Cancer Screening
Fighting cancer with a blood test
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onfidence is growing in the medical and business communities in the potential of new groundbreaking blood tests to detect almost any type of cancer. In January, Illumina Inc., one of the biggest manufacturers of genome sequencing technology, announced the launch of GRAIL, a new company created to develop a pan-cancer screening test to measure the presence of circulating tumour DNA in the bloodstream of otherwise healthy people.
PHOTO CREDIT: MECHANOBIOLOGY INSTITUTE
A simple blood test is changing the way oncologists biopsy cancer cells, opening the door to the development of even more effective individualised therapies to combat cancer
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“We hope today is a turning point in the war on cancer,” Jay Flatley, Illumina chief executive officer and chairman of the board of GRAIL, said in a press release. “By enabling the early detection of cancer in asymptomatic individuals through a simple blood screen, we aim to massively decrease cancer mortality by detecting the disease at a curable stage.” GRAIL’s notable financial supporters include Bill Gates and Bezos Expeditions, the investment firm of Jeffrey Bezos, CEO and founder of Amazon. Another event fanning the enthusiasm for blood testing in the battle against cancer took place last year when a team of scientists from the Mechanobiology Institute and National University of Singapore engineered a new technique to culture circulating tumour cells (CTC) from the blood of breast cancer patients. This raised hopes that the information from such tests could be used to better monitor the course of the disease and upgrade targeted treatments. CTCs are cancerous cells shed by tumours into the bloodstream and are responsible for the formation of metastases, the spreading of cancer from one organ to another. Since patients cannot undergo repeated tissue biopsies, regular CTC-based blood tests can provide real-time data on the progress of the disease along with the most appropriate therapy option, said Professor Lim Chwee Teck, Principal Investigator at the Mechanobiology Institute (MBI) in Singapore and one of the scientists who managed to culture breast CTCs, in an interview with Global Health and Travel. A tissue biopsy is currently the gold standard procedure to accurately diagnose cancer by surgically extracting bits of cancerous tissue and testing them in the laboratory. The operation, however, is invasive and does not always represent a viable option. “As for lung cancer, it is sometimes challenging to perform a biopsy because the lungs are difficult organs to intervene on, meaning that they are not easily accessible,” said Dr. Niki Karachaliou, a medical oncologist with Instituto Oncólogico Dr. Rosell in Barcelona. “In other cases, the material extracted through a biopsy is too little to provide useful information because usually the tumour is no bigger than a few centimetres or millimetres.” Dr. Ava Kwong, Chief of Breast Surgery and Clinical Associate Professor and Assistant Dean at The University of Hong Kong, said conducting biopsies of breast cancer tissue comes with similar challenges, especially when the tumour metastasises to the brain, the liver or the bones. She noted that, because of the limits associated with tissue biopsies, one of the main goals in cancer research over the last ten years has been designing an effective “liquid biopsy” – a clinical method to single out cancer-related biomarkers in the blood that can verify the presence of cancer via a minimally invasive blood draw. Despite the wave of optimism, questions remain as to whether liquid biopsies will end up being a game
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changer in the field of oncology. “We can certainly get a lot of information from liquid biopsy, but whether this information will significantly impact clinical care is still uncertain,” Michael B. Lilly, Associate Director for Translational Research at Medical University of South Carolina’s Hollings Cancer Center, told Global Health and Travel.
CTCs offer a glimpse into cancer progression Despite the uncertainties, research in the field of liquid biopsy shows no signs of letting up. The area of circulating tumour cells, or CTCs, in particular, is burgeoning. It is also the one segment that holds the greatest theoretical promise for charting new territories in cancer treatment. “The advantage of CTCs is that they are living cells, thus they can provide us with more accurate information as they can be used to develop a cell line in the lab to perform further investigations,” said Dr. Karachaliou. Currently, there is one test on the market that already makes use of CTCs to guide therapy. CELLSEARCH, the only CTC-capturing device approved by the US Federal Drug Administration (FDA), enables oncologists to quantify the number of CTCs in patients with metastatic breast, prostate and colorectal cancer, a result that can indicate prognosis. This is because specific CTC “cut-offs” are associated with either a favourable or unfavourable course of the disease. One drawback is that current methods to isolate CTCs only manage to detect a portion of Professor Lim Chwee Teck , Principal circulating tumour cells. By Investigator at the Mechanobiology Institute (MBI) in Singapore targeting only those CTCs carrying a specific biomarker, for example the epithelial cell adhesion molecule (EpCAM), some CTCs are not captured, according to Dr. Lim. This affects the chances of successfully culturing CTCs, with recent efforts achieving only a 20 to 30 percent success rate on average. But a novel technique Lim and his colleagues engineered successfully cultured more than 60 percent of 200 breast CTC samples collected. Their increased success rate is due to a less aggressive methodology, involving the removal of red blood cells while keeping everything else intact, instead of attempts to isolate CTCs. This results in a mix of white cells and CTCs that is subsequently cultured. “In the process of culturing, white cells gradually die away leaving CTCs as the only remaining cells,” explained Dr. Lim. This procedure has enabled researchers to establish a correlation between the tendency of CTCs
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Scientists from the Mechanobiology Institute and National University of Singapore engineered a new technique to culture circulating tumour cells (CTC)
PHOTO CREDIT: MEDICAL UNIVERSITY OF SOUTH CAROLINA’S HOLLINGS CANCER CENTER
to create clusters and how patients are responding Circulating tumour DNA is the genetic material to the treatment. Since the presence of CTC clusters floating around in the blood after detaching from is a sign of poor prognosis, such findings could make dying tumour cells. Easily harvested from blood a big difference in early-stage breast cancer patients samples, it can provide detailed information on the whose CTC levels remain high after surgery, which genetic makeup of cancer. may suggest that they are at higher risk of post“By analysing circulating tumour DNA, you surgery relapses. can see if the patient has mutations or structural “A certain proportion of these patients will abnormalities in the DNA that make tumour cells go on to relapse years after undergoing surgery proliferate, or that contribute to treatment resistance because of micrometastases that or sensitivity” Dr. Lilly said. currently cannot be measured by He explained that being able any available test,” explained Dr. to locate such mutations case-byLee Soo Chin, associate director case will be key to administering and senior consultant of the tailor-made medications that can Department of Haematologyneutralise and halt a tumour’s Oncology at the National University growth. Cancer Institute Singapore (NCIS) The benefit of such a procedure and clinical leader of the team that was well-demonstrated in a case developed the procedure, during a involving a 30-year-old woman press conference. treated by Dr. Karachaliou for Dr. Lee stressed the importance NSCLC. A tissue biopsy showed that of being able to track patients in the patient had epidermal growth order to confirm the effectiveness factor receptor (EGFR) mutations, of the new test, given the potential a common abnormality in lung for significant clinical applications. cancers. But, when she didn’t “If patients don’t have any respond to the standard treatment measurable CTC after surgery for EGFR mutation, a new blood test we could potentially spare them revealed another genetic alteration from routine post-operative affecting a specific gene, ALK, chemotherapy,” she said. which was producing an abnormal Dr. Niki Karachaliou, medical oncologist at Instituto Oncólogico Dr. Rosell in But, the most ambitious aim is amount of protein. Doctors were Barcelona using the culturing technique to then able to change the treatment create a tumour on a chip – a microenvironment that and the administration of drugs blocking the will enhance the development of the tumour in the proliferation of the ALK protein led her to remission. lab so as to observe the factors that either encourage “The little material you obtain from a tissue or discourage its growth, concluded Dr. Lim. biopsy is not representative of the entire tumour, so in this case additional information from a liquid A shorter path to customised oncology biopsy proved to be essential in treating the patient,” said Dr. Karachaliou. Despite their therapeutic value, CTCs have certain drawbacks preventing researchers from making the The dream of a screening test most of them. “Not every tumour releases a high number of “Liquid biopsy may be the beginning of the ultimate CTCs in the blood,” according to Dr. Karachaliou. “For blood test that tells you everything you need to know instance, it is very difficult to isolate CTCs about cancer,” said Greg Powell, President of Howe from non-small cell lung cancer (NSCLC), Sound Research, a consulting company that recently which is the most common type of lung released a report on liquid biopsy’s business potential. “The little material cancer.” In the wake of GRAIL’s establishment, he estimated you obtain from a Other researchers are also concerned the market would spike to tens or even hundreds of tissue biopsy is not that the limited number of CTCs billions of US dollars in the next ten years if bloodrepresentative of the collected from the blood doesn’t offer a based tests become a regular screening tool. comprehensive view of cancer genomics. However, cancer experts remain sceptical about the entire tumour, so in Cancerous masses are heterogeneous, feasibility of liquid biopsies becoming the mainstay of this case additional even within the same patient, and are cancer diagnostics. information from a characterised by continuing mutation, “I think carrying out a liquid biopsy to screen liquid biopsy proved making them vary substantially. patients for cancer would be fairly impractical at the to be essential in “For this reason circulating tumour moment,” said Dr. Lilly. DNA may be an easier way of getting Diagnosing cancer often implies dealing with treating the patient” a broad genomic picture of the cancer early-stage patients, who don’t have very noticeable Dr. Karachaliou because it is likely to come from a variety traces of the tumour in their bloodstream. Liquid of cancer cells,” said Dr. Lilly. biopsy may not be sensitive enough to detect cancer
PHOTO CREDIT: MECHANOBIOLOGY INSTITUTE
Cancer
and may harm the public health.” biomarkers, he explained. Pathway replied that the The role played by tissue product was not intended for examinations may never be consumers and that physicians replaced by a simple blood test, would be responsible for ordering, agreed Dr. Karachaliou, but reviewing, and following-up on the liquid biopsies have definitely test and its results. the potential to become another “We believe we have performed diagnostic tool that can overcome appropriate validation of the test the challenges associated with as a laboratory developed test, and obtaining sufficient tumour tissue we are in the process of performing for vital genetic analysis. additional studies,” the company Despite these limitations, last stated in a press release. September, Pathway Genomics, Pathway Genomics is not alone, a San Diego-based company however, as the FDA has yet to offering genetic test services, approve any tests measuring launched a commercial blood test circulating tumour DNA, for cancer screening. It claims explained Lilly. its CancerIntercept Detect is Dr. Michael Lilly, Associate Director “Offering circulating tumour able to identify the presence of for Translational Research at Medical University of South Carolina’s Hollings DNA tests doesn’t require any circulating tumour DNA in those Cancer Center approval from the FDA, and using at high risk of developing cancer them to guide treatment decisions from multiple causes, including a in patients with known cancer is relatively low risk,” family history of specific malignancies, like colon he said. “But, if the results are used to diagnose cancer, cancer, and lifestyle choices. The product is aimed at the physician is assuming a considerable risk.” GHT being a complementary instrument for physicians to diagnose cancer. But in response to the product launch, the FDA sent Pathway a letter casting doubts on its efficacy and ILLUMINA.COM HOWESOUNDRESEARCH.COM safety, saying “We believe you are offering a high risk FDA.GOV PATHWAY.COM test that has not received adequate clinical validation CELLSEARCHCTC.COM
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