ESMO Gastrointestinal Oncology最新文献

Background

The programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1)/programmed cell death-ligand 2 (PD-L2) axis is responsible for cancer immune escape, which facilitates disease progression. However, the role of PD-L1 and PD-L2 and tumor-infiltrating lymphocytes (TILs) in metastatic colorectal cancer (mCRC) has not been studied.

Materials and methods

We conducted a post-hoc analysis of the Nationwide Cancer Genome Screening Project GI-SCREEN in mCRC. PD-L1 (22C3) and PD-L2 (MEB123.3G2.038) expression in formalin-fixed paraffin-embedded tumor samples was centrally assessed by immunohistochemical assays. TILs were morphologically evaluated using hematoxylin and eosin staining. Clinical information was extracted from the GI-SCREEN database. Inclusion of patients with BRAF V600E mutation was prioritized.

Results

Two hundred patients with mCRC (median age 65 years and 116 males) were included in the study. Genomic testing identified RAS mutations in 87 (44%) patients, BRAF V600E mutations in 27 (14%), and microsatellite instability-high status in 8 (4%). Positivity of PD-L1 and PD-L2 was 11% and 47% on tumor cells (TC) and 0% and 64% on immune cells, respectively, and that was associated with the presence of TILs (P = 0.011 for PD-L1, 0.024 for PD-L2). PD-L1+ TC was significantly more frequent in BRAF V600E-mutated tumors (P = 0.03). Even in microsatellite stable tumors, BRAF V600E-mutated tumors were significantly associated with higher expression of PD-L1 on TC than BRAF wild-type (25% versus 8%, P = 0.02).

Conclusions

Our study showed a distinct pattern of PD-L1 expression on TC of patients with BRAF V600E-mutated mCRC, which could be a potential therapeutic target for PD-1 blockade.

Background

Recurrence of colorectal cancer has been linked to the presence of methylated circulating tumour DNA (ctDNA) in patient plasma after surgery. The prognostic significance of ctDNA before treatment remains unclear. This study investigated the correlation between pretreatment ctDNA and current radiological [magnetic resonance imaging (MRI)] prognostic markers in patients with rectal cancer and its association with recurrence-free survival and overall survival (OS).

Patients and methods

A total of 42 patients with rectal cancer were enrolled. All patients had staging MRI before treatment. Blood was taken at diagnosis for ctDNA analysis for the presence of either methylated branched chain amino acid transaminase 1 (BCAT1) or IKAROS family zinc finger 1 (IKZF1). The correlation of MRI prognostic indicators and ctDNA test results was assessed with chi-square tests. Univariable and multivariate Cox regression analyses were carried out to determine variables associated with recurrence-free survival and OS.

Results

The mean age of patients was 64.4 years (standard deviation 12.5 years), and the majority were male (30/42, 71.4%). A total of 11, 13, 9 and 9 patients were in stages I, II, III and IV, respectively. Patients were followed up for a minimum of 36 months unless disease recurrence or death occurred earlier. A total of 36 (85.7%) patients received neoadjuvant chemoradiotherapy, and 30 (71.4%) underwent surgical resection. The 3-year survival rate was 64%. About 67% (28/42) of patients were positive for the methylated ctDNA at diagnosis. Further, 11 out of 12 patients with a positive circumferential resection margin (CRM+) were ctDNA positive; univariable analysis showed that prognostic indicators for OS were presence of extramural venous invasion [EMVI; hazard ratio (HR) 2.63, 95% confidence interval (CI) 0.95-7.31], CRM+ (HR 10.69, 95% CI 3.51-32.56), metastatic disease (HR 7.7, 95% CI 2.79-21.67) and ctDNA% methylation (HR 1.04, 95% CI 1.02-1.06). The presence of CRM+ and a positive ctDNA had an HR of 19.57 (95% CI 3.47-110.49). In the multivariate analysis, including adjustment for age and EMVI, only the CRM+/ctDNA+ variable was an independent predictor for poor survival (HR 19.57, 95% CI 3.47-110.49).

Conclusions

In rectal cancer, almost all patients with CRM involvement have ctDNA, and these patients had the worst prognosis. Future studies with longitudinal ctDNA assessment before and after treatment may potentially inform prognosis and help tailor patients’ treatment.

Background

Lung-only relapse following resection of pancreatic ductal adenocarcinoma (PDAC) is rare. While oligometastatic lung disease (OMLD) is detected after PDAC resection, its clinical and molecular features remain unclear. Our goal was to assess if lung metastatic lesion quantity and mutations could predict a better prognosis.

Materials and methods

We carried out a multicentric retrospective analysis of clinical and genomic characteristics in PDAC patients with OMLD and compared them with those with non-oligometastatic lung-only disease (non-OMLD).

Results

Thirty-nine patients meeting inclusion criteria were analyzed (OMLD n = 18, non-OMLD n = 21). OMLD exhibited more frequent unilateral location (87.5% versus 0%) and late recurrence (88.9% versus 47.6%) compared to non-OMLD. The median disease-free survival in patients with OMLD was 23.2 months versus 10.7 months in those with non-OMLD [hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.27-1]. Moreover, OMLD patients had a longer median overall survival (35.7 months) compared to non-OMLD patients (26.2 months) (HR 0.34, 95% CI 0.12-0.96). Both groups shared common PDAC driver mutations (KRAS, TP53, CDKN2A, and SMAD4). Two OMLD patients had pathogenic DNA damage repair gene mutations.

Conclusions

Our study shows an OMLD incidence of 3.4% in PDAC patients after surgical resection. Patients with OMLD have distinct clinical characteristics compared to those with non-OMLD. PDAC driver mutations were found at similar rates in both groups. Further studies are needed for better understanding of OMLD and treatment strategies.

The two key concerns in treating locally advanced rectal cancer (LARC) are as follows: (i) prolonging survival by reducing distant metastases and (ii) maintaining anorectal function and quality of life in surviving patients by safely avoiding rectal resection. To resolve these issues, in recent years, total neoadjuvant therapy (TNT), a preoperative combination of chemoradiotherapy or short-course radiotherapy (SCRT) and systemic chemotherapy, has been developed as a multidisciplinary treatment of LARC. There have been no prospective studies on consolidation triplet versus doublet regimens after SCRT. This randomized phase III trial (the ENSEMBLE trial) aims to test the superiority of consolidation irinotecan, capecitabine, and oxaliplatin over capecitabine and oxaliplatin after SCRT as TNT for LARC. The primary endpoint will be organ preservation-adapted disease-free survival in the intention-to-treat population. Moreover, no predictive biomarkers have been established for LARC. Therefore, to explore the predictive biomarkers for estimating the response to TNT and non-operative management, we planned translational research using multi-omics data, including genomic profiling with whole-genome/transcriptome sequencing of tissue and blood samples, liquid biopsy, radiomics, digital pathology, clinical features by deep learning with artificial intelligence.

Background

The dense stroma of pancreatic ductal adenocarcinoma (PDAC) is thought to impede tumour drug delivery. LSTA1, a novel cyclic tumour-penetrating peptide internalising arginylglycylaspartic acid, promotes tumour-specific drug delivery. In the phase Ib setting, LSTA1 3.2 mg/kg with gemcitabine and nab-paclitaxel showed a 92% disease control rate at 16 weeks and was well tolerated.

Methods/design

This is a multicentre, phase II, double-blinded, placebo-controlled, randomised trial evaluating the activity and safety of LSTA1 in combination with gemcitabine and nab-paclitaxel in untreated advanced PDAC. Initially, participants were randomised 2 : 1 to receive gemcitabine 1000 mg/m², nab-paclitaxel 125 mg/m² and LSTA1 3.2 mg/kg or placebo. The trial design was updated in a protocol amendment (v4.0) to include a second placebo-controlled cohort which receives a second dose of LSTA1/placebo 4 h following chemotherapy. Treatment is administered on days 1, 8, and 15 of each 28-day cycle until progression (progressive disease). The sample size is 155 based on a clinically worthwhile increase in 6-month progression-free survival (PFS) of 16%-63% with 80% power and 95% confidence to exclude the null hypothesis. The recruitment period is 22 months and follow-up 18 months. Study endpoints are: (1) PFS; (2) objective response rate (RECIST 1.1), safety (Common Terminology Criteria for Adverse Events v5.0), overall survival, participant-reported outcomes; (3) predictive/prognostic biomarkers via archival tissue, and to assess whether a second dose of LSTA1 warrants further evaluation.

Since the introduction of immune checkpoint inhibitors (ICI) a few years ago, we have witnessed unprecedented improvement in survival in hepatocellular carcinoma (HCC). Advanced stage HCC now has a median overall survival (OS) of >1.5 years compared to just a little more than 6 months a decade ago. In contrast, survival of early-stage HCC has made little progress due to the lack of effective adjuvant strategy, as recurrence after curative treatment can reach up to 70% at 5 years. Given the success of immunotherapy in advanced stage HCC, there is a growing interest in incorporating immunotherapy in the management of early-stage HCC. Recently, the IMBRAVE050 trial reported positive outcomes showing, for the first time, the use of adjuvant immunotherapy (e.g. atezolizumab), plus bevacizumab, is effective in prolonging recurrence-free survival in early-stage HCC following curative treatment. On the other end of the spectrum, there is an increasing momentum to explore neoadjuvant immunotherapy for early-stage HCC. Preclinical models have shown that neoadjuvant immunotherapy can effectively stimulate a broader range of T cells that can translate into a stronger anti-tumour immune response when the tumour is left in situ. Neoadjuvant immunotherapy has also been shown to effectively improve pathological complete response rates and prolong survival in other cancer types. Under this context, several small-scale, early phase trials have demonstrated promising results using neoadjuvant immunotherapy in early-stage HCC. In this mini review, we will discuss the rationale behind, currently available data, and considerations of study design on evaluating neoadjuvant immunotherapy in early-stage HCC.

With the publication of several recent studies, the therapeutic approach for locally advanced rectal cancer has been radically transformed and now allows for more tailored, patient-centered care. A patient with a cT3N1 rectal cancer may have numerous treatment options based on the explosion of data, so it is critical to understand how to implement the new approaches in clinical practice. This review summarizes the progress in the management of locally advanced rectal cancer based on the recently published clinical trials and critically appraises the literature on the options for sequencing of therapy and omitting components of multimodality therapy. With the expanding management options, a number of important questions remain regarding how to better individualize use of multimodality therapy for patients with Stage II or III rectal cancer, in particular with regard to predicting response to therapy and identifying the appropriate sequencing and/or omission of therapies.

Immune checkpoint inhibition (ICI) has revolutionized cancer therapy, including treatment of hepatocellular carcinoma (HCC) which comprises 80%-90% of all liver cancers, the third most common cause of cancer-related death worldwide. The main targeted pathways are the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoints. Blockade of CTLA-4 with monoclonal antibodies leads to an activation and increase in effector T cells that can interact with tumor cells. Additionally, inhibitory regulatory T cells are reduced, leading to an immunosupportive tumor microenvironment. PD-1/PD-L1 inhibition reduces immunosuppression directly within the tumor tissue and reactivates the immune response to tumor cells. Recently, the HIMALAYA trial has shown that dual ICI with the CTLA-4-blocking antibody tremelimumab and the PD-L1-directed antibody durvalumab (STRIDE regimen) is superior to sorafenib regarding efficacy and safety in advanced HCC and has shown unprecedented long-term survival data for these patients. The combination of PD-L1-directed ICI (atezolizumab) and anti-vascular endothelial growth factor (bevacizumab) significantly improved outcomes compared to sorafenib and has been in clinical use since 2020. Looking at outcome measures for ICI, radiologically assessed endpoints such as progression-free survival and objective response rate only modestly correlate with overall survival. The modified RECIST criteria seem to better identify ICI responders in HCC compared to conventional imaging evaluation criteria. So far, predictive biomarkers in HCC and a robust understanding of the impact of underlying liver diseases are largely lacking. An accurate stratification of patients based on biomarkers and etiology has the potential to further improve outcomes in HCC.