The epidemiology of cancer here has moved toward a more westernised, developed country type of incidence. Previously, stomach, liver and nasopharyngeal cancer were the most common cancers here and prostate cancer was not a significant cancer among males. But now colorectal has shot up to no 1 as an incidence. Lung cancer has come down slightly because of smoking cessation efforts; stomach cancer is going down probably because of better refrigeration, food handling and less use of preserved foods while liver cancer is declining probably because of widespread Hepatitis B vaccinations.

For female cancers, breast cancer is still the top cancer and its incidence is still on the rise. Some of the peculiarities of Asian cancers have also been reflected. For example, the number of female lung cancer patients who do not smoke, is significantly higher than in the West, with up to 30 per cent having this Asian variant (which may be influenced by the patient's genes).

These are some of the latest findings published in the Singapore Cancer Registry Report No.7. This is a worrying trend, says Dr Goh Boon Cher, but one which the newly formed Haematology- Oncology Research Group ( HORG), is prepared to address as he commented on some of the highlights of the report.

Dr Goh himself is no stranger to challenges as daunting as this. He recalls when he decided to become a medical oncologist in 1995: "Medical oncology was an ill defined sub specialty when the role of treatment of cancer with drugs was done by surgeons, radiation oncologists and O& G specialists. But I was convinced that there was tremendous change coming and the new drugs being developed and ground breaking clinical trials going on then would reshape the future and this would be a great new challenge.

Shortly after, the interest in cancer treatments ballooned from conferences attended by a handful to attendances of 30,000. From only a handful of very toxic drugs we have moved to new drugs that are not toxic, more targeted with less collateral damage. More than 800 are in development currently with more coming and more targets validated every day, he said.

To Dr Goh, the advances made during these last 15 or 16 years were the convergence of a lot of people's efforts. It is the work of scientists trying to understand cancer cells, and the drug developers in the industry as well as the clinicians, working together to make this possible. Information has been shared such that they can bring a target to a clinical trial to management of a patient.

Today the HORG Group, formed in early 2011 is organised along the lines of different tumor types and sub specialties with a team trained oncologists and coordinators treating and researching specific cancers especially those relevant to the Asian context.

In the near future, HORG will be working towards raising its visibility and becoming not only a national but a regional and even global center for cancer treatment. This is already happening as Singapore becomes involved in more regional and global clinical trials "and the ultimate aim is to become part of the work done that advances cancer care for patients, particularly in the Asia Pacific."

Prof Goh Boon Cher
Senior Consultant
Department of Haematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

One person who is familiar with these issues and scenarios is Senior Consultant, Dr Lee Soo Chin from the NUHS, who spends most of her time in the area of breast cancer and genetics.

She said of the patients, "They didn't make a mistake, they didn't do anything wrong." But the fact remains that some people, even if they exercise and take lots of health foods, have a cancer risk which is strongly influenced by their genes.

But this is not the end of the world. People still have choices and with dedicated counseling to help them have a better understanding of the issues, they can overcome their doubts, make rational decisions and continue with their lives.

Dr Lee, points out that there are preventive measures that can be taken and some of them involve hard choices which are more drastic in nature. For example, Christina Applegate, a well-known American actress, opted for a double mastectomy when she was diagnosed with breast cancer from a gene passed down in her family. This involved the removal of both breasts, one was removed to treat the cancer and the other to prevent cancer which has a high chance of occurring.

In another example Dr Lee gives, a woman has a rare form of hereditary colorectal cancer, in which she will almost certainly contract the cancer by the time she is in her 20s or 30s. She has just gotten married but wants to have children even though the doctor advises her that there is a 50 per cent chance of passing it on to the child. What does she do? What is fair?

Yet many people after hearing the facts go on to have children. "We have recommendations for what they can do but they are not easy recommendations," she said. Some may decide to go ahead, others may decide not to have children and a few may even decide not to get married.

"But this is not the worst thing that can happen to you. Some people inherit a gene that causes them to die by the age of 10. Others inherit a gene that requires them to have blood transfusions month after month and they may never grow up to be an adult. So there are always worse situations and people faced with cancer in this situation simply have easier choices, and harder choices to make," she said.

To put things in perspective, these are examples of a group which has the highest risk of getting cancer. Though numbering only one in several thousand in the general population, their genetic predisposition makes their risk of getting cancer 10 – 20 times higher than normal. Screening for this group should start in their 20s to 30s. Also, those with this predisposition have a much higher chance of getting a second cancer especially since they are more likely to be diagnosed with cancer earlier, say in their 30s.

A second group consists of those with some family history of cancer. Their chances of getting cancer are 2-3 times higher than the general population and they may have to start screening about 10 years younger than the general population.

Sometimes, the family history of this group can be underestimated because they forget the father's side of the family is as important. The father's sister or the father's mother might have had breast cancer, but it is erroneously thought that the father's side of the family has no impact. A woman can inherit the cancer genes from the father as well as the mother and then she can pass it on to the son. Although it is a "female cancer", the genetic mutation is inherited in exactly the same way by the boys and the girls, said Dr Lee.

The third group is the general population and women are advised to start their mammogram at 40 and for men and women colonoscopy at 50.

At present, the role of genetics in cancer has been established in breast, colon and certain endocrine cancers but is unproven if it plays a big part in other cancers.

Some cancers like liver cancer have not been found to be due to genetics but the cancer does run in the family. This is because family members may all have the hepatitis B virus which has been passed on between spouses by sexual transmission and from mother to child by perinatal transmission.

A/Prof Lee Soo Chin
Head and Senior Consultant
Department of Haematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

Prof Chng, who is at the leading edge of preclinical research in the area of Myeloma – a type of bone marrow cancer, says: "The disease has become more treatable. As recent as 5 years ago I would tell you this is not a curable disease. Previously, in order to achieve a 3-4 year survival you need to undergo chemotherapy and bone marrow transplant. But now, 10%-15% of myeloma is curable and another 40% can be regarded as having a "chronic" illness like patients with high blood pressure as effective treatment can prolong survival for 10 years or more."

"One of the good things about these treatments is that they are targeted drugs and not chemotherapy so patients can tolerate them much better. They won't lose their hair, won't have major vomiting problems, and does not require hospital stay, so the quality of life of these patients while they are receiving treatment has improved a lot over the last 5 years.

"Myeloma therefore is one of these diseases that has made tremendous progress in terms of treatment (options) and patient management. A lot of this is down to active research in the area, said Prof Chng, who is also is also Associate Professor at the NUS School of Medicine.

He points out that research here at HORG has found that, while the benefits of treatments compared to Europe and the US are similar, there are slight differences in side effects. For example, in the use of Thalidomide, which helps the immune system fight cancer cells, some side effects, such as the formation of blood clots as a result of taking the medication, are fewer than in the West. Another effective drug, Velcade, which is injectable, seems to get a better response from Asian patients but also have more side-effects suggesting that we may need to use less drugs for Asians. . These inter-ethnic differences would suggest that there may be something in the genes that is causing this. This is an area HORG is interested in looking into, said Prof Chng.

This body of research pertaining Asian differences in Myeloma, is also likely to expand with the formation of the Asian Myeloma Network earlier this year, a cooperative group involving Singapore, Japan, Korea, Hong Kong, Taiwan and Thailand. HORG, NCIS , is one of the founding centres involved in these studies spanning Asia which will will hopefully improve our understanding of myeloma in Asia and also develop unique ways to treat and manage our patients that is relevant to us.

Much of Prof Chng's laboratory research is at a more basic level "where we try to understand the generics of Myeloma. We try and identify genes and pathways that are abnormal in the myeloma cancer cells and then by targeting these pathways, try and shut them down or reactivate them to see if we can kill the myeloma cells. "Our hope is to make a significant discovery that we can move on to clinical trials", he said.

One of our strategies to advance the research is to partner with drug companies to study drugs they are developing that have not yet reached the patient level. This allows us to test it in or laboratory models of myeloma in a rational fashion based on our knowledge of the biology of the disease. "So far we have identified one or two drugs that are promising and are at the stage of designing clinical trials which we hope to offer to patients in one or two year's time," he said.

At a personal level, Prof Chng finds that although preclinical work can be frustrating and discouraging at times due to setbacks and failures and the long process before he can see impact on patients, he finds the work rewarding and is driven by the ultimate goal of improving patients outcome.

He says: "I am driven by the excitement of that discovery, and the potential impact of this early research. We are participating in a process that can potentially identify and discover something profound and new that can change the way we treat patients and truly make a difference to their disease".

For people who want to do this kind of work, he advises that they have to be fairly thick skinned, and not be afraid to take failures or rejections. "Grants and papers are often rejected. You have to have real perseverance and always remind yourself of what motivates you. Learn from your mistakes and keep going forward. In a way no different from how one should go through life."

Prof Chng Wee Joo
Senior Consultant
Department of Haematology-Oncology, NCIS
Head of Haematologic Malignancy Tumour Group
Senior Principal Investigator, CSI

In the haematologic malignancy research programme, we seek to identify new non-chemotherapy-based treatment strategies and also markers for personalised treatment.

In the said programme, our focus is on different types of blood cancers such as leukaemia, lymphoma and multiple myeloma which are still considered largely incurable and often represent therapeutic challenges. Treatment for these diseases is also expensive and poses significant health burden.

Our main goal is to use genetic-based techniques to better understand the weak points in these tumours so that we can identify medications or treatment strategies that will be effective in these tumours. In addition, we also aim to identify markers which then can be translated into clinical tests. This will allow us to identify patients that have different clinical outcomes and also to identify patients that will respond specifically to different drugs. Moreover, these markers will allow us to decide on who to treat, how intensely to treat and with what drugs to treat. We can therefore eventually deliver personalised medicine.

In support of this research, we have set up an intensive and detailed collection of tumour samples from patients under the strict governance of the Institutional Review Board in Singapore. Using these valuable samples, we can identify what is truly important in patients. We can execute the best strategies we have discovered in our laboratory-based research in the form of clinical trials. These trials provide access to novel treatment options for patients who had often exhausted all standard treatment options. With our pipeline of novel biomarkers in the laboratory and their translation into clinical trials, we hope to have a continuous stream of novel treatment strategies that will benefit patients in the future. As it is, our initial efforts have already been published in prestigious scientific journals and new clinical studies will soon be initiated.

These trials provide access to novel treatment options for patients who often had exhausted all treatment options.

Prof Chng Wee Joo
Senior Consultant
Department of Haematology-Oncology, NCIS
Head of Haematologic Malignancy Tumour Group
Senior Principal Investigator, CSI

Unfortunately, it is also called the 'silent killer' because by the time it has been diagnosed, most of patients are already in a fairly advanced stage disease. "The outcome in this group of patients is not so fantastic even though chemotherapy has been able to prolong survival. However the treatment is still not considered optimal," said Dr Yong, who specialises in gastric cancer.

Dr Yong and his colleagues work on two broad fronts. One area is to find out ways to better identify and determine the patients with advanced gastric cancer who will really benefit from chemotherapy. This will aid in the selection of appropriate drugs for the appropriate patient. This could save a lot of costs and unnecessary toxicity from exposure to the drug.

Another area aims to find out and introduce new drugs, perhaps with less toxicity, other than those from the standard chemotherapy.

He cites two clinical trials which illustrate the headway being made into better understanding and treatment of the disease.

The first trial is for patients who have advanced disease and have never been exposed to chemotherapy but are not suitable for surgery. For this group, it is very clear that chemotherapy does prolong survival for some. But which of the patients actually benefits from treatment? Currently, gastric cancer is sub classified based on histology. That is, using the microscope to determine which of the two main types of tumours is present: the less aggressive intestinal type or the more aggressive diffused type.

Our research has led us to develop a unique genomic signature based on molecular classification that is able to better tell us which subtype is present. In conventional histology, a pathologist may declare a "mixed" result 30-40% of the time. In other words, given the same sample, two pathologists may give different results, said Dr Yong.

By using molecular classification, we are able to achieve an accurate classification of the tumour subtype and therefore predict how well someone will do. If then, there is a differential response to chemotherapy for each subtype, it may mean that therapy can be personalised.

Also, with the current standard of chemotherapy, first line treatment (first time), usually involves the use of two to three drugs. However, while the response rate may be high, the side effects will also be high. But if the patient is selected carefully and accurately, fewer drugs may be used, with less toxicity and less costs but with higher chances of getting a response.

A second study involves patients that have become resistant to chemotherapy. What happens when a patient initially treated with chemotherapy responded well, but suffers a relapse? By the time they have reached the stage when they have become resistant to chemotherapy, they may have become very weak. The question then is: Are we able to develop novel therapies with fewer side effects for this group of patients?

One possible solution we are exploring is in an ongoing cancer vaccine trial, where we try to harness our own immune system to fight against our gastric cancer. Essentially, we hope to inject a cocktail of five different types of peptides, allow our own immune cells to recognise these peptides and attack the cancer cells that over express them, he said.

Dr Yong Wei Peng
Senior Consultant
Department of Haematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

It is a demanding, delicate balance but one that has its rewards in helping patients get well. "Being able to use all this new knowledge and technology in finding new breakthroughs for our patients keeps us going", said A/Prof Koh, who focuses in leukaemia and lymphoma cancer.

But it is in the area of bone marrow or stem cell transplant that he is hoping to find new breakthroughs for patients especially those from Asia. "Most of the established centres are in Europe and America dealing with Caucasian patients. We don't know enough about our Asian patients and these are the different areas we are looking at now," he said.

"Bone marrow or stem cell transplant is a very high risk, very complicated treatment procedure and only performed in a few specialised centres like our hospital. Because of recent advances in treatment and supporting care by doctors and nursing staff, the cure rate over the last 10 years has been higher than before and patients enjoying higher life expectancy"' he said.

"Certainly we are exploring many areas in bone marrow or stem cell transplant using new drugs and antibiotics and new ways of transplanting. We are looking at tumor protocols and allowing many patients to try where previously many are denied because of age and medical condition. They are given a chance to get treatment which may result in better outcomes nowadays."

Describing the nature of the disease, he says that most patients with untreated acute leukemia and lymphoma do not live more than 3-6 months, but if provided good treatment from an established medical institution, the cure rate can be significantly better, with a range of 30-80% cure for many of these cancers."

A/Prof Koh has also been involved in exploring new drug therapies. "We are looking at different chemotherapy drugs and combination agents that can improve the cure yet with low side effects," he said.

Recently, there have been significant breakthroughs and improvements in the drugs we have which have much better effectiveness and lower side effects. Secondly, we have much more effective antibiotics against difficult-to-treat infections. Thirdly, there is much improvement in the technology for diagnosing diseases. "We are more precise in getting correct diagnoses and have more sensitive tests in the labs now," he said.

A/Prof Koh Liang Piu
Senior Consultant
Department of Hematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

Such is the nature of cancer that people encounter it all their lives, either through being aware of it, being vigilant against it, contracting it or being affected by it through relatives and friends. (It is not something that comes and goes like the flu).

Dr Lim, who specialises in breast cancer at the NCIS, is especially concerned that women should not only be made more aware of cancer early but should be further encouraged to come forward to take part in screenings given that there are "cultural differences" that influence their attitudes to cancer.

For example, the take-up rates for cancer screenings in the West are higher than in Asia in general in large part because of these differences. Often Asians, by their more reserved nature, "do not want to know" or speak about cancers. Even among Asian populations, the response is different. Singaporeans women, who are more highly educated and form a large part of the workforce compared with their Asian neighbours, might have higher "resistance" to going for screenings because they may be "too busy", she said.

This has implications further downstream. "Based on our hospital experience, we believe the treatment (largely) has same results as the West. But we still feel that we need to do more because a significant portion of women are still coming to see us when they are in an advanced stage", she said.

However, Dr Lim says there have been big advances over the last 10 years in treatment in surgery, radiation and drug therapies, especially targeted or smart drug therapies.

A large part of Dr Lim's research has been in new drug therapies and clinical trials with large pharmaceutical companies which aim at improving patient treatments and management.

"With this we have been able to make significant improvements in the treatment of the patients. We've also had advances in supportive care for cancer therapy, and new drugs that can help with vomiting and in minimising toxicity.

"Increasingly, we are moving into personalised medicine that may in future years, give us drugs best suited to the individual person with the disease", she said.

"Besides the rise in breast cancer as an Asian disease, our studies and clinical trials have also looked at the differences between Asian and Caucasians in terms of the efficacy, tolerability, side effects and cultural differences".

"On top of doing studies, we have to provide services to our patients through support groups and continuing education and extensive social counseling during and after treatment and after. The whole breast cancer experience is with the doctor and is also the experience with supporting care they get, the family experience and the cultural experience."

We also are interested improving preventive practices like smoking cessation programmes and weight management". At the end of the day, we want to make sure that we help our patients through their journey, she added.

Dr Lim Siew Eng
Senior Consultant
Department of Haematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

It is better to be sure and one should seek medical attention if there is any abnormal vaginal bleeding – even if the symptoms are mild and especially if they are persistent. A little irregular vaginal bleeding can be easily be mistaken as being peri-menopausal bleed, but may prove otherwise.

Almost all cases of cervical cancer are linked to infection with human papilloma virus (HPV). HPV subtype 16 and 18 are responsible for about 70% of all cervical cancer cases. The virus can be sexually transmitted. HPV vaccination has been shown to reduce incidence HPV infection and pre-invasive cervical cancer (CIN). It does not protect against all HPV types and it is not a substitute for Pap smear screening. Vaccination against HPV 16 and 18 is now available and approved for use in Singapore for females age 10-25 years. It is most effective when given before first sexual exposure.

"Certainly, the HPV infection risk is reduced with the vaccine, so if the virus is responsible, it should reduce the incidence of cervical cancer," she said. Ovarian cancer, however, is not so easily detectable in the early stages. There is currently no effective screening test for early detection of ovarian cancer. The ca 125 blood test is not recommended as a screening test for asymptomatic women as it has been shown to be not effective in reducing the death rate from ovarian cancer.

The initial symptoms may be quite vague and many women do not report the symptoms until they get symptoms like abdominal pain with distension from the accumulation of tumour fluid. The majority of ovarian cancer cases (about 75%) are diagnosed at advanced stage 3 or 4, she said. It is important that women experiencing persistent vague abdominal bloating or discomfort seek medical attention.

Dr Lim believes that oncology is an exciting field even though she knows of many who shun it. For her, it is an area where there is intensive research work and is resulting a lot of new treatments that can help prolong people's lives. She says that even if a patient's cancer is diagnosed as incurable there is still something that she can do to try to improve the survival and quality of life and make a difference.

Dr Lim Yi Wan
Senior Consultant
Department of Haematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

Besides, establishing proof of target inhibition, conventional clinical pharmacology concepts still apply. Analysing cancers for specific molecular defects will enhance opportunities to individualise drug therapy.

Since the emergence of these novel targeted drugs, the task of researching them in our Asian environment has taken on a new importance. We have been strongly grounded in clinical pharmacology and molecular biology. This, together with technology and clinical expertise, has formed the basis for the ability to perform cutting edge novel clinical trials especially in early phase drug development.

Through the years, we have focused our efforts on Phase I and proof of concept Phase IIA studies, including successful first-in-world clinical studies that bridged new drugs from animal to human setting. Several of these drugs are now in late phase registration studies. Some have been approved for routine clinical use. For example, we conducted the phase I study of linifanib (ABT 869), defining the early tolerability, pharmacokinetics and drug effects. This led to larger Phase II and III studies, particularly for hepatocellular, lung and renal cell carcinoma. This novel class of antiangiogenic drugs work by altering the blood supply to tumours, resulting in tumour starvation. We are following up our interest in these drugs currently by studying the optimal strategies to combine them with existing drugs that are in clinical use. The first locally developed anticancer drug from a Singapore based biotech company, S*Bio, was put into Phase I clinical trial at HORG.

In recognition of its capabilities, HORG has been engaged in partnerships with academic centres and the pharmaceutical industry to form partnerships in drug development. In addition, we have established a preclinical drug development research team to better understand the combinations of these novel drugs to make greater impact on the treatment of cancer. Through our clinical trials, many patients who have otherwise exhausted their treatment options have benefited in symptom and tumour control. We have also regularly involved patients from the neighbouring countries in our clinical trials.

Prof Goh Boon Cher
Senior Consultant
Department of Haematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

In addition, inter-geographic and inter-ethnic differences and genetics exist that may cause variations in drug response between people from different regions. This has led to increasing interest in research into genetic pathways of drug metabolism so as to optimise treatment efficacy and minimise toxicities for each individual patient.

Today, inter-patient and inter-ethnic variability to drug treatment is observed but the underlying reasons are still not fully understood.

Pharmacogenetics is thus an important area of research to understand these differences to personalise patient care.

The Haematology-Oncology Research Group (HORG) strives to provide the best treatment options and care for our patients through continuous research. In the area of pharmacogenetics, we have established ourselves as one of the global teams studying inter-ethnic variability of anti-cancer drug responses. Through the continuous efforts of our research tea, we have identified inter-ethnic variability in several commonly used anti-cancer drugs. For example, the recommended doses of doxorubicin, an active chemotherapy drug in breast cancer, resulted in more severe blood count toxicities in Chinese compared to Indians or Caucasians. On the contrary, S-1, an oral chemotherapy drug commonly used for the treatment of stomach cancer, is better tolerated in Chinese compared to Caucasians, causing lower incidence of diarrhea in Chinese.

In addition to anti-cancer drugs, warfarin, an oral medicine to treat blood clots that commonly occur in cancer patients, also exhibit inter-ethnic differences in dose requirements with a possible genetic basis. We have found the Chinese and Malays in Singapore to require lower doses of warfarin than Indians because of genetic differences, and have initiated a prospective, randomised study to determine the clinical advantages of a genotype directed dosing algorithm for patients treated with warfarin. This will be the definitive study, and will represent one of the first proof-of-utility studies of pharmacogenetics in the clinic.

Establishment of biological sample banks as a resource to study predictive genetic markers

To expand our ability to identify genetic markers to predict treatment response, our team has initiated biological sample banks to collect blood and tumour samples from cancer patients for genetic studies. These biological sample banks, in conjunction with a comprehensive database of treatment outcomes and toxicities, will be invaluable as a resource for large-scale pharmacogenetics studies in the Asian population.

Knowledge of common genetic variants that affect drug handling can help the physician determine the appropriateness and dosage of many commonly prescribed drugs, a crucial step towards individualisation of cancer therapy. In the foreseeable future, pharmacogenetic testing will be the alternative to the current "one size fits all" and "trial and error" form of prescribing.

A/Prof Lee Soo Chin
Head and Senior Consultant
Department of Haematology-Oncology, NCIS
(A Research Member of Haematology-Oncology Research Group, HORG)

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