Dr. Simon Buczacki

Genomic Medicine in Colorectal Cancer: Why Personalised Therapies are Doomed to Fail

Personalized therapies are a hot topic not only in medical forums but also in society and the press. The dream of personalized therapies in cancer care is to treat each patient according to their specific mutations. But the reality is different. At first, the treatment seems to be effective, with a good response, but has a high recurrence rate. In colorectal cancer treatment, biologic agents such as anti-VEGF (bevacizumab) and anti-EGFR (cetuximab and panatimumab), are available. The former is not directed against any specific mutation, and the latter are not effective in the case of mutated K-ras or BRAF wt. Studies have shown that neither bevacizumab nor cetuximab extend Overall Survival (OS), the most important conclusions of these trials being that targeted biological treatment does not work as an adjuvant therapy - it prolongs life but does not cure the disease. Simon Buczacki, Honorary Consultant Colorectal Surgeon at Cambridge Cancer Center (UK) explains that these drugs target genomic sequences without taking into account the protein expression and the proteomics, and that important changes can occur during that two steps. Also, there is intra-tumoral heterogeneity at the genetic, epigenetic and functional levels. He highlights the importance of microRNA (mRNA) in the classification of colorectal cancer as it includes the developmental route and the microenvironment changes. Difficulties in acquiring proper information from the biopsy due to intratumoral heterogeneity have been recently discovered. In this way, targeted treatment may not actually be targeted, but rather just target subclonal diversity, thus encouraging the expansion of more aggressive clones by limiting clonal competition. The proposed solutions for these problems are to identify how to develop a deep sequence for the entire tumor with multiple biopsies or liquid biopsies associated or not with patient-derived organoids, immunotherapy, and including molecular data on subtypes in future trials.