Precision Cancer Medicines for Colon Cancer
by C.H. Weaver M.D. 8/2018
The purpose of precision cancer medicine is not to categorize or classify cancers solely by site of origin, but to define the genomic alterations in the cancer’s DNA that are driving that specific cancer. Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
By testing an individual’s colon cancer for specific unique biomarkers doctors continue to develop new precision medicines. Individuals not previously tested undergo genomic testing to determine whether newer precision cancer medicines are a treatment option
Not all colon cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing is performed to test for certain genetic mutations or the proteins they produce because the results can help select treatment including newer precision cancer medicines designed to attack specific colon cancer cells with specific genetic mutations.
- **EGFR:**The epidermal growth factor receptor (EGFR) is involved in cellular growth and replication. Some colon cancers produce too much EGFR and this leads to more rapid growth of the cancer. Some medicines specifically target EGFR and the spread of cancer can be reduced or delayed.(1)
- The RAS Genes: KRAS and NRAS are a family of proteins found in cells that when mutated promote cancer cell growth. An estimated 40–50% of colorectal cancers contain these genes. Some colon cancer treatments don’t work if the RAS gene is abnormal. If cancer has a KRAS or NRAS mutation drugs that inhibit cancer cell growth and survival by targeting a protein known as the EGFR are ineffective. Cancers lacking these genetic mutations are referred to as “wild type”.(2,3)
- BRAF: BRAF is also a gene that signals cells to divide. Patients with mutant BRAF genes generally have a poorer prognosis (chance of survival and worse side effects) but may benefit from treatment with a precision cancer medicine.(4)
- PIK3CA: While somewhat new, a growing number of clinicians are testing for mutant PIK3CA genes; particularly in patients who have early-stage colorectal cancer. There is some suggestion that aspirin use may help decrease the risk of recurrent colorectal cancer in patients with early stage disease and PIK3CA mutation.
- Microsatellite Instability High (MSI-H) MSI-H is a DNA abnormality found in about 15% of colon cancers. It is most often found in tumors associated with genetic syndromes like Lynch syndrome but can also occur sporadically. MSI-H is what “happens” when the genes that regulate DNA function don’t work correctly. These DNA regulating genes, known as Mismatch Repair Genes (MMR), work like genetic “spell checkers.” When problems occur in these spell-checking MMR genes, it means that areas of DNA start to become unstable. A high frequency of instability is called MSI-H. Patients with MSI-H tumors may respond differently to certain treatment. It is important to test colon cancers for this trait because it can help determine if the colorectal cancer is related to an inherited family syndrome.
Targeting “Wild type” KRAS & RAS
Erbitux® (cetuximab) andVectibix (panitumumab) are a type of precision cancer medicine called a monoclonal antibody that works by binding to EGFR which is involved in cellular growth and replication,. By targeting EGFR the spread of cancer can be reduced or delayed. Both Vectibix and Erbitux can be combined with chemotherapy to improve outcomes in patients that test positive for EGFR and do not have a RAS mutations.(5,6,1)
Targeting BRAF and EGFR Doubles Progression-free Survival in Metastatic Colorectal Cancer
Zelboraf (vemurafenib) is a novel precision cancer medicine that only works in patients whose cancer has a V600E BRAF mutation. Five to 10 percent of colorectal cancer patients carry a very specific BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF protein that stimulates cancer growth. The addition of Zelboraf to treatment with Erbitux in patients with metastatic colorectal cancer that have a BRAF V600E mutation has been shown to double survival time without cancer progression.4
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells. A diagnostic test to measure the level of PD-L1 is available.(7,8)
PD-1: PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by certain immune cells. Drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer.
Keytruda (pembrolizumab) and Opdivo (nivolumab) belong to a new class of medicines called “checkpoint inhibitors” and both have significant anti-cancer activity in advanced colorectal cancer patients with mismatch repair deficient (dMMR) and microsatellite instability high (MSI-H) abnormalities.(7,8)
Other targeted treatments have emerged to match a person’s genetic makeup or a tumor’s genetic profile. As a result, all patients should undergo molecular testing.
Carcinoembryonic Antigen (CEA) CEA is a protein that may be higher in colorectal cancer patients. High levels of CEA may indicate that cancer is present or a treatment is not working. Low levels may indicate that the body is responding to a treatment.
OncoType DX: Is a test that may help guide treatment decisions for patients with stage II colon cancer. This test estimates the risk of cancer recurrence by evaluating the activity of certain genes in a sample of tumor tissue.9 Risk of recurrence can vary greatly among patients with stage II colon cancer, and adjuvant (post-surgery) therapy is not routinely recommended for all patients with stage II colon cancer, but may be considered for high-risk patients.
Treatment information concerning colon cancer is categorized and discussed by the stage and presence or absence of specific biomarkers. In order to learn more about the most recent information available concerning the treatment of colon cancer, select the appropriate stage.
- Karapetis CS, Khambata-Ford S, Jonker DJ et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. New England Journal of Medicine. 2008;359:1757-65.
- Amado RG, Wolf M, Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology. 2008;26:1626-1634.
- Cunningham D, Humblet Y, Siena S, et al. Cetuximab Monotherapy and Cetuximab plus Irinotecan in Irinotecan-Refractory Metastatic Colorectal Cancer. New England Journal of Medicine 2004;351:337-345.
- Hriesik C, Ramanathan R, Hughes S. Update for Surgeons: recent and noteworthy changes in therapeutic regimens for cancer of the colon and rectum. Journal of the American College of Surgeons2007; 205: 468-478.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Colon Cancer. V.3.2008. © National Comprehensive Cancer Network, Inc. 2008. NCCN® and NATIONAL COMPREHENSIVE CANCER NETWORK® are registered trademarks of National Comprehensive Cancer Network, Inc.