Constrained Peptides and Mini Proteins as Novel Therapeutics Targeting p53
Prof. Sir David Lane FRS
Many important targets for human therapy are deemed “difficult “because of their intracellular location and lack of binding sites for small molecules. This problem is now being addressed by developing new larger molecules that can for example act as excellent inhibitors of protein-protein interactions or promote the correct folding of mutant proteins by acting as molecular chaperons. The p53 pathway provides an outstanding target and test system for these new approaches and we have used synthetic biology methods to develop powerful reporter systems. The challenge of these larger molecules that includes stapled and cyclic peptides, monobodies and other mini-protein domains is ensuring their effective entry into the correct intracellular compartment. The study of natural products and toxins is providing novel insights into this process and the ability of synthetic biology and protein evolution methods to access huge libraries of variants of mini proteins and constrained peptides suggest that a whole new synthetic pharmacy is within reach. Most progress has been made using hydrocarbon stapled peptides where the first generation of molecules that bind and inhibit Mdm2 and Mdm4 and thus activate p53 as a transcription factor are in clinical trial. In this model second generation molecules of great specificity and potency are being developed using novel stapling methods, unnatural amino acids and new delivery methods.
Epstein-Barr Virus and Nasopharyngeal Carcinoma
Associate Prof. Dr. Yap Lee Fah
It is over 50 years since the Epstein-Barr virus (EBV), the first human cancer virus, was discovered. EBV is the most common persistent virus infection in humans with around 95% of the world’s population sustaining an asymptomatic life-long infection. The closest association with EBV infection is seen in undifferentiated nasopharyngeal carcinoma (NPC), a cancer type that is particularly prevalent in southern China and Southeast Asia, including Malaysia. Indeed, many unique characteristics of NPC could be attributable to the virus. The presence of EBV in every tumour cell provides opportunities for biomarker and therapeutic intervention including immunotherapy and/or targeting pathways activated by EBV latent proteins. Recent studies have profiled the mutational landscape of NPC and identified more heterogeneity in the pattern of EBV gene expression than previously suggested. This talk will highlight the contribution of EBV to the pathogenesis of NPC and discuss the exciting prospects for the development of novel treatment strategies for NPC patients.
Pre-clinical Models for the Study of Nasopharyngeal Carcinoma
Dr. Alan Khoo Soo Beng
Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health Malaysia, 1 Jalan Setia Murni U13/52, Setia Alam, 40170 Shah Alam, Selangor, Malaysia
Cell and animal based studies form an important component of cancer research. In vitro and in vivo models are used to study the gene function as well as to study potential targets for therapies. Evidence of drug efficacy in pre-clinical models are useful to justify clinical trials to test candidate drugs.
Nasopharyngeal carcinoma (NPC) is a major cancer in Malaysia. Translational research in NPC is hindered by the limited number of cell lines for in vitro and in vivo studies. Our group have been developing patient-derived xenografts from NPC patients. These PDXs were extensively characterised by histology, immunohistochemistry, EBER in situ hybridization, DNA finger printing, whole genome sequencing, RNASeq as well as RNAScope. The xenograft cells were also grown in short term in vitro 2D and 3D culture systems. The xenograft cells were labelled with GFP-luc2 for in vitro co-culture assays as well as to model skull base invasion (T4 disease) and distal metastasis (M1 disease) in mice. These cells would serve as useful resources for translational research in NPC.
My Journey in Research on Nasopharyngeal Cancer
Prof. Dr. Anne Wing-Mui Lee
My journey started under the inspiration of my first mentor Prof. John Ho, one of the greatest pioneers on nasopharyngeal cancer (NPC). He taught us that cancer treatment must be evidence-based; and if data is lacking, we should initiate our own research. For NPC, with its uniquely skewed distribution, Asian centers play a key role in the needed research.
I started my research to address questions most frequently encountered in clinical management. As a medical doctor working in a busy government service departments, without research grants and supports by other university scientists, the challenges and limitations are obviously formidable. With perseverance and concerted team efforts, we managed to come up with useful messages covering the whole spectrum of clinical issues from staging & prognostication, radiotherapy techniques and dose fractionation, chemotherapy sequence and regimen, late toxicities, and management of recurrence.
In more recent years, I also attempt to conduct studies that can have impact on global health policy and international standards. Furthermore, with taking up of academic post, I began to participate more in translational studies in collaboration with scientists and virologists.
This talk is aimed at sharing of my experience, particularly with young researchers. Summary of my research on NPC and the lessons that I have learnt along my journey will be presented.
Immunotherapy for Solid Cancers: An Update
Assoc. Prof. Dr. Ho Gwo Fuang
Harnessing the body’s ability to mount an immune response against cancer cells is now a well-established strategy to treat cancers. It has been known for many years that the immune system can help to treat cancer; however, initial attempts to utilize its potential had not gain widespread use.
Recently, interest in this strategy has increased, as a result of two main areas of breakthrough:
1. Checkpoint inhibitors using antibody against programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1)
2. Chimeric antigen receptor (CAR) T-cell therapy
Remarkable success has been achieved with many tumour types: pembrolizumab, an anti-PD1 antibody, is approved for treatment of melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck squamous cell carcinoma, classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, urothelial carcinoma, microsatellite instability-high (MSI-H) cancer, gastric cancer, oesophageal cancer, cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, and endometrial carcinoma.
An anti-PD-L1 antibody, atezolizumab, is indicated for the treatment of advanced urothelial carcinoma, NSCLC, SCLC, and for use in combination with abraxane for the treatment of metastatic triple-negative breast cancer.
Despite its impressive result in some patients, checkpoint inhibitors do not work for most patients, with single agent response rate ranging between 10-40%. The search is on for better predictor of response apart from the known PDL-1 and MSI-H, as well as to improve response rate using combined approaches. Tumour mutational burden (TMB) load, gut microbiome, tumour-infiltrating CD8+ lymphocytes and specific gene signatures are some of the candidate biomarkers.
Combining anti-CTLA-4 and anti–PD-1 therapies has been shown to be associated with meaningful survival improvements, and inhibition of CTLA-4 activates T-cell immune responses, leading to a potentially synergistic effect with PD-1/PD-L1 inhibitors. This strategy has been shown to be effective in treating melanoma and NSCLC.
Combining immunotherapy and chemotherapy is now a proven strategy for NSCLC and breast cancer.
Combining immunotherapy and targeted therapy is effective for renal cell carcinoma (axitinib and pembrolizumab), endometrial and hepatocellular carcinoma (lenvatinib and pembrolizumab). This approach is currently investigated for multiple tumour sites.
Despite achieving great success in leukaemia, CAR-T cell therapy has so far made limited impact in solid tumours, with the main limiting factor being tumour heterogeneity. Other T cell approaches: tumour-infiltrating lymphocytes and adoptive T cell transfer, have reported success in small studies in ovarian cancers and nasopharyngeal and head and neck cancers.
Approaches using cancer vaccine: single tumour antigen (peptide, nucleic acid or protein) or multiple antigens (pulsed dendritic cells, whole tumour cell) are still under investigation, with many failed attempts encountered despite initial phase 2 successes. Approaches that utilise tailor-made vaccine, using patient’s own tumour are more likely to be successful, but are much more labour intensive.
Next generation immunotherapy is now subject of intense research, with immune agonist and Bi-specific T-cell (BiTEs) the two main approaches. BiTEs form a link between T cells and tumour cells, causing T cells to exert cytotoxic activity on tumour cells, independent of MHC I or co-stimulatory molecules.
Metastatic Gastric Cancer – Molecular & Clinical Updates
Dr. Sucharit Pongprakyun
Metastatic gastric cancer remains one of the more challenging cancers to treat. According to the GLOBOCAN 2018 data, it is the third most common cause of cancer death worldwide. In Malaysia, it is the 8th most common cancer among males and 10th most common cancer among females but ranks as the 6th most common cause of cancer death for 2018. It has been reported that majority of cases in Malaysia are detected at an advanced stage. Early detection followed by the appropriate treatment would help to improve the survival of patients. Chemotherapy has been used as the mainstay of treatment for many decades in advanced/metastatic disease. The emergence of newer class of drugs such as monoclonal antibodies and immunotherapy have broaden the scope of treatment options available. However, the survival rates although improved with the presence of newer agents, have remained dismal. Specific biomarkers discovered such as HER2 has allowed a more targeted-based treatment to be used in subtypes which harbor this biomarker. It is important to explore further the role of biomarkers in gastric cancer and to be aware of biomarkers currently been used in clinical practice, in clinical trials and in various stages of research.
From Trials to Bedsides and vice versa – the Real-Life Hurdles in Hematologic Malignancies
Dr. Ong Tee Chuan
Evidence based medicine has shaped the current practice of modern medicine, and it has transformed the image of “bloodletting-all” doctor to a modern physician who practices with scientific basis and backed up by clinical trial data. Perhaps a physician-scientist is the best bridge to the gap of basic science knowledge and clinical medical practice, as he can play a 2-in-1 role seamlessly. Academic medicine in the teaching university hospital has traditionally been the cradle for producing physician-scientist, but we do see the push for this culture into public and private service hospitals in recent years. However, the culture of “publish or perish” and “p value obsession” are now being identified as possible unintended consequences of emphasizing evidence based medical practice. Some of these issues will be discussed in this short talk.
Impact of Research in Supportive Care in Oncology
Dr. Marfu’ah Nik Eezamuddin
Over years, we have seen therapeutic advances enabling better survival in cancer patients. This progress have placed an emphasis on the dimension of supportive care in cancer. Supportive care in cancer is the prevention and management of the adverse effects of cancer and its treatment. This entity looks into the symptom management of physical, psychological and treatment toxicities across the continuum of the cancer experience: from diagnosis, through treatment, to post-treatment care.
Prevention or reduction of treatment side-effects translates into improvement in therapy tolerance and compliance, thus increasing benefits of active therapy. Nausea and vomiting, is a major symptom affecting cancer patients. It can be induced by chemotherapy or radiotherapy, or can be part of advanced cancer. The latest guidelines in antiemetic use have included the role of new NK1 receptor antagonists, rolapitant and netupitant, the latter given in combination with palonosetron (NEPA), and the use of olanzapine.
Oral complications secondary to cancer therapy, including mucositis which may affect any part of the digestive tract depending on type of cancer therapy significantly causes distress to patients and caregivers. Extensive research has been made looking into successful interventions for mucositis – anti-inflammatory agents, vitamins, photobiomodulation techniques to name a few – in hope to enable patients to tolerate complications of treatment without compromising quality of life.
Cancer-related fatigue significantly disrupts normal functioning and quality of life for a substantial portion of cancer patients, and may persist for years following cancer therapy. It is the most widespread adverse effect of cancer in adults and children. Meta-analysis of randomized controlled trials of pharmaceutical therapies for cancer-related fatigue reveal a small effect size for all drug classes. Exercise interventions has been more promising. Exercise was found to significantly improve both quality of life and physical function in cancer patients.
There are many other aspect of supportive care in cancer that are growing in interests. Sexual health issues, survivorship and digital healthcare are among contemporary subjects with promising research potential. Alleviation of symptoms and complications of cancer and its therapy makes excellent comprehensive cancer care possible.
The Preclinical and Clinical Development of Apaziquone (EO9) as a Locoregional Therapy for Non-muscle Invasive Bladder Cancer
Professor Dr. Roger Phillips
The development of anti-cancer drugs is a difficult and challenging enterprise that induces excitement and disappointment in equal measure. This is particularly true in the case of Apaziquone (originally known as EO9) which was originally synthesised by Oostveen and Speckamp in the 1980’s at the University of Amsterdam. Following promising preclinical studies, EO9 underwent clinical evaluation in the 1990’s but no complete or partial responses were observed in phase II studies following intravenous administration. The reason for its failure was attributed to poor drug delivery to tumours caused by (i) rapid pharmacokinetic elimination and (ii) poor penetration through avascular tissue. Whilst these properties are clearly unsuitable systemically administered drugs, they are paradoxically ideal for loco-regional therapies where the aim is to have high levels of drug at the site of drug administration. Based on this understanding, a further clinical trial of EO9 against non-muscle invasive bladder cancer (NMIBC) was developed on the basis of (i) intravesical administration of EO9 into the bladder would circumvent the drug delivery problem (ii) retention within the bladder for one hour would increase the duration of drug exposure and (iii) any drug reaching the circulation would be rapidly eliminated thereby reducing the risk of systemic toxicity. Significant anticancer activity was reported in phase I and II clinical trials (67% complete response rate) and this presentation will conclude by describing the current clinical status of EO9 against NMIBC and discussing the implications of this work for drug discovery and locoregional therapies.
Translating Research into Personalized Therapy for Childhood Acute Lymphoblastic Leukaemia
Prof. Dr. Hany Ariffin
Acute lymphoblastic leukaemia (ALL) is the commonest paediatric malignancy, representing a third of all cancers in children. From being a uniformly fatal condition in the 1950s, childhood ALL has become one of the greatest success stories of cancer treatment history. Overall survival rates of >90% have been realized largely through the systematic conduct of multi-institutional clinical trials, improved knowledge of disease biology, along with increased expertise in supportive care. However, the journey to reach these outstanding achievements began with the breakthrough discovery of the folate antagonist, aminopterin, where it was used as monotherapy. Subsequently, more drugs were discovered leading to the development of combination therapies using cytotoxic agents of various classes. In tandem with drug discovery, research into discovering the heterogeneity of leukemic blasts and exploiting these for therapeutic gain was actively pursued. Subsequently, preservation of normal growth and development in affected children became an equally important benchmark for success. Thus, sequentially developed treatment protocols for ALL, as with for most other paediatric cancers, shifted focus to achieving a better balance between improving cure and reducing toxicities. Therapy was risk-adapted and increasingly personalized to reduce late-effects – the latter is now a major area of research due to the large population of survivors of this previously fatal disease. Modern oncology therapy dictates that there is no longer a ‘one-size-fits-all’ way of managing patients with various cancers and childhood ALL is one of the earliest cancers where disease biology determined, and continues to drive, treatment choices.
Making advanced Non-Small Cell Lung Cancer (NSCLC) into chronic disease: What scientists can do?
Prof. Dr. How Soon Hin
Lung cancer is one of the most common cancer, it accounts for about 10% of all cancer cases but associated with 20% of cancer mortality. Most lung cancer patients presented at the late stages. In Malaysia, 90% of them were diagnosed with either stage III or IV at presentation. In the era of chemotherapy, overall survival of treated advanced NSCLC was 9-12 months. The discovery of driver mutation eg. EGFR, ALK, ROS 1 significantly prolong its survival. In profile 1014 study, median overall survival of ALK positive NSCLC patient treated with ALK inhibitors was extended to more than 4 years. In the same study, patients treated with chemotherapy without ALK inhibitor were associated with poorer outcome. In the recent years, immunotherapy had been showed to prolong overall survival of patients with NSCLC without driver mutation. Some of patients who were given immunotherapy had durable response and possible cure. With discovery of more therapeutic agents, better molecular diagnostic tools and improvement in efficacy of current treatment, advanced NSCLC may become chronic disease in future. Scientists play an important role to achieve this goal.
The Thioredoxin System – A Friend or Foe in Disease States and Its Relevance as a Target in Anticancer Treatment
Assoc. Prof. Dr. Chew Eng Hui
The thioredoxin and glutathione systems are the two major thiol redox systems that maintains intracellular redox homeostasis. The thioredoxin (Trx) system comprises Trx, thioredoxin reductase (TrxR) and NADPH. TrxR catalyzes the NADPH-dependent reduction of the active site disulfide of oxidized Trx. To protect cellular proteins from oxidative damage, Trxs use a conserved redox active dithiol/disulfide motif (-Cys-xx-Cys-) to participate in reversible thiol-disulfide exchange reactions. Emerging findings have indicated that the dysregulated levels of the components of the Trx system has led to different disease states. Our laboratory has taken the interest to investigate the Trx system’s involvement in regulating apoptosis and it has been found that thioredoxin-1 (Trx-1) is capable of regulating DNA damage mediated by apoptosis inducing factor (AIF). The identification of the interaction between Trx-1 and AIF has provided opportunities to design and develop strategies that either promote or prevent this protein-protein interaction for treatment of different disease states. While Trx is required for regulation of cell proliferation and apoptosis, on the other hand, in cancer, the biological effects of the Trx system contribute to tumor growth and progression. In the light of the high prevalence of cancer and refractoriness of malignant tumors to clinical agents, novel molecular targets need to be identified and new chemotherapeutics be discovered. Accumulating evidence has indicated that the selenocysteine-dependent TrxR enzyme is a valid molecular target for anticancer drug development. Numerous natural products and synthetic compounds, including several clinically used chemotherapeutics have been recognized to target TrxR. A number of structurally diversified compounds derived from natural sources have also been found to possess potent inhibitory effect against TrxR. In our laboratory, we had evaluated the possible inhibitory effect of a panel of structurally diversified naturally-occurring compounds and their derivatives on TrxR activity. Sharing in common electrophilic centers, these compounds had been found to possess TrxR inhibitory activity correlating to their antiproliferative activity. On this basis, these compounds can be further developed for applications in cancer chemotherapies that may lead to more desirable clinical outcomes.
Can Combination with Phytochemicals Make Platinum Drugs More Desired and Welcome?
Assoc. Prof. Dr. Fazlul Huq
The present study aimed to investigate drug action from the combination of platinum drugs and designed complexes with tumour active phytochemicals including curcumin, EGCG, thymoquinone, resveratrol, ursolic acid and genistein in human ovarian tumour models. Activity of the compounds alone and in sequenced combinations in ovarian and colorectal cancer cell lines including A2780, A2780cisR and A2780ZD0473R were determined using MTT reduction assay. Drug accumulation and drug−DNA binding were determined using established protocols. Proteomic studies involving 2D gel electrophoresis and mass spectrometry were employed to characterize key proteins associated with platinum resistance. Generally but not always sequenced combinations with 2 to 4 h time gap were found to be synergistic. The variation in combined drug action with the change in sequence of administration indicates that the action of one drug is modulated by that of the other. Proteomic studies have identified over thirty proteins believed to be associated with platinum resistance in ovarian cancer. They belong to six major groups including cytoskeletal proteins, molecular chaperone and stress related proteins, proteins involved in detoxification and drug resistance, proteins involved in metabolic processes and mRNA processing proteins. The proteins are restored to normalcy due to treatment with synergistic combinations. If confirmed in vivo, the results suggest that appropriate combinations of targeted therapy and tumour active phytochemicals may provide an effective and affordable means of overcoming drug resistance in ovarian cancer.
Control and Prevention Strategies for Oral Cancer – the Malaysian and Regional Scenario
Prof. Dr. Rosnah binti Mohd Zain
The epidemiology of Oral Cancer is unique and varies from country to country. Its prevalence may differ and in many cases is dependent on the variation of lifestyles and habitual risk factors. Like other cancer research, different aspects of oral cancer research are converging to give an impact on the patients’ quality of life as well as the community. Despite the high volume of literature on oral cancer, patients are still being diagnosed at late stages, especially from the Asian region where almost two-thirds of patients presented with late stage cancers (Stages 3 & 4).
There are two general aspects of oral cancer control strategies which are considered to be of equal importance. One is for those with no cancer where prevention of oral cancer, early detection of oral cancer and prediction of malignant progression are extremely important to reduce the prevalence of oral cancer; whereas for those with oral cancer, effective management strategies can be very challenging due to the heterogeneity of the disease. The search for new strategies and therapeutics in combating oral cancer becomes of utmost importance for curative or palliative intent, which will finally, contributes to improved quality of life of patients.
When considering the Low- and Middle-Income Countries (LMIC), the burden of oral cancer is high and with some countries having inadequate facilities and resources, population-based screening becomes unethical until such a time that the country has enough facilities and human resources to handle the outcome of screening. With this in mind, the move to reduce incidence of oral cancer is to concentrate on efforts on the early detection of oral cancer through public awareness of the disease and the risk behaviors. Prevention through awareness is utmost importance while risk behavior interventions are equally important but may be more challenging to achieve the optimal output.
This presentation will focus on understanding oral cancer (clinicopathologic profiles, risk factors and progression) and their importance in prevention and management strategies in the Malaysian and Regional context.
Policy & Priorities for National Cancer Control Planning in Low & Middle Income Countries: Lessons from the ASEAN Costs in Oncology, ACTION Study
Assoc. Prof. Dr. Nirmala Bhoo-Pathy
Evidence to guide policymakers in developing affordable and equitable cancer control plans are scarce in low- and middle-income countries (LMIC). The ACTION (ASEAN Costs in Oncology) study, examined the human cost of cancer to populations across eight countries in Southeast Asia (Cambodia, Indonesia, Laos, Malaysia, Myanmar, Philippines, Thailand and Vietnam). The study was designed to assess the impact of cancer on household economic wellbeing and patients’ survival as well as quality of life. In this talk, findings from the overall study, and findings specific to Malaysia will be presented, and the policy implications will be discussed.
How Much Are We Shifting Paradigms? Impact of Cancer Research in Malaysia
Dr. Murallitharan Munisamy
The word intervention is defined as action taken to intentionally become involved in a difficult situation in order to bring an improvement to it or to prevent it from worsening. Cancer is one of those situations. Across the cancer control continuum spanning from prevention, early detection, diagnosis, treatment and survivorship there are countless issues which continue to impair and impede patients suffering from cancer from obtaining good treatment outcomes. We increasingly know that the etiology of these conditions are multifactorial; and thus proposed solutions need to be from a multisectoral viewpoint as well.
One of the shining beacons of human civilisation thus far has been science and those who work tirelessly to advance its cause: scientists and researchers. From creating new therapeutic solutions to molecular diagnostics we keep on looking for and discovering newer, better weapons in the armamentarium globally to fight cancer. These new solutions and discoveries need to, at the end of the day, be validated through the rigorous methods which make up intervention research; the culmination of a long journey of multiple small scientific discoveries.
Without a doubt, intervention research is the most difficult, critical step between moving from the controlled ‘laboratory’setting to the ‘real-world’. Rightly so, moving into an intervention phase first requires rigorous planning and methodical stepwise background research before deployment. On the other hand, however, too much caution and a propensity to ‘play safe’ by researchers will continue to limit the amount of interventional research actually being carried out; and thus really making an impact directly on patients especially in the cancer landscape.
Is there a rich, robust scene of interventional research in the local Malaysian landscape in terms of cancer? That is thought-provoking question that needs to be raised and if not, we need to think and act on shifting the paradigm on this, to assist all Malaysians in tackling the cancer burden.
Patient Navigation Program: A New Horizon for Breast Cancer Care
Dato’ Seri Dr. Mohamed Yusof Bin Hj Abdul Wahab
Late stage presentation and poor adherence to treatment protocol remains a major contributor to poor survival for patient with breast cancer in Malaysia. Most women experience psychological distress throughout the course of their journey in battling this disease. It can be related to physical problems like illness or disability, psychological problems, family issues and social concerns such as those related to employment, insurance and supportive care access. Addressing the physical demands of the disease is just one component of the comprehensive treatment regimen for breast cancer; treatment must account for patient’s psychological needs as most of the patient will link cancer with death which results in anxiety and depression.
In Ministry of Health Hospital, breast cancer patients are managed either by the general surgeon or the breast surgeon. In Hospitals where the cases are manage by the general surgeon, the challenge is to offer personalized and dedicated care. Realising this need, in 2004 breast cancer patients presenting to HTAR was manage by a dedicated team (Medical Officer and nurse). Process of care was monitored closely with timeline for both investigation and treatment define. However, the defaulter rate was still high (11.5% in 2014). We realized we needed other initiatives to improve the compliance to treatment.
In 2015, HTAR Surgical Department established a partnership with Cancer Research Malaysia (CRM) and integrated patient navigation program (PN) in the management of breast cancer patient. We named our centre providing patient navigation as Pink Ribbon Centre (PRC). Our aim is to improve the overall compliance of patient to treatment plan. To achieve these, navigators who are qualified nurses in general nursing, oncology and breast care and surgery became part of our management team. Navigators provided patient and family with education tools, supportive care and visit, and practical help in overcoming individual patient barriers. A community navigator from CRM was also placed to address patients’ social welfare needs that hinder completion of cancer care. In addition, the PRC had increased clinic days, dedicated phone lines and implemented an appointment reminder call.
We audited our outcome as regards to timeliness of our work process. Compared to the cohort of patients in the year prior to PN, women with PN received timely mammography (96.4% vs. 74.4%, p<0.001), biopsy (92,5% vs. 76.1%, p=0.003), and communication of news (80.0% vs. 58.5%, p <0.001). PN reduced treatment defaulter rates (4.4% vs. 11.5%, p=0.048). Among navigated patients, late stage at presentation was independently associated with having emotional and language barriers (p=0.01). Finally, the main reason reported for delay, default, or refusal of treatment was the preference for alternative therapy. PN is feasible in addressing barriers to cancer care when integrated with a breast clinic in HTAR. Its implementation resulted in improved diagnostic timeliness and reduced treatment default. Wider adoption of PN could be a key element of cancer control in Malaysia.