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10519 Background: BRCA1/2 genes ( BRCA) play a prominent role in the Homologous Recombination Repair (HRR) pathway. Following the technological progress and deeper knowledge on BRCA-related cancers, the demand for genetic testing is rapidly increasing. Beyond BRCA1/2, other genes are involved in the HRR, including ATM, PALB2, RAD51, and BARD1. Due to the important role in the cellular repair process, deleterious variants in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. The role of BRCA1/2 as predisposing condition to cardiac dysfunction is debated, and the contribution by no- BRCA genes is still unknown. Methods: This is a multicenter, retrospective, study to investigate the risk of heart-insults from anthracyclines on adjuvant setting in BC patients carrying germline pathogenic or likely pathogenic variant (PV) (classes IV and V) in BRCA and no- BRCA HRR pathway genes. We collected genetic and clinical data, and evaluated the left ventricular ejection fraction (LVEF) at cardiac ultrasound, before starting ACR therapy, and at subsequent time points, according to clinical indications. Results: Three hundred and sixty (360) BC patients, aging 22 to 80, were included in this study; 131 patients were carriers of germline PVs in HRR pathway genes: 52 in BRCA1 gene (39.7%), 48 in BRCA2 gene (36.6%), and 31 harbored PVs in no- BRCA HRR pathway genes (23.7%), including PVs in PALB2, CHEK2, ATM, RAD51C, RAD50 and BARD1 genes. In the cohort of 229 patients without PVs, 47 showed variant of uncertain significance (VUS, class III), and 173 had genetic testing not informative. When LVEF between the groups was compared, the difference was not significant for the pre-treatment values. Notably, individuals carrying BRCA or other HRR gene deleterious variants, showed a statistically significant reduction of LVEF > 5% at the second time-point (3 month), compared to the LVEF pre-treatment values (p = 0.001). A marked LVEF reduction was in mutated patients treated with risk-reducing bilateral salpingo-oophorectomy prior to age 40, body mass index > 25, and type-II diabetes mellitus. The latter risk factor was probably related to increased risk developing insulin-resistance reported for BRCA-mutated patients. Conclusions: Our data suggest that PVs in BRCA or other genes involved in HRR pathway, can lead to impaired homologous recombination, thus increasing sensitivity of cardiac cells to DNA damaging chemotherapy in BC patients. In this subgroup of patients, other measurements such as the global longitudinal strain (GLS), and a more in-depth assessment of risk factors, could be proposed to optimize cardiovascular risk-management and to improve long-term survival.

e21525 Background: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer, associated with a worse prognosis. The link between MCC and immune suppression is well demonstrated. The population of patients with MCC is frequently elderly and frail, making it essential to determine whether the results of clinical trial can be replicated in a real-world setting. Despite the introduction of immune-checkpoint inhibitors (ICIs) has provided great benefit for some patients with advanced MCC (aMCC), it remains a subsets of patients who are refractory to ICIs or develop acquired resistance over time. Thus, there is a clinical need for predictive factors of ICI response. Methods: Twenty patients with aMCC treated with avelumab were included. The treatment was administered as I or II line. Clinical-pathological characteristics, Body Mass Index (BMI), and response to avelumab were analyzed from a MCC System database prospectively collected. An explorative analysis was performed, for available samples, to investigate: i) the plasma levels of soluble PD-1 (sPD-1), and PD-L1 (sPD-L1) collected at baseline, measured using homemade ELISA assays not yet commercially available, and designed according to investigator specifications; ii) IHC for PD-L1 in tumor samples; iii) the presence/absence/class (brisk vs no-brisk) of tumor-infiltrating lymphocytes (TILs) in tumor samples. The primary outcome investigated was the Time to Treatment Failure (TTF). Results: From February 2019 to January 2022, twenty (20) patients were included in the study. The median age was 74 (range 56-83); 10 patients were men (50%) and 10 were women (50%). Seventeen (17) patients (85%) were treated with avelumab as I line, and 3 patients (15%) as II line. The overall response rate was 65% (70.6% in I line patients). One (1) patient (5%) had a complete response (CR), 13 patients (65%) partial response (RP), 4 patients (20%) stable disease (SD), and 2 patients (10%) had a progression disease (PD). Overall median TTF was 22 months (95% confidence interval [CI]: -13.0-30.9). At the time of data analyses, a total of 9 events (progression or death) occurred (45%). Notably, a BMI ≥ 30 was significantly associated with longer TTF (p = 0.004) and objective response rate (p = 0.01). In the explorative biomarker analysis, preliminary data on 6 tumor and plasma samples, showed that plasma sPD-1 > 3.8 ng/ml, and the presence of PD-L1 and brisk TILs on tumor samples, were associated to longer TTF. Conclusions: These finding highlight the complex immune-metabolic interplay in the immunotherapy response. These data extends the previous finding on “obesity paradox” and the role of BMI as predictive factors of ICIs. The data on biomarker analysis warrants further prospective validation.

e17551 Background: Ovarian cancer (OC) is the 10th tumor occurring in women, it accounts for 30% of all malignant tumor affecting female genital tract in Italy. There are several factors that contribute to OC development; in 15-25% of cases family history of breast and ovarian cancer represent the main risk factor. It is well known that pathogenic variants (PVs) occurring in BRCA1/2 genes strongly increase the risk of developing OC, ranging from 50% in BRCA1 PVs carriers to 30% in BRCA2 PVs carriers. Recently genetic polymorphism has been shown to increase cancer risk, consequently polymorphisms in BRCA1/2 genes could represent low penetrance susceptibility alleles and contribute to determine specific clinicopathological features in OC patients harboring BRCA1/2 PVs. Methods: From 2015 to 2021, 338 patients diagnosed with epithelial OC (not mucinous, not borderline) were subjected to BRCA1/2 analysis. After obtaining informed consent, blood samples were processed for genomic DNA isolation; DNA was used for library preparation with the BRaCa Screen kit. Sequencing was performed on the IonS5 platform; variant annotation was performed with Amplicon Suite software. We collected data of both PVs and polymorphisms in BRCA1/2 genes with the aim to evaluate whether a cluster of specific polymorphisms could impact clinicopathological features in BRCA1 PVs carriers. Results: Among the 338 screened EOC, BRCA1/2 PVs were reported in 85 patients (25%). 66% of patients harbored BRCA1 PVs and 34% in BRCA2. The most frequent BRCA1 PVs were the c.4964_4982del (5083del19), c.514delC and c.181T > G; the first and the last are known for their founder effect in Italy and Eastern Europe. Looking at BRCA1 gene, in 75% of patients we identified a polymorphisms cluster (c.2082C > T, c.2311T > C, c.2612C > T, c.3113A > G, c.3548A > G, c.4308T > C, c.4837A > G). The c.514delC and c.181T > G PVs are always associated with the cluster and two additional polymorphisms, the c.2077G > A and the c.1067A > G respectively. Conversely, the cluster seems not to be associated with the PVs 5083del19. Interestingly in BRCA1-5083del19 PV carriers median age at OC diagnosis was 50 years (range 45-69). On average, these patients developed ovarian cancer 6 years earlier than other BRCA1 PV carriers (median age at diagnosis 57 years; range 30-81). Bilateral tumors were frequent and occurred in 57% of the patients versus 33% in OC patients carrying other BRCA1 PVs. Therefore, it seems that the cluster has a “protective” effect and that its absence reduces age at diagnosis. Conclusions: Despite this study has the main limitation of a small sample size, we have reported a possible association between polymorphisms cluster and clinicopathological features in BRCA1 PVs carriers. By further investigating this aspect in a larger cohort, we might be able to prove the role of this cluster in increasing or reducing OC risk and providing clinicians more information useful for patients’ stratification.

e14035 Background: The immune response to melanoma has been shown to be locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk (infiltrating the entire base of the invasive tumor), non-brisk (infiltrating only focally) and absent. Several studies showed that greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and a higher survival rate. Since recent studies revealed an association between PD-1/PD-L1 expression levels and tumor response, the aim of our study was to investigate the correlation between plasma PD-1 and presence/absence/class of TILs in metastatic melanoma patients. Methods: The plasma PD-1 levels were analyzed in 28 patients with metastatic melanoma using a specific ELISA assay. The characterization of TILs in tumor tissue was performed by immunohistochemistry. Statistical analysis was assessed using t-Student and ANOVA tests. Survival curves were estimated by using the Kaplan-Meier method and log-rank test to evaluate significant differences among them. Results: 16 out of 28 patients showed the presence of TILs in primary tumor, 10 of which brisk and 6 nonbrisk. The plasma PD-1 levels were analyzed in relation to the presence/absence of TILs (p = 0.022), brisk TILs versus nonbrisk/absent TILs (p = 0.014), and brisk vs nonbrisk vs absent TILs (p = 0.032). In particular, low plasma PD-1 levels have been shown to be associated with brisk TILs in primary melanoma, intermediate values with nonbrisk TILs, and high expression with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant association between the plasma PD-1 expression levels and overall survival (OS) depending on the absence or presence of TILs (brisk/nonbrisk), however the median survival of patients having brisk TILs was five months higher than other 2 groups of patients with absent and nonbrisk TILs, respectively. Conclusions: This work highlights, for the first time, the potential ability of using the plasma PD-1 levels to predict prognosis also in patients with metastatic melanoma at diagnosis for which it is not possible to identify the primary tumor.

e15006 Background: Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have demonstrated efficacy in combination with chemotherapy as second line for metastatic colorectal cancer (mCRC). However, there is still a paucity of evidence or guidelines suggesting the right sequential treatment in all RAS (KRAS/NRAS) wild type(wt)mCRC. Therefore, we aimed to evaluate the impact of these targeted therapies by reviewing literature data. Methods: We used Cochrane, EMBASE and Medline databases to select phase III clinical trials containing efficacy and safety data about chemotherapy (CT) or CT + targeted agents combination (Anti-VEGF and Anti-EGFR) in second line mCRC setting. We performed direct comparisons to obtain pooled data for anti-VEGF + CT versus CT and anti-EGFR +CT versus CT comparisons. Then we performed indirect comparisons between anti-EGFR and Anti-VEGF. Outcomes were disease control rate (DCR), response rate (RR), progression-free survival (PFS), overall survival (OS) and most common G3-G5 toxicities. Results: Eight eligible RCTs (6793 pts) were included: 5 studies compared anti-VEGF + CT and 3 anti-EGFR + CT combinations to CT. After direct comparisons, pooled indirect results showed significantly improved OS (HR 0.83, 95% CI 0.72–0.94) and DCR (HR 1.27, 95% CI 1.04–1.54) favouring anti-VEGF combinations in overall population; however, no statistically significant differences in all RAS wt patients was observed (HR 0.87, 95% CI 0.70–1.09). Additionally, anti-EGFR combinations significantly increased ORR in all patients (RR 0.54, 95% CI 0.31–0.96), showing a trend in all RAS wt patients (RR 0.63, 95% CI 0.48–0.83) too. Furthermore, no significant difference in PFS and DCR all RAS was registered. Anti-VEGF combination significantly increased Only a significant asthenia difference (RR 1.34, 95% CI 1.03–1.75) was registered. Conclusions: At our knowledge, our indirect comparisons between anti-VEGF and anti-EGFR combinations showed for the first time better OS and DCR for anti-VEGF combinations, whereas better RR is observed for anti-EGFR combinatory regimens, defining a role of both targeted agents in second line mCRC setting.

e16109 Background: Predicting which patient with metastatic renal cell carcinoma (mRCC) will benefit from immune checkpoints inhibitors (ICPIs) still remain an issue. Biological factors particular to certain individuals have a clear effect on variation in response. Emerging evidence suggests that small non-coding RNA, such as microRNAs (miRNAs), are critical modulators of numerous cellular processes, including immune surveillance. The main aim of this study was to analyze the lymphocyte miRNA expression profile in mRCC patients and dynamic changes after the treatment with ICPI, in order to investigate the molecular mechanisms and signaling pathways involved in ICPI response and their potential role as predictive biomarker. Methods: Total RNA and miRNAs were isolated from peripheral lymphocytes of 14 mRCC patients, treated with nivolumab as second line. The blood samples were collected before nivolumab treatment (T0) and at progression disease (T1). The quality and quantity of miRNAs were assessed using the miRNeasy Mini Kit, 2100 Bioanalyzer and spectrophotometer NanoDrop ND-1000. Through a TaqMan Low Density Array A human microRNA microarray analysis, the expression profile of 377 lymphocyte miRNAs was analyzed. A cut off of fold change > 2 was considered for up-regulated miRNAs and < 0.3 for down-regulated. The patients were divided into 2 groups: patients with PD within 6 months of treatment (G1), and patients with stable therapy response (RC, RP or SD) over 12 months (G2). Results: Microarray analysis showed a subset of 59 miRNAs involved in several cancer-related processes, including cell cycle regulation, PI3K/Akt, FOXO and HIF-1 signaling pathways, differentially expressed in peripheral lymphocytes of mRCC of G1 and G2 group of patients. Among all miRNAs analyzed, several were deregulated, such as miR-155, miR-22, miR-24, miR-484, miR-335 and miR-492, some up-regulated and others down-regulated. This deregulation of specific miRNAs was different into G1 and G2 groups, and seem to be related with the duration of response to ICPI. Conclusions: Our data, for the first time, study the expression profile of miRNAs in the peripheral lymphocytes, and show a correlation between deregulation of miRNAs and response to Nivolumab. These knowledge could help to identify potential biomarkers predictive of response to ICPIs for the personalization of treatment.

11032 Background: GISTs are the most common mesenchymal tumors of the digestive tract. As of recent, new links are being made between GISTS and secondary malignancies. However, whether the coexistence of GISTs with other tumors is stochastic, or the result of related pathogenetic mechanisms is still unknown. Methods: We retrospectively reviewed clinical and molecular features from all GIST patients with second tumors treated in seven Italian GIST reference centers. Qualitative variables were compared using the Fisher exact test. Results: Clinical data of 184 patients with diagnosis of GIST were evaluated. Median age at diagnosis was 66 years, KIT exon 11 resulted the most frequent mutation (73%) while seven patients (3.8%) had a genetic syndrome. The most common primary GIST localizations were stomach (54%) and small intestine (33%). Second tumors arose mostly from gastrointestinal and genitourinary tract. Fourtythree patients had two primary tumors other than GIST and five patients had three other primary malignancies. According to Miettinen criteria, 45% of non-metastatic patients at diagnosis belong to low or very low-risk classes. We highlighted a significant correlation (P=0.002) between risk class and second/third tumor localization, with considerably high percentage of GI second malignancies in low/very low risk GISTs (table). Conclusions: The high frequency of second/third tumors reported in low and very low GIST calls for a careful follow-up also in these patients. Furthermore, this population requires further genetic investigation, NGS analysis is ongoing. [Table: see text]

11038 Background: We retrospectively collected data from metastatic Italian GIST patients treated with imatinib or sunitinib reintroduction after progression to conventional three or four lines of therapy. Methods: 82 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected in the present analysis from 6 cancer centres. All patients received all three standard kinase inhibitors. Imatinib dose increase as active second line or 800 mg upfront in exon 9 mutant GIST were allowed. Specific mutations were recorded if available (deletion versus others) and correlated with survival and response according to RECIST 1.1 or CHOI criteria. Results: Seventy-four of 82 patients received Imatinib 400 mg as rechallenge, while 8 patients were treated with sunitinib at personalised dose and schedule according to the physician’s choice. Mutational status was available in all patients and in 68 patients details about type of mutation were achievable. The median follow-up was 13 months (range 1-42 months). The median time to progression (TTP) in patients receiving a rechallenge therapy was 5.4 months (95% CI 1.9-13.5) and Overall Survival (OS) was 10.6 months (95% CI 2.8-26.9). Apparently, in this setting a correlation between mutational status and response rate, TTP or OS was not found. On the contrary, considering only exon 11 mutated patients and comparing patients with deletion vs non deleted ones a significant difference was identified both in terms of TTP and OS (respectively, P = 0.04 and P = 0.02). Conclusions: Our retrospective data confirm that the rechallenge of imatinib or sunitinib is a reasonable option in advanced GIST patients after failure of previous treatments. As expected, imatinib is the most frequently prescribed option in the Italian real-life setting, demonstrating a TTP and OS longer than those observed in previous studies. Also the prognostic value of the specific type of exon 11 KIT mutations has been confirmed in our series.

e22517 Background: Since the first steps of its clinical development, trabectedin was noticed to be extremely active against myxoid liposarcoma (MLS), whose pathogenesis seems to be associated to the presence of the t(12;16)(q13;p11) translocation, resulting in the expression of FUS-DDIT3 fusion genes. Therefore, the drug seems to induce a maturation of MLS lipoblasts, with transition of the residual spindle non-lipogenic cells into mature vacuolated lipoblasts. This effect could be prevented by the increase of leptin circulating levels in obese patients. For these reasons we designed this retrospective analysis in order to evaluate the BMI status (measure of total adipose content) as a predictors or efficacy of trabectedin in MLS patients. Methods: Patients were treated in cancer centers with trabectedin at the approved dose of 1.5 mg/m2, given as a 24-hour infusion every 3 weeks. This retrospective analysis was preformed on the basis of clinical charts or databases. For the purpose of this analysis only patient with a BMI > 18.5 were included and an the population divided into two categories: normal weight if BMI < 25, overweight > 25. An analysis of the correlation between BMI and objective response (OR) rate, tumor control (TC) rate (OR+stable disease lasting ≥3 months), progression-free survival (PFS) and overall survival (OS) was performed. Results: 62 adult patients with recurrent MLS were enrolled (M/F: 33/29; median age: 53 ys). All patients were doxorubicin-pretreated. The median BMI in the whole population was 22.5 (range: 1.85 – 29.8). No statistically significant differences were identified in terms of OR or TC. On the contrary, PFS (6.8 vs. 3.7 months; p< 0.026, log rank test) and OS (14.9 vs. 8.3 months; p< 0.0001, log rank test) were significantly prolonged in normal weighted patients vs over weighted patients. Six and 12-months Kaplan-Meier PFS estimates and survival rates at 12, 24 and 36 months were also better in those patients. Conclusions: these results seem confirm a role o adipose content as a predictor of resistance to trabectedin in MLS patients. Further studies are warranted to confirm this preliminary observation and understand the biological mechanisms of this relationship.

20514 Background: CEUS with second-generation contrast agents has been proposed to monitor tumor response to imatinib in patients with metastatic GIST. There are no data in patients with other sarcomas. Our aim was to assess the value of CEUS as a marker of tumor response in retroperitoneal liposarcoma, in addition to its ability to render the baseline malignancy grade of the disease. Methods: CEUS was performed after a SonoVue injection (Bracco, Milano, Italia). SonoVue is a suspension of microbubbles of exafluoride sulphure gas (average diameter 3 μm) with a phospholipidic shell. A low mechanical index (MI No significant financial relationships to disclose.