Background Patients with solid or hematological tumors or neurological and immune-inflammatory disorders are potentially fragile subjects at increased risk of experiencing severe coronavirus disease 2019 and an inadequate response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Methods We designed a prospective Italian multicenter study to assess humoral and T-cell responses to SARS-CoV-2 vaccination in patients (n = 378) with solid tumors (ST), hematological malignancies (HM), neurological disorders (ND), and immunorheumatological diseases (ID). A group of healthy controls was also included. We analyzed the immunogenicity of the primary vaccination schedule and booster dose. Results The overall seroconversion rate in patients after 2 doses was 62.1%. Significantly lower rates were observed in HM (52.4%) and ID (51.9%) than in ST (95.6%) and ND (70.7%); a lower median antibody level was detected in HM and ID versus ST and ND (P < .0001). Similar rates of patients with a positive SARS-CoV-2 T-cell response were found in all disease groups, with a higher level observed in ND. The booster dose improved the humoral response in all disease groups, although to a lesser extent in HM patients, whereas the T-cell response increased similarly in all groups. In the multivariable logistic model, independent predictors of seroconversion were disease subgroup, treatment type, and age. Ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (P < .0001) but had no effect on T-cell responses. Conclusions Immunosuppressive treatment more than disease type per se is a risk factor for a low humoral response after vaccination. The booster dose can improve both humoral and T-cell responses.

Background: Patients with solid or hematological tumors, neurological and immune-inflammatory disorders represent potentially fragile subjects with increased risk to experience severe COVID-19 and inadequate response to SARS-CoV2 vaccination. Methods: We designed a prospective Italian multicentric study to assess humoral and T-cell response to SARS-CoV2 vaccination in patients (n=378) with solid tumors (ST), hematological malignancies (HM), neurological (ND) and immuno-rheumatological diseases (ID). The immunogenicity of primary vaccination schedule and of the booster dose were analyzed. Results: Overall, patient seroconversion rate after two doses was 62.1%. A significant lower rate was observed in HM (52.4%) and ID (51.9%) patients compared to ST (95.6%) and ND (70.7%); a lower median level of antibodies was detected in HM and ID versus the others (p<0.0001). A similar rate of patients with a positive SARS-CoV2 T-cell response was observed in all disease groups, with a higher level observed in the ND group. The booster dose improved humoral responses in all disease groups, although with a lower response in HM patients, while the T-cell response increased similarly in all groups. In the multivariable logistic model, the independent predictors for seroconversion were disease subgroups, type of therapies and age. Notably, the ongoing treatment known to affect the immune system was associated with the worst humoral response to vaccination (p<0.0001), but had no effects on the T-cell responses. Conclusions: Immunosuppressive treatment more than disease type per se is a risk factor for low humoral response after vaccination. The booster dose can improve both humoral and T-cell response.

Background: Systemic immunosuppression characterizing cancer patients represents a concern regarding the efficacy of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, and real-world evidence is needed to define the efficacy and the dynamics of humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines. Methods: We conducted an observational study that included patients with solid tumors who were candidates for mRNA anti-SARS-CoV-2 vaccination at the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. The primary objective was to monitor the immunologic response to the mRNA anti-SARS-CoV-2 vaccination in terms of anti-spike antibody levels. All the patients received two doses of the mRNA-1273 vaccine or the BNT162b2 vaccine. Healthcare workers served as a control group of healthy subjects. Results: Among the 243 patients included in the present analysis, 208 (85.60%) and 238 (97.94%) resulted seroconverted after the first and the second dose of vaccine, respectively. Only five patients (2.06%) had a negative titer after the second dose. No significant differences in the rate of seroconversion after two vaccine doses were observed in patients as compared with the control group of healthy subjects. Age and anticancer treatment class had an independent impact on the antibody titer after the second dose of vaccination. In a subgroup of 171 patients with available data about the third timepoint, patients receiving immunotherapy with immune checkpoint inhibitors seem to have a higher peak of antibodies soon after the second dose (3 weeks after), but a more pronounced decrease at a late timepoint (3 months after). Conclusions: The systemic immunosuppression characterizing cancer patients did not seem to dramatically affect the humoral response to anti-SARS-CoV-2 mRNA vaccines in our population of patients with solid tumors. Further investigation is needed to dissect the interplay between immunotherapy and longitudinal dynamics of humoral response to mRNA vaccines, as well as to analyze the cellular response to mRNA vaccines in cancer patients.

Background uterine tumor resembling sex-cord tumors of the ovary (UTROSCT) is a rare form of mesenchymal uterine tumor of uncertain malignancy. Sporadic cases of advanced disease are reported, but little is known about its management in the metastatic setting. Pazopanib is a multi-tyrosine kinase inhibitor (TKI), approved for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcomas, which affects several targets, including VEGFR1-2-3, PDGFRα-β and FGFR1-3. Case Presentation here we report a case of metastatic UTROSCT with strong and prolonged clinical response to pazopanib. Conclusions these findings suggest that this anti-angiogenic approach should be considered in planning future therapeutic strategies for this rare disease. Furthermore, we noted the importance of including patients with rare diseases in clinical trials and investigating molecular pathogenesis.

Background: Several genomic alterations beyond RAS and BRAFV600E mutations have been preclinically validated as primary resistance drivers to EGFR inhibition in mCRC. We showed that our PRESSING panel (including PIK3CA exon 20/AKT1/PTEN mutations, ERBB2/MET amplification and ALK/ROS1/RET/NTRKs fusions) is useful to promote a new paradigm of negative hyper-selection, since patients with RAS/BRAF wt MSS mCRC and PRESSING alterations achieve significantly worse survival upon anti-EGFRs. With the aim of further refining molecular selection (negative ultra-selection), we investigated the clinical impact of candidate resistance alterations with even lower frequency (PRESSING2 panel) in a cohort of hyper-selected patients. Methods: A prospective dataset was developed at 3 Italian Academic Hospitals and included 650 mCRC patients with comprehensive genomic profiling of FFPE tumor tissue by means of FoundationOne CDx. We selected those with RAS/BRAF wt, MSS and PRESSING negative treated with anti-EGFRs. Alterations of the PRESSING2 panel were selected based on their actionability and biological value, as follows: ALK, ROS1, NTRKs, ERBB2/3/4, NF1, ARAF, MAP2K1 pathogenic mutations, PTEN loss, KRAS and AKT1-2 amplification, FGFR2 amplification/fusions, EGFR fusions. PRESSING2 status was correlated with progression-free survival (PFS) and overall survival (OS). Results: 163 molecularly hyper-selected patients with PRESSING negative status were identified; 30 (18%) had PRESSING2 alterations, which were mutually exclusive in 26 (87%) samples. No significant differences in baseline clinical and pathological characteristics - including sidedness - were found in PRESSING2 positive vs negative patients. The median follow-up was 34.6 months (IQR 23.5-49.3). Patients with PRESSING2 positive status had significantly worse PFS and OS vs those with PRESSING2 negative disease (median PFS 7.0 and 13.0 months; HR 3.54, 95%CI 2.26-5.52, P&lt;0.001; median OS 24.5 and 51.2 months; HR 2.91, 95%CI 1.64-5.18, P&lt;0.001). In the multivariable model, the adjusted HRs were 3.40 for PFS and 2.71 for OS, respectively. 121 (74%) patients received an anti-EGFR agent upfront. In this first-line cohort, median PFS were 8.1 vs 13.2 months for PRESSING2 positive and negative subgroups (HR 3.24, 95%CI 1.89-5.57; P&lt;0.001; adjusted HR 2.96), whereas median OS were 26.2 vs 49.9 months, respectively (HR 2.28, 95%CI 1.15-4.54, P=0.018; adjusted HR 2.34). Conclusions: In the era of comprehensive genomic profiling, several resistance alterations with extremely low prevalence may be detected, especially in CRCs that do not bear other genomic drivers. Negative ultra-selection may represent a relevant step forward in precision medicine in patients with RAS/BRAF wt MSS mCRC potentially eligible for EGFR blockade. Citation Format: Giovanni Randon, Giulia Maddalena, Marco Maria Germani, Filippo Pagani, Francesca Bergamo, Mirella Giordano, Chiara Pircher, Caterina Sposetti, Luca Zambelli, Francesca Corti, Marta Bini, Alessandro Rametta, Andrea Spagnoletti, Aldo Montagna, Matteo Fassan, Alessandra Boccaccino, Guglielmo Vetere, Silvia Damian, Massimo Milione, Filippo de Braud, Chiara Cremolini, Sara Lonardi, Filippo Pietrantonio. Negative ultra-selection of patients with RAS/BRAF wild-type (wt), microsatellite stable (MSS) metastatic colorectal cancer (mCRC) receiving anti-EGFR-based therapy: The PRESSING2 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1269.