Study Highlights Need To Look For Changes in Multiple Genes From Cancers

Samuel Klempner, M.D. Assistant Professor Division of Hematology/Oncology UC Irvine Health Orange, CA 92868

Dr. Klempner Interview with:
Samuel Klempner, M.D. Assistant Professor
Division of Hematology/Oncology
UC Irvine Health
Orange, CA 92868 

Medical Research: What is the background for this study? What are the main findings?

Dr. Klempner: The background for our series is the concept that little is known about the genetic landscape of rare tumors such as acinic cell tumors, and that understanding genetic changes in tumors can identify treatment options.  This paradigm can, and should, be extended beyond rare tumor types and many researchers are currently studying various tumor types.  Another important background idea is that tumor genomic alterations may be more important than that anatomic site of origin. For example, I would argue that a breast cancer that harbors an EGFR mutation common to lung cancer could be treated similar to a lung cancer based on the genomic changes.

In our study we found another way that the BRAF protein and its downstream signaling may become activated through duplicating part of the protein called the kinase domain.  This genetic event causes the pathway to be always “on” which is not normal, and likely drives cancer growth.  However, BRAF kinase domain duplication appears sensitive to currently available drugs that target the BRAF pathway, as evidenced by the response in our patient.  Thus, finding this change is important and may be able to guide a more personalized therapy choice.  Importantly, we found BRAF kinase domain duplication across multiple different tumor types, suggesting this may be a recurrent event in some cancers.  A very similar finding, involving duplication of the EGFR kinase domain, was also just reported (Cancer Discovery 2015;5:1155-1163) lending further validation to this mechanism of pathway activation in cancer.

Medical Research: What should clinicians and patients take away from your report?

Dr. Klempner: One of the key take home points is the need to look for changes in multiple genes from cancers.  The idea that if you don’t look you won’t find it is increasingly important in cancer.  Technologies looking at only single genes or parts of genes called hot-spots would not have identified duplication in the BRAF kinase domain, and the patient would never have been considered for the targeted therapy she received.  There are several methods to look at comprehensive genomic profiling and my opinion is that this type of testing should be considered for nearly all cancer patients.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Klempner: Our study provides strong support for the importance of BRAF kinase domain duplication as a new target for cancer therapies, but more scientific work is needed to investigate the fine details of how this happens and exactly which pathways in the cell get turned on.  Testing BRAF kinase domain duplications in cancer cells in the lab may help us further optimize the best therapeutic approach (which drugs work best) to further improve patient outcomes.  Further research is also needed to investigate how cells may become resistant to targeting BRAF kinase domain duplication.


Klempner SJ, Bordoni R, Gowen K, et al. Identification of BRAF Kinase Domain Duplications Across Multiple Tumor Types and Response to RAF Inhibitor Therapy.JAMA Oncol. Published online November 12, 2015. doi:10.1001/jamaoncol.2015.4437.

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Samuel Klempner, M.D. (2015). Study Highlights Need To Look For Changes in Multiple Genes From Cancers