Sunday, June 1, 2014

Clinical Trials to Support KRAS Mutations and Cetuximab Resistance

To conclude my series of blog posts, I will focus on the last important piece of the paper that I have been dissecting. My other posts focused on the data of the cellular models used to explain the molecular basis of the secondary acquired resistance. Through two different models, the authors concluded that KRAS amplification and/or mutation had an effect on resistance to cetuximab. To determine if these conclusions are clinically relevant, the researchers examined tumor biopsies from colorectal cancer patients.
The results are presented in this figure.  

This study compares the KRAS mutational statuses of colorectal cancer patients who had chemotherapy resistant tumors and those with anti-EGFR resistant tumors. The patients with anti-EGFR resistant tumors have either been treated with cetuximab or panitumumab. The other group had been treated by cytotoxic chemotherapy and had not been previously exposed to anti-EGFR therapies. Through multiple methods of sequencing, KRAS mutations in the patients’ tumors were identified. Some patients who had anti-EGFR therapies, shown in table (b), acquired KRAS mutations, while the chemotherapy patients, table (a), were all wild type for KRAS.

The sample size for the chemotherapy group is sufficient because they all are wild type, but a larger sample size for the anti-EGFR group would be rewarding and valuable to this study. This could show possibly a variety of mutations as well as the frequency of these mutations in colorectal cancer patients. Also, three anti-EGFR patients are KRAS wild type, leading to the question of what caused their acquired resistance? Would it be similar to the chemotherapy patients?

The molecular experiments focused solely on the drug cetuximab, but this study allows patients who have also used panitumumab. How similar are these drugs to assume that panitumumab could also lead to the same mutations? The authors of this paper made their conclusions in terms of cetuximab, so incorporating panitumumab data may weaken the strength of their claim. The type of sequencing also differed for some patients, which could lead to inconsistencies in the data.

The number of mutated reads from sequencing quantifies the total number of KRAS mutations for the two groups of patients. Graph (c) illustrates the significant difference between the two groups, including a small p-value, supporting the significance. However, this study focused on sequencing KRAS in patients that have already had a form of treatment, but without the knowledge of their KRAS status before the treatment, one cannot say that anti-EGFR therapy causes KRAS mutations, leading to resistance. We only know from this data that there is a correlation, but in combination with the molecular data, other assumptions can be made.



Sandra Misale, Rona Yaeger, Sebastijan Hobor, Elisa Scala, Manickam Janakiraman, David Liska, Emanuele Valtorta, Roberta Schiavo, Michela Buscarino, Giulia Siravegna, Katia Bencardino, Andrea Cercek, Chin-Tung Chen, Silvio Veronese, Carlo Zanon, Andrea Sartore-Bianchi, Marcello Gambacorta, Margherita Gallicchio, Efsevia Vakiani, Valentina Boscaro, Enzo Medico, Martin Weiser, Salvatore Siena, Federica Di Nicolantonio, David Solit, and Alberto Bardelli. “Emergence of KRAS mutations and acquired resistance to anti EGFR therapy in colorectal cancer.” Nature (2012) 486:7404. Web May 3, 2014.