, genetic mutations and cancer, including latest research and treatments across many cancer types (including bowel cancer).
| APC (Adenomatous polyposis coli)
APC is altered in 56.75% of bowel cancer patients.
| BRAF (B-Raf proto-oncogene, serine/threonine kinase)
BRAF is altered in 12.45% of colon cancer patients with BRAF V600E present in 9.19% of all colon cancer patients.
BRAF is altered in 4.02% of rectal cancer patients with BRAF V600E present in 1.57% of all rectal cancer patients.
BRAF is a predictive biomarker for use of cetuximab (Erbitux), panitumumab (Vectibix) and encorafenib (Braftovi) in patients.
| KRAS (Kirsten rat sarcoma viral oncogene homolog)
KRAS is mutated in 39.02% of colon cancer patients and 36.83% of rectal cancer patients.
KRAS is a predictive biomarker for use of cetuximab (Erbitux) and panitumumab (Vectibix) in patients.
| MSI-H/dMMR (Microsatellite Instability High) / (Deficient DNA Mismatch Repair)
MSI-H/dMMR constitute around 5% of metastatic bowel cancer cases.
MSI-H/dMMR is a predictive biomarker for use of nivolumab (Opdivo), pembrolizumab (Keytruda) and fluorouracil (5-FU) in patients.
| NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog)
NRAS is mutated in 4.19% of colon cancer patients and 4.41% of rectal cancer patients.
NRAS is a predictive biomarker for use of cetuximab (Erbitux) and panitumumab (Vectibix) in patients.
| PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha)
PIK3CA is mutated in 19.51% of colon cancer patients and 10.19% of rectal cancer patients.
| TP53 (Tumour protein p53)
TP53 is mutated in 58.35% of bowel cancer patients.
Human KRAS protein. (Image by Sarangan Ravichandran, Ph.D., Frederick National Laboratory for Cancer Research). Source: National Cancer Institute
| What is RAS?
The RAS gene family – which includes KRAS, NRAS and HRAS - produces proteins (RAS proteins) that are involved in cell signalling.
RAS proteins play an important role in the regulation of cell growth, cell division and cell death.
Everyone has RAS genes because we need them for cells to grow normally.
Normal RAS genes are also called 'wild-type' RAS genes.
Some people will develop an abnormal or 'mutated' version of the RAS gene.
Mutated RAS genes result in RAS proteins being locked into a permanently 'switched on' state. Like a car with an accelerator that won't release and brakes that won't engage, cell growth and divisions become out of control and evade signals to die.
RAS mutations can also allow cells to resist available targeted therapies.
Why is RAS status important?
RAS status is important as it gives your oncologist the information they need to decide if adding a targeted therapy to your chemotherapy treatments may work for you. It does not affect the way your chemotherapy is prescribed.
About half of metastatic bowel cancers will have RAS 'wild-type' genes and about half will have 'mutated' RAS genes.
Patients with 'wild-type' RAS genes may respond to treatments with the targeted therapies Erbitux (cetuximab) or Vectibix (panitumumab). It is therefore important to know the RAS status of a cancer before your treatment commences.
Personalising (or tailoring) medical treatment according to your genetic make-up helps:
• avoid potential adverse effects from ineffective treatments
• avoid delay in seeking alternative treatments which may be effective
• reduce the costs of ineffective treatment
Patients with 'mutated' RAS genes are unlikely to benefit from Erbitux or Vectibix.
If this is the case, patients may still benefit from targeted therapies which work in a different way such as Avastin (bevacizumab).
What is RAS biomarker testing?
RAS testing is currently performed on a small sample of tissue taken from the cancer during a biopsy or surgery.
DNA from the cancer cells is extracted, purified and tested for known mutations on the RAS genes.
Until recently, testing was only available for specific mutations at a couple of sites on the KRAS gene.
However, new knowledge and improved testing has shown that additional mutations on the KRAS gene, and on the NRAS gene, are also implicated in cancer resistance to EGFR inhibitors. In the near future, RAS tests may also be available via a blood test.
| Frequently asked questions
When should I be tested?
RAS testing is recommended as soon as you are diagnosed with metastatic bowel cancer.
Do I need another biopsy or more surgery to provide the sample for testing?
Initial RAS testing can be performed on samples stored from the original surgery. Those samples may have been frozen or fixed in formalin.
Will I only need one RAS test?
There is evidence that some people will develop acquired resistance to EGFR inhibitors. A RAS test may need to be repeated if the treatment is no longer working and/or the cancer progresses.
Is RAS testing expensive?
RAS testing is reimbursed by Medical Benefits Scheme; Item No: 73338.