The tight junction protein claudin-18 (CLDN18), is often expressed in various cancer types including gastric (GC) and gastroesophageal adenocarcinomas (GECs). In the last years, the isoform CLDN18.2 emerged as a potential drug target in metastatic GCs, leading to the development of monoclonal antibodies against this protein. CLDN18.2 is the dominant isoform of CLDN18 in normal gastric and gastric cancer tissues. In this work, we evaluated the immunohistochemical (IHC) profile of CLDN18 and its correlation with clinical and histopathological features including p53, E-cadherin, MSH2, MSH6, MLH1, PMS2, HER2, EBER and PD-L1 combined positive score, in a large real-world and mono-institutional series of advanced GCs (n = 280) and GECs (n = 70). The association of IHC results with survival outcomes was also investigated. High membranous CLDN18 expression (2+ and 3+ intensity ≥75%) was found in 117/350 (33.4%) samples analyzed. CLDN18 expression correlated with age <70 (p = 0.0035), positive EBV status (p = 0.002), high stage (III, IV) at diagnosis (p = 0.003), peritoneal involvement (p < 0.001) and lower incidence of liver metastases (p = 0.013). CLDN18 did not correlate with overall survival. The predictive value of response of CLDN18 to targeted agents is under investigation in several clinical trials and further studies will be needed to select patients who could benefit from these therapies.

Background: FLOT regimen is the standard perioperative treatment in Western countries for patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC). High microsatellite instability (MSI-H) and Mismatch Repair deficient (dMMR) demonstrated a favorable prognostic role and a concomitant negative predictive impact on the benefit of perioperative 5-fluorouracil-based doublets; however, its role in pts receiving FLOT chemotherapy is still unclear. Methods: This is a retrospective, multicenter observational study of 265 pts with GC/GEJC treated with perioperative FLOT regimen in 11 Italian oncology centers between January 2017 to December 2021 and analyzed for microsatellite status. Results: The MSI-H phenotype was found in 27 (10.2%) of 265 analyzed tumors. Compared to microsatellite stable (MSS) and Mismatch Repair proficient (pMMR) cases, MSI-H/dMMR were more frequently female (48.1% vs. 27.3%, p = 0.0424), elderly pts (age > 70 years, 44.4% vs. 13.4%, p = 0.0003), Laurens’s intestinal type (62.5% vs. 36.1%, p = 0.02) and pts with a primary location tumor in the antrum (37 vs. 14.3%, p = 0.0004). A statistically significant difference in the rate of pathologically negative lymph node emerged (63% vs 30.7%, p = 0.0018). Compared to the MSS/pMMR tumor population, the MSI-H/dMMR subgroup had a better DFS (median not reached [NR] vs. 19.5 [15.59–23.59] mos, p = 0.031) and OS (median NR vs. 34.84 [26.68–47.60] mos, p = 0.0316). Conclusions: These real-world data confirm that FLOT treatment is effective in daily clinical practice for locally advanced GC/GEJC, also in the MSI-H/dMMR subgroup. It also showed a higher rate of nodal status downstaging and a better outcome of MSI-H/dMMR pts in comparison to MSS/pMMR.

Background The efficacy of immune checkpoint inhibitors (ICIs) in patients with microsatellite instability (MSI)-high metastatic colorectal cancer (mCRC) is unprecedented. A relevant proportion of subjects achieving durable disease control may be considered potentially ‘cured’, as opposed to patients experiencing primary ICI refractoriness or short-term clinical benefit. We developed and externally validated a nomogram to estimate the progression-free survival (PFS) and the time-independent event-free probability (EFP) in patients with MSI-high mCRC receiving ICIs. Methods The PFS and EFP were estimated using a cure model fitted on a developing set of 163 patients and validated on a set of 146 patients with MSI-high mCRC receiving anti-programmed death (ligand)1 (PD-(L)1) ± anticytotoxic T-lymphocyte antigen 4 (CTLA-4) agents. A total of 23 putative prognostic factors were chosen and then selected using a random survival forest (RSF). The model performance in estimating PFS probability was evaluated by assessing calibration (internally—developing set and externally—validating set) and quantifying the discriminative ability (Harrell C index). Results RFS selected five variables: ICI type (anti-PD-(L)1 monotherapy vs anti-CTLA-4 combo), ECOG PS (0 vs >0), neutrophil-to-lymphocyte ratio (≤3 vs >3), platelet count, and prior treatment lines. As both in the developing and validation series most PFS events occurred within 12 months, this was chosen as cut-point for PFS prediction. The combination of the selected variables allowed estimation of the 12-month PFS (focused on patients with low chance of being cured) and the EFP (focused on patients likely to be event-free at a certain point of their follow-up). ICI type was significantly associated with disease control, as patients receiving the anti-CTLA-4-combination experienced the best outcomes. The calibration of PFS predictions was good both in the developing and validating sets. The median value of the EFP (46%) allowed segregation of two prognostic groups in both the developing (PFS HR=3.73, 95% CI 2.25 to 6.18; p<0.0001) and validating (PFS HR=1.86, 95% CI 1.07 to 3.23; p=0.0269) sets. Conclusions A nomogram based on five easily assessable variables including ICI treatment was built to estimate the outcomes of patients with MSI-high mCRC, with the potential to assist clinicians in their clinical practice. The web-based system ‘MSI mCRC Cure’ was released.

PURPOSE: Patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) resectable gastroesophageal adenocarcinoma (GEA) have better survival after surgery and scant/no benefit from chemotherapy. Preoperative immune checkpoint inhibitors (ICIs) demonstrated a high proportion of major complete pathologic response, possibly allowing chemotherapy/surgery-free approaches. METHODS: Individual patient data pooled analysis was performed to determine an optimal strategy for resectable dMMR/MSI-H GEA. Patients were stratified across four groups: neoadjuvant dual CTLA-4/PD-(L)1 ICIs with or without surgery, perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) and surgery, and surgery alone or with older perioperative/adjuvant chemotherapy regimens. Primary end points were pathologic complete and major complete pathologic response proportion (pathologic complete response [pCR], tumor regression grade [TRG]1a, major pathologic response [MPR], TRG1a/b Becker criteria) in resected patients. Secondary end points were event-free survival (EFS) and overall survival (OS) in the overall population. RESULTS: Among 197 patients, 49 received ICIs, 27 FLOT, 33 surgery alone, and 88 older chemotherapy regimens. Among 69 patients who underwent surgery after ICIs or FLOT, ICIs demonstrated significantly higher pathologic response versus FLOT (pCR, 61.9% v 3.7%; odds ratio [OR], 54.8; P = .002; MPR, 78.6% v 10%; OR, 39.3; P < .001) and lower ypN+ (14.3% v 37%; OR, 4.2; P = .015) and ypT (OR, 16.4; P < .001) stage. No significant differences in EFS/OS were observed (the 36-month EFS and OS were 70.4% v 80.6% and 72.7% v 90.4% with ICI v surgery alone). Residual nodal disease (ypN+) or ypT4 status after neoadjuvant ICIs or FLOT and nonpathologic response status were associated with inferior progression-free survival/OS. CONCLUSION: In resectable dMMR/MSI-H GEA, neoadjuvant ICIs significantly increase pathologic response and downstaging versus FLOT, with comparable EFS/OS with surgery with or without chemotherapy. The higher proportion of ypN0 and lack of ypT4 after neoadjuvant ICIs versus FLOT should drive preoperative treatment choices in clinical high-risk disease. The high proportion of pCR/MPR with ICIs provides rationale for exploring organ-sparing surgery or nonoperative management.