THU055 The Acro-TIME Score: A New Clinical, Pathological And Immune Integrative Approach To Early Identify Acromegaly Patients Resistant To Treatment With First Generation Somatostatin Ligands

Disclosure: S. Chiloiro: None. A. Giampietro: None. M. Gessi: None. L. Lauretti: None. M. Pier Paolo: None. A. Carlino: None. A. Olivi: None. G. RIndi: None. A. Pontecorvi: None. L. De Marinis: None. F. Doglietto: None. A. Bianchi: None. Introduction: Somatotropinomas are benign neoplasia, with a heterogenous clinical behavior. The acromegaly control is reached in 25%-65% of patients (pts) treated with first generation somatostatin ligands (fg-SRLs). Tumor microenvironment reflects the interaction between tumor cells and the host immune system, potentially regulating tumor behavior and therapy outcome. We aim to develop a score that includes clinical, pathological and immune markers to early identify fg-SRLs resistant acromegaly pts, that require second line treatments. Patients: 43 consecutive acromegaly pts were included according the following criteria (1) first line treatment with surgery, (2) post-surgical fg-SRLs therapy (3) availability of tumor samples for experiments. Pts not-naïve to acromegaly therapies before surgery, with history of radiotherapy of head and neck within 10 years before pituitary surgery, with immune-related disease were ruled out. Results: Eighteen pts (41.9%) were fg-SRLs resistant: 14 were females (77.8%), with a median age of 36.5 (IQR:13) and with cavernous sinus invasion in 12 cases (66.7%). At histological examination, Ki-67 was <1.5% in 17 cases (39.5%). The SSTR2A Volante scores were 0-1 in 5 cases (11.6%) and 2-3 in 38 cases (88.4%). Tumor-infiltering CD4+ lymphocytes was 4.9/HFP (IQR: 8), CD8+ lymphocytes was 11/HFP (IQR:14) and CD68+ cells was 60/HFP (IQR:69). The ratio CD68+/CD8+ cells was 5.2 (IQR: 5). We analysed 18 clinical, pathological and immune features as possible predictors of fg-SRLs response. Fg-SRLs resistance was associated to age at acromegaly diagnosis <37 years (AUC: 0.72 OR: 2 95%IC: 1.1-4 p=0.04), cavernous sinus invasion (OR: 9.3 95%IC:1.4-61 p<0.001), Ki-67>1.5% (OR: 3.2 95%IC:1.2-13.1 p=0.04), score 0-1 of SSTR2A (OR: 2.7 95%IC: 1.7-4.1 p=0.03), ratio CD68+/CD8+ cells<5.7/HPF (AUC: 0.709 OR: 4.9 95%IC:1.2-19.2 p=0.03) and persistence of post-surgery residual tumor (OR: 2.5 95%IC:1.3-4.7 p=0.004). These variables were analysed in a logistic regression model, yielding a beta coefficient of 3.7 for age >37 years; of -3 for cavernous sinus invasion; of -0.2 for Ki-67>1.5%; of 20 for SSTR2A score 2-3; of -0.9 for CD68+/CD8+cells ratio >5.7/HFP; and of -0.9 for persistence of post-surgery residual. We assigned a score to each covariate proportional to its beta coefficient, yielding a cumulative score for each pts. The score values ranged from 18.5 to 24 in cases responsive to fg-SRLS and from -5.5 to 21.5 in fg-SRLs resistant cases. A score <19 was chosen as cut-point to identify fg-SRLs resistance (AUC: 0.059 p<0.001 95%IC: 0.0-0.126). A score <19 was associated to fg-SRLs resistance in 84.6% of cases (p<0.001 OR: 3.7 95%IC:1.7-6.7). Conclusions: This new score integrates clinical, pathological, immunological data and may predict fg-SRLs resistance and the need of second line therapies. This study was supported by 2022 Arrigo Recordati International Prize Presentation: Thursday, June 15, 2023