Resected Pancreatic Adenocarcinoma Patients Research Articles

Specific human leukocyte antigen class I genotypes predict prognosis in resected pancreatic adenocarcinoma: a retrospective cohort study.

Patients with resected pancreatic adenocarcinoma (PAAD) often experience short-term relapse and dismal survival, suggesting an urgent need to develop predictive and/or prognostic biomarkers for these populations. Given the potential associations of the human leukocyte antigen class I ( HLA -I) genotype with oncogenic mutational profile and immunotherapy efficacy, we aimed to assess whether differential HLA -I genotype could predict the postoperative outcomes in resected PAAD patients. HLA -I ( A , B , and C ) genotyping and somatic variants of 608 Chinese PAAD patients were determined by targeted next-generation sequencing of matched blood cells and tumor tissues. HLA - A / B alleles were classified with the available definition of 12 supertypes. The Kaplan-Meier curves of disease-free survival (DFS) and multivariable Cox proportional-hazards regression analyses were performed to determine the survival difference in 226 selected patients with radical resection. Early-stage (I-II) patients constituted the majority (82%, 185/226) and some stage I-II individuals with high-quality tumor samples were analyzed by RNA-sequencing to examine immunophenotypes. Patients with HLA-A02 + B62 + B44 - had significantly shorter DFS (median, 239 vs. 410 days; hazard ratio=1.65, P =0.0189) than patients without this genotype. Notably, stage I-II patients carrying HLA-A02 + B62 + B44 - had sharply shorter DFS than those without HLA-A02 + B62 + B44 - (median, 237 vs. 427 days; hazard ratio=1.85, P =0.007). Multivariate analysis revealed that HLA-A02 + B62 + B44 - was associated with significantly inferior DFS ( P =0.014) in stage I-II patients but not in stage III patients. Mechanistically, HLA-A02 + B62 + B44 - patients were associated with a high rate of KRAS G12D and TP53 mutations, lower HLA-A expression, and less inflamed T-cell infiltration. The current results suggest that a specific combination of germline HLA-A02/B62/B44 supertype, HLA-A02 + B62 + B44 - , was a potential predictor for DFS in early-stage PAAD patients after surgery.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients

BackgroundActivities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients MethodA single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. Results742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56–0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53–0.86],p = 0.002) for overall survival. ConclusionIn this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

Perioperative blood transfusions and survival in resected pancreatic adenocarcinoma patients given multimodality therapy.

The impact of perioperative blood transfusion (PBT) on outcomes for pancreatic ductal adenocarcinoma (PDAC) patients given multimodality therapy (MMT) remains undefined. We sought to evaluate the association of PBT with survival after PDAC resection. Pancreatectomy patients (July 2011-December 2017) who received MMT were abstracted from a prospective database. Overall survival (OS) was compared by PBT within 30 days, 24 h (24HR-BT), or 24 h until 30 days (Postop-BT). Most (76.6%) of 312 MMT patients underwent neoadjuvant therapy (NT). Eighty-nine patients (28.5%) received PBT; 58 (18.6%) 24HR-BT, and 31 (9.9%) Postop-BT. Compared with surgery-first, NT patients received more 24HR-BTs (22.2% vs. 6.8%, p = 0.003) and PBTs overall (32.6% vs. 15.1%, p = 0.004). Overall median OS was 45 months. The association of PBT with shorter median OS appeared limited to first 24-h transfusions (34 months 24HR-BT vs. 48 months Postop-BT vs. 53 months no-PBT, p = 0.009) and was dose-dependent, with a median OS of 52 months for 0 units 24HR-BT, 35 months for 1 unit, and 25 months for ≥2 units (p = 0.004). Independent predictors of OS included node-positivity (hazard ratio [HR]: 1.93, p < 0.001), perineural invasion (HR: 1.64, p = 0.050), postoperative pancreatic fistula (HR: 1.94, p = 0.018), and 24HR-BT (HR: 1.75, p = 0.001). Transfusions given within 24 h are associated with dose-dependent decreases in survival after pancreatectomy for PDAC.

Abstract 2678: Tumoral CXCR4 and CXCL12 but not CXCR7 nor PD-L1 expression predicts disease free survival (DFS) and cancer specific survival (CSS) in resected pancreatic adenocarcinoma patients

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumor types and the 4th leading cause of tumor-related mortality in developed nations. PDAC is characterized by a highly fibrotic stroma that can physically exclude cytotoxic T cells from the vicinity of tumor cells. Targeting the axis CXCR4-CXCL12 improved T cell access to PDAC Tumor Microenvironment (TME) making tumors more susceptible to anti-PD-1/anti PD-L1 therapy. With the intent to evaluate the role of the entire CXCR4-CXCL12-CXCR7 axis in a context of PD-1/PD-L1 expression, 80 primary pancreatic cancers were evaluated in cancer cells and TME. Methods: 80 primary PDAC samples from patients undergone surgery collected at Ospedale P. Pederzoli Peschiera del Garda (Verona, Italy) were included in the study. Immunohistochemistry was conducted using primary antibodies: Anti-CXCR7/RDC-1 clone 11G8; Anti-CXCL12 Clone #79018; two commercial anti-CXCR4 clones #44716 and the UMB-2; two commercial anti-PD-L1, clone E1L3N and 22C3. Results: CXCR4 was expressed in 53 out of 73 tumors (72.6%). CXCL12 was predominantly identified into the membrane of cancer cells in 16 out of 75 (21.3%) tumors. CXCR7 staining was detectable in 44 out of 76 (57.8%) tumors. PD-L1 identified into the membrane of cancer cells in 35 out of 70 (50%) tumors. Patients with high CXCR4 tumor expression experienced worse outcome (DFS: 11.77 vs 22.85 months p=0.0071; CSS: 21.83 vs 35 months p&amp;gt;0.05, not significant) and predicted short DFS in R0 patients subgroup (n=48) (DFS: 11.20 months vs 33.40 months p=0.0140). CXCL12 expression predicted DFS (p=0.0002) and CSS (p=0.0046). Of note CXCL12 predicted short DFS (p=0.0015) and CSS (p=0.0213) in R0 patient's subgroup (n=48). Although stromal expression of CXCR4, CXCL12 and CXCR7 were not prognostic, CXCR4 positive inflammatory cells and tumoral CXCL12 significantly and directly correlated with the vascular invasion. Neither tumoral nor stromal expression of PD-L1 was prognostic but PD-L1 interestingly stained the perineural invasion and tumor-infiltrating inflammatory cells of body or tail tumors. In multivariate analysis, tumoral CXCR4 expression (p=0.0043), perineural invasion (p=0.0030) and AJCC lymph node status (p=0.0016) were independent prognostic factors for DFS. Tumoral CXCL12 expression (p=0.01467), AJCC Stage (p=0.0004) and perineural infiltration (p=0.03164) were independent prognostic factors for CSS. Conclusion: Tumoral CXCR4 and CXCL12 were prognostic factors at the univariate and multivariate analysis as for DFS and CSS in PDAC. Stromal PD-L1 stained perineural infiltration and stromal CXCR4 characterized inflammatory cells in the vascular invasion. Thus tumoral and stromal characterization for CXCR4 and CXCL12 in PDAC is worth to identify prognostic categories and to orient therapeutic approach. Citation Format: Crescenzo D'Alterio, Alessandro Giardino, Giosuè Scogmaliglio, Fabiana Tatangelo, Giovanni Butturini, Luigi Portella, Giuseppe Guardascione, Isabella Frigerio, Stefano Gobbo, Gerardo Botti, Stefania Scala. Tumoral CXCR4 and CXCL12 but not CXCR7 nor PD-L1 expression predicts disease free survival (DFS) and cancer specific survival (CSS) in resected pancreatic adenocarcinoma patients [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 2678.

Clinical Implications of NRAS Overexpression in Resectable Pancreatic Adenocarcinoma Patients.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and its incidence is rising worldwide. Although survival can be improved by surgical resection, when detected at an early stage, this type of cancer is usually asymptomatic, and disease becomes only apparent after metastasis. Adjuvant treatment does not improve survival, thus after surgery there is a lack of predictive and prognosis biomarkers to predict treatment response and survival. The mitogen-activated protein-kinase and phosphoinositide 3-kinase signalling pathways play a crucial role in cancer development and progression. Especially, activated RAS proteins promote cell proliferation through constitutive stimulation of the downstream effectors RAF-MEK-ERK and PI3K-AKT. Mutational status of NRAS is required in several types of cancer like colorectal or cutaneous melanoma. However, mutations in this gene are very scarce in PDAC patients, and NRAS determination is not usually performed in clinical practice for this kind of tumor. In this study, we analyse the association between NRAS protein expression and progression-free survival and overall survival of an homogenous cohort of pancreatic ductal adenocarcinoma patients from a single-centre. Interestingly, we found that patients with high expression not only showed longer progression-free survival than those patients with low expression (22 versus 9months, respectively) (P=0.013), but also longer overall survival (43 versus 19months, respectively) (P=0.020). These results confirm NRAS expression could be used to differentiate patients according to their prognosis. Proportional hazard model revealed NRAS expression together with grade of differentiation as pathological variables to predict patient's outcome.

A novel role of the tumor size in pancreatic cancer as an ancillary factor for predicting resectability.

Pancreatic adenocarcinoma (PCA) is a devastating disease. Only surgery can provide effective treatment. The resectability of pancreatic cancer is mainly determined by image studies. However, half of the patients deemed as operable, radiologically, are found to be inoperable during surgery. Previously, we have showed that both CA 19-9 and tumor size could predict PCA resectability, independently. Here, we aimed to determine the cut-off value for tumor size permitting PCA resectability by receiver operating characteristic (ROC) curve analysis. We retrospectively reviewed 372 patients undergoing surgery for histopathologically proven PCA. We compared tumor sizes of patients in resectable and unresectable groups and analyzed them by the ROC curve. The tumor size in unresectable groups is significantly larger than that in the resectable group. The area under the ROC curve was 0.73 (95% confidence interval [CI], 0.665-0.789), which represented a good correlation between the tumor size and pancreatic cancer resectability. The PCA patients with a tumor diameter of > 4.8 cm had a 5.043-fold higher chance of unresectability than did those with a tumor diameter < 4.8 cm (odds ratio, 5.043; 95% CI, 3.221-7.894). A tumor diameter > 4.8 cm is a potential ancillary parameter for determining the resectability of PCA in addition to traditional image studies. Diagnosis laparoscopy may be indicated for radiologically resectable PCA patients with tumor size > 4.8 cm to prevent unnecessary laparotomy.

Correlation of CXCR4 expression in resected pancreatic adenocarcinoma (PA) with relapse and survival after adjuvant radiochemotherapy (RCT)

e22022 Background: The chemoreceptors CXCR4, CXCR7 and the hypoxia inductible factor-1 alpha (HIF-1α) are implicated in PA growth, dissemination and angiogenesis. These protagonists are expected to play a key role in radiotherapy and chemotherapy resistance in PA. Methods: We conducted a retrospective study of patients undergoing curative surgery (R0 resection) for PA between 2001 and 2006 in our institution. All were treated with adjuvant RCT (treatment group). The treatment group was case-matched with resected PA patients who did not receive any adjuvant therapy (control group). FFPE specimens were subjected to immunohistochemical analysis using tissue microarray and monoclonal antibodies against human CXCR4, CXCR7, and HIF-1α. Based on the intensity (I) and the extend (E) of staining, cases were stratified into those with high (E x I&gt;3) or low (E x I ≤ 3) expression of CXCR4, CXCR7 and HIF-1α and results were correlated with disease-free survival (DFS) and overall survival (OS). Results: 31 PA patients (median age: 57years, range: 39–76) were analysed in the treatment group and 30 (median age: 59 years, range: 38–81) in the control group. The two groups were well-matched in terms of age, sex, tumor stage (T1-T2 vs T3-T4), tumor differentiation (poor vs well-moderate), lymph node (LN) status (N0 vs N+), lymphatic and vascular embols. In univariate analysis, CXCR4 expression and LN status were associated with DFS and OS (OS, CXCR4low/high: HR, 5.43, 95%CI: 2.03–14.49, p=0.001; N0/N+: HR: 4.62, 95% CI, 1.33–13.12, p=0.016; DFS: CXCR4low/ CXCR4high : HR, 3.01, 95%CI: 1.21–7.46, p=0.018; N0/N+: HR: 3.30, 95% CI, 1.09–9.90, p=0.034) in the treatment group while in the control group LN status was the only variable significantly correlated with DFS and OS. CXCR4 appeared to be the only independant predictor for DFS (CXCR4low/high: HR, 4.95, 95%CI: 1.68–14.71, p=0.007) and OS (CXCR4low/high: HR, 4.76, 95%CI: 2.03–14.49, p=0.004) in the treatment group but not in the control group. Conclusions: CXCR4 was an independant predictor for DFS and OS after adjuvant RCT in resected PA patients. This chemoreceptor could be implicated in the resistance of pancreatic cancer cells to RCT and its targeted inhibition deserves clinical evaluation. No significant financial relationships to disclose.