[ Title ]
- A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance
[ Journal ]
- CANCER GENE THERAPY
[ Author ]
- Dietel, M Johrens, K Laffert, MV Hummel, M Blaker, H Pfitzner, BM Lehmann, A Denkert, C Darb-Esfahani, S Lenze, D Heppner, FL Koch, A Sers, C Klauschen, F Anagnostopoulos, I
[ 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.
[ URL ]
- http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;UT=WOS:000361928100001