Precision Medicine in Colorectal Cancer: Targeting EGFR, BRAF, and MEK Pathways

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• Personalized Medicine Overview
• EGFR Inhibitors and KRAS Status
• Anti-Angiogenic Therapy Limitations
• BRAF Mutations and New Treatment
• Combination Therapy Advances
• Future Treatment Directions
• Full Transcript

Personalized Medicine Overview in Colorectal Cancer

Personalized medicine for colorectal cancer is improving but is not yet optimal. Dr. Hans-Joachim Schmoll, MD, states that patient selection for clinical trials is critical for successful colon cancer treatment. He explains that the current arsenal includes about four chemotherapy medications, with more coming to market. The interview with Dr. Anton Titov, MD, highlights the need for additional antibody-based therapeutics that target the tumor's blood vessels and microenvironment.

EGFR Inhibitors and KRAS Status

Targeting the epidermal growth factor receptor (EGFR) pathway is a key strategy. Dr. Hans-Joachim Schmoll, MD, notes that 45% to 50% of patients have a mutation in the EGFR pathway, specifically a KRAS mutation. For patients with wild-type KRAS (no mutation), antibodies against the EGFR receptor, such as cetuximab (Erbitux) and panitumumab (Vectibix), can improve the efficacy of chemotherapy. This approach represents a form of personalized medicine, as treatment is only effective for a specific genetic subgroup.

Anti-Angiogenic Therapy Limitations

Dr. Schmoll clarifies that anti-angiogenic medications like bevacizumab (Avastin) lack a personalized approach. These drugs target tumor vasculature but are not selected based on a patient's specific tumor biomarkers. While they are a nice improvement, Dr. Hans-Joachim Schmoll, MD, emphasizes they are not the ultimate solution. Their action is not tailored to individual genetic profiles, unlike EGFR inhibitors.

BRAF Mutations and New Treatment

A crucial new target exists in a small but important subgroup of patients. Dr. Hans-Joachim Schmoll, MD, explains that approximately 5% of colorectal cancer patients have BRAF mutations. These patients have a very poor prognosis, and traditional chemotherapy is largely ineffective, leading to very short survival. This dire need has driven the search for new, targeted treatment options derived from other cancers.

Combination Therapy Advances

A highly effective combination therapy has emerged for BRAF-mutant colorectal cancer. Dr. Schmoll describes adopting a strategy developed for melanoma, where BRAF mutations are also common. A combination of inhibitors targeting the BRAF, EGFR, and MEK pathways has proven to be surprisingly very active in last-line treatment. Dr. Hans-Joachim Schmoll, MD, confirms this potent regimen is now moving into first-line colorectal cancer treatment protocols.

Future Treatment Directions

The goal remains to develop more relevant and specific medication targets. Dr. Schmoll points to the tumor's "immunobiome," which includes lymphocytes and other immunoactive cells in the connective tissue around the tumor. Dr. Anton Titov, MD, and Dr. Hans-Joachim Schmoll, MD, discuss the need for treatments that influence this microenvironment. The future of precision medicine lies in hitting colon cancer tumors with even more targeted and effective treatments.

Full Transcript

Dr. Anton Titov, MD: How to use mutations in EGFR, BRAF, and MEK molecules to select a personalized treatment plan in colorectal cancer? When to use immune checkpoint inhibitors in colorectal cancer?

Colorectal cancer patients, especially with stage 4 metastatic colon cancer, often participate in clinical trials. Clinical trials test new colon cancer treatments and regimens.

Dr. Anton Titov, MD: Patient selection for clinical trials is a critical determinant of whether the colon cancer treatment is successful or not. How do you use personalized medicine for selection of the right patients for the right clinical trial of new colon cancer treatments?

Dr. Hans-Joachim Schmoll, MD: Personalized medicine for colon cancer is still not good enough, but it is getting better. We have about four chemotherapy medications. Another colon cancer chemotherapy medication is coming to market now.

There are several active medications, but they are not extremely active. We also need additional antibody-based therapeutics. They should target the blood vessels of the tumor.

New medications should influence the microenvironment of the tumor. They should target vessels in the "tumor bed." New medications must target connective tissue around the tumor.

There are many lymphocytes and other immunoactive cells. We call this the "immunobiome." This will help reduce colon cancer tumors.

Another colon cancer medication targets the epidermal growth factor receptor pathway. Forty-five to fifty percent of the patients have a mutation in the EGFR pathway. This mutation is called a KRAS mutation. KRAS is a specific part of this EGFR pathway.

In these colon cancer patients, an antibody against the EGFR receptor is working. It is improving the efficacy of the chemotherapy. We treat colon cancer with classic chemotherapy plus EGFR mutation-targeting antibodies.

But our treatment methods are still not specific enough to target tumor vasculature. There is no personalized method possible with anti-angiogenic medications like bevacizumab or ranibizumab.

The action of EGFR inhibitors is personalized. It means this: only patients with an EGFR mutation in the colon cancer tumor should be treated with EGFR inhibitors like panitumumab, cetuximab, or ramucirumab.

But EGFR inhibitors only work in 50% or 60% of colon cancer patients. EGFR inhibitors are also not working 100%. They have some efficacy. There is a reduction of colon cancer tumor size, but not eradication of the tumor.

EGFR inhibitors and anti-angiogenic medications are a nice improvement, but they are not what we really want to have. So I would not call this personalized medicine.

We are looking for more relevant medication targets. We want to hit colon cancer tumors with more specific targeted treatments.

Now we have two new targets for colon cancer treatment. They are very good for developing new medications. One new target exists in a subgroup of colon cancer. It is about 5% of all colorectal cancer patients.

Five percent of colon cancer patients have BRAF mutations. It is not a RAS mutation, but a BRAF mutation is also in the pathway of the EGF receptor.

Patients with colon cancer tumors with a BRAF mutation have a very poor prognosis. Traditional chemotherapy is not working for them. Patients with a BRAF mutation have very short survival.

We have to look for new treatments. Now we take the treatment that has been developed for melanoma. Fifty percent of melanoma tumors have a BRAF mutation.

Surprisingly, treatment of colon cancer with medications targeting three molecular pathways is effective. These are inhibitors of BRAF, EGF receptor, and also MEK pathways.

Now this type of combination is surprisingly very active in last-line treatment of colon cancer. This is now going for first-line colorectal cancer treatment. At least it forms a part of the first-line colon cancer treatment.

I will explain next how we do these treatments. Colon cancer targeted therapy with BRAF inhibitors. Colorectal cancer precision therapy—EGFR, BRAF, and MEK inhibitors show activity in difficult-to-treat and advanced colorectal cancer.

BRAF inhibitors include dabrafenib, sorafenib, and vemurafenib. These are inhibitors of BRAF, EGF receptor, and also MEK pathways.

Precision medicine therapy also uses panitumumab, cetuximab, and ramucirumab in metastatic stage 4 colorectal cancer. Forty-five to fifty percent of the patients have a mutation in the EGFR pathway. This mutation is called a KRAS mutation. KRAS is a specific part of this EGFR pathway.

There is no personalized approach possible with anti-angiogenic medications like bevacizumab or ranibizumab. Personalized medicine depends on correct selection of patients for the best colon cancer and rectal cancer therapy.