A prolonged response to platinum‐based therapy in a patient with metastatic urothelial carcinoma harboring a single rearranged and truncated NF2 gene

Abstract

Tumor genome sequencing has become an invaluable resource in determining targets for new therapies. In this report, we describe the case of a patient with metastatic urothelial carcinoma with sarcomatoid features. Sarcomatoid differentiation is a rare histologic subtype that confers a more aggressive course. The first-line treatment for patients with urothelial carcinoma is platinum-based chemotherapy. Next generation tumor sequencing performed using the FoundationOne assay revealed loss of one NF2 allele and an unbalanced der(22)t(10;22)(p11.22;q12.2) chromosomal rearrangement involving the other NF2 allele, resulting in truncation and predicted loss of function. Fluorescence in situ hybridization (FISH) analysis confirmed the presence of one NF2 signal. NF2 mutations have been found in a variety of cancers and result in activation of the mTOR pathway. As such, the use of mTOR inhibitors, such as everolimus are thought to be particularly effective in the case of NF2 loss. Our patient had a dramatic response to first-line chemotherapy, but unfortunately experienced subsequent progression of his cancer and could not tolerate everolimus. Although our patient's tumor demonstrated unique acquired genetic features including both loss of heterozygosity and truncation of the NF2 locus, he still achieved a meaningful response to platinum-based chemotherapy.

JAK2, PD-L1, and PD-L2 (9p24.1) amplification in metastatic mucosal and cutaneous melanomas with durable response to immunotherapy

“…The expression of ligands such as PD-L1, PD-L2 and CD80 (also known as B7.1/ CD28LG) on the tumor cell surface allow them to bind receptors on T-cells within the tumor microenvironment, such as PD-1 and CTLA4, to downregulate the host immune response (2,13). FDA approved immune checkpoint inhibitors such as ipilimumab (anti-CTLA4), pembrolizumab and nivolumab (humanized and fully human anti-PD-1 monoclonal antibodies, respectively) counteract this immune evasion and have shown promising responses (2,13). Response rates as high as 50% and durable response to therapy in many cases, with concurrent or sequential therapy with ipilimumab and nivolumab, in one study, highlight the success of these agents (2, 13).…”

“…The primary biomarker used to predict response to immunotherapeutic agents is PD-L1 protein expression assessed by immunohistochemistry, while others include CD8 positive Tcell density and specific transcriptional signatures (2,13). Recently TMB, a surrogate metric for assessing tumor immunogenicity by determining the load of neo-epitopes, has emerged as a promising biomarker for predicting response to immunotherapy (4,14).…”

Case Report: Systemic Treatment and Serial Genomic Sequencing of Metastatic Prostate Adenocarcinoma Progressing to Small Cell Carcinoma

“…We observed that both samples shared the most recent common ancestor (MRCA) encompassing 23 mutations and an exon1-exon13 truncation of the neurofibromin 2 ( NF2 ) gene, indicating their common origin ( Figure 3 ). Notably, a double deletion of TP53 and RB1 was identified at the initiation of neuroendocrine stages, while a truncation of NF2 resulted in sensitivity to platinum chemotherapy ( 9 ). A specific subclone harboring 37 mutated genes and an AR amplification was observed in the M-sample.…”