Molecular Prediction of Response and Survival in NSCLC

Neha Vapiwala, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 14, 2003

Presenter: Gerold Bepler, MD PhD
Affiliation: H. Lee Moffitt Cancer Center

Pharmacogenomic research offers the potential for improving upon the results of conventional treatments in managing lung cancer. Currently, the choice of treatment strategy is typically based on site, histopathology, stage, performance status, convenience, and personal preference. With the incorporation of emerging data from pharmacogenetic studies, questions will emerge regarding which patients are most likely to benefit, with minimal treatment-related morbidity.

A particularly promising area of study involves the human RRM1 gene, located on chromosome 11 in a region of frequent allele loss (11p15.5). RRM1 is one of two components of ribonucleotide reductase, and is involved in regulating conversion of nucleotides from RNA to DNA (deoxygenating the ribonucleic acid chains). Migration and invasion assays performed in lung cancer cell lines have shown that increased RRM1 expression impairs a tumor cell's ability to invade and metastasize. Furthermore, syngeneic animal survival studies using mice transfected with human RRM1 have found that overexpression of RRM1 not only prevents tumor migration, but more importantly translates into a significant survival benefit.

To apply these laboratory findings to the clinic, studies involving patient subgroup have been designed. First, surgical specimens from a validation cohort of 77 patients with resected stage IA - IV lung cancer were analyzed; expression of RRM1 above the median level correlated with improved disease-free survival (p=0.002) as well as overall survival (p=0.011), compared to those patients expressing RRM1 below the median.

As RRM1 plays a role in DNA synthesis and repair, and is in fact the target of gemcitabine chemotherapy, the question arose as to the effect of RRM1 expression on response to chemotherapy. Thus, a smaller exploratory cohort of 18 patients with stage IV cancer previously treated with gemcitabine chemotherapy was also analyzed, and the results demonstrated that LOWER expression of RRM1 actually resulted in better survival than higher expression. This is presumably because less RRM1 activity enhances the effect of gemcitabine and thus these patients benefit more from their chemotherapy.

Based on the suggestive results described above, researchers of RRM1 and other potential pharmacogenetic markers would encourage future trials in lung cancer to start stratifying for RRM1 expression, along with the more traditional parameters like stage and performance status.