Diagonstics & Imaging Week Correspondent

LONDON — A study in Finland of more than 2,000 women with breast cancer has identified a genetic variant that makes it possible to predict whether a woman will respond well to a common type of chemotherapy.

The discovery raises the possibility that women with breast cancer could have a simple blood test to find out if they carry the variant, with specific cancer drugs prescribed based on those test results.

Researchers also will want to probe how the variant has its effect, to help direct future development of drugs to treat cancer.

"This marker does not seem to be related to a woman's risk of developing breast cancer, but it is a marker of poor prognosis once the diagnosis has been made," Carl Blomqvist, professor of oncology at Uppsala University in Sweden and Consultant in Oncology at the Department of Oncology of the University of Helsinki in Finland, told told Diagnostics & Imaging Week's sister publication BioWorld International.

Possibly the most important finding in the study, he added, is the identification of a new pathway that influences survival following treatment for breast cancer.

"This marker has never been implicated before as an important pathway," Blomqvist said. "Further investigations may allow us to find new types of drugs to treat cancer."

An account of the study appears in the May 30 issue of Nature Genetics, in a paper titled, "NAP(P)H:quinone oxidoreductase 1 NQ012 genotype (P187S) is a strong prognostic and predictive factor in breast cancer."

The variant affects an enzyme called NQ01. The normal version of that enzyme is thought to play a role in protecting against oxidative stress and guarding against carcinogenesis. There is some evidence, for example, that it helps to stabilize the tumor suppressor protein, p53. Knockout mice lacking functional NQ01 are more susceptible than wild-type mice to the development of chemically-induced tumors.

In humans, between 4% and 20% of the population are homozygous for a variant that results in a missense protein, called NQ12. Previous studies have shown that cells that are homozygous for NQ12 have no measurable activity of the kind that is normally carried out by NQ01. In children having treatment for acute lymphoblastic leukemia, those with the NQ12 variant are more likely to relapse or die than those with normal NQ01.

Blomqvist, working with Heli Nevanlinna of the Helsinki University Central Hospital, and colleagues, began by genotyping more than 1,000 women with breast cancer. They then compared the women's survival, according to both their NQ01 genotype and the type of treatment they received.

They found that among those women who were homozygous for NQ12, and who were treated with anthracycline-based adjuvant chemotherapy with epirubicin, only 17 percent survived five years, compared with 75% of those with other NQ01 genotypes who were given the same sort of drugs.

In an attempt to validate those findings, the team genotyped a further group of more than 1,000 women with breast cancer. But in that group, only three women who were homozygous for NQ12 had been treated with anthracycline drugs for their tumors, so that part of the study lacked statistical power.

Because of that difficulty, Blomqvist said, it would be important to carry out further validation work to confirm the findings.

"If our results can be verified, this is a very important finding, because we currently don't have any good, strong markers for chemotherapy response in breast cancer nor for many other tumors," he said, adding that "there is no reason to think that this finding will be restricted to breast cancer only. Anthracyclines are also used for many other tumors."

The finding could mean that women diagnosed with breast cancer could be tested to determine their NQ01 genotype and then allocated to an appropriate treatment. "The aim would be both to spare women the unpleasant side effects of treatments that they will not benefit from, and to give them alternative cytotoxic agents that might be more effective than anthracyclines," Blomqvist said.

He and his colleagues suggest that it will be important to conduct a randomized clinical trial on women homozygous for NQ12 to compare the survival of those given anthracycline drugs with those given other cytotoxic drugs, to see whether the interaction between NQ01 and anthracycline treatment can be confirmed.