Precision chemotherapy of colorectal cancer. EGFR, BRAF, MEK inhibitors. 4-1

How to use mutations in EGFR, BRAF and MEK molecules to select personalized treatment plan in colorectal cancer? When to use immune check point inhibitors in colorectal cancer?

Colorectal cancer patients, especially with stage 4 metastatic colon cancer often participate in clinical trials. Prof. Dr. Hans-Joachim Schmoll, MD. 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. Dr. Anton Titov, MD. How do you use personalized medicine for selection of the right patients for the right clinical trial of new colon cancer treatments? Personalized medicine for colon cancer is still not good enough. But it is getting better. We have about 4 chemotherapy medications. Another colon cancer chemotherapy medications 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 microenvironment of the tumor. Prof. Dr. Hans-Joachim Schmoll, MD. They should target vessels in “tumor bed”. New medications must target connective tissue around the tumor. There are many lymphocytes and other immunoactive cells. We call this “immunobiome”. This will help reduce colon cancer tumors. Another colon cancer medication targets epidermal growth factor receptor pathway. 45% to 50% of the patients have a mutation in EGFR pathway. Prof. Dr. Hans-Joachim Schmoll, MD. This mutation is called KRAS mutation. KRAS is a specific part of this EGFR pathway. in these colon cancer patients, an antibody against 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; Bevacizumab , Ranibizumab ] Action of EGFR inhibitors is personalized. It means this. Only patients with EGFR mutation in colon cancer tumor should be treated with EGFR inhibitors. [panitumumab cetuximab , 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. Prof. Dr. Hans-Joachim Schmoll, MD. There is a reduction of colon cancer tumor size. But not eradication of the tumor. EGFR inhibitors and anti-angiogenic medications are 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. 5% of colon cancer patients have BRAF mutations. It is not RAS mutation. But BRAF mutation is also in the pathway of the EGF receptor. Patients with colon cancer tumors with BRAF mutation have very poor prognosis. Dr. Anton Titov, MD. Traditional chemotherapy is not working for them. Patients with BRAF mutation have very short survival. Prof. Dr. Hans-Joachim Schmoll, MD. We have to look for new treatments. Now we take the treatment this has been developed for melanoma. 50% of melanoma tumors have BRAF mutation. [BRAF inhibitors: dabrafenib , Sorafenib , Vemurafenib ] 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. Prof. Dr. Hans-Joachim Schmoll, MD. This is now going for first-line colorectal cancer treatment. Dr. Anton Titov, MD. 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: dabrafenib (Tafinlar), Sorafenib (Nexavar), Vemurafenib (Zelboraf). These are inhibitors of BRAF, EGF receptor, and also MEK pathways. Precision medicine therapy also uses [panitumumab (Vectibix) cetuximab (Erbitux), Ramucirumab (IMC-1121B, Cyramza) in metastatic stage 4 colorectal cancer. 45% to 50% of the patients have a mutation in EGFR pathway. This mutation is called KRAS mutation. KRAS is a specific part of this EGFR pathway. There is no personalized approach possible with anti-angiogenic medications; Bevacizumab (Avastin), Ranibizumab (Lucentis). Personalized medicine depends on correct selections of patients for best colon cancer and rectal cancer therapy. Leading colorectal cancer expert discusses precision medicine treatment of colorectal cancer with BRAF inhibitors, EGFR targeted therapy and anti angiogenesis medications.