ESMO Gastrointestinal Oncology最新文献

Background

The majority of pancreatic ductal adenocarcinomas (PDACs) are driven by mutant (mt) KRAS. How mt KRAS and co-driver mutations affect the immune cell (IC) landscape of PDAC remains uncertain. Herein, we characterize the types of IC in the PDAC tumor microenvironment (TME) and the prevalence of immuno-oncologic (IO) biomarkers by genomic and transcriptomic analysis in the context of KRAS status.

Materials and methods

4142 PDAC and 3727 colorectal cancer (CRC) cases with KRAS mt were analyzed using next-generation DNA sequencing, immunohistochemistry, and whole-transcriptome RNA sequencing. Microsatellite instability and deficiency in mismatch repair (MSI-H/dMMR) and tumor mutational burden (TMB) were also assessed.

Results

We found KRAS mt in 81% of PDAC, with the most common variant being G12D in PDAC, and fewer cases of KRAS mt were co-expressed with the predictive IO marker MSI-H/dMMR than KRAS-wild-type (wt). However, KRAS^G12D, KRAS^G12V, and KRAS^Q61 mutations had significantly lower TMB than KRAS wt tumors in PDAC. The IC environment of KRAS mt PDAC showed significant differences in nearly all IC types; a similar pattern was observed in CRC but was less pronounced.

Conclusions

Therapeutic IO targets like programmed death-ligand 1 are enriched in pancreatic adenocarcinoma cases harboring specific targetable variants of KRAS mt PDAC. Better understanding of the TME could lead to tailored immunotherapeutic strategies to overcome these barriers in KRAS mt PDAC, possibly in combination with molecularly targeted treatment strategies.

The ‘immune pattern’ of the esophagogastric junction and gastric cancer (GC) has been related to tumour progression and/or response to therapies. GC can be classified as immunogenic or immune-resistant based on the infiltration of the tumour microenvironment (TME) from different immune cells (ICs), the most significant of which are activated lymphocytes (a-Ly) CD8+ and CD4+. From the amount of a-Ly infiltration in TME, we can identify tumours with high Immunoscore (IS) which correlates with better prognosis in terms of disease-free survival and overall survival (OS). IC activation and consequent immunogenic TME requires high nutrient absorption and synthesis and accumulation of protein, lipid, and nucleotides. However, tumour cells (TCs) promote their own proliferation by stealing micronutrients to ICs, therefore leading to an immunosuppressive TME phenotype. This proof-of-concept protocol aims to assess whether a controlled enteral immune nutrition (EIN) supplementation can revert the TME in favour of ICs over TCs, in both auxotrophic and non-auxotrophic malignancies, witnessed by an increase in IS in surgical specimen over biopsy controls. Secondary endpoints are: (i) tumour regression grade assessment compared to historical data from FLOT4/AIO; (ii) combined proportion score ratio; (iii) relapse-free survival at 3 years and OS; and (iv) quality of life by the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (EORTC QLQ)-30.

Background

Addition of immunotherapy to standard chemotherapy marginally improved outcomes in gastroesophageal adenocarcinoma (GEAC). Recently, dual immunotherapy has shown efficacy in melanoma and non-small-cell lung cancer over single checkpoint inhibition. We sought to decipher the expression landscape of commonly targeted immune checkpoints in GEAC with a particular attention to their co-expression with programmed death-ligand 1 (PD-L1).

Materials and methods

Targeted RNA sequencing was carried out on 65 metastatic GEAC tumors obtained from, and gene expression was measured for 394 immune transcripts. Co-expression analyses were conducted by calculating Pearson correlations for every possible pair of 15 checkpoint genes and clustering groups of similarly expressed genes. These analyses were validated using a 90-patient cohort identified from The Cancer Genome Atlas database.

Results

The clinical cohort was primarily male (86.2%), Caucasian (93.9%), and had positive PD-L1 status (63.1%). The correlation matrix delineated two clusters of co-expression with the first including PD-L1, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG3), and indoleamine 2,3-dioxygenase-1 (IDO1) and the second included programmed cell death 1 ligand 2 (PD-L2), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3), and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) genes. LAG3 and IDO1 genes showed strong co-expression with PD-L1 in both cohorts and PD-L1-positive and -negative subgroups. Interestingly, CD8 showed strong co-expression with CTLA-4, PD-1, LAG3, and TIGIT.

Conclusions

We show that immune checkpoints are often co-expressed in GEAC, suggesting possible common underlying mechanisms for checkpoint expression. Strong correlation between checkpoints like LAG3, TIM3, and IDO1 with PD-1/PD-L1 axis in GEAC argues for developing dual checkpoint inhibition therapy in this patient population. Future preclinical and clinical studies are needed to evaluate the efficacy and safety of these potential immunotherapy combinations.

Background

Esophageal cancer [esophagogastric adenocarcinoma (OGA)] shows heterogeneity at the molecular level, leading to lower efficacy rates and highlighting the need for personalized treatment strategies. We have developed a computational model that uses both mechanistic and statistical approaches to integrate a patient’s genomic aberrations, revealing signaling pathway dysregulation and variable drug response. The model output, Therapy Response Index (TRI), has been used to predict therapeutic outcomes in this study.

Design

TRI’s ability to predict patient outcomes was retrospectively evaluated in a prospectively collected cohort of patients with operable OGA from the UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) consortium receiving neoadjuvant chemotherapy. Stratified random sampling was used to split the data into training and validation subsets. Multivariate Cox proportional hazard and proportional odds models were used to predict survival and pathological response as a function of TRI and clinical thresholds compared with clinical factors.

Results

A total of 270 patients with OGA were selected who had 50× whole genome sequencing carried out on tissue derived from either biopsy or resection. Patients were treated with chemotherapy drugs or regimens according to UK clinical guidelines. The association of TRI with overall survival (OS) was significant above and beyond standard clinical factors (P = 0.0012). A significant association was also observed with disease-free survival (DFS; P = 0.0288). A TRI optimized for tumor regression grade also displayed a significant association (P = 0.0011).

Conclusions

TRI was predictive of OS and DFS beyond clinical factors. These positive results suggest the potential utility of personalized biosimulation-informed therapy selection and that further assessment in prospective clinical studies is warranted.

Background

International guidelines recommend universal screening for Lynch syndrome (LS) through somatic DNA mismatch repair deficiency (dMMR) testing in all colorectal cancers (CRCs). However, LS remains largely underdiagnosed. Mainstreaming LS diagnosis through oncologist-driven genetic testing could increase detection rates, thus extending the benefits of precision prevention to patients with LS and their families. We aim to evaluate the feasibility of the mainstreaming diagnostic algorithm for LS.

Patients and methods

ItaLynch is an ongoing, prospective, observational, multicenter, multidisciplinary, Italian study in patients with dMMR CRC. Being descriptive in nature, it does not attempt to test any specific, a priori, hypothesis. Patients with dMMR CRC are selected by universal screening by immunohistochemistry (IHC). In MLH1-deficient patients, reflex testing for BRAF^V600E and, when appropriate, for MLH1 promoter hypermethylation is carried out. For all dMMR CRC, a ‘Lynch Alert’ is added to the pathology report: positive when a patient is at high risk for LS, due to reflex testing results or to loss of non-MLH1 proteins. Conversely, a ‘Lynch Alert’ is negative when the patient is likely to be a nonhereditary case (i.e. MLH1 loss and BRAF^V600E or MLH1 promoter hypermethylation). In patients with a positive ‘Lynch Alert’, after providing a brief explanation about the risks and benefits of genetic testing, the oncologist asks patients for their consent to mainstream genetic testing. Thus a blood sample is drawn for constitutional variants of the MMR genes. Carriers of a germline variant are then referred to post-test genetic counseling. Referral to clinical genetic services is also advised for patients with clinical suspect criteria.

Background

Trifluridine (FTD)/tipiracil (TPI) is a standard salvage treatment for advanced gastric cancer (AGC). This study aimed to assess the efficacy and safety of FTD/TPI in heavily pretreated patients with AGC in clinical practice.

Materials and methods

This retrospective cohort study conducted at a single Japanese institute between November 2019 and May 2022 included patients with inoperable advanced or recurrent gastric cancer (GC) who received FTD/TPI with or without ramucirumab (RAM) in the third-line or later setting. Univariate and multivariate analyses were carried out to examine the clinical factors associated with disease progression and survival.

Results

A total of 98 consecutive patients, including 2 patients treated with RAM, were enrolled. Eighty-five patients had prior immune checkpoint inhibitor administration before FTD/TPI and 86 patients were treated with FTD/FPI as the fourth or later line of treatment. Objective response rate was 2.3% (2/87), and disease control rate was 40.2% (35/87). Nausea, anorexia, and diarrhea were the observed adverse events (AEs) in 45, 24, and 19 patients, respectively. The most common grade 3 or 4 AE was neutropenia. Multivariate analysis revealed that performance status (PS) ≥1, elevated serum carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9) levels, and primary tumor location were independently associated with shorter progression-free survival. In terms of overall survival, PS ≥1, elevated serum CEA and/or CA19-9, and the presence of moderate to severe ascites demonstrated statistically significant associations with poorer survival.

Conclusions

FTD/TPI could be a therapeutic option for AGC patients previously treated with nivolumab in clinical practice. AEs associated with FTD/TPI were manageable in heavily pretreated patients with AGC.

Background

Systemic therapy for hepatocellular carcinoma (HCC) can prolong survival, but outcomes vary, and predictors of response are not fully defined. Frailty is associated with worse outcomes in cirrhosis and liver transplantation, but its impact on patients with advanced HCC is unknown.

Patients and methods

An international, multicentre, prospective, observational cohort of adults commencing systemic therapy for HCC from 2019 to 2022 was analysed. Frailty was assessed by the Liver Frailty Index (LFI). The primary outcome was overall survival; secondary outcomes were disease progression, adverse events, and treatment discontinuation.

Results

Among 102 patients, 80% were male and the median age was 67 years [interquartile range (IQR) 60-73 years]. Most had viral hepatitis (hepatitis C virus 39%, hepatitis B virus 29%), were Child–Pugh A (75%), Eastern Cooperative Oncology Group (ECOG) 0-1 (89%), and Barcelona Centre Liver Cancer (BCLC) stage C (59%). Similar proportions received tyrosine kinase inhibitors (54%) and immunotherapy (46%). The median LFI was 4.13 (IQR 3.81-4.43): 4% were robust (LFI <3.2), 75% were pre-frail (LFI 3.2-<4.5), and 22% were frail (LFI 4.5+). LFI was independently associated with death (adjusted hazard ratio 1.74, 95% confidence interval 1.17-2.59, P = 0.006), after adjustment for Child–Pugh score and albumin–bilirubin grade. The optimal cut-off for survival at 1 year was LFI 4.2 (area under the curve 0.658), significant on univariable and multivariable analyses at predicting death. Frailty was associated with earlier systemic therapy discontinuation, despite similar rates of disease progression and adverse events; cessation of treatment due to functional decline was more common among frail patients. Sensitivity analysis excluding patients above Child–Pugh B8 or ECOG 2 did not change results.

Conclusion

The LFI is an independent predictor of death among patients with HCC undergoing systemic therapy.