Genetic testing can help predict treatment response in colorectal
17 September 2008
Genetic testing can identify a group of patients with advanced
colorectal cancer who are likely to survive on average twice as long if
treated with the drug cetuximab, new results have shown.
At the 33rd Congress of the European Society for Medical Oncology (ESMO)
in Stockholm this week, Dr Christos Karapetis from Flinders University
in Australia reported on a genetic analysis of 394 patients who took
part in a phase III study comparing the monoclonal antibody cetuximab
with best supportive care.
The latest analysis compared the effect of mutations in the K-Ras
gene on overall survival and progression-free survival. The gene encodes
a protein that is a key component of cellular signalling pathways,
conveying extracellular growth signals from the cell surface to the
nucleus. When growth factors bind to cell surface receptors, including
epidermal growth factor receptor (EGFR), K-Ras is temporarily activated,
facilitating regulated cell growth and proliferation.
The K-Ras gene is mutated in up to 35% of colorectal cancers. These
mutations keep K-Ras stuck in its active form, switching on signalling
without the requirement for EGFR stimulation.
Dr Karapetis and colleagues found that patients with mutated forms of
K-Ras had a median overall survival of 4.6 months when treated with
cetuximab, and 4.5 months with supportive care. In contrast, among those
with wild-type forms, overall survival jumped to 9.5 months when treated
with cetuximab, compared to 4.8 months with best supportive care.
The results show that determining K-Ras mutation status should be
considered a new standard of care for selecting patients for targeted
therapies against EGFR, the authors say.
Also at the congress, Professor Eric Van Cutsem from University
Hospital Gasthuisberg, Leuven in Belgium will present data on the impact
of K-Ras mutations from the Crystal study, in which patients were
randomized to either the chemotherapy combination “FOLFIRI” or FOLFIRI
plus cetuximab, in first line metastatic colorectal cancer.
Professor Van Cutsem recently reported that the combination of
cetuximab and FOLFIRI significantly improves progression free survival
and response rate in patients with a K-Ras wild type. In Stockholm he
will present new data on survival in the Crystal trial.
“Overall survival in all patients included in the trial was identical
in both treatment arms. There was however a strong trend towards a
longer survival in patients with a K-Ras wild type tumor treated with
cetuximab/FOLFIRI,” he said. The median survival was 24.9 months for
patients who received the cetuximab combination, versus 21.0 months (HR:
0.84). The overall survival results in patients with K-Ras mutant tumors
did not differ in the two study arms.
In another study, Dr Miriam Koopman from the University Nijmegen
Medical Centre St. Radboud in The Netherlands, reports that the number
of tumor cells found circulating in the blood of patients with advanced
colorectal cancer is another valuable predictor of survival.
Her group studied 467 patients who were being treated within a
prospective clinical trial (CAIRO2 of the Dutch Colorectal Cancer Group)
with chemotherapy plus bevacizumab, with or without the addition of
cetuximab. In each patient they measured levels of circulating tumor
cells before treatment, and at different stages during treatment.
“Circulating tumour cell (CTC) level might be an indicator of the
aggressiveness of disease,” Dr Koopman explained. “Thus, a high CTC
level before initiating therapy in metastatic colorectal cancer patients
is an inferior prognostic factor in our study.”
The results show that the median progression-free survival time for
patients with less than three CTC in every 7.5mL of blood was 10.5
months, compared to 8.2 months for those with three or more. Furthermore
the median overall survival time for patients with less than three CTC
in every 7.5mL of blood was 22.2 months, compared to 13.7 months for
those with three or more.
“In our study CTC in metastatic colorectal cancer patients proves to
be an early prognostic marker,” Dr Koopman said. “Prospective trials are
needed to investigate whether a change in therapy based on CTC is