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VOLUME 134, NUMBER 12

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DECEMBER 2017AKC GAZETTE 13

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FEATUREA breeder-veterinarian describes a remarkable new breakthrough in caninebladder-cancer detection. BY MARCIA DAWSON, DVM

The

of Gift

We live in amazing times. It seems just yesterdaythat we awoke to the rising threat of bladdercancer (also known as transitional cell carci-

noma [TCC]/urothelial carcinoma [UC]) in our dogs, withnew cases being diagnosed far too frequently. An epidemio-logic study done at Purdue in 2001 examined the host andrisk factors for TCC/UC in the Scottish Terrier, and in thecourse of this study we learned that in North American vet-erinary teaching hospitals the incidence of dogs diagnosedwith the disease had increased by more than 600 percent

Beagles

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AKC GAZETTE 14 DECEMBER 2017

FEATUREbetween l975 and 19951. There areseveral breeds with a higher-than-average risk of developing TCC/UC,including the American Eskimo Dog,Australian Cattle Dog, AustralianShepherd, Beagle, Bichon Frise,Border Collie, Parson Russell Terrier,Lhasa Apso, Rat Terrier, RussellTerrier, Scottish Terrier, ShetlandSheepdog, West Highland WhiteTerrier, and Wire Fox Terrier. Thesebreeds combined account for morethan a third of all diagnosedTCC/UC cases in purebred dogs.Over the past 15 to 20 years, many

dedicated researchers have followed avariety of paths leading to betterunderstanding of TCC/UC, devel-oping better diagnostic protocols andnew therapeutic options. With thesequencing of the canine genome,biomedical research has rocketed for-ward. And we now have a remark-able new tool available, a urine testthat will profoundly change theapproach to early diagnosis ofTCC/UC in dogs.

AN AMAZING DISCOVERYIn his laboratory at the NorthCarolina State University College ofVeterinary Medicine, Dr. Matthew

Breen, Ph.D., CBiol, FRSB, professorof genomics and the Oscar J.Fletcher Distinguished Professor ofComparative Oncology Genetics,has been a busy man. Adding to along list of successful research proj-ects and published works, Dr. Breen’sresearch team has developed a newfree-catch urine test that truly wel-comes us into a new age. But first, a bit of background.In the complex and miraculousmachinery of all cells, there are

West Highland White Terrier pups

Dr. Matthew Breen

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DECEMBER 2017AKC GAZETTE 15

FEATUREmany processes at work. And deepin this machinery is an importantcog, a protein called BRAF. Part ofa whole family of proteins calledRAF, the BRAF protein is an essen-tial component that regulates theactivity of normal, healthy cells. Butwhen there is a mutation in theBRAF gene that codes for the pro-tein, the cell machinery is thrown offcourse. The altered protein results inactivation of a pathway that trans-forms normal cells into cancerouscells. The BRAF mutation was identi-fied as early as 2002 in human can-cers including melanoma, leadingto new monitoring procedures andtargeted therapies for people diag-nosed with these cancers. Two yearsago, a similar BRAF mutation wasidentified in the cells from dogs withbladder cancer and prostate cancer.Two independent research centers,Dr. Breen’s laboratory at NCState2,3 and Dr. Elaine Ostander’slaboratory at the National Institutesof Health4, zeroed in on this muta-tion. Amazingly, once again, canineand human cancer patients arehelped by one another, their can-cers serving as models across the

species. As a result of his discovery, Dr.Breen’s team developed the CAncerDETection (CADETSM) BRAFMutation Detection Assay, a nonin-vasive, free-catch urine test so sensi-tive that it can detect the BRAFmutation in as few as 10 TCC/UCcells from the urine of a dog. Thismutation is not found in the urineof healthy dogs or in dogs withnoncancerous bladder polyps,inflammation or infection. Thismeans there are no false positives.The mutation is present in 85 per-cent of TCC/UC cases, whichmeans that 15 percent of cases willavoid detection by the test, or, putanother way, there is a 15 percentchance that there is cancer presentin spite of a negative result.Hundreds of veterinarians acrossAmerica are now using the CADETBRAF test to identify (and also ruleout) the presence of TCC/UC indogs with symptoms of the disease,and to subsequently monitor theimpact of treatment in dogs shownto have a BRAF positive cancer. With its forensic level of detec-tion, the test can also be used toreveal the presence of BRAF-

The author: “As a Scottish Terrierbreeder for the past 30 years and aretired veterinarian, I am well awareof the typical course of TCC/UC in ahigh-risk breed.”

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DECEMBER 2017AKC GAZETTE 16

FEATUREmutated cancer cells in the urineseveral months before the dog startsshowing any symptoms. This pro-vides an opportunity to detect thecancer very early in the course ofthe disease and may thus offer newopportunities to intervene sooner.

THE MIRACLE OF EARLYDETECTIONAs a Scottish Terrier breeder for thepast 30 years and a retired veterinar-ian, I am well aware of the typicalcourse of TCC/UC in a high-riskbreed. Many times, I have heard fromfellow Scottie breeders and ownerswith a similar story. First, the ownernotices unusual symptoms in the dog,such as blood in the urine (often notseen until a snowy day), accidents inthe house, and a prolonged time tourinate. Other than these subtle symptoms,the dog is acting completely fine. A

trip to the veterinarian results in acourse of antibiotics, and, for a fewweeks, the problem seems to beresolved. Inevitably the symptomsreturn, and another round of antibi-otics may be prescribed. But onceagain, the symptoms return.Meanwhile, if there is a tumor form-ing in the bladder of this dog, time isthe enemy! By now, several weeks tomonths have gone by. When the can-cer is finally diagnosed, the disease isadvanced and often has spread. It isalso less responsive to treatment. Thelesson for those of us who ownScotties or any other high-risk breedis: We cannot afford the luxury ofwaiting around to see if anothercourse of antibiotics might work.These days we all know that routinemedical screening in our own lives andearly diagnosis of cancer are the keysto a more successful outcome. Themiracle of Dr. Breen’s CADET BRAF

test for our dogs is that it can detectthe presence of the mutation inremarkably few cells shed in urine,long before there are any symptoms ofTCC/UC, before blood is noticed inurine, before the straining to urinateand frequency of urination, and evenin some cases, before the abnormalitycan be seen on ultrasound. In short,the new CADET BRAF test is the giftof time.The CADET BRAF MutationDetection Assay for early detection ofcanine TCC/UC can now beobtained here for AKC registrants.The test is available as an annualscreening subscription package,allowing owners to proactively testtheir dogs on a regular basis. Theservice pack includes three tests forone dog, one to be carried out everyfour months, instructions, urine potsfor sample collection, and prepaidFedEx shipping labels to send sam-

ples directly to the testing laboratory. For breeders, Sentinel Biomedicaland the AKC offer a bulk pricing sothat breeders can screen all theirdogs at once for a reduced rate. Themore tests a breeder orders, thelower the individual test price. Oncethe testing laboratory receives sam-ples, owners, breeders, and their des-ignated veterinarian, will receiveresults within two weeks. In addition, a diagnostic and moni-toring version of the test is availabledirectly from Sentinel Biomedicalhere. The results of these expeditedorders are returned to the veterinaryprofessional with 2 to 3 business daysof receipt of the urine sample at thetesting laboratory.Included with all test kits is aquestionnaire for owners to com-plete and submit with each sample.If owners choose to complete thequestionnaire, the information pro-

vided is being used as part of anationwide research study aimed atfinding the cause of TCC/UC anddetermining any link betweengenetic and environmental factors.All participants who complete thequestionnaire will be automaticallyincluded on updates on the researchfindings. Should your dog’s test resultscome back positive for the presenceof the mutation, your primary careveterinarian and/or veterinaryoncologist/internist will help youdecide on the best strategy for fur-ther diagnostics and therapeuticinterventions. But keep in mind:The earlier the diagnosis, the betterthe outcome!—Marcia Dawson,DVM ©2017

LinksMore informationCADET BRAF Breeder Pack

1. Glickman LT, Raghavan M, KnappDW, Bonney PL, Dawson MH (2004):Herbicide exposure and the risk oftransitional cell carcinoma of the uri-nary bladder in Scottish Terriers. J

Am Vet Med Assoc 224: 1290–1297.2. Mochizuki H, Breen M (2015) Com-parative Aspects of BRAF Mutationsin Canine Cancers. Veterinary Sci-ences 2: 231.

3. Mochizuki H, Shapiro SG, Breen M(2015) Detection of BRAF Mutation inUrine DNA as a Molecular Diagnosticfor Canine Urothelial and ProstaticCarcinoma. 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 inNaturally Occurring Canine BladderCancer–Evidence for a RelevantModel System and Urine-based Diag-nostic Test. Mol Cancer Res.

Footnotes

DECEMBER 2017AKC GAZETTE 17

FEATURE

Mary Mahaffey, DVM, MS,professor emeritus, College ofVeterinary Medicine, University ofGeorgia:I consider the CADET

BRAF Mutation DetectionAssay to be an amazing advancein the fight against TCC. Own-ers of high-risk dogs, such asShelties, can use this test periodi-cally to screen for TCC and detectit before the dog shows clinicalsigns! Early detection and subse-quent treatment is essential toimproving the outcome for thedog and extending its life. As aShetland Sheepdog owner and aveterinarian, I am very pleased toknow that the CADET BRAF Mu-tation Detection Assay isavailable and can help our dogslive longer, more comfortablelives.

Kay McGuire, DVM, MS, Ash-cot West Highland White Terriers,AKC Breeder of Merit:

The CADET BRAF test, from aveterinary standpoint is an excit-ing new diagnostic tool. As a vet-erinarian, I have been faced withnumerous patients in practicethat I might suspect haveTCC/UC, due to recurrent hema-turia or bloody urine. Until, now,even if the cancer has progressedto the point of shedding abnormallooking transitional cells in theurine, since such cells may not bedue a cancer, it is not until a massis large enough to be detected byultrasonography/imaging andbiopsied that a reliable diagnosecan be made. As a breeder, I know that if I had

a case of transitional cell carci-noma show up in my line, I wouldbe screening all related individu-als. The availability of buying aseries of tests that can be sub-mitted to test these animals threetimes a year not only allows earlydetection of the cancer, it alsoprovides time to opt for early

treatment and to consider breed-ing decisions involving that line.

Ruth Darlene Stewart, AlaDarBeagles, AKC Breeder of Merit:Multiple trips to the vets, multi-

ple rounds of antibiotics, multiplecatheterizations, multiple ultra-sounds, no a confirmed diagno-sis: This is the scenario that Ihave encountered more thanonce in my years as a Beaglebreeder. I recall very clearly thatfor one of my dogs the entiretime we were working his case Iwas concerned that it was blad-der cancer due to the increasedrisk all Beagles have for TCC andthe family history. The ultra-sounds did show some general-ized thickening of the bladderwall, but they could not identify amass. The Beagle was started onoral meds but unfortunately pro-gressed so rapidly that he wasPTS within six months. The opportunity to assist in find-

ing Beagles with TCC for Dr.Breen’s initial research was anoffer for hope. Hope that therewould be a method to diagnosisquicker, start treatment sooner,provide more treatment optionsand increase post diagnosis sur-vival time periods. The CADETBRAF test is that method. Own-ers and breeders of Beaglesknow that our wonderful breed isat higher risk for TCC. They needto communicate with their veteri-

narian to establish a screeningprotocol for older Beagles and orwith Beagles with recurring UTIs. The test is not the cure, but

early diagnosis will allow time forowners and veterinarians to indi-vidualize the treatment plan for af-fected Beagles. Having theopportunity to vary/research/de-velop treatment options may inthe future lead to better out-comes and maybe HOPE againfor a discovery of a cure.

CADET BRAF Testimonials