Selected Articles from This Issue

Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. Prior research suggested treatment with a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) could benefit ASPS patients. Nguyen and colleagues conducted a randomized clinical trial of potent VEGFR TKIs cediranib and sunitinib in aggressive ASPS. The drugs were well tolerated, and the overall response rate was 6.7% and 7.1% for cediranib and sunitinib, respectively. Most patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). The selection of patients with aggressive disease that progressed in the 6 months preceding enrollment may account for the lower objective response rates compared to previous reports. This data indicates that prior TKI therapy does not preclude clinical benefit from subsequent TKI treatments, suggesting that sequential TKI therapy may benefit patients with ASPS.

Myeloid-derived suppressor cells (MDSCs) limit the efficacy of immune checkpoint inhibitors (ICIs), including anti-PD-1. Tobin and colleagues sought to target MDSCs using the differentiating agent all-trans retinoic acid (ATRA) to enhance the efficacy of the anti-PD-1 antibody pembrolizumab in anti-PD-1 naïve stage IV melanoma patients. In this phase 1/2 clinical trial, the combination was well tolerated, and the recommended phase 2 dose was established. The combination effectively lowered the number of circulating MDSCs. The median progression-free survival was 20.3 months. When compared to prior clinical trials with single agent pembrolizumab, or clinical trials testing combinations of ICIs, the combination of ATRA and pembrolizumab has a favorable overall response rate of 71%, with 50% of patients experiencing a complete response. These results provide initial evidence for the safety and efficacy of this approach in the frontline setting for stage IV melanoma patients.

Determination of recurrence-risk in localized renal cell carcinoma (RCC) informs subsequent decision making. To explore the role of genomics in refining individual risk prediction, Vasudev and colleagues examined the mutation status of a 12-gene panel in 943 clear cell RCC tissues. Almost 80% of tumors could be classified into one of 4 groups, with highly divergent relapse-risk, independent of tumor stage and grade. Patients who may be both spared, and prioritized for, adjuvant therapy are identified. The classifier could help to personalize adjuvant treatment discussions and may be readily applied to the clinic.

Cerebrospinal fluid (CSF) has been proposed as a source of circulating tumor DNA for broad genetic profiling of gliomas. Orzan and colleagues showed that, at first clinical presentation, glioma DNA retrievable in CSF by lumbar puncture is often too scanty for NGS analysis. To maximize the extraction of information from CSF, they developed a high-sensitivity ddPCR-based protocol detecting a selected panel of genetic alterations (IDH and TERT promoter mutations, EGFR amplification, CDKN2A/B deletion: ITEC). This protocol enables a tissue-agnostic, presumptive molecular diagnosis of adult diffuse gliomas according to WHO 2021 criteria in >60% of cases.