We appreciate the comments from Dr. Botton and colleagues regarding our article entitled “BRAF Fusions Define a Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition” (1). In response to their letter, we make the following points:
We reviewed the histopathology of the 2 BRAF-fusion containing melanomas reported in our study and both specimens did display Spitzoid morphology. Since publication, FoundationOne™ genotyping has identified four additional tumors with concurrent BRAF fusions and Spitzoid morphology. For comparison, 10 non-fusion specimens also genotyped by FoundationOne™ and considered “pan-negative” for common drivers in BRAF, NRAS, KIT, GNAQ and GNA11 did not display Spitzoid morphology. Thus, Spitzoid morphology does appear to be associated in this limited dataset with BRAF fusions.
Thus far, our data do not support that Spitzoid-like, fusion-containing melanomas occur in younger patients (2); however, our cohort is relatively small. Of the 6 BRAF-fusion melanomas we report above, only two patients were under the age of 40. In increasing order, ages were 24, 27 (PAPSS1-BRAF), 45, 54, 59 (TRIM24-BRAF), and 60.
We previously stated that tumors harboring BRAF fusions would be susceptible to “MEK, but not BRAF, inhibition”. We should clarify that we meant lack of sensitivity to BRAF V600-mutant specific inhibitors such as vemurafenib and dabrafenib. Two other studies have cited modest RAF-inhibitor responses in cells harboring BRAF fusions (3, 4) and corroborate our findings that MEK inhibition is more effective (3). Moreover, the patient with an undifferentiated spindle cell neoplasm harboring a KIAA1549-BRAF fusion that responded to therapy received sorafenib, temsirolimus, and bevazicumab, making it difficult to know exactly to which drug the tumor was sensitive (5). We are planning a Phase I/II clinical trial to test prospectively the efficacy of MEK inhibition in melanomas harboring BRAF fusions.
We again thank Botton and colleagues for highlighting the association of BRAF fusions with Spitzoid morphology in metastatic melanomas. This information should inform clinical decision-making in the treatment of patients with melanoma.
Acknowledgments
Financial Support: Financial support was provided by the James C. Bradford Family Foundation (VICC investigators), the Mary Hendrickson-Johnson American Cancer Society Melanoma Professorship (J.A. Sosman), the National Institutes of Health/National Cancer Institute 5K24 CA097588-09 (J.A. Sosman), a Stand Up To Cancer Innovative Research Grant, Grant Number SU2C-AACR-IRG0109 (W. Pao) (Stand Up To Cancer is a Program of the Entertainment Industry Foundation administered by the American Association for Cancer Research) and the Joanna M. Nicolay Melanoma Foundation 2013 Research Scholar Award (K.E. Hutchinson).
Conflicts of Interest: J.A. Sosman has participated on advisory boards for GlaxoSmithKline. All Foundation Medicine, Inc. (FMI) authors are employees and stockholders in FMI.
References
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