Genomic Profiling of Parathyroid Carcinoma Reveals Genomic Alterations Suggesting Benefit from Therapy

Abstract

Background Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life‐threatening hypercalcemia. We queried whether comprehensive genomic profiling (CGP) of PC might identify genomic alterations (GAs), which would suggest benefit from rationally matched therapeutics. Methods We performed hybrid‐capture‐based CGP to identify GAs and tumor mutational burden (TMB) in tumors from patients with this malignancy. Results There were 85 total GAs in 16 cases (5.3 GAs per case), and the median TMB was 1.7 mutations per megabase (m/Mb), with three cases having >20 m/Mb (18.7%). The genes most frequently harboring GA were CDC73 (38%), TP53 (38%), and MEN1 (31%). All MEN1‐mutated cases also had loss of heterozygosity at that locus, but in contrast all CDC73‐mutated cases retained heterozygosity. GAs suggesting potential benefit from matched targeted therapy were identified in 11 patients (69%) and most frequently found in PTEN (25%), NF1 (12.5%), KDR (12.5%), PIK3CA (12.5%), and TSC2 (12.5%). A patient whose tumor harbored KDR T668 K and who was treated with cabozantinib experienced a > 50% drop in parathyroid hormone level and radiographic partial response of 5.4 months with duration limited by toxicity. Conclusion CGP identified GAs in PC that suggest benefit from targeted therapy, as supported by an index case of response to a matched tyrosine kinase inhibitor. Moreover, the unexpectedly high frequency of high TMB (>20 m/Mb) suggests a subset of PC may benefit from immune checkpoint inhibitors. Implications for Practice Parathyroid carcinoma (PC) is a rare endocrine malignancy that can cause life‐threatening hypercalcemia. However, its molecular characteristics remain unclear, with few systemic therapeutic options available for this tumor. Hybrid‐capture‐based comprehensive genomic profiling of 16 primary cancers demonstrated presence of potentially actionable genomic alterations, including PTEN, NF1, KDR, PIK3CA, and TSC2, and a subset of hypermutated cancers with more than 20 mutations per megabase, the latter of which could benefit from immune checkpoint inhibitor therapy. A case benefiting from rationally matched targeted therapy for activating KDR mutation is also presented. These findings should be further investigated for their therapeutic potential.

PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis

“…Targeted next generation sequencing revealed a mutation rate of 7.5% in OSCCs [92]. Novel mutations in PIK3CA were recently reported as candidate driver events in human papillomavirus (HPV)-positive OSCCs [93].…”

The genomic profile of parathyroid carcinoma based on whole‐genome sequencing

“…Recently, PC was linked to immune‐naïve and immune‐tolerant microenvironments, as fewer tumour‐infiltrating lymphocytes (CD3 + and CD8 + ) were found in PC tissue than in atypical adenoma tissue, and increased numbers of tumour‐infiltrating macrophages (CD68 + ) were correlated with the relapse of PC 40 . Although the distribution of immunocytes was not assessed in our present PC cohort, the WGS data provide new evidence supporting the potential involvement of immunoregulation, especially for the wild‐type CDC73 subtype 41 …”

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: New and future perspectives for parathyroid carcinoma

“…Going forward, case selection criteria should be defined in detail, and best practices in next generation sequencing (NGS) methodology and interpretation should be followed. Recent studies have suggested that in addition to CDC73, MAPK signaling of the AKT/mTOR/PI3K pathways may be oncogenic pathways (Kasaian et al 2013, Pandya et al 2017, Cui et al 2019, Kang et al 2019. Mutations involving PI3K or TP53 pathways have been reported in about 10-30% of PC in several genomic profiling studies in PC (Yu et al 2015, Pandya et al 2017.…”

“…Recurrent genetic alterations in other genes such as AKAP9, ZEB1, KDM5C, ADCK1, and PRUNE2 have been reported. Mutations in NF1, SDHA, FAT3, TNRC6A, PTEN, KDR, TERT promoter, DICER1, TSC1 and TSC2 have also been found (Yu et al 2015, Pandya et al 2017, Kang et al 2019, as has amplification and overexpression of the cyclin D1 gene CCND1 (Vasef et al 1999, Zhao et al 2014, Pandya et al 2017 are common in parathyroid carcinoma. A number of these genes, but not all, can potentially be targeted by newer or emerging therapeutic agents.…”