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International guidelines recommend severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine for patients with cancer. A substantial risk of developing vaccine-related autoimmune toxicities could be hypothesised for patients with thymic epithelial tumours (TETs) due to their high risk of autoimmune disorders (ADs). Moreover, a cross-reaction between SARS-CoV-2 spike protein antibodies and various tissue proteins has been shown, and antibodies against nucleoproteins showed overlaps in the autoimmune cross-reaction with antibodies to spike protein. Due to the rarity of TETs, no data addressing this hypothesis are available.Patients with TETs who received SARS-CoV-2 vaccine, treated in 4 referral centres of the Italian Collaborative Group for ThYmic MalignanciEs (TYME) network between February 2021 and September 2021, were interviewed through a standardised 15-items questionnaire in order to describe the safety of SARS-CoV-2 vaccine in patients affected by TETs.Data from 245 doses of vaccine administered to 126 patients (41 = thymic carcinoma, 85 = thymoma; 38 with AD, of which 26 with active AD) were collected. Nine patients had a previous COVID-19-positive swab. No cases of AD reactivation or worsening of a pre-existing AD were seen in the study population. A new diagnosis of myasthenia gravis likely unrelated to the vaccine was made in two patients after the vaccination. Sixty-four patients (51%) experienced a total of 103 adverse events, all G1/G2, most commonly fatigue, new or worsening muscle pain and chills. None AE required patients' hospitalisation.SARS-CoV-2 mRNA vaccines appear to be safe in patients with TET, even in case of active or pre-existing AD.

Background: Hyperprogressive disease (HPD) has been described in ≃14-25% of pretreated non-small cell lung cancer (NSCLC) patients upon single-agent (SA) PD-1/PD-L1 inhibitors (ICI) and has not been reported upon platinum-based chemotherapy (PCT) and ICI combinations. So far, no predictive biomarkers are available for HPD early detection. Methods: NSCLC patients treated with 1st line SA-ICI or PCT-ICI were assessed for HPD and circulating neutrophils. HPD was defined as delta tumor growth rate (TGR) >50% and/or TGR ratio ≥2. Circulating low density neutrophils (LDNs) were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs and immature subtypes as CD10− LDNs. The LDNs predictive role was assessed by penalized model-based tests. Results: 144 NSCLC patients were included: 75 treated with SA-ICI, 69 with PCT-ICI. In the SA-ICI cohort, HPD occurred in 8 (11%) patients, while progressive disease (PD) and response or stable disease (PR/SD) occurred in 33 (44%) and 34 (45%) of patients respectively. Immature circulating CD10− LDNs were significantly higher in baseline blood samples of HPD patients [median (ME): 39.3, interquartile range (IQR): 28.7] compared to PD [ME: 7.4, IQR: 14.9, p Conclusions: Baseline circulating immature neutrophils characterize HPD upon 1st line SA-ICI and a 30.5% cut-off of immature neutrophils could select NSCLC patients to be addressed to PCT-ICI combinations. Citation Format: Roberto Ferrara, Giuseppe Lo Russo, Chiara Maura Ciniselli, Annamaria Piva, Barbara Bassani, Elena Jachetti, Giuseppina Calareso, Valeria Duroni, Settimio Di Gregorio, Claudia Proto, Arsela Prelaj, Alessandro De Toma, Mario Occhipinti, Marta Brambilla, Sara Manglaviti, Laura Mazzeo, Arturo Rinaldi, Teresa Beninato, Monica Ganzinelli, Filippo De Braud, Marina Chiara Garassino, Paolo Verderio, Mario Paolo Colombo, Sabina Sangaletti. Circulating immature neutrophils early detect hyperprogressive disease upon first-line PD-1/PD-L1 inhibitors in non-small cell lung cancer patients selecting best candidates for platinum-based chemotherapy and PD-1/PD-L1 inhibitors combinations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5506.

Background Radically resected early uterine leiomyosarcoma (eULMS) is still marked by a poor prognosis. Adjuvant strategies investigated up to now have not been corroborated by controlled studies. We retrospectively reviewed the clinical outcome of eULMS patients treated with adjuvant anthracycline-based or gemcitabine-based chemotherapy at two Italian reference centers. Methods In this explorative, retrospective, cohort analysis, we included all the consecutive patients with radically resected eULMS treated at two centers between 1997 and 2017. Results A total of 109 consecutive patients were included. Sixty-six (60%) received an anthracycline-based regimen, whereas 43 (40%) received a gemcitabine-based regimen. Median disease-free survival (DFS) was 41.3 months with anthracycline-based regimens compared to 20.9 months with gemcitabine-based regimens (HR: 0.49; 95% CI: 0.30–0.80; P = 0.004). In the multivariable model, anthracycline-based regimens were independently associated with a better DFS. No difference in terms of overall survival was observed. Conclusions DFS was not the same by using an anthracycline-based or a gemcitabine-based adjuvant chemotherapy for patients with radically resected eULMS. The results of our study are in line with recent prospective controlled evidence in limb and superficial trunk soft tissue sarcomas. The role of anthracycline-based adjuvant chemotherapy should still be viewed as a research issue in eULMS.

Exocrine pancreatic neoplasms represent up to 95% of pancreatic cancers (PCs) and are widely recognized among the most lethal solid cancers, with a very poor 5-year survival rate of 5%-10%. The remaining < 5% of PCs are neuroendocrine tumors that are usually characterized by a better prognosis, with a median overall survival of 3.6 years. The most common type of PC is pancreatic ductal adenocarcinoma (PDAC), which accounts for roughly 85% of all exocrine PCs. However up to 10% of exocrine PCs have rare histotypes, which are still poorly understood. These subtypes can be distinguished from PDAC in terms of pathology, imaging, clinical presentation and prognosis. Additionally, due to their rarity, any knowledge regarding these specific histotypes is mostly based on case reports and a small series of retrospective analyses. Therefore, treatment strategies are generally deduced from those used for PDAC, even if these patients are often excluded or not clearly represented in clinical trials for PDAC. For these reasons, it is essential to collect as much information as possible on the management of PC, as assimilating it with PDAC may lead to the potential mistreatment of these patients. Here, we report the most significant literature regarding the epidemiology, typical presentation, possible treatment strategies, and prognosis of the most relevant histotypes among rare PCs.

Simple Summary In this paper, the authors show that artificial intelligence (AI) and machine learning (ML) are useful approaches to integrate multifactorial data and helpful for personalized prediction. In detail, compared to PD-L1 for advanced non-small cell lung cancer (NSCLC), ML tools predicted better responder (R) and non-responder (NR) patients to immunotherapy (IO). It was also able to indirectly foresee OS and PFS of R and NR patients. Given the high incidence of NSCLC, and the absence of reliable biomarkers to predict the response to IO other than PD-L1, the authors believe this research may be of great interest to anyone involved in thoracic oncology. Furthermore, given the growing interest from the scientific community in AI and ML, the authors believe that this manuscript could represent a fascinating topic to anyone who needs to exploit the enormous potential of these tools in the treatment of cancer. Abstract (1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO.

9057 Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]

Introduction: In advanced Non-Small Cell Lung Cancer (NSCLC), Programmed Death Ligand 1 (PD-L1) remains the only used biomarker to candidate patients to immunotherapy (IO) with many limits. Given the complex dynamics of the immune system it is improbable that a single biomarker could be able to profile prediction with high accuracy. A promising solution cope with this complexity is provided by Artificial Intelligence (AI) and Machine Learning (ML), which are techniques able to analyse and interpret big multifactorial data. The present study aims at using AI tools to improve response and efficacy prediction in NSCLC patients treated with IO.MethodsReal world data (clinical data, PD-L1, histology, molecular, lab tests) and the blood microRNA signature classifier (MSC), which include 24 different microRNAs, were used. Patients were divided into responders (R), who obtained a complete or partial response or stable disease as best response, and non-responders (NR), who experienced progressive or hyperprogressive disease and those who died before the first radiologic evaluation. Moreover, we used the same data to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. For A literature review and forward feature selection technique was used to extract a specific subset of the patients’ data. To develop the final predictive model, different ML methods have been tested, i.e., Feedforward Neural Network (FFNN), Logistic Regression (LR), K-nearest neighbours (K-NN), Support Vector Machines (SVM), and Random Forest (RF).Results 200 patients were included. 164 out of 200 (i.e., only those patients with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the LR and included 5 features: 2 clinical features including the ECOG performance status and IO-line of therapy; 1 tissue feature such as PD-L1 tumour expression; and 2 blood features including the MSC test and the neutrophil-to-lymphocyte ratio (NLR). The model predicting R/NR of the patient achieves accuracy ACC= 0.756, F1 score F1=0.722, and Area Under the ROC Curve AUC=0.82. The use of the PD-L1 alone has an ACC=0.655. The accuracy of the ML models excluding some of the features from the model were as follow: without PD-L1 value (ACC=0.726), MSC (ACC=0.750), and both PD-L1 and MSC (ACC=0.707), i.e., considering only clinical features. At data cut-off (Nov 2020), median Overall Survival (mOS) for R was 38.5 months (m) (95%IC 23.9 - 53.1) vs 3.8 m (95%IC 2.8 - 4.7) for NR, with pConclusionsThe results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to improve personalized selection of NSCLC patients candidates to IO. In particular, compared to PD-L1 alone the expected improvement was around 10%. In particular, the model shows that the higher the ECOG, NLR value, IO-line, and MSC test level the lower the response, and the higher PD-L1 the higher the response. Considering the difference in survival among R and NR groups, these results suggest that the model can also be used to indirectly predict survival. Moreover, a second model was able to predict long survival patients with good accuracy.

BackgroundHyperprogression (HPD) has been described in ≃14–26% of NSCLC patients upon single-agent ICI1 and has not been reported upon ICI and platinum-based chemotherapy (PCT) combinations. Both high circulating neutrophils2 and senescent T-cells3 correlated with HPD, however the exact neutrophils-T-cells interplay and the role of specific neutrophils subsets in driving HPD is unknown.MethodsNSCLC patients treated with 1st line ICI as single-agent or in combination with PCT were assessed for HPD and circulating neutrophils’ phenotype. HPD required 3 assessment (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) (TGR upon ICI – TGR before ICI) >50% and/or TGR ratio (TGR upon ICI/TGR before ICI) ≥2. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry on peripheral blood mononuclear cells (PMBCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10- LDNs. T-cells were isolated from healthy donors and cocultured with patients‘ LDNs to characterize the neutrophils-T-cells interplay. LDNs subtypes were isolated from patients and treated in-vitro with cisplatin to assess cell death.Results46 NSCLC patients were treated with single-agent ICI and 17 with PCT+ICI (table 1). In the ICI single-agent cohort, PD and HPD occurred in 21 (41%) and 4 (9%) patients. Before ICI start, HPD patients had significantly higher median% of circulating immature CD10- LDNs neutrophils [43.5 (min 29.5; max 82.6) vs 10.3 (min 0.1; max 79.4), p=0.01] compared to PD patients (figure 1). In the ICI-PCT cohort no HPD was reported. 5 patients had baseline CD10- LDNs ≥ 43.5% (median% of CD10- LDNs in HPD patients upon single-agent ICI), 2 of them had stable disease and 3 PD upon ICI-PCT. In these 5 patients, CD10- LDNs significantly decreased during ICI-PCT compared to what observed in HPD patients upon single-agent ICI [median variation -43.4 (min -67.6, max -31.6) vs +6.9 (min -33, max +44), p= 0.03] (figure 2). After 7 days of coculture with T-cells, immature CD10- LDNs significantly reduced T-cells survival and promoted a T-cell senescent phenotype (CD28 loss, CD57 gain) impairing T-cells proliferation and increasing IFN-gamma production (figure 3). Cisplatin treatment significantly increased necrotic cell death among CD10- LDNs compared to CD10+ LDNs (figure 4).Abstract 15 Table 1Patients characteristics in the single-agent ICI and PCT+ICI cohortsAbstract 15 Figure 1Patterns of response, progression and hyperprogression to single-agent ICI and correlation with mature (CD10+) or immature (CD10-) LDNs’ subtypesAbstract 15 Figure 2Neutrophils dynamic variation upon treatment (5 patients with high baseline CD10- LDNs and PD/SD to chemo-ICI vs 4 patients with HPD upon single-agent ICI)Abstract 15 Figure 3Mature (CD10+) and immature (CD10-) LDNs in coculture with T-cells from an healthy donor differently influence CD8 and CD4 T-cells survival, proliferation, IFN-gamma production and expression of a senescent (CD28- CD57+) phenotype.Abstract 15 Figure 4Cisplatin in-vitro treatment at different concentration (1 uM and 5 uM) increases necrotic (7AAD expression) cell death preferentially of immature (CD10-) rather than mature (CD10+) LDNsConclusionsHigher baseline immature CD10- LDNs impair T-cell survival and promote T-cell senescence being a circulating biomarker of HPD upon single-agent ICI. The addition of PCT prevents HPD by inducing immature neutrophils cell death.ReferencesFerrara R, Mezquita L, Texier M, Lahmar J, Audigier-Valette C, Tessonnier L, et al. Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with pd-1/pd-l1 inhibitors or with single-agent chemotherapy. JAMA Oncol 2018;4:1543–52. https://doi.org/10.1001/jamaoncol.2018.3676Kim Y, Kim CH, Lee HY, Lee S-H, Kim HS, Lee S, et al. Comprehensive clinical and genetic characterization of hyperprogression based on volumetry in advanced non-small cell lung cancer treated with immune checkpoint inhibitor. J Thorac Oncol 2019;14:1608–18. https://doi.org/10.1016/j.jtho.2019.05.033Ferrara R, Naigeon M, Auclin E, Duchemann B, Cassard L, Jouniaux JM, et al. Circulating T-cell immunosenescence in advanced non-small cell lung cancer patients treated with single agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy. Clin Cancer Res 2020. https://doi.org/10.1158/1078-0432.CCR-20-1420.Ethics ApprovalPatients blood was obtained after signature of informed consent and within an observational prospective study (INT 22_15) approved by local Institutional Ethical Committee.

Hyperprogressive disease (HPD) is a novel pattern of response during immunotherapy treatment. Several retrospective studies have evaluated its prevalence among various cancer types and, in particular, in nonsmall cell lung cancer patients, based on different definition criteria. If HPD is a just a typical phenomenon of immunotherapy is still an unsolved concern. This paper summarized the available data about HPD in other cancer treatments. Hyperprogressive disease (HPD) is a novel pattern of response during immunotherapy treatment. Several retrospective studies have evaluated its prevalence among various cancer types and, in particular, in non-small cell lung cancer patients, based on different definition criteria. If HPD is a just a typical phenomenon of immunotherapy is still an unsolved concern. This paper summarized the available data about HPD in other cancer treatments.

Background The PI3K/AKT/mTORC1 axis is implicated in hormone receptor-positive HER2-negative metastatic breast cancer (HR+ HER2− mBC) resistance to anti-estrogen treatments. Based on results of the BOLERO-2 trial, the mTORC1 inhibitor everolimus in combination with the steroidal aromatase inhibitor (AI) exemestane has become a standard treatment for patients with HR+ HER2− mBC resistant to prior non-steroidal AI therapy. In the recent SOLAR-1 trial, the inhibitor of the PI3K alpha subunit (p110α) alpelisib in combination with fulvestrant prolonged progression-free survival (PFS) when compared to fulvestrant alone in patients with PIK3CA-mutated HR+ HER2− mBC that progressed after/on previous AI treatment. Therefore, two different molecules targeting the PI3K/AKT/mTORC1 axis, namely everolimus and alpelisib, are available for patients progressing on/after previous AI treatment, but it is unclear how to optimize their use in the clinical practice. Main body of the abstract Here, we reviewed the available clinical evidence deriving from the BOLERO-2 and SOLAR-1 trials to compare efficacy and safety profiles of everolimus and alpelisib in advanced HR+ HER2− BC treatment. Adding either compound to standard endocrine therapy provided similar absolute and relative PFS advantage. In the SOLAR-1 trial, a 76% incidence of grade (G) 3 or 4 (G3/G4) adverse events was reported, while G3/G4 toxicities occurred in 42% of patients in the BOLERO-2 trial. While alpelisib was only effective in patients with PIK3CA-mutated neoplasms, retrospective analyses indicate that everolimus improves exemestane efficacy independently of PIK3CA mutational status. Conclusions Based on the available efficacy and safety data, the “new” alpelisib may be burdened by higher incidence of severe adverse events, higher costs, and anticancer efficacy that is limited to PIK3CA-mutated tumors when compared to the “old” everolimus. Therefore, the everolimus-exemestane combination remains an effective and reasonably well-tolerated therapeutic option for HR+ HER2− mBC patients progressing after/on previous AI treatment, independently of PIK3CA mutational status.

Background: Single-agent capecitabine (C) is a moderately effective chemotherapeutic compound in the treatment of patients with HER2-negative metastatic breast cancer (mBC). The capecitabine-vinorelbine (CV) combination is also used due to a good tolerability profile, but no studies have demonstrated its superiority over single-agent C. Methods: We conducted a retrospective analysis to compare overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and incidence of adverse events (AEs) in patients with HER2-negative mBC treated with CV vs. single-agent C. Results: Out of 290 patients included in this study, 127 (43.8%) received single-agent C, while 163 (56.2%) patients were treated with CV. Median PFS was similar in patients treated with single-agent C or CV, while CV was associated with significantly longer OS in patients with hormone receptor-positive (HR+) BC. This OS advantage was confirmed at multivariable analysis also after propensity score-based matching of patients according to relevant clinical or tumor characteristics. When compared with single-agent C, CV was associated with higher incidence of G3/G4 and any-grade nausea/vomiting, diarrhea and increased transaminases. Conclusions: While prospective studies are needed to confirm our findings, the potential OS advantage of CV over single-agent C in HR+ mBC patients must be weighed against a significantly higher incidence of AEs.

Background: HPD has been described in 14-26% of NSCLC pts upon single agent ICI and correlates with poor survival. Currently, HPD occurrence has not been explored upon ICI-PCT and biomarkers of HPD are lacking. Although high circulating neutrophils (Ns) correlated with HPD in NSCLC pts, the role of specific Ns subsets is unknown. Methods: NSCLC pts treated with 1st line ICI as single agent or in combination with PCT were assessed for HPD and circulating Ns' phenotype. Tumor response was evaluated by RECIST 1.1. HPD required 3 assessment (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) (TGR upon ICI - TGR before ICI) >50% and/or TGR ratio (TGR upon ICI/TGR before ICI) ≥2. Circulating low density Ns (LDNs) subtypes were assessed by flow cytometry (FC) on peripheral blood mononuclear cells (PBMCs). LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10- LDNs. Fatty acids (FA) (bodipy-palmitate) uptake was assessed by FC. T-cells of healthy donors were isolated and activated in vitro with CD3/CD28 beads in presence or not of pts' Ns to characterize their interplay. Results: Of 63 NSCLC pts, 22% had PD-L1 on tumor cells ≥50%. In the ICI single agent cohort (N=46), PD and HPD occurred in 21 (41%) and 4 (9%) pts, respectively. Before ICI start, HPD pts had significantly higher median percentage (%) of circulating immature CD10- LDNs [43.5 (min 29.5; max 82.6) vs 10.3 (min 0.1; max 79.4), p=0.01] compared to PD pts. In the ICI-PCT cohort (N=17), PD occurred in 4 (23%) pts, no HPD was reported. 5 pts had baseline CD10- LDNs ≥ 43.5% (median % of CD10- LDNs in HPD pts upon single agent ICI), 2 of them had SD and 3 PD upon ICI-PCT. In these 5 pts, CD10- LDNs significantly decreased during ICI-PCT compared to what observed in HPD pts during single agent ICI [median variation -43.4 (min -67.6, max -31.6) vs +6.9 (min -33, max +44), p= 0.03]. CD10- LDNs did not impair T-cells proliferation and IFNγ production, measured after 7 days of coculture but significantly reduced T-cell survival compared to CD10+LDNs. Baseline metabolic profile assessment showed that immature CD10- LDNs had a predominant lipid metabolism with a higher FA uptake [bodipy-palmitate mean florescence intensity (MFI) ± standard deviation (SD): 46754±11562] compared to lymphocytes [bodipy-palmitate MFI ±SD: 11542±405]. Conclusion: Higher baseline immature CD10- LDNs is a circulating biomarker of HPD upon single agent ICI. The addition of PCT prevents HPD reducing the immature Ns subset. The FA metabolism of immature LDNs does not affect T-cells proliferation/activation but reduces T-cells survival, suggesting that these two processes are differently regulated and that immature Ns reduce T-cells life span by metabolic competition. Citation Format: Roberto Ferrara, Elena Jachetti, Giuseppina Calareso, Marta Brambilla, Giuseppe Lo Russo, Claudia Proto, Arsela Prelaj, Diego Signorelli, Giulia Galli, Alessandro De Toma, Mario Occhipinti, Sara Manglaviti, Alice Labianca, Monica Ganzinelli, Sestina Maria Spanò, Giuliano Molino, Antonia Martinetti, Francesca Gabriella Greco, Marta Bini, Teresa Beninato, Filippo de Braud, Mario Paolo Colombo, Marina Chiara Garassino, Sabrina Sangaletti. Immunometabolism of circulating neutrophils in hyperprogressive disease (HPD) upon first-line PD-1/PD-L1 inhibitors (ICI) alone or in combination with platinum-based chemotherapy (PCT) in non-small cell lung cancer (NSCLC) patients (pts) [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 1669.

Background On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti–epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice. Patients and Methods A real-life database of 5530 patients treated at 6 institutions was queried. Included were patients who were retreated with anti-EGFRs, who had RAS/BRAF wild-type–status tissue samples, who had received a first-line anti-EGFR–based regimen with at least stable disease as best response, and who had received at least one further line of therapy before anti-EGFR retreatment. The association with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of variables potentially related to anti-EGFR sensitivity was investigated. Results A total of 86 patients were identified. The ORR during anti-EGFR retreatment was 19.8%; median PFS and OS were 3.8 and 10.2 months, respectively. No significant association of clinical features of anti-EGFR sensitivity with ORR, PFS, and OS was observed. Among the 56 patients with a time from the last anti-EGFR administration to first-line progressive disease of 2 prior therapy lines and a longer anti-EGFR–free interval were associated with higher ORR, but not with longer PFS or OS. Conclusion Clinical features we deemed surrogates of anti-EGFR sensitivity were not reliable predictors of benefit from anti-EGFR retreatment.

(1) Background. The onset of a drug–drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line, ECOG PS 0–2, taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN®. (3) Results. Ninety-two patients, median age of 68.5 years (range 43–89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified, the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02, HR 0.281, 95% CI 0.096–0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.

Introduction In advanced Non-Small Cell Lung Cancer (aNSCLC), Programmed Death Ligand 1 (PD-L1) remains the only used biomarker to candidate patients (pts) to immunotherapy (IO) even if its predictive accuracy is not satisfactory. Indeed, given the complex dynamics underlying the cross-talk between the tumor and its microenvironment, it is unlikely that a single biomarker could be able to profile prediction with high precision. Artificial Intelligence (AI) and machine learning (ML) are techniques able to analyze and interpret big data, which cope with this complexity. The present study aims at using AI tools to improve response and efficacy prediction in aNSCLC pts treated with IO. Methods A classification task to determine if a pt is likely to benefit from IO was formulated using complete clinical data, PD-L1, histology, molecular data, and the blood microRNA signature classifier (MSC), which include 24 different microRNAs. Pts were divided into responders (R), who obtained a partial response or stable disease as best response, and non-R, who experienced progressive disease. A forward feature selection technique based on the Akaike Information Criterion was used to extract a specific subset of the pts data, being the most informative ones for the task. To develop the final predictive model, different ML methods have been tested: K-nearest neighbors, Logistic Regression, Kernel Support Vector Machines, Feedforward Neural Network, and Random Forest. Results Of 164 enrolled pts, 73 (44.5%) were R and 91 (55.5%) non-R. At data cut-off (Nov 2020), median Overall Survival (mOS) was 10.1 (95%IC 7.0 - 13.2) months (m). mOS for R pts was 38.5 m (95%IC 23.9 - 53.1) vs 3.8 m (95%IC 2.8 - 4.7) of non-R, p Citation Format: Arsela Prelaj, Mattia Boeri, Alessandro Robuschi, Claudia Proto, Giuseppe Lo Russo, Roberto Ferrara, Giulia Galli, Alessandro De Toma, Marta Brambilla, Mario Occhipinti, Sara Manglaviti, Alice Labianca, Teresa Beninato, Marta Bini, Mavis Mensah, Monica Ganzinelli, Nicoletta Zilembo, Filippo de Braud, Gabriella Sozzi, Marcello Restelli, Alessandra Pedrocchi, Marina Chiara Garassino, Francesco Trovo. Artificial intelligence to improve selection for NSCLC patients treated with immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-065.

Background Metastatic pancreatic cancer (mPAC) is a devastating disease with few therapeutic options. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene and there are reports of MGMT alterations in various gastrointestinal cancers, including colorectal cancer and mPAC. Low MGMT expression by immunohistochemistry (IHC) and MGMT promoter methylation ultimately result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This report presents data on MGMT testing mPAC pts admitted at our center. Methods Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), to assess MGMT promoter methylation, and IHC, to assess protein expression. Furthermore, Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI) were performed. Results Archived FFPE tissue sections obtained from 90 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to April 2019 were analyzed. At the time of this report, 60 samples (66%) had adequate tissue for extended analyses. As expected, 55 (92%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 (5%), 4( 6%) and 2 (3%) pts, respectively. MGMT promoter methylation was found in 21 pts (35%), of which 13 (61%) had low/negative MGMT protein expression. Of note, amongst MGMT methylated pts, there were 5 (23%) BRCA1/2 somatic mutant and 2 (9%) MSI, suggesting possible genomic instability. Conclusions MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 35% of patients with mPAC. This data warrant further prospective confirmation; nevertheless, considering the growing interest in the role of DNA-damage response genes in mPAC, there is definitely a rationale in investigating MGMT methylation as a predictive and prognostic biomarker in mPAC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Morano: Honoraria (self): Servier. F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy: Servier; Research grant / Funding (institution): BMS. F.G.M. De Braud: Advisory / Consultancy: TizianaLife Sciences; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy: Amgen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Octimet Oncology; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: AstraZeneca. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Background Biliary Tract Cancers (BTC) are a devastating and molecularly heterogeneous group of diseases, with significant differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and Gall bladder (GB) cancer. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Reductions in MGMT expression and MGMT promoter methylation result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This alterations have been described in BTC in small reports with variable frequencies. Here we present data on MGMT methylation tested in BTC pts admitted at our center. Methods MGMT promoter methylation was studied via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), while protein expression was assessed with immunohistochemistry (IHC). Formalin-fixed paraffin-embedded (FFPE) tissue samples were also examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®”). Results Archived FFPE tissue sections from 100 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to February 2019 were analyzed. Amongst the 89 samples with adequate tissue, 73% were ICC, 16% were ECC and 8 % were GC. 34 pts (38%) had MGMT promoter methylation, while low/negative MGMT protein expression was found in 45 pts (50%). MGMT methylation was identified in 38% of ICC, 26% of ECC and 62% of GC. As expected, we identified IDH1/2 mutations in 15%, all affected by ICC. Of note, amongst MGMT methylated pts, there were 4 pts (11%) with concomitant IDH1/2 mutations, which are reported to be associated with CpG Island Methylator Phenotype. Conclusions MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in gastrointestinal cancer, with phase II studies showing a response rate of 10% in chemorefractory MGMT- methylated colorectal cancer treated with TMZ. In our single center experience, MGMT methylation was found in 38% of patients with BTC. This data warrant further confirmation, but there is a growing interest in novel targeted therapies exploiting the role of MGMT methylation as a predictive and prognostic biomarker in BTC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Morano: Honoraria (institution): Servier. F. Pietrantonio: Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: EMD Serono; Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Servier; Research grant / Funding (self): BMS. M. Di Bartolomeo: Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: ACCMED; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Fondazione Menarini; Speaker Bureau / Expert testimony: MSD. All other authors have declared no conflicts of interest.