Molecular pathology and diagnostics of non-small cell lung carcinoma

Abstract

Of all the molecular alterations that may have predictive value in non-small cell lung cancer (NSCLC), testing for EGFR mutations is usually the first step in determining course of adjuvant therapy. Activation of EGFR mutations, and perhaps amplification, predicts the response of NSCLC to tyrosine kinase inhibitors (TKIs). The presence of activating KRAS mutations predicts resistance to TKI therapy, but the value of this test is questionable in NSCLC given that the coexistence of both EGFR and KRAS mutations in the same patient is extremely rare and the presence of a KRAS mutation may not have much different significance than the absence of an EGFR mutation. In patients who are considered for gemcitabine therapy, measurement of ribonucleotide reductase subunit 1 (RRM1) expression levels may help predict which patients are less likely to respond, as higher levels of RRM1 have been shown to overcome the anti-metabolite of this drug. Similarly, in patients being considered for platinum-based therapy, determination of excision-repair cross complementing-1 protein (ERCC1) expression level may help predict which patients are less likely to respond, given that ERCC1 repairs platinum-induced DNA damage. The use of these predictive factors ideally will help target therapy to individual tumors to achieve the best chance for long-term survival and to avoid side effects from medications that are unlikely to have any effect. Further studies will continue to refine testing and treatment algorithms.