Intra-Tumour Genetic Heterogenity High in Metastatic CRC

Metastatic colorectal cancer shows intra-tumour genetic heterogeneity that may require combinations of targeted treatments

medwireNews: Metastatic colorectal cancer (mCRC) has a high level of intra-tumour genetic heterogeneity, say Italian researchers who believe this is likely to affect response to targeted treatments.

Using data from the CAPRI–GOIM trial of cetuximab plus chemotherapy in patients with KRAS exon-2 wild-type mCRC, the team calculated the heterogeneity score (HS) for each tumour, where a HS of 100 indicates that all neoplastic cells carry the mutation.

Thus, a HS score of less than 100 indicates that a fraction of cells have the mutation and greater than 100 implies a copy number variation from a gain of a mutant allele or loss of the wild-type allele, the researchers explain.

Analysis revealed that the majority of the neoplastic cells carry mutant KRAS and NRAS, with median HSs of 84.4 and 117.1, whereas the HSs were 54.3 and 47.3 for BRAF and PIK3CA.

“It has long been debated whether it is possible to identify within KRAS mutant tumors a threshold to separate tumors resistant to EGFR monoclonal antibodies from those that might be responsive to these agents”, explain Nicola Normanno, from Istituto Nazionale Tumori “Fondazione Giovanni Pascale” in Napoli, and co-authors in the Annals of Oncology.

When applied to the CAPRI–GOIM trial participants, 70.0% of the 10 patients with a HS score below 33 responded to cetuximab plus chemotherapy. This compared with just 45.7% of those with a HS above 33; this is a proportion expected from the chemotherapy alone and in line with that of RAS mutated tumours, the team says.

The researchers note, however, that median progression-free survival of the patients with high and low KRAS was similar, at 7.97 and 8.37 months, respectively, although the small sample size does not allow further analysis.

“These data might suggest that a low content of KRAS mutant alleles is sufficient to produce resistance to EGFR monoclonal antibodies”, they write but admit that around 70% of both high and low KRAS tumours also had other mutations affecting PIK3CA, TP53 and other known genes.

Tumours with low KRAS had more additional PIK3CA mutations than those with high KRAS, at 60% and 23%, respectively.

“These findings raise the question of whether resistance to EGFR targeting agents is driven in these patients by the low level KRAS mutant, by the mutations in PIK3CA, in BRAF or even other genes not included in our panel, or by a cooperative effect of these pathways, which is likely to be the case”, the team comments.

They suggest that classifying tumours by a single mutation is “too simplistic” and that assessing mutational load could help identify the “priority target” for therapeutic intervention, concluding that the “complexity revealed by our study suggests that for many tumors combinations of [target] based agents will likely…be necessary to control tumor growth.”


Normanno N, Rachiglio AM, Lambiase M, et al. Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial. Ann Oncol 2015; Advance online publication 7 April. doi: 10.1093/annonc/mdv176

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