Peeke, Stephen

Abstract ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

64 Background: According to recent reports, ~1 in 4 patients with metastatic prostate cancer may harbor alterations in DNA damage repair (DDR) genes. Clinical trial data demonstrates that prostate cancer patients with DDR mutations may respond to poly-ADP ribose polymerase (PARP) inhibitors. Less is known about the mutational profile in minority patients with prostate cancer. We sought to determine the genomic profile of prostate cancer in an ethnically diverse patient population at a single center. Methods: We performed a retrospective review of men with prostate cancer at the Montefiore-Einstein Cancer Center who had next generation sequencing (NGS) with FoundationOne solid tumor testing between 2/2016 - 8/2019. Individual chart review was used to obtain clinical and demographic data including self-reported race/ethnicity. Results: NGS was attempted on archival tissue from 95 patients and results were obtained for 85. Among patients with results, the self-reported race/ethnicity was: Hispanic (H) 37.6%, Non-Hispanic Black (NHB) 52.9%, Non-Hispanic White (NHW) 4.7%, and Other (O) 4.7%. At the time of tissue sampling, 61 patients had metastatic disease and 10 were castration-resistant. 63 samples were from the prostate, 7 from bone, 7 from lymph node, 3 from liver and 5 from other soft tissue sites. The most commonly altered genes included: TP53 (26%), TMPRSS2-ERG fusion (23%), and PTEN (17%). Alterations in the androgen receptor were identified in 5 samples (all with CRPC). 32.8% had alterations in DDR genes including BRCA2 9 (10.6%), ATM 7 (8.2%), ATR 4 (4.7%), BRIP1 2 (2.3%), CDK12 3 (3.5%), FANCA 2 (2.3%), and PALB2 1 (1.2%). Alterations in mismatch repair genes (MSH2, MLH1, MSH6, PMS2) were present in 4 (4.7%) patients (3 of these were MSI-H). In samples where tumor mutational burden (TMB) was reported, 4 (4.7%) were TMB-high (3 MSI-H and 1 with POLE mutation). Conclusions: DDR gene mutations are common in this primarily minority population. As DDR mutations become more common in the CRPC setting, our data may underestimate the frequency of DDR mutations as only 10 patients had CRPC at the time of tissue sampling. Minority men, like all men, with prostate cancer should be considered for genomic analysis as results are likely to guide therapeutic decisions.