DNA-Repair Genes Predict Survival in Early Lung Cancer

TAMPA, Fla., Feb. 22 -- Tumor expression of two DNA-repair genes, RRM1 and ERCC1, signified a survival advantage for patients with early-stage non-small-cell lung cancer given only surgical treatment, researchers reported.

Disease-free and overall survival at 10 years was significant only for patients who had stage I tumors with high expression of both RRM1 and the ERCC1 protein, according to a report in the Feb. 22 issue of the New England Journal of Medicine.

Although patients with high expressions of these proteins did well with surgery alone, these same markers predicted resistance to gemcitabine (Gemzar) and platinum drugs in patients with advanced non-small-cell lung cancer, representing a two-edged sword.

RRM1, the regulatory subunit of ribonucleotide reductase, is involved in carcinogenesis, tumor progression, and the response of non-small-cell lung cancer to treatment, said Gerold Bepler, M.D., Ph.D., of the Moffitt Cancer Center of the University of South Florida here, and colleagues.

Using an automated quantitative determination of the RRM1 protein in routinely processed histologic specimens, the researchers measured the expression of RRM1 and two other proteins relevant to non-small-cell lung cancer: the excision repair cross-complementation group 1 (ERCC1) protein and the phosphatase and tensin homologue (PTEN), an inhibitor of cell proliferation.

The investigators compared the genetic results with the clinical outcomes in 187 patients with Stage I non-small-cell lung cancer who had not received chemotherapy or radiation therapy before resection. The patients were a subgroup of all patients who had a resection of a primary Stage I lung cancer at the investigators' institution between 1991 and 2001. The biomarker data were integrated into clinical decision-making.

RRM1 expression correlated with the expression of ERCC1 (P<0.001) but not with the expression of PTEN (P = 0.37), they reported.

The median disease-free survival exceeded 120 months in the group of patients with tumors that had high expression of RRM1 (gene expression score of 40.5 or greater) and was 54.5 months in the group with low expression of RRM1 (hazard ratio for disease progression or death in the high-expression group, 0.46; P = 0.004).

This statistically significant difference had a hazard ratio of low versus high expression of 2.2, the researchers said.

The median overall survival was more than 120 months for patients with tumors with high expression of RRM1 and 60.2 months for those with low expression of RRM1 (hazard ratio for death, 0.61; P = 0.02).

Significantly, when the patients were divided into four groups, according to high and low expression of the individual proteins, the researchers found that 55 patients (30%) with high expression of both RRM1 and ERCC1 had undergone potentially curative lung-cancer surgery at 10 years.

Although high expression of either protein alone was associated with a good prognosis, coexpression of the two proteins characterized the group with an excellent outcome, they said.

In a multivariate analysis that included RRM1 expression, tumor state, ECOG performance status, sex, and smoking, RRM1 was the only variable associated with disease-free survival but not with overall survival.

The apparent lack of an association between RRM1 and PTEN contrasts with the previously reported positive correlation between these genes at the RNA level. The discrepancy may be due to differential, post-translational processing for the two genes, or to technical issues, the researchers said.

Noting the previous technical difficulties of assessing RRM1 expression, the researchers said that the development of an immunohistochemical technique and the integration of a fully automated and quantitative system have made gene expression for RRM1 and ERCC1 "objective, reliable, and reproducible."

This technical development is important, the researchers said, in the context of recent data showing that high expression of RRM1 and ERCC1 predict resistance of non-small-cell lung cancer to gemcitabine and platinum drugs.

"Given that high levels of expression of both genes are associated with long survival among patients with completely resected lung cancer and are also associated with a poor response to chemotherapy containing gemcitabine and platinum, a trial comparing the current standard of care with adjuvant treatment selected on the basis of RRM1 and ERCC1 expression appears to be warranted," Dr. Bepler's team concluded.

In an accompanying research perspective, Adi Gazdar, M.D., of the University of Texas in Dallas, described the role of these markers in predicting survival but also resistance to chemotherapy, as the "two faces of Janus."

The article by Dr. Zheng and colleagues suggests that these two crucial but very different needs may be filled by a single pair of markers, Dr. Gazdar said. How can the overexpression of the same two proteins, he asked, be both a marker for improved survival in untreated early non-small-cell lung cancer and a marker for chemoresistance and poor survival in patients with advanced cancers?

Answering his question, Dr. Gazdar wrote that overexpression of RRM1 has been linked to the tumor's resistance to platinum drugs and to gemcitabine. Removal by the nucleotide excision pathway of drug-DNA adducts formed after chemotherapy may lead to drug resistance, and the role of ERCC1 as a marker for drug resistance has already been reported.

By preventing mutagenesis, DNA repair may not only prevent cancer but may retard molecular events related to progression in established tumors. Thus, high expression of these two markers may indicate a favorable outcome in these untreated patients by identifying tumors that have progressed relatively little at the molecular level.

Knowledge of these two gene markers could affect two major aspects of the management of non-small-cell lung cancer: the selection of patients with resected early-stage tumors who do not require adjuvant therapy and the selection of patients who are not likely to benefit from conventional chemotherapy for advanced cancer. The latter group may be candidates for therapies that inhibit epidermal growth-factor-receptor signaling or angiogenesis, and other new forms of treatment.

Because it has a role in both cancer susceptibility and drug resistance, DNA repair has been called a double-edged sword. However, overactive nucleotide excision repair and DNA replication systems may yield clinically relevant clues regarding both a favorable prognosis and drug resistance, Dr. Gazdar concluded.

Dr. Bepler reported having a patent application pending on the use of RRM1 with or without ERCC1 as a prognostic marker of outcome in cancer and for the prediction of response to therapy. No other potential conflict of interest relevant to this article was reported.