Alexander Drilon

Sarcoid-like reactions in patients treated with checkpoint inhibitors for advanced solid tumors

Abstract Importance While new intrathoracic adenopathy in a patient with cancer can represent progression of disease, the differential diagnosis is broad. Sarcoid-like reactions (SLR) remain an underreported source of lymphadenopathy in patients treated with immune checkpoint inhibitors (ICI), with limited reports in patients with cancers other than melanoma. Objective To characterize SLRs among patients treated with ICI for advanced solid tumors. Methods Data were collected on the clinical, pathologic, and radiographic presentation of patients treated with ICI who developed clinical or imaging findings suggestive of an SLR, including the presence of hilar or mediastinal lymphadenopathy, cutaneous/subcutaneous involvement, and/or worsening of existing sarcoidosis on ICI. Results Twelve patients were identified as having experienced an SLR. While 6 patients had melanoma, SLRs were also observed among patients with lung, gynecologic, and genitourinary cancers, including high-grade serous ovarian carcinoma, and an angiomyolipoma. Median time from initiation of ICI to diagnosis of an SLR was 3.4 months (range: 1.8-9.1). All but one patient (92%) were deemed to have had a radiographic response to ICI. Conclusions and relevance Clinicians should maintain the awareness of the possibility of SLRs in patients receiving ICI, particularly in patients whose scans show evidence of “mixed” response, with decreases in certain lesions coupled with new/increasing intrathoracic lymphadenopathy and/or other systemic signs of sarcoid.

Spectrum ofBRAFMutations and Gene Rearrangements in Ovarian Serous Carcinoma

PURPOSELow-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF. The BRAFV600Emutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF-driven tubo-ovarian and primary peritoneal serous tumors.METHODSRetrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600Eoncoprotein expression was assessed by immunohistochemistry on selected cases.RESULTSBRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAFV600Ehotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1, and AGAP3). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit.CONCLUSIONRecognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.