Background: The aim of this study was to determine the frequency of alterations in BRAF and other RAS/RAF genes, as well as other targetable pathways in malignant peripheral nerve sheath tumors (MPNSTs). Patients and Methods: Pathology specimens were available for 2 cohorts: (1) patients with MPNST at Swedish Cancer Institute (n=17) from 2004 through 2016, and (2) patients with MPNST evaluated for >300 genomic alterations at Foundation Medicine from 2014 through 2016 (n=186; including 2 Swedish patients with BRAF-mutated MPNST). Results: Of 201 MPNSTs, 13 (6.5%) demonstrated BRAF alterations. In the Foundation Medicine cohort, 10 of 84 tumors (11.9%) with no NF1 alterations had BRAF mutations (5 were V600E, 5 other), as did 3 of 102 (2.9%) tumors with NF1 alterations (1 V600E, 2 other). In the Foundation Medicine cohort, 47% of patients had an alteration in at least one other gene in the RAS/RAF pathway (not including NF1 or BRAF); 46% had alterations in the PI3 pathway, with 70% having alterations in at least 1 of the 2 pathways; 57% had a CDKN2A alteration (80% in BRAF-mutated and 71% in NF1-altered patients); and 70% had an alteration in DNA repair genes. MPNST, both NF1 wild-type and NF1-mutated, often harbor alterations in the RAS/RAF pathway as well as changes related to DNA repair and CDKN2A/B. V600E and other mutations occur in BRAF, suggesting the need for second-generation activating BRAF inhibitors. The concurrence of BRAF and/or NF1 alterations with CDKN2A/B mutations, in particular, may be significant in the transformation of neurologic tumors from benign to malignant. Conclusions: All MPNSTs would benefit from a comprehensive genomic analysis. Treatments targeted to RAS/RAF, DNA repair, and CDKN2A/B pathways should be used and/or developed to treat this uncommon tumor.
Henry G. Kaplan, Steven Rostad, Jeffrey S. Ross, Siraj M. Ali and Sherri Z. Millis
James Saller, Christine M. Walko, Sherri Z. Millis, Evita Henderson-Jackson, Rikesh Makanji and Andrew S. Brohl
Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti–PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample. Molecular profiling data from 8 additional male patients with KS were reviewed and compared with those of the index case. The genomic profile of the index case was notable for higher-than-typical somatic mutational burden, including pathogenic mutation in multiple well-described cancer genes, such as TP53, CDKN2A, NOTCH1, and KRAS. Our case suggests that further clinical study of checkpoint inhibitor therapy in classic KS is warranted, and provides a hypothesis for future immunogenomic biomarker analysis in this disease.