Some colon cancer patients should not undergo chemotherapy because it offers no benefit, and may in fact reduce survival times, new research says.

The study says that 15 per cent of patients with so-called deficient DNA mismatch repair (dMMR) tumours do not respond to treatment with the chemotherapy 5-fluorouracil (5-FU), which is commonly used to treat colon cancer.

Patients with dMMR tumours make up about 15 per cent of colon cancer cases. These tumours are unable to repair DNA damage via the mechanism known as DNA mismatch repair, a common system in the body for recognizing and fixing DNA mutations.

The other 85 per cent of colon cancers are characterized by a cellular problem known as chromosomal instability, a common characteristic of most cancers that leads to an imbalance of chromosomes in the body's cells.

For their study, the researchers analyzed data from more than 1,000 men, 16 per cent of whom had dMMR tumours.

They found that the patients who had the chromosomal instability type of tumour and who were treated with chemotherapy had a five-year survival rate of 74 per cent. Those who did not receive chemotherapy had a five-year survival rate of 66 per cent.

However, among those with dMMR tumours, the five-year survival rate with chemotherapy was 75 per cent compared to a 93 per cent survival rate among those that did not receive chemotherapy.

"We think it is very important for patients and their doctors to have this information before considering treatment in a patient with stage II colon cancer," Daniel Sargent, a Mayo Clinic biostatistician, said in a statement.

"It could save patients the toxicity, inconvenience and expense of treatment from which they will receive no benefit."

The study says that before diagnosing a treatment regimen, doctors should test stage II colon cancer patients to determine which tumour subtype they have. In stage II cancer, the disease has not yet spread to the lymph nodes.

The research from the Mayo Clinic, conducted along with American and Canadian scientists, was released Thursday in advance of the meeting of the American Society of Clinical Oncology in Chicago at the end of the month.

In 2003, the same team of researchers published a study in the New England Journal of Medicine that recommended that patients with dMMR tumours should not undergo chemotherapy. With this research, the scientists have confirmed their earlier findings.

Because many laboratories are already familiar with the dMMR test, the researchers said that it should be an easy transition to make it standard procedure when treating patients with colon cancer.

Scientists still need to study why chemotherapy does not help patients with dMMR tumours. The researchers speculated that chemotherapy causes these cancer cells to mutate and become more aggressive because they cannot repair damage caused by the treatment.

It could also be that chemotherapy compromises the innate healing responses of dMMR cancers (as evidenced by the stronger survival rate among those who did not receive chemotherapy).

Abstract:

Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): a pooled molecular reanalysis of randomized chemotherapy trials.

Author Block: D. J. Sargent, S. Marsoni, S. N. Thibodeau, R. Labianca, S. R. Hamilton, V. Torri, G. Monges, C. Ribic, A. Grothey, S. Gallinger; Mayo Clinic, Rochester, MN; SENDO Foundation, Milano, Italy; Mayo Clinic, Rochester, MN; Ospedali Riuniti, Bergamo, Italy; MD Anderson, Houston, TX; Mario Negri Institute, Milano, Italy; Institut Paoli Calmettes, Marseille, France; University of Toronto, Toronto, ON, Canada; Mayo Clinic, Rochester, MN; Mount Sinai Hospital, Toronto, ON, Canada

Background: Patients (pts) with CC demonstrating high-frequency MSI (MSI-H) have a stage-independent improved survival compared to pts with microsatellite- stable (MSS) tumors. We have previously published that MSI status is a predictive marker for lack of response to 5-FU-based chemotherapy (rx) (Ribic, NEJM 2003). dMMR by immunohistochemistry for MMR proteins is an almost perfect predictor for MSI status. We sought to confirm the value of dMMR as a predictor of survival benefit from adjuvant rx in stage II & III CC pts in an independent dataset drawn from randomized clinical trials.

Methods: MSI or IHC analyses were performed on tumors from pts enrolled in trials conducted by the NCCTG (N=135), GIVIO (N=183), and ECOG (N=23) that have not been used in previous MSI or dMMR analyses. All trials randomized pts with stage II and III CC to either 5-FU based rx (either 5-FU + Levamisole or 5-FU + Leucovorin, N=166)) or no post-surgical rx (N=175). XX microsatellite loci from the National Cancer Institute panel were used to amplify genomic DNA and determine MSI status (GIVIO); IHC testing for hMLHI and hMSH2 was used for the NCCTG and ECOG trials. Patients with MSI-H tumors or negative IHC staining were classified as dMMR; the remainder were considered to have proficient MMR (pMMR). Median follow-up on living pts was 6.4 years with a primary outcome of overall survival (OS).

Results: 341 tissue specimens were examined, of which 47 (13.8%, 20 treated, 27 untreated) exhibited dMMR. Adjuvant rx had a significant beneficial effect on OS (HR = 0.69, p= 0.047) and DFS (HR = 0.59, p = 0.004 in pts with pMMR tumors. However, pts with dMMR tumors receiving 5-FU rx had no trend toward improved OS (HR = 1.26, p = 0.68) or DFS (HR=1.41, p = 0.53) compared to those randomized to no rx. Results were maintained in multivariate models adjusted for stage and age.

Conclusions: Stratification of pts according to MMR status provides a more tailored approach to the use of adjuvant rx in CC. Our data suggest that in a patient being considered for 5-FU alone rx (i.e. a stage II pt), MMR status should be assessed and considered in rx decision making.