Two Genes Predict Survival in Early Lung Cancer

Among patients with early-stage non–small-cell lung cancer (NSCLC) undergoing potentially curative surgery, the coexpression of 2 gene proteins identifies a subgroup with an excellent prognosis.

Investigators from the Lee Moffitt Cancer Center (Tampa, FL, USA) reported in the February 22, 2007, issue of the New England Journal of Medicine that the two genes, both involved in DNA synthesis and repair, are the regulatory subunit of ribonucleotide reductase (RRM1) and the excision repair cross-complementation group 1 (ERCC1). About 30% of the patients investigated (55 of 184) had high levels of both gene markers, and clinical records showed that they had excellent outcomes.

Patients who have high expression of these two gene proteins do not need to receive adjuvant chemotherapy, as almost all of these patients are truly cured by surgery, said senior author Gerold Bepler, M.D., Ph.D.

Adjuvant chemotherapy is given to most patients with completely resected lung cancer, usually immediately after surgery, Dr. Bepler explained. The aim is to prevent disease recurrence, which occurs in about half the patients. However, this treatment has resulted in an approximately 10% improvement in patients' survival, meaning that many patients get chemotherapy after surgery without getting a benefit, and some will even be harmed by this.

For their study, Dr. Bepler and colleagues developed a process for automative quantitative determination of the RRM1 protein in routinely processed histologic specimens. They also measured expression of ERCC1 and another protein, the phosphatase and tensin homolog (PTEN), but found that this third marker was not correlated with survival.

The researchers commented that analysis of RRM1 has been technically difficult in the past, but the system they developed allows gene-expression analysis of both RRM1 and ERCC1 that is objective, reliable, and reproducible.

The same 2 gene markers have previously been shown to predict which patients with advanced NSCLC have a poor response to chemotherapy with gemcitabine and platinum compounds.

RRM1 and ERCC1 are important in controlling the 'integrity' of the DNA during cell doubling, Dr. Bepler explained. We already know that chemo does not work well in patients with high expression of both genes, because chemo works by causing DNA damage, which is fixed by these genes. Hence, patients with low levels of these genes have a more aggressive cancer and benefit most from chemotherapy, he said.


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Lee Moffitt Cancer Center