A study to determine the feasibility of molecular selection of therapy using KRAS, BRAF and topo-1 in patients with metastatic or locally advanced colorectal cancer

Individualising treatment for patients with advanced bowel cancer – can we do it?

What was this study about?

Over 16,000 people die from bowel cancer in the UK every year. There are now molecular tests that can be done on tumour samples from patients with advanced bowel cancer which may help selection of the best treatment options for an individual patient. FOCUS 3 looked at the feasibility of this approach in the UK NHS setting. 240 patients were scheduled to be randomised to the trial at 24 centres across the UK.

Two tests were performed on the tumour before a patient was considered eligible for randomisation: the first assessed the levels of a protein called topo-1 and the second assessed the KRAS and BRAF status. KRAS and BRAF are two genes that are often altered in bowel cancer. About half of patients with bowel cancer have low levels of topo-1 and half have high levels. Similarly, about half of patients with bowel cancer have a change (mutation) in either the KRAS or the BRAF gene and about half do not. When the tests are completed, the cancer will be classed as one of four molecular types, and thus give four sub-groups of patients:

  • Type 1: low topo-1, KRAS and BRAF normal
  • Type 2: low topo-1, KRAS and BRAF mutation
  • Type 3: high topo-1, KRAS and BRAF normal
  • Type 4: high topo-1, KRAS and BRAF mutation

Within each subgroup each patient will be randomised to one of 3 arms; a control arm which is common to each of the 4 subgroups and two alternative, research arms, which have been chosen based on results from previous research. The control arm (A) is irinotecan and fluorouracil (IrFU). The two alternative research arms will depend on the molecular type of the tumour and will include the following regimens: (B) fluorouracil (FU), (C) irinotecan, oxaliplatin and fluorouracil (IrOxFU), (D) irinotecan, fluorouracil (IrFU) and cetuximab, and (E) irinotecan, fluorouracil (IrFU) and bevacizumab. The primary aims of the trial are to test the feasibility of testing tumour samples before randomisation and will look at whether results of the tests can be provided within 10 working days to allow randomisation.

What difference did this study make?

FOCUS3 was a feasibility study designed to address the challenges of patient acceptability, technical logistics, and to test a novel design for examining the predictive role of biomarkers for first-line therapy of advanced colorectal cancer.

Our results showed that such studies are feasible and very well received by participants. A total of 332 patients were registered, and 244 randomised. Among randomised patients, biomarker results were provided within 10 working days in 71% of participants, 15 working days in 91% of participants and 20 working days in 99% of participants. DNA mutation analysis was 100% concordant between two laboratories.

Over 90% of participants reported excellent understanding of all aspects of the trial.

The central trial design concepts have been taken forward into the FOCUS4-molecular selection of therapy in colorectal cancer programme.

Type of study

Randomised trial

Contact details

Who funded the study?

The trial was paid for by the Medical Research Council. The pharmaceutical company Merck provided the drug cetuximab, free of charge. Roche provided an educational grant for colorectal trials.

When did it take place?

The trial opened to recruitment in February 2010 and is now closed.

Where did it take place?

24 hospitals throughout the UK

Who was included?

People with advanced colorectal (bowel) cancer.