The Women’s Cancers Programme encompasses research on gynaecological cancers as well as breast cancer. Our multi-disciplinary team includes medical, surgical, and radiation oncologists; gynaecologists; basic and translational scientists; and computational biologists, with our research interests spanning from circulating tumour cells, patient-derived xenografts, multi-omics, genetics and stem cells to novel diagnostic and therapeutic methods, personalised therapy, clinical trials and health outcomes.
NCCS GYNAECOLOGICAL CANCER PROGRAMMEThe mission of the NCCS Gynaecological Cancer Programme is to leverage research to improve clinical outcomes for patients with gynaecological cancers in Singapore.
PRE-CLINICAL STUDIES AND CLINICAL TRANSLATION
Ovarian Cancer Xenograft ProgrammeOne of the programme’s main efforts is the treatment of chemotherapy-resistant ovarian cancers, particularly clear cell, endometrioid, and mucinous sub-groups, all of which are common in Singapore. In collaboration with Prof. The Hung Huynh, our group has developed one of the world’s largest repositories of ovarian cancer patient-derived xenograft lines. We have systematically explored the therapeutic potential of many new anti-cancer agents and their combinations using these xenograft lines, and evaluated novel strategies for overcoming innate and acquired chemotherapy resistance. The marriage of individual patient treatment outcome data with mouse xenograft data has further improved the accuracy and predictive capacity of our pre-clinical models. As such, various strong commercial partnerships with multinational pharmaceutical companies has been established over the years, thus allowing Singapore to participate in early-stage global drug development.
Ovarian Cancer Tissue Collection ProgrammeDr. Elaine Lim is the Principal Investigator of an ovarian cancer tissue collection project that conducts basic research through molecular profiling the use of cellular models and immunophenotyping to ascertain the link between ovarian cancer and endometriosis.
Clinical TrialsOver the past three years, our group has been active in initiating and conducting investigator-initiated early-phase trials in gynaecological cancers. A phase I MUC-1-CD40L cancer vaccine study is recruiting patients with ovarian cancer, among other epithelial cancers. Dr. Tira Tan presented the interim analysis of an open-label, single-arm phase II trial of regorafenib in patients with multiply treated epithelial ovarian cancer at the ESMO Asia2017 Congress and won Best Poster in the Gynaecological Cancers category. This study is nearing completion, with restriction to the clear cell subtype to investigate the efficacy signal. Dr. Jack Chan is leading an investigator-initiated phase Ib/IIa study of the novel combination of nivolumab immune checkpoint inhibition with an anti-CA 125 vaccine, oregovomab, in patients with recurrent epithelial ovarian cancer. Through the newlyestablished Gynaecological Cancers Group Singapore (GCGS), we have also become a participating site of a randomised phase II trial of durvalumab versus physician’s choice chemotherapy for clear cell ovarian cancer. Other investigator-initiated trials for ovarian and endometrial cancers are being planned.
We have also participated in industry-sponsored phase III trials, such as the Z-100 adjuvant immunomodulator trial for cervical cancer, and the avelumab versus chemotherapy versus avelumabchemotherapy trial for platinum-resistant ovarian cancer. We are pleased to announce GCGS’s provisional membership entry into the Gynaecological Cancer InterGroup and look forward to collaborating with other partners within and outside of Singapore in conducting gynaecological cancer trials.
HIPEC (Hyperthermic Intraperitoneal Chemotherapy)Ovarian cancer is a peritoneal-based disease, and our group, has recruited to date more than 60 ovarian cancer patients who are on the Centre’s HIPEC protocol. Our group remains committed to developing new and relevant protocols for gynaecological cancers and optimising patient selection strategies for HIPEC among those with recurrent ovarian cancer. The team aims to reduce the toxicity of HIPEC and has published several quality-of-life analysis studies for patients receiving this therapy.
Gynaecological Radiation Oncology TeamOur group is undertaking studies to ascertain the impact of radiation therapy on quality of life in patients with cervical cancer. This study will provide longitudinal follow-up data and enable clinicians to better counsel patients concerning the short- and long-term impact of radiation therapy, and form the basis for cost-effectiveness and health economic analyses. It will also provide baseline information for the eventual comparison of the efficacy of proton therapy with conventional radiotherapy.
NCCS BREAST CANCER PROGRAMMEWith an incidence rate of 65.3 cases per 100,000 person-years from 2011 to 2015 and accounting for nearly 1 in 3 incident cancers in females, breast cancer is undoubtedly the most common cancer among Singaporean women (Singapore Cancer Registry Annual Registry Report 2015, National Registry of Diseases Office). As the largest centre managing breast cancer patients in Singapore, we have the unique prospect of being able to synthesise opportunities for Singapore’s investment in basic research through to survivorship care, generating the best outcomes possible for all.
The Breast Cancer Programme encompasses an integrated team of physician-scientists recognised for their contributions to breast cancer research and treatment. The overarching goal of the Breast Cancer Programme is to improve our understanding of the intricacies of the biology, genetics and biochemistry of breast cancer, with the concomitant application of this knowledge towards diagnostic, therapeutic, and screening/preventive strategies for improved outcomes in each patient. To this end, the Clinical Breast Cancer programme is driven by an interdisciplinary approach incorporating basic research, clinical/translational research, and public health/behavioural/health outcomes research.
The Clinical Breast Cancer programme comprises a team of radiologists, surgeons, medical oncologists, medical geneticists, and plastic surgeons offering the full spectrum of clinical and support services from screening/diagnostics to prevention, treatment and care for long-term cancer survivors. We offer patients a wide variety of clinical trials encompassing a spectrum that provides the latest advancements in breast cancer clinical care and treatment/prevention. There are weekly meetings of our multidisciplinary Breast Cancer Tumour Boardas well as weekly basic/translational research meetings. Our physicians are leading investigator-initiated, cooperative groups (Breast International Group and Michelangelo Foundation) and coordinate with industry-run international clinical trials that span phases I to III.
PRECLINICAL STUDIES AND CLINICAL TRANSLATIONBreast fibroepithelial tumours constitute a distinct category in breast disease. Distinct from breast carcinoma, they comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant Phyllodes tumours. Prof. Bin Tean Teh’s team has recently profiled the genomic landscape of this group of tumours. First, MED12 mutations were frequently found in both fibroadenomas and Phyllodes tumours, emphasising theimportance of these mutations in fibroepithelial tumorigenesis. Second, Phyllodes tumours exhibited additional mutations in, for example, TERT, MED12, FLNA, SETD2 and KMT2D, suggesting a role for them in driving Phyllodes tumour development. Third, borderline and malignant Phyllodes tumours harboured additional mutations in common cancer-driver genes, such as p53, RB1, EGFR and PI3K.These step-wise mutations can potentially be employed to assist in clinical diagnoses. A study involving about 1,000 fibroepithelial tumours from different countries is being carried out to validate these findings before they are translated into clinical application.
Assoc. Prof. Ann Lee’s team have research interests in hereditary breast and/or ovarian cancer and in the development of bloodbased tests for breast cancer diagnosis or prognosis. They published the first Asian study using a 25-gene panel of breast cancer susceptibility genes for the largest Asian series of cases. More recently, the group identified new breast cancer risk loci using a novel targeted next-generation sequencing strategy. A blood based diagnostic assay for breast cancer is also being developed based on circulatory microRNA signatures in a multisite study involving NCCS, National University Hospital Singapore, Tan Tock Seng Hospital, SingHealth Polyclinics, NUS, A*STAR and MiRXES Pte. Ltd. We are currently engaged in studies to discover novel genes involved in breast cancer predisposition, and also in refining our microRNA signatures to improve assay accuracy.
On the translational research front, Medical Oncologists Dr. Yoon Sim Yap and Dr. Elaine Lim are carrying out studies on circulating cancer markers and tissue collection; these studies, respectively, interrogate breast cancer through a multi-omics approach, as well as through immunophenotyping, with support from collaborators at the Singapore Immunology Network (SIgN) and Dr. Wai Leong Tam at the Genome Institute of Singapore (GIS). These studies have culminated in clinical research, with a planned pilot study of bexarotene differentiation therapy in patients with metastatic triple-negative breast cancer. Among our Breast Surgeons, Dr. Veronique Tan and Adj. Assoc. Prof. Benita Tan, together with Prof. Kanaga Sabapathy, received the NCCS Project Grant to investigate how the microenvironment of a breast cancer influences cancer growth.
Finally, Senior Resident Dr. Huren Sivaraj was awarded, under the mentorship of Assoc. Prof. Rebecca Dent and Prof. Puay Hoon Tan, an educational grant by Foundation Medicine (FM) to perform next-generation molecular sequencing using the FM platform on 150 triple-negative breast cancers from the SGH Pathology database and compare these to similar profiles in Caucasians. These preliminary results will likely have clinically important implications for targeted novel therapies. The manuscript is currently being prepared in collaboration with Prof. Bin Tean Teh and Prof. Steven Rozen.
Young Women’s Breast Cancer ProgrammeBreast cancer in women under the age of 40 years is more prevalent in Asia than in the West; 18% of breast cancers in Singapore are found in patients aged 44 years and below. Given the multiple, unique challenges facing young patients with breast cancer, we are developing a tailored treatment programme that advocates a multidisciplinary approach. Dr. Guek Eng Lee was awarded a National Medical Research Council (NMRC) grant to study the Programme for Young Women with Breast Cancer in the Dana-Farber Cancer Institute, the first such programme in the United States. We aim to establish a clinical model for our local population, and create a programme for young women with breast cancer. From a research standpoint, this programme brings together clinical researchers and scientists dedicated to improving our understanding of breast cancer in young women, including the biology of the disease, patient responses to therapy, as well as the psychosocial and survivorship concerns. It will also be a platform to participate in multinational trials. Research efforts to date have led to a poster presentation at the 3rd ESO-ESMO Breast Cancer in Young Women International Conference. In addition, related work has been published in BMD Women’s Cancers and Breast Cancer Research and Treatment. Currently, we are actively collaborating in a multinational study for young women with breast cancer, correlating treatment details with survival outcomes.
Dr. Yoon Sim Yap’s manuscript on the molecular profiling of a cohort of young breast cancer patients treated at the NCCS and Asan Medical Centre, South Korea, is in press.
Supportive Care Breast Cancer Programme
A key ongoing project is exploring the utility of cryotherapy in mitigating taxane-induced peripheral neuropathy among early breast cancer patients. This project is supported by Terry Fox (NCCS) and subsequently Khoo Pilot Award (Duke-NUS) grants. In addition, we are looking into collaborative research in the field of Cardio-Oncology with colleagues at the National Heart Centre Singapore, with the aim to understand the incidence and landscape of cardiotoxicities from anti-cancer therapies in our local patient cohort. Our group also study a wide array of other cancer supportive care and survivorship issues among breast cancer patients, including chemotherapy-associated cognitive impairment and fatigue, myelosuppression, and chemotherapy-induced nausea and vomiting.
Future research plans in breast cancer supportive and survivorship care include studies examining the role of exercise in alleviating common treatment-related toxicities in patients with breast cancer, as well as the role of a comprehensive supportive and survivorship multidisciplinary care framework on breast cancer survivors.
Breast Preoperative Programme
This multidisciplinary programme for patients receiving preoperative systemic therapy is led by Advanced PracticeNurses. Launched in 2014, this programme has now been entrenched in our Centre, enrolling more than 80 patients a year. The goal is to provide consistent, high-quality, multi-disciplinary care for women with high-risk, early-stage or locally advanced breast cancer. This Programme has enabled our participation in global neoadjuvant phase Ib and randomised phase III immunotherapy-based trials in triple-negative breast cancer.
Breast Phase I ProgrammeThrough the Experimental Cancer Therapeutics Research Unit’s IMPACT programme, many of our breast cancer patients have had their metastatic tumours molecularly profiled, facilitating their timely access to phase I clinical trials. Dr. Tira Tan, the programme lead, is undergoing a fellowship in early drug development at the Princess Margaret Cancer Centre in Toronto, Canada, under the mentorship of Dr. Phil Bedard and Dr. Lillian Siu. The number of breast cancer patients recruited to phase I trials over the last 3 years has increased by more than 50% to 23 in 2017. Under the leadership of Dr. Yoon Sim Yap, Singapore is now engaged in first-in-human, breast-specific, phase I trials (such as ER receptor oral degraders) along with other major international cancer centres, such as the MD Anderson Cancer Center, the Memorial Sloan Kettering Cancer Center, among others.
Breast Clinical Trials ProgrammeOur team has 15 to 20 active phase II and III trials for breast cancer, both investigator-initiated and industry-sponsored. Many of these trials are early phase II trials and thus provide early access for patients to new therapies. In addition, our team has been actively engaged in protocol development for these trials and leads upcoming new international trials. The NCCS was intimately involved in the LOTUS trial evaluating the role of AKT inhibition in metastatic triple-negative breast cancer. The interim overall survival results will be presented as an oral presentation at the upcoming 2018 ASCO scientific meeting by one of our principal investigators, Assoc. Prof. Rebecca Dent. The DORA trial is a global, investigator-initiated trial (IIT) evaluating the role of the poly (ADP-ribose) polymerase inhibitor, Olaparib, or Olaparib in combination with checkpoint inhibition, as a maintenance therapy in patients with platinumresponsive, metastatic, triple-negative breast cancer. This is an AstraZeneca supported IIT (US$3.4M) and is due to open in August 2018 in the USA, Korea and Singapore, with Assoc. Prof. Dent as the global study chair. This study was enabled by Dr. Tira Tan before her departure for her fellowship and she will continue to serve as an active co-Principal Investigator. Dr. Tan and Assoc. Prof. Dent have also been awarded a Duke–Duke Collaboration grant to facilitate the translational component of the study. The trial is being conducted through the academic research organisation, Duke Clinical Research Institute.
BREAST SURGICAL ONCOLOGY TEAMOngoing clinical research includes characterising aspects of breast cancer in the Asian population. We explore the spectrum of breast carcinomas, from ductal in situ carcinoma to locally advanced cancers, and analyse special populations, such as pregnancy-associated breast cancers, genetic carriers, young patients, and advanced, older patients, to identify peculiarities and unmet needs.
Significant efforts are devoted to advancing the loco-regional treatment of breast cancer. We are running a phase II trial on the use of INTRABEAM intra-operative radiotherapy for ductal carcinoma in situ and have also embarked on pilot studies on the role and utility of the novel tracer SentiMag® for sentinel lymph node identification. We further are investigating the use of targeted axillary dissection in conjunction with sentinel node biopsy for patients with clinical complete nodal response postneoadjuvant systemic therapy.
In addition to the extensive successful collaborations with scientists and clinicians at NCCS, SGH and Duke-NUS, we also partner with other institutions both locally and overseas. These include multiple collaborations with researchers at the NUS Saw Swee Hock School of Public Health to study our national breast cancer cohort epidemiology and economic dimensions; regional breast cancer survival and outcomes in partnership with the University of Malaya Medical Centre, Malaysia; as well as a genomic assay validation study with the Koo Foundation Sun Yat-Sen Cancer Centre, Taiwan.
BREAST RADIATION ONCOLOGY TEAMTogether with the team of radiation therapists, physicists and dosimetrists, clinicians in NCCS’ Division of Radiation Oncology are continuously engaged in research and in the implementation of new clinical programmes.
With the help of our colleagues, we have created a highresolution, multi-centre Joint Breast Cancer Research (JBCR)database. Today, it is a robust and prospectively maintained database with 25,000 patients and counting. The JBCR has collaborated with both local and international researchers. The ongoing research spans a wide range of topics: this includes 1) the study of ethnic differences in mortality among Singaporean patients with breast cancer, which is done in collaboration with Dr. Jingmei Li from GIS; 2) understanding the impact of imaging findings after oncoplastic breast conserving surgery with Dr. Chee Hao Leong from SGH’s Division of Diagnostic Radiology; 3) investigating the outcomes of gestational breast cancer with NCCS’ Division of Medical Oncology; and 4) investigating the role of radiotherapy in borderline and malignant Phyllodes in conjunction with SGH’s Department of Pathology. In 2017, we published some of these efforts, including the outcomes in young patients with breast cancer, the outcomes in screened and non-screened Malay patients with breast cancer cohorts, and the outcomes of a validation study of the AJCC 8th prognostic staging system, to name a few. Usingresults from the JBCR and in collaboration with programmers and analysts from the Department of Cancer Informatics, a programme has been started to offer real-time matched-cohort analysis to provide clinicians and patients with information on outcomes specific to an individual’s risk factors and stage.
Our team has also spearheaded a few novel clinical programmes. We have previously conducted dosimetric studies on the relative coverage of supra-clavicular (SCF) nodes, which have since influenced the way treatment plans are prepared to optimise the coverage of the SCF region. To enhance patient’s body image satisfaction, we have studied the use of invisible (UV) tattoo ink for radiotherapy set-up verification, to avoid the permanent tattoo marks on our patients. In terms of motion management, we have commissioned the use of a breath-hold SDX® gating system to minimise lung and cardiac radiation doses. For patients with large pendulous breasts, we explored immobilisation and treatment planning in the prone position as a way to reduce the radiation doses to the heart and lung. Of late, we are also implementing the Chabner® bra, which supports and immobilises the breasts during radiotherapy for set-up accuracy, and minimises infra-mammary dermatitis without attenuating radiation beams. For patients who require re-irradiation of the chestwall or breast, the team is studying the feasibility of using pulsed low-dose rate radiotherapy to minimise toxicities and increase cell killing in refractorytumour cells.
In collaboration with surgeons, the team has treated more than 80 patients in a prospective protocol on the use of the Intrabeam, an intra-operative, single-dose, partial breast radiotherapy for low-risk patients. For other low-risk patients, we have also started offering partial breast irradiation.
Following recent trials that showed an advantage of irradiating the internal mammary nodal regions for high-risk patients, the team has assessed different radiotherapy techniques. In anticipation of our upcoming proton beam centre, we are looking at how proton therapy can be used in the treatment of complex and high-risk, node-positive patients.
YOUNG INVESTIGATORConsultant Breast Surgeon and clinician-scientist, Dr. Yirong Sim, is passionate about investigating breast cancer biology with the goal of improving diagnosis, treatment and clinical outcomes for breast cancer patients in Singapore. She won the SingHealth Strategic Scientific Start-up Grant of $225,000 to characterise the molecular profiling of breast fibroepithelial lesions. She is developing a novel genomic assay as a potential adjunctive diagnostic tool, in collaboration with Prof. Puay Hoon Tan of SGH’s Division of Pathology and NCCS’ Integrated Genomics Platform headed by Prof. Bin Tean Teh. She is also the Principal Investigator of an epidemiological study of locally advanced breast cancers in Singaporean women. This project aims to elucidate patient, physician and systemic factors that contribute to delays in the diagnosis and treatment of breast cancer which progress to locally advanced states, and to formulate potential intervention strategies to overcome such delays.
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