Biomarkers That Currently Affect Clinical Practice: EGFR, ALK, MET, KRAS

Abstract

New drugs such as pemetrexed, the epidermal growth factor receptor (egfr) tyrosine kinase inhibitors, and the Alk inhibitor crizotinib have recently enabled progress in the management of advanced non-smallcell lung cancer (nsclc). More drugs, especially Met inhibitors, will follow. However, the benefits of these agents are not uniform across the spectrum of nsclc, and optimizing their utility requires some degree of subgrouping of nsclc by the presence or absence of certain biomarkers.The biomarkers of current or imminent value are EGFR and KRAS mutational status, ALK rearrangements, and MET immunohistochemistry. As a predictor of benefit for anti-egfr monoclonal antibodies, EGFR immunohistochemistry is also of potential interest.Some of the foregoing biomarkers (EGFR, ALK, MET) are direct drivers of the malignant phenotype. As such, they are, quite rationally, the direct targets of inhibitory drugs. However, KRAS, while definitely a driver, has resisted attempts at direct pharmacologic manipulation, and its main value might lie in its role as part of an efficient testing algorithm, because KRAS mutations appear to exclude EGFR and ALK mutations. The indirect value of KRAS in determining sensitivity to other targeted agents or to pemetrexed remains controversial. The other biomarkers (EGFR, ALK, MET) may also have indirect value as predictors of sensitivity to chemotherapy in general, to pemetrexed specifically, and to radiotherapy and molecularly targeted agents.These biomarkers have all enabled the co-development of new drugs with companion diagnostics, and they illustrate the paradigm that will govern progress in oncology in the immediate future. However, in nsclc, the acquisition of sufficient biopsy material remains a stubborn obstacle to the evolution of novel targeted therapies.

Diagnostic Challenges in Non-Small-Cell Lung Cancer: An Integrated Medicine Approach

“…Low-level differential expression of ALK protein means that careful optimization of antibody clone and detection system is required [52]. A number of antibodies are now in development, and IHC may become a standard of care diagnostic (potentially with augmentation) [53,59]. There is also some clinical evidence to suggest that diagnosis based on FISH only may less accurately predict response to crizotinib than combined FISH/IHC/RT-PCR (ORR 81% for patients diagnosed based on combined tests vs 48% for patients diagnosed by FISH only; p=0.007) [60].…”

“…For example, although FISH is the FDA-approved clinical standard that detects all variants and is suitable for FFPE specimens [52,53], not all patients with NSCLC who may benefit from ALK inhibitor treatment are identified [54][55][56]. FISH has a number of disadvantages, being both more time-consuming and technically demanding than some other methods, with variability among observers, and scoring complications [52][53]57]. By contrast, IHC is a less time-consuming [58], relatively simple and widely available procedure [52].…”

Current Treatment Algorithms for Patients with Metastatic Non-Small Cell, Non-Squamous Lung Cancer

“…As mutation testing expands to include new targets including human epidermal growth factor receptor 2 ( HER2 ), BRAF, RET and MET and effective treatments are found, the treatment algorithms will increase in complexity (3). …”

Epigenetics and Biomarkers in Lung Cancer: Emerging Blood-Based Molecular Biomarkers for Detection and Monitoring

“…We believe that the co-development of new drugs with companion diagnostics will govern the progress in oncology in the immediate future. The role of companion biomarkers in guiding treatment in patients with cancer has been recently very nicely reviewed (Duffy and Crown 2013;Ong et al 2012;Vincent et al 2012) (Table 3).…”

“…EGFR mutations may also have indirect value as predictors of sensitivity to chemotherapy and to radiotherapy and molecularly targeted agents (Vincent et al 2012). Murtaza et al have recently identified in plasma an increased representation of a resistance-conferring mutation in EGFR following treatment with gefitinib in association with the emergence of therapy resistance.…”