Charting New Paths in Cancer Research: Insights from the Frontiers in Cancer Science Conference 2024.

The 16th annual Frontiers in Cancer Science conference convened leading experts to discuss the latest developments in cancer research. Key research themes included mechanisms of treatment resistance and innovative strategies to target resistant cancer cells, metabolic plasticity and its therapeutic vulnerabilities, modulation of the tumor microenvironment to enhance therapeutic efficacy, recent advances in immunotherapies and engineered immune cells, and strategies to overcome tumor immune evasion. The conference also highlighted the development of advanced spatial transcriptomic technologies as a powerful tool to decipher tumor heterogeneity and identify novel therapeutic targets.

NEXUS: a phase I dose escalation study of selinexor plus nivolumab and ipilimumab in Asian patients with advanced/metastatic solid malignancies.

Background: Selinexor (SEL) is an oral inhibitor of nuclear export protein Exportin 1 (XPO1) previously shown to upregulate programmed cell death protein 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression.

Objective: To investigate the safety and antitumor activity of SEL, nivolumab (NIVO), and ipilimumab (IPI) in Asian patients with treatment-refractory solid organ cancers.

Design: Phase I study of escalating doses of SEL in combination with NIVO + IPI.

Personalized dose selection platform for patients with solid tumors in the PRECISE CURATE.AI feasibility trial.

In oncology, the conventional reliance on the maximum tolerated dose (MTD) strategy for chemotherapy may not optimize treatment outcomes for individual patients. CURATE.AI is an AI-derived platform that utilizes a patient's own, small dataset to dynamically personalize only their own dose recommendations.

Molecular profiling of metastatic breast cancer and target-based therapeutic matching in an Asian tertiary phase I oncology unit.

Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre.

Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022).

Cost-effectiveness analysis of atezolizumab plus bevacizumab compared with sorafenib as first-line treatment in advanced hepatocellular carcinoma in Singapore.

Objectives: This study aims to explore the cost-effectiveness of atezolizumab plus bevacizumab against sorafenib for first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC) in Singapore.

Methods: A partitioned survival model was developed from a healthcare system perspective, with a 10-year lifetime horizon. Clinical inputs and utilities were obtained from the IMbrave150 trial.

State-of-the-Art Management of Colorectal Cancer: Treatment Advances and Innovation.

Colorectal cancer (CRC) remains a significant global health challenge, ranking among the leading causes of cancer-related morbidity and mortality worldwide. Recent advancements in molecular characterization have revolutionized our understanding of the heterogeneity within colorectal tumors, particularly in the context of tumor sidedness. Tumor sidedness, referring to the location of the primary tumor in either the right or left colon, has emerged as a critical factor influencing prognosis and treatment responses in metastatic CRC.

Early onset pancreatic cancer-exploring contemporary treatment and outcomes using real-world data.

Background: Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting.

Methods: A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated.

Reducing Chemotherapy Waiting Times in the Ambulatory Setting of a Tertiary Cancer Centre Using a Design Thinking Approach.

Introduction: Chemotherapy is complex. We hypothesized that a design thinking approach could redesign preparatory processes and reduce wait times.

Methods: A multidisciplinary process mapping exercise was undertaken to understand the current processes, followed by proposing and testing solutions.

Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

Purpose: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents.

Methods: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284).

Results: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .

Clinical relevance of PD-1 positive CD8 T-cells in gastric cancer.

Background: We evaluated the relevance of PD-1CD8 T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME).

Methods: Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the "3G" chemotherapy trial and an immunotherapy phase 2 trial.

Incident Cardiovascular Diseases Among Survivors of High-Risk Stage II-III Colorectal Cancer: A Cluster-Wide Cohort Study.

Background: The incidence and survival of colorectal cancer (CRC) are increasing. There is an increasing number of long-term survivors, many of whom are elderly and have comorbidities. We conducted a population-based study in Hong Kong to assess the long-term cardiovascular disease (CVD) incidence associated with adjuvant fluoropyrimidine-based chemotherapy among CRC survivors.

Outcomes of a Phase II Study of Intraperitoneal Paclitaxel plus Systemic Capecitabine and Oxaliplatin (XELOX) for Gastric Cancer with Peritoneal Metastases.

Background: Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM.

Methods: Forty-four patients with GCPM received IP PTX (40 mg/m, Days 1, 8), oral capecitabine (1000 mg/m twice daily, Days 1-14) and intravenous oxaliplatin (100 mg/m, Day 1) in 21-day cycles.

Rational drug combination design in patient-derived avatars reveals effective inhibition of hepatocellular carcinoma with proteasome and CDK inhibitors.

Background: Hepatocellular carcinoma (HCC) remains difficult to treat due to limited effective treatment options. While the proteasome inhibitor bortezomib has shown promising preclinical activity in HCC, clinical trials of bortezomib showed no advantage over the standard-of-care treatment sorafenib, highlighting the need for more clinically relevant therapeutic strategies. Here, we propose that rational drug combination design and validation in patient-derived HCC avatar models such as patient-derived xenografts (PDXs) and organoids can improve proteasome inhibitor-based therapeutic efficacy and clinical potential.

Use and outcomes from neoadjuvant chemotherapy in borderline resectable pancreatic ductal adenocarcinoma in an Australasian population.

Background: Use of neoadjuvant (NA) chemotherapy is recommended when pancreatic ductal adenocarcinoma (PDAC) is borderline resectable METHOD: A retrospective analysis of consecutive patients with localized PDAC between January 2016 and March 2019 within the Australasian Pancreatic Cancer Registry (PURPLE, Pancreatic cancer: Understanding Routine Practice and Lifting End results) was performed. Clinicopathological characteristics, treatment, and outcome were analyzed. Overall survival (OS) comparison was performed using log-rank model and Kaplan-Meier analysis.

A phase 1 study of the safety, pharmacokinetics and pharmacodynamics of escalating doses followed by dose expansion of the selective inhibitor of nuclear export (SINE) selinexor in Asian patients with advanced or metastatic malignancies.

Purpose: This phase 1 study aims to evaluate the tolerability and the recommended phase 2 dose of selinexor in Asian patients with advanced or metastatic malignancies.

Experimental Design: A total of 105 patients with advanced malignancies were enrolled from two sites in Singapore (National University Hospital and the National Cancer Centre, Singapore) from 24 February 2014 to 14 January 2019. We investigated four dosing schedules of selinexor in a 3 + 3 dose escalation design with an additional Phase 1b expansion cohort.

Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor-Positive Breast Cancer.

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer.

Patients And Methods: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial.

Phase Ib Dose-Finding Study of Varlitinib Combined with Weekly Paclitaxel With or Without Carboplatin ± Trastuzumab in Advanced Solid Tumors.

Background: Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers.

Objective: We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab.

Statistical Process Control Charts for Monitoring Next-Generation Sequencing and Bioinformatics Turnaround in Precision Medicine Initiatives.

Purpose: Precision oncology, such as next generation sequencing (NGS) molecular analysis and bioinformatics are used to guide targeted therapies. The laboratory turnaround time (TAT) is a key performance indicator of laboratory performance. This study aims to formally apply statistical process control (SPC) methods such as CUSUM and EWMA to a precision medicine programme to analyze the learning curves of NGS and bioinformatics processes.

Liver transplantation for non-resectable colorectal liver metastases: the International Hepato-Pancreato-Biliary Association consensus guidelines.

Colorectal cancer is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Despite advances in improving resectability, most patients present with non-resectable colorectal liver metastases requiring palliative systemic therapy and locoregional disease control strategies. There is a growing interest in the use of liver transplantation to treat non-resectable colorectal liver metastases in well selected patients, leading to a surge in the number of studies and prospective trials worldwide, thereby fuelling the emerging field of transplant oncology.

MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models.

The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models.

Analysis and Validation of Human Targets and Treatments Using a Hepatocellular Carcinoma-Immune Humanized Mouse Model.

Background And Aims: Recent development of multiple treatments for human hepatocellular carcinoma (HCC) has allowed for the selection of combination therapy to enhance the effectiveness of monotherapy. Optimal selection of therapies is based on both HCC and its microenvironment. Therefore, it is critical to develop and validate preclinical animal models for testing clinical therapeutic solutions.

PIPAC-OX: A Phase I Study of Oxaliplatin-Based Pressurized Intraperitoneal Aerosol Chemotherapy in Patients with Peritoneal Metastases.

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m. We conducted a phase I study to establish safety and tolerability.