Abstract P3-08-32: Predictive value of SAMHD1 expression in early relapse breast cancer
Authors: Mireia Margeli, Eudald Felip, Maica Gomez, Pedro Fernandez, Laia Pérez-Roca, Eva Riveira-Muñoz, Anna Martinez-Cardús, Iris Teruel, Margarita Romeu, Beatriz Cirauqui, Vanesa Quiroga, José A. Este, Ester Ballana
Journal: Cancer Research (2020)

Abstract Introduction: SAMHD1 is a triphosphohydrolase that catalyzes the degradation of deoxynucleoside triphosphates (dNTP). SAMHD1 expression and function are coordinated during the cell cycle and tightly linked to cell cycle progression and proliferation. SAMHD1 affects nucleotide and antimetabolite drug susceptibility and has been identified as a biomarker of cytarabine treatment in acute myeloid leukemia (AML)1.Here, we explore the potential impact of SAMHD1 expression in breast cancer (BC) outcome, and its role as a modulator of response to antimetabolites. Material and methods: We evaluated the effect of SAMHD1 function on the efficacy of a wide range of nucleotide analogues used in cancer therapy, using established cell lines modified to express or not SAMHD1 and primary cells where SAMHD1 expression was modulated by Vpx-mediated degradation. We performed tissue microarray of tumor tissue from metastatic (M) BC patients (P) treated with capecitabine, and evaluated SAMHD1 status using inmunohistochemistry (anti-SAMHD1 polyclonal antibody 12586-1-AP, Proteintech). SAMHD1 positivity was defined as cellular positivity ≥25%. Statistical analysis was performed using Chi-square test for qualitative covariables, Kaplan-Meier survival curves and log Rank function, considering a p &amp;lt; 0.05 as statistically significant.Results: In vitro, SAMHD1 effectively modified the efficacy of all nucleotide analogues tested. Interestingly, SAMHD1 could either enhance (gemcitabine, capecitabine, fluorouracil and floxuridine) or inhibit (Ara-C, fludarabine, cladribine, clofarabine and nelaravine) potency of nucleotide analogues, an effect that was not dependent on the specific nucleotide targeted. In our cohort of 30 BCP, the median age was 52 years, 63% were classified as luminal according to hormone receptor (HR) and epidermal growth factor receptor-2 (HER2) status, 10% were HER2 positive and 27% as triple negative. 33.3% p presented as de novo metastatic disease, 36.7% presented m disease with a disease free interval (DFI) ≤ 5 years and 30% presented m disease with a DFI &amp;gt;5 years. P were treated with capecitabine as first line therapy in 33.3% of cases, second in 33.3%, third in 13.3%, four in 10%, and fifth in 10%. 33% of P presented response to capecitabine, 40% presented stabilization of disease, and 27% progressed. Median time to progresion to capecitabine was 12.5 months, and median overal survival was 26.6 months. SAMHD1 expression was positive in 63.3% (n: 19) of p and negative in 33.3% (n: 10) of p. SAMHD1 positivity was significantly enriched in cases with de novo disease, and DFI ≤ 5 years (Chi-Square test; p=0.022). According to survival analysis, SAMHD1 positivity was associated with DFI ≤ 5 years (Log Rank; p=0.047). SAMHD1 was not associated with clinical characteristiques or inmunohistochemical subtypes.SAMHD1 positivity was associated with better response to capecitabine and less grade 3/4 toxicity, although these differences did not reach statistical significance. These results were in line with the evaluation of susceptibility to capecitabine in cell culture. Conclussion: SAMHD1 modifies the efficacy of a wide variety of nucleoside analogues used to treat cancer. In vivo, SAMHD1 expression is a predictor of early relapse in BCP independently of the subtype. Moreover, it could be a potential predictive factor of capecitabine efficacy in MBCP. Thus, modulation of SAMHD1 function may constitute a promising target for the improvement of multiple therapies. 1. Rassidakis GZ, Herold N, Myrberg IH et al. Low-level expression of SAMHD1 in acute myeloid leukemia (AML) blasts correlates with improved outcome upon consolidation chemotherapy with high-dose cytarabine-based regimens. Blood Cancer J. 2018 Oct 19;8(11):98. Citation Format: Mireia Margeli, Eudald Felip, Maica Gomez, Pedro Fernandez, Laia Pérez-Roca, Eva Riveira-Muñoz, Anna Martinez-Cardús, Iris Teruel, Margarita Romeu, Beatriz Cirauqui, Vanesa Quiroga, José A. Este, Ester Ballana. Predictive value of SAMHD1 expression in early relapse breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-32.