Researchers quantify proportion of different genetic mutations in individual bowel cancers

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

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

Now, for the first time, a study published in the leading cancer journal Annals of Oncology [1] today (Monday), has quantified the different mutational profiles of these clusters of cells in individual tumours in patients with bowel cancer that has spread to other parts of the body (metastasised). The researchers in Italy have correlated the intra-tumour heterogeneity with the way the patients responded to specific drugs, such as cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, which is a common treatment for patients with metastatic bowel cancer.

"Our study has shown there is a high degree of variability between different groups of cancer cells within one tumour, and we have been able to quantify this for the first time.

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 bowel cancer patients in whom resistance to anti-EGFR drugs may be driven by the complex mutational make-up of the tumour, rather than the molecular alteration of a single gene," said Dr Nicola Normanno, Director of the Cell Biology and Biotherapy Unit and Director of the Laboratory of Pharmacogenomics, Centro di Ricerche Oncologiche di Mercogliano, at the Istituto Nazionale Tumori "Fondazione Giovanni Pascale" IRCCS, Naples, Italy, who led the study.

"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 personalised medicine for patients with bowel cancer and possibly with other types of cancers," he said.

The researchers used "next generation sequencing", which can provide information on several different genes in a single analysis, to investigate the mutational profiles of 182 tumour samples taken from patients in the CAPRI-GOIM trial - a multi-centre 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 two weeks when their cancer progressed [2,3].