Comprehensive genomic profiling of parathyroid carcinoma.

Abstract

6088 Background: Parathyroid carcinoma (PC) is a rare endocrine malignancy, which can cause life-threatening hypercalcemia. Initial surgery is often noncurative, and adjunctive radiotherapy and previous chemotherapies have not been shown to be effective. Previous studies identified recurring mutations in CDC73 and PRUNE2in a limited number of patients. We queried whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 13 consecutive cases of relapsed/metastatic PC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 672x for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Total of 13 specimens were identified from 7 male and 6 female patients. The mean age of the patients in this study was 54 years (range 38 to 76 years). All (100%) cases were Stage IV at the time of CGP. Tumor mutation burden was generally low - median mutation load per mega base was 1.8. There were 58 total GA (4.5 GA/sample) and 10 CRGA (0.8 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (31%) and CDC73 (31%). MEN1 mutations were identified in 23% of cases. Frequent alterations in genes controlling cell cycle progression at G1 including CDKN1B, CDKN2A, CDKN2B and CDKN2C were identified (30%). The most frequent CRGA involved PTEN (23%), NF1 (23%) and KDR (15%). No alterations in BRAF or RETwere identified. A patient with KDR mutation treated with cabozantinib experienced > 50% drop in PTH level and radiographic partial response in 3 months. Conclusions: CGP identified previously unreported TP53 mutations in PCs and potentially actionable genomic alterations including PTEN, NF1 and KDR. Clinical benefit and response observed in a patient treated with VEGFR targeted therapy suggest that patients with this rare tumor may be candidates for targeted therapies.