Abstract LB112: SAMHD1: A new Prognostic Marker in Breast Cancer (BC)

Abstract

Abstract Introduction SAMHD1 is a triphosphohydrolase that catalyzes the degradation of deoxynucleoside triphosphates (dNTP), and its function is tightly linked to cell cycle progression and proliferation. SAMHD1 has been also related to the replication stress response, preventing chronic inflammation. Here, we explore the potential rol of SAMHD1 expression in metastatic breast cancer (MBC) Matherial and Methods SAMHD1 effect on cell differentiation and proliferation, efficacy of capecitabine and gemcitabine and sensitivity to DNA damaging agents was evaluated in vitro, using breast cancer cell lines modified to express or not SAMHD1. In patients, a cohort of capecitabine-treated MBC (n=46) patients were retrospectively selected to evaluate SAMHD1 expression by immunohistochemistry (anti-SAMHD1 polyclonal antibody 12586-1-AP, Proteintech) on tissue microarrays from primary tumour or metastasis. 28% of patients were diagnosed with metastàtic disease, 35% relapsed inthe first 5 years, and 37% after 5 years of follow up. Median time to progresion (TTP) to capecitabine in MBC cohort was 13 months (m) and median overal survival (OS) was 28.8 m. SAMHD1 positivity was defined as cellular positivity ≥1%. SAMHD1 gene was also sequenced from tumor biopsies in a subgroup of patients with none (n=10) or high (n=10) expression of the protein, to identify somatic mutations. Statistical analysis was performed using Chi-square test for qualitative covariables, Kaplan-Meier survival curves and log Rank function, considering a p < 0.05 as statistically significant. Results SAMHD1 knock-out cells showed higher sensitivity to carboplatin-induced cell death. Interestingly, in patients SAMHD1 positivity was strongly associated with ki67 >15% (Chi-Square test; p<0.001). and high grade of proliferation (Chi-Square test; p=.004). SAMHD1 positivity was associated with patients diagnosed with metastasic disease and those who presented early relapse (dissease free survival (DFS) ≤ 5 years) (Chi-Square test; p=.005). In multivariate analysis for DFS including ki67, histological Grade, and SAMHD1; SAMHD1 and ki 67 were the most important factors, being SAMHD1 the most significant. Interestingly, a higher proportion of gene mutations was found in sequences from SAMHD1 null patients. SAMHD1 positivity was also associated with worst OS from BC diagnosis (Chi-Square test; p=.001), and with worst OS from the diagnosis of metastàtic disease (Chi-Square test; p=.05). These diferences were mantained if we analyse diferent biological subgrups determined by inmunohistochemistry. SAMHD1 positivity was associated with worst overall response to Capecitabine (OR of 27% versus 52%; p=.001); and worst clinical benefit (CB of 44% versus 01%; p=.006). SAMHD1 positivity was not correlated with time to progression to capecitabine, but when we considered patients who progressed in the first six months of therapy with capecitabine; SAMHD1 positivity was associated with short TTP (p=.04). SAMHD1 positivity was also associated with worst 5 years OS from starting capecitabine (p=.014). Conclusions SAMHD1 expression may represent a new strong prognostic factor in breast cancer. Moreover, SAMHD1 expression modulates efficacy of capecitbine treatment both in vitro and in vivo. Thus, modulation of SAMHD1 function may constitute a promising target for the improvement of multiple cancer therapies. Citation Format: Mireia Margeli, Eudald Felip, Lucia Gutierrez Chamorro, Eva Riveira, Laura Layos, Teresa Moran, Margarita Romeo, Anna Matinez-Cardús, Ester Ballana. SAMHD1: A new Prognostic Marker in Breast Cancer (BC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB112.