ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in three 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 (seven and twelve 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-ERK, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, while 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, ten 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.

Background: Immune regulation plays an important role in tumor growth and sustainability. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been reported as peripheral blood surrogates of tumor inflammation and immune response, and have been studied as prognostic markers of treatment response in breast cancer. Cyclin-dependent kinase (CDK) 4/6 inhibitors have shown to enhance the immune response against tumor cells. We aimed to evaluate the impact of NLR and PLR as prognostic biomarkers in patients with estrogen-receptor positive (ER+), human-epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) treated with first line CDK4/6 inhibitors. Methods: This retrospective single cohort study analyzed patients with ER(+)/HER2(-) MBC treated with first line CDK4/6 inhibitors at Albert Einstein Cancer Center. Demographic, clinicopathological, laboratory and treatment characteristics were collected from electronic medical records. Absolute neutrophil count, absolute lymphocyte count and platelet count, were obtained at baseline (T0) and after three months (T3) of treatment with CDK4/6 inhibitors. Optimal cutoff points to define NLR and PLR high vs. low were identified using time-dependent receiver operator curves. Progression free survival (PFS) was calculated from the time of CDK4/6 inhibitor initiation to disease progression, death, or last clinical encounter. PFS was compared among patients with high vs. low ratios at T0 (NLR0HIGH vs. NLR0LOW and PLR0HIGH vs. PLR0LOW) and at T3 (NLR3HIGH vs. NLR3LOW and PLR3HIGH vs. PLR3LOW) of CDK 4/6 inhibitor treatment, using Cox-proportional regression models. Results: A total of 89 patients were evaluated. The median age was 61 years [interquartile range (IQR): 61-69]. Of these, 60% were Non-Hispanic, 40% were Hispanic, 46% were Black, 19% were Caucasian and 6% were Asian. Premenopausal and postmenopausal status was identified in 21% and 75% of patients, respectively. The median Charlson Comorbidity Index (CCI) was 8 [IQR: 7-9]. Visceral metastases were seen in 67% of patients. Palbociclib, Abemaciclib and Ribociclib were used in 78%, 16% and 7% of patients, respectively; with an endocrine therapy backbone of Letrozole, Fulvestrant and Anastrozole in 64%, 24% and 10% of patients, respectively. The median NLR0 and NLR3 were 2.6 [IQR: 1.8-3.6] and 1.3 [IQR: 0.8-2.3], respectively. The median PLR0 and PLR3 were 158 [IQR: 115-250] and 142 [IQR: 94-290], respectively. The cutoff points for defining ratios as being high vs. low for NLR0, NLR3, PLR0, and PLR3 were 3.7, 2.2, 108, and 309, respectively. The median PFS was 10 vs. 19 months for NLR0HIGH vs. NLR0LOW [Hazard Ratio (HR):1.8, 95% Confidence Interval (CI):0.95-3.49, p=0.07] and 12 vs. 19 months for NLR3HIGH vs. NLR3LOW (HR:1.46, CI:0.71-3.00, p=0.3). In multivariable models adjusted for age, CCI, and visceral metastases, neither NLR0(p=0.1) nor NLR3 (p=0.2) was associated with PFS. The median PFS was 13 months vs. not-reached for PLR0HIGH vs. PLR0LOW (HR: 5.5, CI:1.3-23.0, p=0.018), and 32 vs. 16 months for PLR3HIGH vs. PLR3LOW (HR:0.62, CI:0.23-1.64, p=0.3). In multivariable models adjusted for age, CCI, and visceral metastases, an increased PLR0 was associated with worse PFS (HR 4.67, 95%CI 1.1-20, p=0.04), while PLR3 was not associated (p=0.37). Conclusions: Our study is the first in the United States to evaluate NLR and PLR as prognostic biomarkers in MBC patients receiving CDK4/6 inhibitors. PLR0 is a potential biomarker for prognostic stratification in this setting. NLR0, NLR3, and PLR3 were not independent factors for PFS in this setting when other clinicopathological factors were considered. Further studies with a larger sample size are required to validate our results. Citation Format: Ashley Weiner, Laura S. Munoz-Arcos, Heidi Ko, Jesus Anampa. Neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio as prognostic biomarkers in patients with metastatic breast cancer treated with CDK4/6 inhibitors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-30.

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