ESMO Gastrointestinal Oncology最新文献

Gastrointestinal (GI) cancer—an umbrella term for cancers that affect the digestive system and other abdominal organs—includes some malignancies with the lowest survival rates. To improve patient outcomes, patients must have access to optimal treatment including precision oncology, a method of determining the most effective treatment for an individual cancer patient by identifying predictive biomarkers through the use of advanced molecular diagnostics. While many powerful molecular profiling technologies have already been developed, their uptake in the management of GI cancers could be improved. To bridge this gap, better coordination among three interdependent stakeholders—scientists, clinicians, and industry professionals—is essential. The first Translational and Precision GI-Oncology—Bench to Bedside Meeting was held on 23-28 April 2023 in Freiburg, Germany. The 3-day meeting offered the opportunity for scientists, clinicians, and industry professionals in the field of GI cancer to exchange ideas about how to improve the translation of basic science into clinical practice. One-hundred and twenty participants attended the meeting, which featured 47 presentations covering the following five topics: bedside, analytical approaches for treatment and real-world data, new ideas and biomarkers, novel technologies, and drugs. A summary of the 2023 meeting is provided in this report.

International treatment guidelines recommend tumor resection for patients with oligometastatic colorectal cancer (CRC). Despite this, recurrence occurs in ∼60% of patients post-surgery, indicating that the role and optimal type of perioperative systemic therapy has not been fully defined. In the COSMOS-oligo trials, comprising two studies, we are evaluating the potential role of circulating tumor DNA (ctDNA) analysis in clinical decision making and exploring adjuvant therapy strategies for patients with resectable metastatic CRC. The COSMOS-CRC-03 study aims to evaluate the prognostic value of post-operative minimal residual disease as detected by ctDNA and to explore the role of ctDNA in detecting disease recurrence. We plan to assess the predictive accuracy of ctDNA results for recurrence using blood collected 28 days post-surgery. We will additionally explore whether regular post-operative ctDNA test can detect recurrence earlier than standard imaging. Post-operative adjuvant therapy will not be administered to ctDNA-negative patients. The complementary AURORA trial is a randomized phase II study designed to test whether post-operative mFOLFOXIRI plus bevacizumab is superior to standard mFOLFOX6 for patients with metastatic CRC when the ctDNA status is positive after curative-intent surgery for patients enrolled in the COSMOS-CRC-03 study. Both studies will only include patients with resectable distant metastases of CRC. We designed these studies to stratify patients based on the results of a ctDNA assay and to determine the optimal treatment for patients at the highest risk for recurrence.

Background

Although incidence and mortality rates of colorectal cancer have progressively decreased during the past decades, early-onset rectal cancer (EORC; <50 years old) is rising alarmingly. EORC is often diagnosed at advanced stages and presents intrinsic molecular alterations. New strategies are necessary to increase early diagnosis and to improve therapeutic management. We present the analysis of our locally advanced EORC patients evaluating their specific response to chemoradiotherapy.

Materials and methods

Patients diagnosed with locally advanced rectal cancer (LARC) and treated with curative surgery after neoadjuvant treatment (NAT) with chemoradiotherapy were retrospectively analysed, comparing differences between EORC and late-onset rectal cancer (LORC). Incidence rates between 2001 and 2020, as well as diagnostic and treatment response variables, were compared.

Results

Up to 1140 patients were diagnosed with rectal cancer and underwent curative surgery. From them, there were 399 patients with LARC who received NAT before surgery, and 9% of them had EORC (36 patients). The incidence of locally advanced EORC increased from 6.6% to 12.7% (2001-2020). No differences were found considering diagnostic variables between the early- and late-onset cohorts, although slightly more deficient mismatch repair tumours were found within the EORC cohort. Mean disease-free survival and mean cancer-specific survival were similar. Notwithstanding, EORC patients achieve higher rates of pathological complete responses (pCRs), compared with LARC (36.3% versus12.4%; P = 0.000).

Conclusions

Our analyses confirm the increase in incidence of EORC from 2001 to 2020 in Navarra. EORC patients achieved a higher pCR rate, thus suggesting that the role of organ preservation strategies should be further investigated in this unique population.

Background

Programmed cell death protein 1 (PD-1) blockade improved the survival of patients with mismatch repair deficient (dMMR) and/or microsatellite instability-high (MSI-H) tumors, leading to tumor-agnostic approval of pembrolizumab in this population. Whether anti-programmed death (ligand)-1 [PD-(L)1] agents may achieve similar efficacy in dMMR/MSI-H metastatic gastric cancer (mGC) compared to metastatic colorectal cancer (mCRC) is unclear.

Materials and methods

We conducted a multicenter cohort study to collect data on patients with dMMR/MSI-H mGC or mCRC treated with anti-PD-(L)1 monotherapy globally at 17 tertiary cancer centers. Clinical features were balanced according to tumor type through the inverse probability of treatment weighting (IPTW) method. The primary endpoint was overall survival (OS), as evaluated from the first anti-PD-(L)1 administration.

Results

The cohort included 398 mCRC and 121 mGC patients, with a median follow-up of 34.6 and 25.1 months, respectively. The two populations differed for several baseline clinical features: patients with mCRC had younger age (60 versus 68 years, P < 0.001), better performance status (PS 0: 46% versus 34%, P = 0.062), higher frequency of primary tumor resection (82% versus 49%, P < 0.001) and liver metastases (38% versus 24%, P = 0.005), yet lower rates of distant nodal metastases (57% versus 83%, P < 0.001) and synchronous presentation (51% versus 76%, P < 0.001). After IPTW adjustment, patients with mGC showed no significant difference in progression-free survival (PFS) and OS compared to those with mCRC [PFS: hazard ratio (HR) 0.55, P = 0.077; OS: HR 0.65, P = 0.200].

Conclusions

Despite patients with dMMR/MSI-H mGC being enriched with poor prognostic factors as compared to the mCRC counterpart, anti-PD-(L)1 monotherapy’s efficacy appears similar in the two tumor types.

Colorectal cancer (CRC) constitutes a significant portion of cancer-related deaths in the United States, topping cancer-related mortality among males under 50 years of age. Despite an increase in overall survival throughout the years, the prognosis of metastatic CRC remains poor. In addition to the classic molecular targets in CRC that include epidermal growth factor receptor, BRAF, and vascular endothelial growth factor pathways, human epidermal growth factor receptor 2 (HER2) amplification is an emerging target that has been successfully targeted in advanced CRC, particularly with anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. With the introduction of potent HER2-directed antibody–drug conjugates, the number of patients who might be eligible for anti-HER2 therapy is expected to increase dramatically as tumors with lower expression of HER2 (termed HER2 low) have shown relevant response rates across several histologies. Yet, several challenges remain to be addressed in this field, including the standardized method to define HER2-low disease and the most efficient payload in this setting, among others. Future studies will help to further characterize HER2-low CRCs, identify additional predictive biomarkers, and assist in the development of better treatments.

Background

How distinct KRAS alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, KRAS is now partly targetable with novel specific inhibitors targeting KRAS_G12 (G12C or G12D), but specific outcomes of these subgroups of patients is poorly described. In this study, we compared clinical/genomic characteristics and outcomes of PDAC depending on codon-specific KRAS mutant (G12 versus others), as well as gene expression profiles and in vitro drug sensibility using organoids.

Patients and methods

All metastatic patients with PDAC and available molecular profile from 2015 to 2022 were eligible, and patients with KRAS mutation were included. Transcriptomic data from 69 KRAS-mutated tumors were also analyzed.

Results

Overall, 263 patients were included—239 KRAS_G12 (91%) and 24 (9%) KRAS_other. There was no difference between KRAS_G12 and KRAS_other regarding clinicopathological characteristics and potentially actionable alterations, except for BRAF that was found in 13% of KRAS_other (P = 0.01). G protein subunit alpha S (GNAS) was found more altered in KRAS_other tumors (P = 0.002) suggesting potential intraductal papillary mucinous neoplasm precursors. The median overall survival from metastatic diagnosis was 16.7 months [95% confidence interval (CI) 14.3-18.3 months] in KRAS_G12 and 24.9 months (95% CI 17.4-43.4 months) in KRAS_other [hazard ratio (ref: KRAS_G12) = 0.56 (0.34-0.94), P = 0.04 adjusted]. The first-line treatment response was not different between groups (overall response rate and progression-free survival), as confirmed with a similar organoid in vitro sensibility. Transcriptomic analyses showed a significant and exclusive up-regulation of immune pathways in KRAS_G12 tumors.

Conclusions

Codon-specific KRAS mutations are not equal and we report that KRAS_G12 patients have a worst prognosis than KRAS_other patients in PDAC. These results warrant to be confirmed in larger-scale studies.

Background

Neoadjuvant radiotherapy and chemotherapy, followed by surgical resection, are standard treatments for locally advanced rectal cancer (LARC). Emerging evidence has shown the efficacy of anti-programmed cell death protein 1 (anti-PD-1) therapy for patients with mismatch repair-deficient (dMMR) colorectal cancer, particularly in managing metastatic disease. Several ongoing clinical trials evaluating the efficacy of anti-PD-1 therapy in patients with dMMR LARC have reported outstanding responses.

Patients and methods

Here, we present the VOLTAGE-2 study (EPOC 2201), a non-randomized, single-arm, phase II trial that aims to investigate the efficacy and safety of nivolumab monotherapy for 1 year in patients with dMMR-resectable LARC. Patients with clinical complete response (cCR) or near-complete response (nCR) will be observed with non-operative management (NOM) using the Memorial Sloan Kettering Regression Schema.

The primary endpoint will be investigator-determined 2-year cCR rate for nivolumab monotherapy. We will investigate the surrogacy of circulating tumor DNA assay as a cCR using whole-genome sequencing (WGS)-based molecular residual disease (MRD) assay and will evaluate the biomarkers of the response to anti-PD-1 antibody using whole-exome sequencing (WES) plus whole-transcriptome sequencing (WTS)-based tumor genomics and immune microenvironment evaluations. We plan to carry out spatiotemporal trans-omics analyses using artificial intelligence and deep learning-driven genomics, transcriptomics, radiomics, pathomics, colonoscopic imaging, quality of life, and clinical features.

Background

In clinical oncology, it is widely recognized that data sharing and the integration of completed clinical trials can promote research and development (R&D). The Foundation Aide et Recherche en Cancérologie Digestive (ARCAD) database project was initiated in Europe and the United States in 2006. Approximately 40 000 individual patient data (IPD) for metastatic colorectal cancer were collected and constructed as an integrated database.

Materials and methods

ARCAD-Asia was launched in 2021 and has been actively collecting Asian clinical trials. In addition, ARCAD-Asian data were periodically transferred to the Mayo Clinic, and IPD was integrated into the ARCAD database. Finally, all data were shared with three data centers, ARCAD-Asia and ARCAD, located in Europe, the United States, and Japan. We have developed a reproducible and reliable data conversion procedure based on the methodology established by ARCAD.

Results

From September 2021 to April 2023, 2318 IPD from four first-line, two second-line, and three third-line trials for metastatic colorectal cancer were integrated and stored in ARCAD-Asia. By autumn 2023, three more trials (1565 IPD) will be included, resulting in 12 trials (3883 IPD) in the Asia database. These are transferred and shared with ARCAD. After integrating Asian data, the ARCAD database contained 70 trials with ∼50 000 IPD.

Conclusions

Based on our active collaboration, ARCAD-Asia was established, and a global integrated database was constructed. As a next step, we will continue to collect Asian IPD and expand the cancer types, leading to a more comprehensive and available global database.

Background

Immunoglobulin G1 (IgG1) monoclonal antibodies (mAbs), such as trastuzumab and ramucirumab, are utilized in advanced gastroesophageal adenocarcinoma (aGEA). The important mechanism of mAb therapeutic effect is engagement by natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC). Certain high-affinity FcγRIIIA receptor variants (substituting phenylalanine for valine at amino acid 158) on NK cells enhance fragment C receptor’s affinity for the IgG1 fragment crystallizable (Fc) domain, leading to stronger mAb antitumor effects. Three genotypes are possible at amino acid 158 position (V/V, V/F, and F/F). We attempted to determine whether FcγRIIIA genotype affected real-world responses to mAbs in aGEA patients.

Patients and methods

Whole blood was available from 74/80 patients in the PANGEA trial (NCT02213289). We identified 35 additional aGEA patients (‘non-PANGEA patients’) treated with mAbs at our institution. Utilizing PCR, we determined patient allotypes at amino acid position 158 for the FcγRIIIA gene. We calculated/compared 3-year overall survival (OS) rates between the three FcγRIIIA genotypes.

Results

The highest affinity (V/V) and heterozygotic (V/F) variants were present in 18% (20/109) and 50% (55/109) of patients, respectively. Median OS was similar across all three genotypes in PANGEA patients. In non-PANGEA patients, there was a trend towards increased survival in higher-affinity patients (i.e. V/V or V/F patients) compared to low-affinity patients (mOS 43.4 versus 23.1 months, P = 0.07); in non-PANGEA patients, higher-affinity patients had significantly higher 36-month OS (50% versus 13%, P = 0.04) compared to low-affinity patients. Non-F/F patients had an exceptional response to mAbs.

Conclusions

We report the first real-world data analyzing how FcγRIIIA genotype impacts mAb response in aGEA. Other significant molecular/clinical variables affect mAb responses. Results reiterate the importance of ADCC in aGEA. Further work is needed to elucidate why certain patients are ‘exceptional responders’ to mAb.