Recent reports have indicated that EGFR gene copy number using FISH assay may be more sensitive and consistent than an IHC assay and such information successfully predicted responses in some studies. HER2) expression on anti-HER2 mAb, trastuzumab (Herceptin) therapeutic efficacy.3,4 Because its efficacy was dependent on HER2 expression, Herceptin was approved in 1998 for patients with tumors evaluated to overexpress HER2 or to have HER2 gene amplification as evidenced by the HercepTest immunohistochemistry (IHC) test or the PathVysion fluorescent in situ hybridization (FISH) assay respectively. Such patient selection has limited trastuzumab use to 20% of breast cancer patients with HER2 overexpressing tumors, the subpopulation most likely to benefit from the anti-HER2 treatment. Although trastuzumab was the first mAb therapy to be approved with a companion diagnostic assay, Lifitegrast patient selection based on antigen protein expression has previously been used to support rituximab (Rituxan, an anti-CD20 antibody), treatment in CD20-positive hematological malignancies, such as non-Hodgkin’s lymphoma (NHL). In contrast, it remains ambiguous whether EGFR protein expression levels are predictive of clinical responses to anti-EGFR mAb treatment.2 Potential reasons for this inconsistency may include biopsy sampling errors, poor IHC assay sensitivity, or faulty IHC reading and scoring methodology. Recent reports have indicated Rabbit Polyclonal to ACAD10 that EGFR gene copy number using FISH assay may be more sensitive and consistent than an IHC assay and such information successfully predicted responses in some studies. However, use of IHC and FISH assay results may still suffer from temporal differences in expression, depending upon the time the sample was obtained (at diagnosis) and when the therapy was applied (at relapse). In order to reduce sampling error and assay real-time expression levels, minimally-invasive or non-invasive techniques for measuring antigen expression and its heterogeneity within different lesions in the same patient would be highly desirable. Circulating tumor cells may provide such an information source for a near real-time survey of the tumor cell EGFR mutation status5 as well as EGFR gene copy numbers.6 High affinity, high selectivity antigen imaging reagents have also been designed to meet this objective, and utilize both monovalent and multivalent antigen binding strategies.7,8 These imaging reagents could be used to identify antigen-expressing subpopulations. Hypotheses linking specific subpopulations to molecular phenotypes and therapeutic response require validation in Lifitegrast Phase 1 and 2 studies, but real-time, non-invasive imaging could be used to drive selection of appropriate sub-populations of patients in pivotal Phase 3 studies. More recently, the efficacy of mAb therapies has also been found to be dependent on the mutational status of oncogenes that are part of the pathways engaged by target antigen proteins. Among anti-EGFR mAbs, clinical efficacy of panitumumab (Vectibix) and cetuximab (Erbitux) in metastatic colorectal cancer (mCRC) has been shown to Lifitegrast be critically dependent on the mutational status of the oncogene. Panitumumab monotherapy efficacy in mCRC is confined to patients with wild type (WT) tumors.9 Based on compelling clinical evidence, Vectibix was approved in the European Union (EU) for patients with refractory metastatic colorectal cancer with non-mutated (WT) genes. This marks the first mAb therapeutic approved with a companion genetic mutation diagnostic assay, TheraScreenK-RasCompanion Diagnostic Kit by DxS. The lack of efficacy of EGFR-targeting mAbs in patients with activating mutation is at least in part Lifitegrast due to the underlying EGFR signaling pathway. The target antigen protein, EGFR, activates three predominant pathways including the Ras/Raf/mitogen-activated kinase (MAPK), phosphatidylinositol-3-kinase (PI-3K)/Akt and signal transducer and activator of transcription (STAT) pathways. Activating mutations, downstream of EGFR, lock the Ras/Raf/MAPK pathway in a constitutively activated state and therefore render tumors with such mutations resistant to anti-EGFR mAbs. Indeed, such activating mutations are predictive for lack of responses to cetuximab, in both monotherapy and.