Proportion of different genetic mutations quantified in individual colorectal cancers

Researchers have quantified the mutational profiles of clusters of cells in individual colorectal cancer tumors that have metastasized. Intratumor heterogeneity correlated with the way patients responded to specific drugs, such as cetuximab. This research was published in the Annals of Oncology (2015; doi:10.1093/annonc/mdv176).

Colorectal cancer is often driven by mutations in one of several different genes, and one patient's cancer can have a different genetic make-up compared with another patient's cancer. Identifying the molecular alterations involved in each patient's cancer enables doctors to choose drugs that best target their specific alterations.

However, it is also becoming clear that while some cancers may be driven by a single gene mutation, individual tumors are often composed of groups of cancer cells, with each group having different molecular alterations from the others. This is known as intratumor heterogeneity, and it could have important consequences on the efficacy of therapies: in these mixed tumors, some tumor cell clusters might be sensitive to a targeted therapy while others are resistant.

"Our study has shown there is a high degree of variability between different groups of cancer cells within one tumor, and we have been able to quantify this for the first time,” said study leader Nicola Normanno, MD, of Centro di Ricerche Oncologiche di Mercogliano, at the Istituto Nazionale Tumori "Fondazione Giovanni Pascale" IRCCS, Naples, Italy.

“The variability is likely to affect patients' responses to drugs targeting specific genetic mutations, and our results also suggest that there is a subset of colorectal cancer patients in whom resistance to anti-EGFR drugs may be driven by the complex mutational make-up of the tumor, rather than the molecular alteration of a single gene."

"It is difficult to predict when these findings can be translated into the clinic and we don't want to create false expectations in the patients. However, we feel that by being able to quantify the relevant mutations, we will be able to improve personalized medicine for patients with colorectal cancer and possibly with other types of cancers," said Normanno.

The researchers used next generation sequencing, which can provide information on several different genes in a single analysis. They investigated the mutational profiles of 182 tumor samples from patients in the CAPRI-GOIM trial, which is a multicenter study of patients with metastatic colorectal cancer who were treated with chemotherapy and cetuximab, followed by a slightly different chemotherapy with or without cetuximab every 2 weeks when their cancer progressed.

“We found that different genes involved in colorectal cancer behave in a different manner; for example, when a tumor has a mutation in the KRAS or NRAS genes, usually all the cells are mutant, whereas for other genes such as BRAF and PIK3CA only a fraction of tumor cells is mutant. In addition, we identified tumors that are clearly formed by multiple groups of cells with different molecular alterations," said Normanno.

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