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Gastrointestinal Cancers

Gastrointestinal (GI) cancers—collectively oesophageal, stomach, small intestinal, colon, rectal and anal cancers—rank amongst the world’s most frequent cancers and are the leading cause of cancer-related deaths. Globally, stomach cancer is the second-leading cause of cancer death. In Singapore, colorectal cancer is the most frequent cancer among males and the second-most common among females.

To frame the pertinent questions that our scientists and clinicians (identified by name in the appropriate sections below) are addressing together, here we describe several observations of the natural history of GI cancers and the corresponding treatment paradigms employed for patients with different stages of pre-invasive and invasive cancer. We are also keen to work with like-minded collaborators to advance our knowledge and understanding of GI cancers.

1. Cancer Predisposition

Gastric cancer is disproportionately common in Asia. Colorectal cancer is the most common form of cancer in Singapore and the fourth-most common cancer globally. The epidemiological, environmental, and genetic factors that contribute to these high prevalence cancers are not certain.

What epidemiological factors and gene–environment interactions predict predisposition to developing
GI cancers? What biological insights could inform interventions that may mitigate GI cancer risk for predisposed individuals?
Investigators: Dr. Dawn Chong, Dr. Joanne Ngeow

2. Pre-invasive Disease and Diagnosis of Early-Stage GI cancers

Pre-invasive lesions are well recognised in both stomach and colon cancers, and stepwise models of the molecular events underlying their progression from pre-invasive to invasive disease have been proposed. However, interventions that can retard or reverse these processes are currently unknown. In colon cancer, randomised trials show that population-based screening and targeted screening in high-risk populations can lead to reductions
in population colon cancer-specific mortality. In gastric cancer, population-based screening is also employed in high-risk countries. The current techniques involve invasive procedures for which test capability can be improved.

What are the key oncogenic processes in early disease that determine progression to invasive cancer? What novel
biological insights might inform innovative technologies that enable the early detection of pre-invasive disease
and novel treatment strategies to halt the progression of pre-invasive lesions to invasive disease? What biological insights inform innovative screening interventions or improve existing methods that allow for the early detection/diagnosis of GI cancers at a stage of disease early enough that intervention can lead to a population
cancer-specific mortality reduction?
Investigators: Dr. Dawn Chong, Dr. Iain Tan

3. Treatment of Early-Stage GI Cancer

Surgery is curative in only a proportion of patients with GI cancers. Many patients develop locally recurrent disease and/or metastasis. Adjuvant chemotherapy and/or radiotherapy prevent metastasis in a small subset of patients, further improving the cure rate. It is not presently possible to accurately predict which patients will (1) only require surgery; (2) be cured with adjuvant therapy; or (3) relapse and develop clinical metastasis despite optimal therapy.

What is required to risk-stratify patients and thus prescribe optimal therapy without unwarranted adverse effects? What biological insights about the metastatic process could inform the development of innovative treatments?
Investigators: Dr. Clarinda Chua, Dr. Iain Tan, Adj. Prof. Melissa Teo, Dr. Michael Wang, Dr. Matthew Ng, Dr. Francis Chin

4. Surveillance in Initial Early-Stage GI Cancer

In colon cancer, randomised studies show that surveillance programmes designed to monitor and detect early recurrence can improve overall survival. However, current techniques still lack sensitivity and specificity.

Can we develop better tools to permit the early detection of recurrent GI cancers to lead to better cure rates amongst patients with recurrent GI cancers?
Investigators: Dr. Iain Tan, Dr. Matthew Ng, Dr. Clarinda Chua

5. Survivorship in Early-Stage GI Cancers

Most patients with early-stage GI cancers can be cured of their cancer.

Can we scientifically assess the needs of patients with early-stage colon cancer and develop better platforms to enhance survivorship programmes in patients with early-stage GI cancers?
Investigators: Dr. Dawn Chong, Adj. Prof. Melissa Teo

6. Treatment of Advanced GI Cancer

Some patients with stage IV colon cancer disease can be cured. In a proportion of patients with oligo-metastatic disease, a combination of surgery to remove all visible disease and postoperative chemotherapy can lead to durable disease remission and even cure. Nonetheless, advanced GI cancers are incurable for most patients. However, advances in palliative systemic chemotherapy and locoregional therapy, such as radiation, have substantially prolonged overall survival, provided palliation of symptoms, and improved quality of life. The major impediment to durable disease control is the almost inevitable emergence of resistance to therapy. Peritoneal carcinomatosis—common in GI cancers in particular— contributes to substantial morbidity and mortality.

Can we improve the effectiveness of cytoreductive therapies to increase the proportion of patients with
advanced GI cancer who can be considered for surgery with curative intent? Can we leverage on biological
insights to identify novel targets, develop new treatment strategies, and re-purpose existing treatments to improve the quality and duration of life in patients with advanced colorectal cancer? Can we better understand the mechanisms underlying drug resistance and formulate therapeutic approaches to prevent or overcome drug resistance?
Investigators: Dr. Matthew Ng, Dr. Clarinda Chua, Adj. Prof. Melissa Teo, Dr. Iain Tan

7. Peritoneal Disease

Approximately 20% of patients with colorectal and gastric cancers develop peritoneal metastasis during the course of their disease. Diagnosis is often late due to the lack of specific symptoms and low sensitivity of diagnostic imaging. Unlike liver and lung metastasis, systemic chemotherapy has limited efficacy against peritoneal metastasis. However, the introduction of cytoreductive surgery combined with hyperthermic intra-peritoneal chemotherapy (HIPEC) has provided hope for a curative treatment for a subset of patients. Up to 20% of patients with colorectal peritoneal metastasis can now hope for a 5-year survival with this therapy, without evidence of disease. Despite this, an analysis of more than 10,000 patients with colorectal cancer clearly defined peritoneal metastasis as the worst prognostic factor when compared to those with liver and lung metastasis. Our team in the NCCS has identified critical paracrine factors involved in the pathogenesis of colorectal peritoneal carcinomatosis. Currently, we are exploiting the advantage of being able to administer high doses of monoclonal antibodies and biologics into the peritoneal cavity in mouse models in vivo. From a clinical front, we are testing the efficacy of adjuvant HIPEC in colorectal cancers at high risk of developing peritoneal metastasis. Over the next 3 years, we envisage combining our scientific breakthroughs with our experience in early-phase clinical studies to plan a phase III study tackling peritoneal carcinomatosis in colorectal cancer.

Can we improve the effectiveness of cytoreductive therapies to increase the proportion of patients with advanced GI cancer who can be considered for surgery with curative intent? Can we leverage on biological insights to identify novel targets, develop new treatment strategies, and re-purpose existing treatments to improve the quality and duration of life in patients with advanced colorectal cancer? Can we better understand the mechanisms underlying drug resistance and formulate therapeutic approaches to prevent or overcome drug resistance?
Investigators: Dr. Matthew Ng, Dr. Clarinda Chua, Adj. Prof. Melissa Teo, Dr. Grace Tan

8. Immuno-refractory State of GI Cancers

Immunorefractoriness is a state that characterises most GI cancers (except for those with high-level microsatellite instability) with poor (gastric) to nearly no (microsatellite stable metastatic colorectal cancer) clinical responses with PD1/PDL1 axis checkpoint inhibition. Yet, data suggests that native immune responses in GI cancers are related to prognosis and outcomes. This argues against the therapeutic immune-refractoriness of GI cancers and represents a large area of unmet need and untapped potential. We have a multi-omics, multi-platform profiling study of the tumour immune microenvironment in colorectal cancers. We also have a neoantigen vaccine study in advanced colorectal and liver cancer. We have an ongoing prospective study evaluating the intratumoral PD-L1 expression and tumour infiltrating lymphocyte density in oesophageal cancer treated with neoadjuvant
chemoradiation (PLuTON).

Can we characterise the immune milieu/tumour microenvironment in GI cancers to identify modalities
of immune evasion and potential therapeutic opportunities to deploy different immune therapeutics, including different immune checkpoint inhibitors, adoptive cell therapy, and neoantigen vaccines?
Investigators: Dr. Si-Lin Koo, Dr. Iain Tan, Assoc. Prof. Han Chong Toh, Dr. Connie Yip

Dr. Iain Bee-huat Tan serves as NCCS’ overall lead for the luminal GI comprehensive disease programme. He is a Senior Consultant Medical Oncologist and clinician-scientist. His PhD was in Genomic Sciences and he is a Nationally awarded clinicianscientist (NMRC CSA). He heads the Colorectal Cancer Clinical Service and Research Programme within the Division of Medical Oncology. He holds a concurrent appointment as faculty (Senior
Clinician-scientist at the Genome Institute of Singapore). Dr Tan’s primary interest is employing next-generation diagnostics and therapeutics intelligently in novel therapeutic windows (e.g., ctDNA to detect minimal residual disease and anti-metastatic therapies, including immunotherapeutics designed specifically to truncate the metastatic process). His three broad areas of research are: real-time diagnostics, metastasis, and immune-oncology. He is a PI on several nationally funded research projects and clinical trials as well as consortium efforts in non-invasive diagnostics and novel immunotherapeutics. Details of his research can be found in his laboratory’s write-up in this book.

Adj. Prof. Melissa Teo is the Head of Division of Surgical Oncology and is a Senior Consultant Surgical Oncologist with an interest in pelvic oncology and peritoneal metastases. Peritoneal metastasis is a major cause of morbidity and mortality in patients with GI cancers. Her work is focused on identifying prognostic markers, carcinogenic pathways, and novel therapeutic targets that can be used to detect peritoneal metastases from gastric and colorectal as well as those of an ovarian and primary peritoneal origin. Her work includes molecular profiling of these tumours to identify potential biomarkers and therapeutic targets (in collaboration with Prof. Bin Tean Teh) and the establishment of cell line and xenograft models to understand the biology of disease.

Dr. Grace Tan is a Consultant Surgical Oncologist with an interest in the clinical management of peritoneal carcinogenesis and dissemination. She is the PI of a clinical trial evaluating the prophylactic use of HIPEC in patients with GI malignancies who are at high risk of peritoneal dissemination.

Asst. Prof. Johnny Ong is an Associate Consultant Surgical Oncologist with an interest in the mechanism of peritoneal carcinomatosis and dissemination. He is a nationally awarded clinician-scientist (NMRC TA), with a PhD in cancer biology. He examines the critical paracrine factors involved in the pathogenesis of colorectal peritoneal carcinomatosis, administering high doses of monoclonal antibodies and biologics into the peritoneal cavity in mouse in vivo models.

Dr. Matthew Ng is a Senior Consultant Medical Oncologist with an interest in experimental therapeutics. He heads up the Upper GI Cancer Clinical Service and Research Programme in the Division of Medical Oncology. His current research is focused on the development of biomarker-driven, early-phase clinical studies, particularly in oesophageo-gastric cancers, through molecular profiling of patients’ tumours and on the evaluation of pharmacodynamic indicators of oncogenic pathway modulation.

Dr. Clarinda Chua is a Consultant Medical Oncologist focused on colorectal cancer research, particularly in metastases. She oversees a prospectively maintained, relational colorectal cancer clinical database evaluating the demographic, biological and therapeutic determinates of outcomes in our patients. She is a nationally awarded clinician-scientist (NMRC TA) with a Masters in Clinical investigation (MCI). With her collaborators (mainly Dr. Dasgupta Ramanaj, GIS), she has established multiple patient-derived tumour models designed to evaluate the metastatic cascade and drug response and resistance.

Dr. Si-Lin Koo is a Consultant Medical Oncologist with an interest in cancer immunology. She is the PI of several studies evaluating the neoantigenic landscape in colorectal cancer and its relation to immune response. She also evaluates the immunometabolic axis in GI cancers and its relation to immunological priming and immune response and evasion.

Dr. Dawn Chong is a Consultant Medical Oncologist with an interest in cancer and molecular epidemiology in GI cancers as well as in cancer metabolism. She has a Masters in Public Health (MPH). She is the PI of studies evaluating the metabolic milieu of GI cancers and epidemiological studies evaluating the metabolic dependencies of GI cancers.

Dr. Michael Wang is a Senior Consultant Radiation Oncologist with a focus on radiation technology, radiobiology and clinical trials in GI cancers.

Dr. Francis Chin is a Senior Consultant in Radiation Oncology specialising in GI cancers. He is the lead PI in several radiation quality improvement projects involving total body irradiation and algorithm contouring for tumour and normal organs for irradiation.

Dr. Connie Yip is a Consultant in Radiation Oncology specialising in GI cancers. She is the PI of an ongoing prospective study evaluating the intratumoral PD-L1 expression and tumour infiltrating lymphocyte density in oesophageal cancer treated with neoadjuvant chemoradiation (PLuTON).

Dr. John Chia is a (visiting) Senior Consultant Medical Oncologist. He is a Principal Investigator for the Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers: an international, multi-centre, double-blind, randomised, placebo-controlled Phase III trial. This is a global, leading, potentially paradigm-changing Phase III trial evaluating if aspirin may be used to prevent recurrence and increase cure rates in patients with colorectal cancer.

MAJOR ACHIEVEMENTS SINCE INCEPTION

Collectively, our researchers have published many well-cited papers in Nature, Nat Genet, Nat Med, Sci Transl Med and J Clin Oncol. We are internationally recognised subspecialists, members of international guideline committees, and expert panels, and are leading contributors to local and international research consortiums. We have received multiple, nationally funded, research grants and research awards. More importantly, we are a unit set up for leading-edge clinical trials, clinical research, translational research, and productive collaborations across the continuum of research in GI cancers. We focus on using research to empower future clinical care.

Researchers:

​Dr. John CHIA​Dr. Dawn CHONG​Dr. Clarinda CHUA​Dr. Si-Lin KOO
​Dr. Matthew NG​Assistant Prof Johnny ONG​Dr. Grace TAN​Dr. Iain TAN
​Adj Prof Melissa TEO​Dr. Michael WANG ​Dr. Connie YIP