Lung cancer updates on genetic profiling for chemotherapy selection

There were interesting presentations highlighting our evolving understanding of the some of the molecular mechanisms of non-small cell lung cancer chemoresistence this weekend at the 2008 ASCO Annual Meeting. Those markers which have had the most investigation thus far include RRM1, ERCC1, BRCA1, and TS. Of these RRM1 and ERCC1 were explored in detail during the presentations. Ribonucleotide reductase is necessary for DNA synthesis and repair and RRM1 gene expression changes dramatically in mouse lung and colon cancer cell lines in response to gemcitabine, presaging resistance. These findings have held up in pancreas cancer cell lines and reducing RRM1 re-sensitizes these cells to gemcitabine chemotherapy. Thus, a low RRM1 expression pattern predicts response to gemcitabine.

Similarly, ERCC1 predicts response to carboplatin/gemcitabine. In a tumor sample from the large IALT trial, called IALT-BIO, the tissue bank analysis confirmed that low tumor ERCC1 expression predicted in vivo response (HR= 0.67; P<.006) while high expression was associated with no response (HR=1.18;P=.29).

So here was convincing additional information that there are emerging markers which may predict chemosensitivity, in particular RRM1 and ERCC1. Neither of these markers is available for clinical use. In fact, they are difficult to perform, requiring fresh frozen tissue for RT-PCR processing.

I am excited to see continued growth in this area for lung cancer where there is a clear need to find mechanisms to predict response in patient populations to minimize those patients who are exposed to toxicity without chance for benefit.

Although not mentioned in the presentation, readers should be aware that EGFR mutation analysis can be performed, but is not ready for mainstream clinical use at this time.

Similarly, KRAS mutations predict resistance to EGFR TKI therapy. Although KRAS mutation analysis may also be performed it is not yet ready for routine clinical use.