Light Shed on Lung Cancer Drug-Resistance Mechanisms

PARIS, Sept. 6 -- Testing non-small-cell lung tumors for the presence of an enzyme that aids in DNA repair can predict whether patients will benefit from platinum-based chemotherapy, European researchers reported.

Patients whose tumors lacked the enzyme, called excision repair cross-complementation group 1 (ERCC1), lived significantly longer if they underwent adjuvant chemotherapy with a Platinol (cisplatin)-based regimen.

But patients whose tumors were positive for the enzyme did better without chemotherapy, wrote Ken A. Olaussen, Ph.D., of the University of Paris, and colleagues in the International Adjuvant Lung Cancer Trial Collaborative Group, in the Sept. 7 issue of the New England Journal of Medicine.

"Our results suggest that determination of ERCC1 expression in non-small-cell lung cancer cells before chemotherapy can make a contribution as an independent predictor of the effect of adjuvant chemotherapy," the investigators wrote.

In a separate study reported in the early online edition of the Journal of Clinical Investigation, researchers at Boston's Massachusetts General Hospital and Dana-Farber Cancer Institute, and other centers, reported that they have identified a different mechanism that appears to confer on non-small-cell lung tumors resistance to Iressa (gefitinib) and Tarceva (erlotinib).

Dr. Olaussen and colleagues noted that even when tumors are completely resected, one-third of patients with stage IA non-small-cell lung cancer, and three-fourths of those with stage IIIA disease, die within five years.

They had previously shown that adjuvant chemotherapy with a Platinol-based regimen produced an absolute five-year overall survival benefit of 4.1% compared with observation alone.

"However, adjuvant chemotherapy has only a modest effect in prolonging survival, with an absolute improvement in five-year overall survival ranging from 4 to 15%, whereas such treatment is associated with serious adverse effects," they wrote

To get a handle on the factors that could predict which patients could benefit from platinum-based chemotherapy, they focused on DNA repair mechanisms that may confer resistance to Platinol.

The object of their attention, ERCC1, appears to circumvent the action of Platinol, which destroys malignant cells, by binding to DNA and creating platinum-DNA adducts that in turn form cross-links between DNA strands to inhibit replication.

ECCR1 has been linked to platinum resistance in cell lines for ovarian, cervical, testicular, bladder, and for non-small-cell lung cancers.

"These data led us to hypothesize that expression of ERCC1 by the tumor could predict a survival benefit from cisplatin-based adjuvant chemotherapy in non-small-cell lung cancer," the investigators wrote.

The authors examined 761 non-small-cell tumors specimens obtained during excisional surgery from patients enrolled in the International Adjuvant Lung Cancer Trial. They used immunohistochemistry to detect the presence of the ERCC1 protein, and compared the results against the clinical outcomes of the patients.

They found that ERCC1 expression was positive in 44% of the tumors, and negative in the remaining 56%. They also saw that patients with ERCC1-negative tumors had a significant benefit from Platinol-based adjuvant chemotherapy (test for interaction, P=0.009).

Among patients with ERCC1-negative tumors on chemotherapy (compared with observation) the adjusted hazard ratio for death was 0.65 (95% confidence interval, 0.50 to 0.86, P=0.002).

But among patients with ERCC1-positive tumors the adjusted hazard ratio for death was only 1.14 (95% CI, 0.84 to 1.55, P=0.40). In fact, among patients who did not receive adjuvant chemotherapy, those with ERCC1-positive tumors survived longer than those with ERCC1-negative tumors (adjusted hazard ratio for death, 0.66, 95% CI, 0.49 to 0.90, P=0.009).

"ERCC1 is the limiting factor in nucleotide excision repair, which removes platinum-DNA adducts," the authors wrote. "ERCC1 may also be involved in the repair of DNA double-strand breaks, especially those induced by interstrand cross-links. For this reason, the mechanism by which ERCC1 contributes to cisplatin resistance probably involves more than nucleotide excision repair. It is possible that the presence of ERCC1 reflects an inherent biologic characteristic of the tumor."

They added that the effect of ERCC1, if any, on other chemotherapy regimens for non-small-cell lung cancer is not known.

Elsewhere, Jeffrey Engelman, M.D., Ph.D,, and colleagues of Massachusetts General Hospital and Dana-Farber Cancer Institute in Boston, and other institutions, reported that often overlooked mutations in the gene encoding for epidermal growth factor receptor (EGFR) appear to be a mechanism whereby non-small-cell lung tumors can develop resistance to the EGFR inhibitors Iressa and Tarceva.

Using an Iressa-resistant cell line they created by exposing cancer cells to the drug in vitro for prolonged periods, they found that acquired mutation in T790M, which has previously been implicated in resistance to EGFR inhibitors, went undetected by direct gene sequencing, and could only be identified by a highly sensitive high performance liquid chromatography technique.

The mutation appears to prevent drug-induced inhibition of the P13K signal transduction pathway, which is believed to be involved in the malignant transformation of cells.

"These findings suggest that allelic dilution of biologically significant resistance mutations may go undetected by direct sequencing in cancers with amplified oncogenes and that restoration of PI3K activation via either a T790M mutation or other mechanisms can provide resistance to gefitinib," the authors wrote.