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The Gift A breeder-veterinarian describes a remarkable new breakthrough in canine bladder-cancer detection. BY MARCIA DAWSON, DVM Time of We live in amazing times. It seems just yesterday that we awoke to the rising threat of bladder cancer (also known as transitional cell carcinoma [TCC]/urothelial carcinoma [UC]) in our dogs, with new cases being diagnosed far too frequently. An epidemiologic study done at Purdue in 2001 examined the host and risk factors for TCC/UC in the Scottish Terrier, and in the course of this study we learned that in North American veterinary teaching hospitals the incidence of dogs diagnosed with the disease had increased by more than 600 percent Beagles BREED PHOTOS: WIKIMEDIA COMMONS AKC GAZETTE 13
between l975 and 1995 1. There are several breeds with a higher-thanaverage risk of developing TCC/UC, including the American Eskimo Dog, Australian Cattle Dog, Australian Shepherd, Beagle, Bichon Frise, Border Collie, Parson Russell Terrier, Lhasa Apso, Rat Terrier, Russell Terrier, Scottish Terrier, Shetland Sheepdog, West Highland White Terrier, and Wire Fox Terrier. These breeds combined account for more than a third of all diagnosed TCC/UC cases in purebred dogs. Over the past 15 to 20 years, many dedicated researchers have followed a variety of paths leading to better understanding of TCC/UC, developing better diagnostic protocols and new therapeutic options. With the sequencing of the canine genome, biomedical research has rocketed forward. And we now have a remarkable new tool available, a urine test that will profoundly change the approach to early diagnosis of TCC/UC in dogs. AN AMAZING DISCOVERY In his laboratory at the North Carolina State University College of Veterinary Medicine, Dr. Matthew Dr. Matthew Breen Breen, Ph.D., CBiol, FRSB, professor of genomics and the Oscar J. Fletcher Distinguished Professor of Comparative Oncology Genetics, has been a busy man. Adding to a long list of successful research projects and published works, Dr. Breen s research team has developed a new free-catch urine test that truly welcomes us into a new age. But first, a bit of background. In the complex and miraculous machinery of all cells, there are West Highland White Terrier pups LEFT: COURTESY NC STATE AKC GAZETTE 14
many processes at work. And deep in this machinery is an important cog, a protein called BRAF. Part of a whole family of proteins called RAF, the BRAF protein is an essential component that regulates the activity of normal, healthy cells. But when there is a mutation in the BRAF gene that codes for the protein, the cell machinery is thrown off course. The altered protein results in activation of a pathway that transforms normal cells into cancerous cells. The BRAF mutation was identified as early as 2002 in human cancers including melanoma, leading to new monitoring procedures and targeted therapies for people diagnosed with these cancers. Two years ago, a similar BRAF mutation was identified in the cells from dogs with bladder cancer and prostate cancer. Two independent research centers, Dr. Breen s laboratory at NC State 2,3 and Dr. Elaine Ostander s laboratory at the National Institutes of Health 4, zeroed in on this mutation. Amazingly, once again, canine and human cancer patients are helped by one another, their cancers serving as models across the species. As a result of his discovery, Dr. Breen s team developed the CAncer DETection (CADET SM ) BRAF Mutation Detection Assay, a noninvasive, free-catch urine test so sensitive that it can detect the BRAF mutation in as few as 10 TCC/UC cells from the urine of a dog. This mutation is not found in the urine of healthy dogs or in dogs with noncancerous bladder polyps, inflammation or infection. This means there are no false positives. The mutation is present in 85 percent of TCC/UC cases, which means that 15 percent of cases will avoid detection by the test, or, put another way, there is a 15 percent chance that there is cancer present in spite of a negative result. Hundreds of veterinarians across America are now using the CADET BRAF test to identify (and also rule out) the presence of TCC/UC in dogs with symptoms of the disease, and to subsequently monitor the impact of treatment in dogs shown to have a BRAF positive cancer. With its forensic level of detection, the test can also be used to reveal the presence of BRAF- The author: As a Scottish Terrier breeder for the past 30 years and a retired veterinarian, I am well aware of the typical course of TCC/UC in a high-risk breed. Lhasa Apso LEFT: COURTESY AUTHOR AKC GAZETTE 15
mutated cancer cells in the urine several months before the dog starts showing any symptoms. This provides an opportunity to detect the cancer very early in the course of the disease and may thus offer new opportunities to intervene sooner. THE MIRACLE OF EARLY DETECTION As a Scottish Terrier breeder for the past 30 years and a retired veterinarian, I am well aware of the typical course of TCC/UC in a high-risk breed. Many times, I have heard from fellow Scottie breeders and owners with a similar story. First, the owner notices unusual symptoms in the dog, such as blood in the urine (often not seen until a snowy day), accidents in the house, and a prolonged time to urinate. Other than these subtle symptoms, the dog is acting completely fine. A trip to the veterinarian results in a course of antibiotics, and, for a few weeks, the problem seems to be resolved. Inevitably the symptoms return, and another round of antibiotics may be prescribed. But once again, the symptoms return. Meanwhile, if there is a tumor forming in the bladder of this dog, time is the enemy! By now, several weeks to months have gone by. When the cancer is finally diagnosed, the disease is advanced and often has spread. It is also less responsive to treatment. The lesson for those of us who own Scotties or any other high-risk breed is: We cannot afford the luxury of waiting around to see if another course of antibiotics might work. These days we all know that routine medical screening in our own lives and early diagnosis of cancer are the keys to a more successful outcome. The miracle of Dr. Breen s CADET BRAF test for our dogs is that it can detect the presence of the mutation in remarkably few cells shed in urine, long before there are any symptoms of TCC/UC, before blood is noticed in urine, before the straining to urinate and frequency of urination, and even in some cases, before the abnormality can be seen on ultrasound. In short, the new CADET BRAF test is the gift of time. The CADET BRAF Mutation Detection Assay for early detection of canine TCC/UC can now be obtained here for AKC registrants. The test is available as an annual screening subscription package, allowing owners to proactively test their dogs on a regular basis. The service pack includes three tests for one dog, one to be carried out every four months, instructions, urine pots for sample collection, and prepaid FedEx shipping labels to send samples directly to the testing laboratory. For breeders, Sentinel Biomedical and the AKC offer a bulk pricing so that breeders can screen all their dogs at once for a reduced rate. The more tests a breeder orders, the lower the individual test price. Once the testing laboratory receives samples, owners, breeders, and their designated veterinarian, will receive results within two weeks. In addition, a diagnostic and monitoring version of the test is available directly from Sentinel Biomedical here. The results of these expedited orders are returned to the veterinary professional with 2 to 3 business days of receipt of the urine sample at the testing laboratory. Included with all test kits is a questionnaire for owners to complete and submit with each sample. If owners choose to complete the questionnaire, the information provided is being used as part of a nationwide research study aimed at finding the cause of TCC/UC and determining any link between genetic and environmental factors. All participants who complete the questionnaire will be automatically included on updates on the research findings. Should your dog s test results come back positive for the presence of the mutation, your primary care veterinarian and/or veterinary oncologist/internist will help you decide on the best strategy for further diagnostics and therapeutic interventions. But keep in mind: The earlier the diagnosis, the better the outcome! Marcia Dawson, DVM 2017 Links More information CADET BRAF Breeder Pack Footnotes 1. Glickman LT, Raghavan M, Knapp DW, Bonney PL, Dawson MH (2004): Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers. J Am Vet Med Assoc 224: 1290 1297. 2. Mochizuki H, Breen M (2015) Comparative Aspects of BRAF Mutations in Canine Cancers. Veterinary Sciences 2: 231. 3. Mochizuki H, Shapiro SG, Breen M (2015) Detection of BRAF Mutation in Urine DNA as a Molecular Diagnostic for Canine Urothelial and Prostatic Carcinoma. PLoS ONE 10(12): e0144170. doi:10.1371/journal.pone.0144170. 4. Decker B, Parker HG, Dhawan D, Kwon EM, Karlins E, Davis BW, et al. (2015) Homologous Mutation to Human BRAF V600E is Common in Naturally Occurring Canine Bladder Cancer Evidence for a Relevant Model System and Urine-based Diagnostic Test. Mol Cancer Res. AKC GAZETTE 16
CADET BRAF Testimonials Mary Mahaffey, DVM, MS, professor emeritus, College of Veterinary Medicine, University of Georgia: I consider the CADET BRAF Mutation Detection Assay to be an amazing advance in the fight against TCC. Owners of high-risk dogs, such as Shelties, can use this test periodically to screen for TCC and detect it before the dog shows clinical signs! Early detection and subsequent treatment is essential to improving the outcome for the dog and extending its life. As a Shetland Sheepdog owner and a veterinarian, I am very pleased to know that the CADET BRAF Mutation Detection Assay is available and can help our dogs live longer, more comfortable lives. Kay McGuire, DVM, MS, Ashcot West Highland White Terriers, AKC Breeder of Merit: The CADET BRAF test, from a veterinary standpoint is an exciting new diagnostic tool. As a veterinarian, I have been faced with numerous patients in practice that I might suspect have TCC/UC, due to recurrent hematuria or bloody urine. Until, now, even if the cancer has progressed to the point of shedding abnormal looking transitional cells in the urine, since such cells may not be due a cancer, it is not until a mass is large enough to be detected by ultrasonography/imaging and biopsied that a reliable diagnose can be made. As a breeder, I know that if I had a case of transitional cell carcinoma show up in my line, I would be screening all related individuals. The availability of buying a series of tests that can be submitted to test these animals three times a year not only allows early detection of the cancer, it also provides time to opt for early treatment and to consider breeding decisions involving that line. Ruth Darlene Stewart, AlaDar Beagles, AKC Breeder of Merit: Multiple trips to the vets, multiple rounds of antibiotics, multiple catheterizations, multiple ultrasounds, no a confirmed diagnosis: This is the scenario that I have encountered more than once in my years as a Beagle breeder. I recall very clearly that for one of my dogs the entire time we were working his case I was concerned that it was bladder cancer due to the increased risk all Beagles have for TCC and the family history. The ultrasounds did show some generalized thickening of the bladder wall, but they could not identify a mass. The Beagle was started on oral meds but unfortunately progressed so rapidly that he was PTS within six months. The opportunity to assist in finding Beagles with TCC for Dr. Breen s initial research was an offer for hope. Hope that there would be a method to diagnosis quicker, start treatment sooner, provide more treatment options and increase post diagnosis survival time periods. The CADET BRAF test is that method. Owners and breeders of Beagles know that our wonderful breed is at higher risk for TCC. They need to communicate with their veterinarian to establish a screening protocol for older Beagles and or with Beagles with recurring UTIs. The test is not the cure, but early diagnosis will allow time for owners and veterinarians to individualize the treatment plan for affected Beagles. Having the opportunity to vary/research/develop treatment options may in the future lead to better outcomes and maybe HOPE again for a discovery of a cure. AKC GAZETTE 17