A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance

Abstract

In April 2013 our group published a review on predictive molecular pathology in this journal. Although only 2 years have passed many new facts and stimulating developments have happened in diagnostic molecular pathology rendering it worthwhile to present an up-date on this topic. A major technical improvement is certainly given by the introduction of next-generation sequencing (NGS; amplicon, whole exome, whole genome) and its application to formalin-fixed paraffin-embedded (FFPE) tissue in routine diagnostics. Based on this 'revolution' the analyses of numerous genetic alterations in parallel has become a routine approach opening the chance to characterize patients' malignant tumors much more deeply without increasing turn-around time and costs. In the near future this will open new strategies to apply 'off-label' targeted therapies, e.g. for rare tumors, otherwise resistant tumors etc. The clinically relevant genetic aberrations described in this review include mutation analyses of RAS (KRAS and NRAS), BRAF and PI3K in colorectal cancer, KIT or PDGFR alpha as well as BRAF, NRAS and KIT in malignant melanoma. Moreover, we present several recent advances in the molecular characterization of malignant lymphoma. Beside the well-known mutations in NSCLC (EGFR, ALK) a number of chromosomal aberrations (KRAS, ROS1, MET) have become relevant. Only very recently has the clinical need for analysis of BRCA1/2 come up and proven as a true challenge for routine diagnostics because of the genes' special structure and hot-spot-free mutational distribution. The genetic alterations are discussed in connection with their increasingly important role in companion diagnostics to apply targeted drugs as efficient as possible. As another aspect of the increasing number of druggable mutations, we discuss the challenges personalized therapies pose for the design of clinical studies to prove optimal efficacy particularly with respect to combination therapies of multiple targeted drugs and conventional chemotherapy. Such combinations would lead to an extremely high complexity that would hardly be manageable by applying conventional study designs for approval, e.g. by the FDA or EMA. Up-coming challenges such as the application of methylation assays and proteomic analyses on FFPE tissue will also be discussed briefly to open the door towards the ultimate goal of reading a patients' tissue as 'deeply' as possible. Although it is yet to be shown, which levels of biological information are most informative for predictive pathology, an integrated molecular characterization of tumors will likely offer the most comprehensive view for individualized therapy approaches. To optimize cancer treatment we need to understand tumor biology in much more detail on morphological, genetic, proteomic as well as epigenetic grounds. Finally, the complex challenges on the level of drug design, molecular diagnostics, and clinical trials make necessary a close collaboration among academic institutions, regulatory authorities and pharmaceutical companies.

Validation of a Multiplexed Gene Signature Assay for Diagnosis of Canine Cancers from Formalin‐Fixed Paraffin‐Embedded Tissues

“…Combining molecular information with histopathology and clinical staging, individual treatment strategies can be designed for maximum effectiveness 5, 14. Indeed, gene expression studies are accepted in human oncology as a validated method to discover biomarkers of disease and determine treatment options for example in lymphoma,15 breast,16 bladder cancers,17 sarcomas,18 and other tumor types 19. With the sequencing of the canine genome, similar biomarker strategies can be developed for veterinary diagnostics.…”

Precision Oncology: The Promise of Big Data and the Legacy of Small Data

“…In cancer experiments, the malignant phenotypes represent a variety of possible detections obtainable in multiple ways. Hundreds of genes are currently targeted, but only a few are actionable, i.e., effectively and/or successfully "drugged" according to approved drugs (Alyass et al, 2015;Dietel et al, 2015). Then, different marker types will become central to future analyses, from prognostic markers (focused on disease outcomes) to predictive markers (focused on identifying patient sub-groups responsive to specific treatments).…”

Role of Pathologist in Driver of Treatment of CNS Tumors

“…Zhao et al [40] published their observations in 2009 and showed that the mutations (IDH1 R132 or IDH2 R172) reduce the affinity of the enzyme toward the substrate and, moreover, inactive heterodimers which dominantly block the WT-IDH1 activity. The rapid understanding of the molecular pathways of the pathogenesis of brain tumors especially in glial tumors led to the detection of reliable diagnostic, prognostic and predictive molecular markers and new molecular signatures [41]. Three molecular markers, namely 1p19q co-deletion, MGMT promoter methylation mutation and mutation in IDH1/2 genes, stand out in the management of disease course and surgical neuropathology routine at the basis of various clinical trials.…”