Next-Generation Sequencing For Colon Cancer
- Next-generation sequencing (NGS) is a new technique for studying genes which can help doctors understand cancer better.
- Several gene tests are available to check if you have some specific mutation such as MMR/MSI-h, KRAS, BRAF or
HER2 mutations. - These tests can help determine if you are likely to respond to targeted therapies.
- Targeted therapies focus on specific aspects found on cancer cells only (as opposed to chemotherapy, which can damage healthy cells in the process of fighting cancer).
- Most testing is covered by insurance. However, coverage can vary based on the specific insurance and the tests needed.
SurvivorNet has put together this piece thinking of you, who live in the D.C. Metro area.
Read MoreNGS has various names, which can be a bit puzzling. NGS is the same as next-generation testing, comprehensive genomic profiling, broad molecular profiling or high-throughput sequencing. It is also commonly referred to as molecular testing.
NGS isn’t a particular test for a specific type of cancer. Instead, it’s a group of tests or a technique that searches for all the genetic changes in a tumor’s genes.
If you live in the D.C. Metro area, Dr. Madan could help you, or a loved one, understand what the importance of these tests are.
Colon Cancer Mutations
These are specific mistakes in the DNA that fuel tumor growth. Below you can find the most common mutations that drive colon cancer.
- MMR/MSI
- KRAS
- BRAF
- NRAS
- APC
- TP53
- HER2
Notably, MSI testing and KRAS testing are some of the most common tests used.
MMR/MSI testing
“A very significant part of colon cancer treatment involves testing for a mismatch repair and MSI microsatellite instability testing, which is done through immunohistochemistry, says Dr. Madan.
Mismatch repair (MMR) genes are responsible for helping to correct a certain type of error in which the DNA might be accidentally “mismatched” when cells replicate. When the MMR system is defective, it causes specific proteins (MLH1, MSH6, PMS2, MSH2) to be unable to perform this job. Thus, a mismatch repair deficiency (dMMR) allows errors to accumulate due to the lack of repairs.
The accumulation of errors affects areas of the cell’s genes responsible for keeping the cell from dividing out of control (a hallmark of cancer), and is known as High Microsatellite Instability (MSI-H).
There are two kinds of laboratory tests for this biomarker, both involve a tissue sample (biopsy) of the tumor. Depending on the method used, an abnormal result is called either microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR)
Patients with MSI-H or dMMR make up about 15% of patients with colorectal cancer and it is recommended that all patients with newly diagnosed colon cancer, regardless of stage or spread, undergo MMR/MSI testing.
How do the results help?
“Patients who are MMR deficient or MSI high have a high response rate to use of immunotherapy with pembrolizumab. So we need this kind of information before starting treatments. Another thing with the MSI testing is that it predicts lack of response to 5FU-based chemotherapy (standard chemotherapy) in stage two tumors. So in those patients we omit that kind of adjuvant therapy and we use this information prior to treating them,” adds Dr. Madan.
MMR/MSI testing is recommended for anyone diagnosed with colon cancer, according to the National Comprehensive Cancer Network guidelines.
KRAS and NRAS mutations
Around 40-45% of colorectal cancer patients have KRAS mutation in their tumors. This mutation is not hereditary and will not be passed from one generation to another — it’s completely random. NRAS mutations are much less common, though both KRAS and NRAS are part of the RAS oncogene family.
Testing is indicated in all patients with metastatic colon cancer.
“Then you have your KRAS and NRAS mutations that need to be checked. If a patient … [does] not have KRAS or NRAS mutations, they have a better response to therapies such as cetuximab and panitumumab in addition to chemotherapy. Those who have those mutations are treated with bevacizumab,” says Dr. Madan.
It’s important to know if your tumor is KRAS-mutated because these cancers have poor response to EGFR-inhibitor medications (such as cetuximab or panitumumab). Therefore, they shouldn’t be treated with those drugs, but rather with conventional chemotherapy such as FOLFOX or FOLFIRI, with or without the addition of bevacizumab.
BRAF Mutation
Patients with a BRAF mutation have a higher risk of the cancer coming back.
Like the KRAS mutation, BRAF gene mutation happens randomly and it’s not hereditary. But unlike KRAS, it’s not that frequent. Studies have shown that the BRAF gene mutation is found in about 10% of colorectal cancer patients. Knowing about a BRAF gene mutation indicates the need for aggressive treatment, since the mortality risk for patients with a BRAF mutation is more than two times higher than for those with a normal BRAF gene.
“In those patients, we know they are bit chemo resistant. Hence they do better when treated with triple drug therapy as compared to two drug therapy, which is standard of care. We also use medications such as encorafenib or dabrafenib for BRAF mutated tumors,” adds Dr. Madan.
HER2 Testing
HER2 is a mutation that is commonly seen in breast cancers — but about 15% of colorectal cancers can be HER2 positive as well.
The human epidermal growth factor receptor 2 (HER2) is a receptor on the surface of almost all the cells in our body, and it is responsible for the communication between the cells to promote their growth, division, repair, and survival (called an oncogene). Approximately 3% of colorectal cancers have amplification of the HER2 oncogene. This mutation is also not hereditary and will not pass from one generation to another.
According to NCCN Guidelines, patients whose tumors are positive for KRAS or BRAF mutation do not need to undergo HER2 testing. Doctors may be able to recommend a more effective therapy combination if a HER2 amplification is detected.
Testing is essential for patients with metastatic colon cancer.
HER2 positive treatment
For these specific patients, there is a drug called HERceptin. It can be used in combination with chemotherapy to treat HER2-activated colon cancers.
Types of NGS Testing On The Market
There are a number of tests you may encounter, depending on where you are getting treatment and what you are getting treatment for. Here are some of the common ones currently on the market:
- FoundationOne®CDx looks at 324 genes in solid tumors and says it can takes up to 12 days for results. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB) to help inform immunotherapy decisions.
- OmniSeq Insight provides comprehensive genomic and immune profiling for all solid tumors. It looks for 523 different genes. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB), as well as PD-L1 by immunohistochemistry (IHC).
- Cobas EGFR Mutation Test v2 identifies 42 mutations in exons 18, 19, 20 and 21 of the epidermal growth factor receptor (EGFR) gene. It is designed to test both tissue and plasma specimens with a single kit, and allows labs to run tissue and plasma on the same plate simultaneously.
Being a Washington DC resident dealing with colon cancer brings specific questions and concerns. Where can you find the best medical facilities in the DMV area? How does the urban lifestyle affect treatment and recovery? MedStar Health in Washington, D.C., could be an option for you.
You should ask your healthcare team if the brand of molecular testing they are doing is optimal for your cancer type.
Questions to Ask Your Doctor
- Should I have next-generation sequencing testing?
- Do you need both the tissue sample and blood samples for NGS testing?
- Do I have any genetic mutation that would change the course of my treatment?
- Am I eligible to receive targeted therapy?
- Is there a clinical trial that would be relevant for me?
Learn more about SurvivorNet's rigorous medical review process.