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.
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.
References:
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.
