Molecular Testing in Colon Cancer
- Colorectal cancer has a prevalent genetic component, and it is important to know the available genetic and molecular testing options available.
- Germline testing for inherited cancer-causing genetic mutations is indicated if specific personal or family criteria are met, including a strong personal or family history of colon polyps and specific cancers (especially if diagnosed with multiple cancers or at a young age).
- If you are concerned about your personal or family history, please discuss potential germline testing with your healthcare team.
- Somatic tumor testing looks at the tumor tissue itself and various mutations that can drive disease and response to certain therapies.
- The importance of somatic tumor testing becomes more important with more advanced stage and metastatic disease and can help tailor cancer treatment and potential enrollment in ongoing clinical trials.
- The role of molecular and genetic testing in colon cancer will continue to evolve, and treatment will become more personalized as we understand more about how genetic changes drive the disease.
When discussing molecular testing, we typically refer to germline and tumor-based somatic testing. Germline testing looks at inheritable DNA that we pass on from generation to generation. Somatic tumor testing attempts to understand what mutations are in the DNA and molecular alterations in the tumor itself that are driving the cancer.
Germline Testing – Why to Get TestingRead More
Because specific inherited DNA mutations often present with cancer in specific organs, people who are carriers of these DNA mutations and do not have a known diagnosis of cancer can be more proactive in protecting themselves by undergoing regular screening early to catch cancers at an earlier and more treatable stage.
Germline Testing – When to Get Testing
The most common inherited syndromes with an increased risk of colorectal cancer among other cancer types include Lynch Syndrome (hereditary non-polyposis colorectal cancer, or HNPCC) and familial adenomatous polyposis (FAP).
Not everyone diagnosed with colon cancer is recommended to undergo germline testing, and the criteria for germline testing are complex. Certain characteristics in your personal or family history can help guide testing recommendations, including:
- A known Lynch syndrome or FAP diagnosis in the family
- A personal history of a Lynch syndrome related cancer diagnosed <50 years old or multiple diagnoses of cancer
- A personal or family history of multiple colon polyps
- A family history of Lynch syndrome cancers that have been diagnosed <50 years old, individuals that developed multiple cancers, or multiple family members with cancer
- A known MMR deficiency in your colon cancer or a specific mutation seen on testing of colon cancer
Lynch syndrome-related cancers include colorectal, endometrial, gastric, ovarian, pancreatic, urothelial, brain, biliary tract, and small intestine.
If you meet the criteria or if there is a concern for an inherited genetic component when you are evaluated by the healthcare team, you will typically be referred to a genetic counselor for additional, more extensive questioning to evaluate the need for germline genetic testing.
If you are concerned about your personal or family history of cancer and would like to know more about germline testing, please discuss further with your healthcare team so you may get appropriate help.
Somatic Tumor Testing – Why to Get Testing
Somatic tumor testing analyzes the cancer itself “to figure out what mutations or molecular alterations within the tumor itself may be driving the cancer or may produce treatment vulnerabilities that we can exploit to try to address the tumor,” says Dr. Eric Christenson, a Medical Oncologist at Johns Hopkins with a focus in gastrointestinal malignancies.
This additional testing gives us a few pieces of information that are really important in guiding future therapy. It can tell us how well someone is likely to do going forward regardless of treatment type, but it also tells us how well the cancer will respond to specific cancer therapies. We use all of this information, including your overall health and goals of care to make treatment recommendations and decisions. Molecular testing can also help to determine candidacy for ongoing clinical trials.
There are multiple different types of molecular testing that can be performed on the tumor tissue itself. Each test asks a different question, seeks to identify different available targeted therapies, and is recommended at different times over the course of the disease.
As we continue to learn more about genetics and the specific pathways that lead to colon cancer, these recommendations will continue to change, and treatment will become even more personalized.
Somatic Tumor Testing – When to Get Testing
Patients can present at any stage in their disease with colon cancer thanks to effective screening and early detection with colonoscopies. With earlier-stage disease that is more localized and has not spread distantly, fewer molecular testing options are recommended.
If colon cancer is metastatic (Stage IV), meaning it has spread distantly, additional molecular testing is indicated to identify other potential targeted therapies that can be used.
The main types of somatic tumor testing used include:
- Mismatch Repair (MMR)/Microsatellite Instability (MSI)
- Human Epidermal Growth Factor Receptor 2 (HER2)
Mismatch Repair (MMR) and Microsatellite Instability (MSI)
Changes in this DNA then alter how well the tumor cell can repair other DNA. According to Dr. Christenson, “while this DNA damage may have ultimately led to the cancer developing in the first place through the accumulation of additional mutations that conferred a growth advantage. There’s also because all these mutations accumulate, it makes the tumor look very different than the other normal cells within the body.”
When the tumor appears very different from other normal cells in your body, it is more easily identified by your immune system, which helps to keep the cancer at bay. It also means immunotherapy, which helps to boost your immune system against the cancer, is very effective in these types of cancers.
All patients with newly diagnosed colon cancer, regardless of stage or spread, are recommended to undergo MMR/MSI testing. About 5-15% of early-stage colon cancer has these features.
In stage I and low-risk stage II colon cancer, meaning smaller tumors that are not invading surrounding tissue, surgery is often all that is required, and no medication or chemotherapy is required after surgery. The testing and results become more important when colon cancer is higher stage and requires treatment after the surgery or if the cancer is unable to be removed or spread distantly.
KRAS, NRAS, and BRAF
Testing is indicated in all patients with metastatic colon cancer.
These can be tested individually with PCR tests or as part of a larger next-generation sequencing (NGS) panel that analyzes multiple parts of the tumor DNA.
With the KRAS mutation, “It represents about 40 to 50% of colorectal cancers. And of these, it helps us to understand what is the likelihood of the cancer responding to therapy targeting the epidermal growth factor receptor,” according to Dr. Christenson. This means that patients with a KRAS mutation in their colon cancer tend not to respond well to therapy that targets this receptor. However, a specific KRAS mutation, G12C, is becoming increasingly important in colon cancer, with clinical trials demonstrating effective targeted therapies against this specific gene mutation.
Testing of NRAS and BRAF also informs us on potential therapies to avoid when these mutations are present because certain therapies are ineffective.
Testing of HER2 is also indicated in all patients with metastatic colon cancer. It is an alternation in the DNA that is more common in breast cancers but also seen in about 3% of colorectal cancers. In these patients, targeted therapies are available as well.