Oral squamous cell carcinoma, or OSCC, is a formidable enemy in canine medicine. Oral tumors affect an estimated half a percent of dogs over their lifetimes and account for about six percent of the canine cancer burden, with OSCC making up roughly nineteen percent of all oral tumors. The disease is locally invasive, growing through multiple anatomical planes of the jaw and surrounding tissue, causing severe pain, difficulty eating, and in some cases pathological fractures of the bone. Up to twenty percent of affected dogs show signs of metastasis by the time they are diagnosed. Left untreated, it is deadly.

The current standard of care is blunt: wide-margin surgical excision. While surgery is highly effective when non-metastatic tumors are completely removed, with very low recurrence rates, it is also highly invasive and invariably disfiguring. Roughly thirty percent of dogs have difficulty eating after surgery, and larger operations bring longer healing times, greater postoperative pain, and higher risks of complications. Radiation is occasionally used for tumors that cannot be surgically removed or as an adjunct to surgery, but the fundamental treatment paradigm has not changed in decades, even as researchers have made major strides in understanding the molecular machinery driving the disease.

That machinery centers on the RAS signaling pathway. Recent studies have shown that canine OSCC displays highly activated RAS signaling compared with healthy gingival tissue, a finding confirmed by gene set enrichment analysis comparing tumor samples with normal tissue. RAS is a small GTPase that, when activated by extracellular signals binding to receptors on the cell surface, launches a cascade of molecular events that ultimately drive cell growth and survival. The most important arm of this cascade for tumor growth is the RAS-RAF-MEK-ERK pathway, which ends with ERK initiating the gene transcription programs that keep a tumor expanding. The question facing the Cornell team was whether this pathway could be pharmacologically attacked in a way that would benefit dogs whose tumors are driven by a variety of different upstream mutations.

The answer they settled on was trametinib, a small molecule that inhibits MEK1 and MEK2, the kinases sitting in the middle of the pathway. Trametinib binds to the non-phosphorylated form of MEK in an allosteric pocket near the ATP binding site, blocking its catalytic activity and its ability to activate ERK. Crystal structures show the drug does more than simply plug the pocket: it also prevents BRAF from binding to MEK and appears to stabilize MEK’s association with KSR, the kinase suppressor of RAS, further reducing MEK’s affinity for BRAF. Crucially, the team chose trametinib precisely because it works on wildtype, unmutated proteins. Since RAS itself is rarely mutated in canine OSCC and BRAF mutations appear in only about a third of tumors, drugs like sotorasib, which bind only mutant RAS, would have left most patients out in the cold. Trametinib, by contrast, targets the pathway regardless of what triggered its activation.

The drug also came with a reassuring safety pedigree. It is FDA-approved in humans for BRAF-mutant melanoma and non-small cell lung cancer, typically alongside the BRAF inhibitor dabrafenib. A phase I trial in eighteen dogs had already demonstrated an acceptable safety profile over nine weeks of treatment, and the European Medicines Agency reported the drug was well tolerated in beagles over thirteen weeks and fully eliminated within about seven days. Its high oral bioavailability in both species meant it could be given at home, avoiding the stress and expense of repeated hospital visits.

The trial itself was designed with a do-no-harm philosophy. Twenty dogs with histologically confirmed OSCC were enrolled between October 2023 and February 2025, after approval by Cornell’s Institutional Animal Care and Use Committee and with informed consent from owners. Dogs received daily oral trametinib at doses escalating from 0.015 to 0.035 milligrams per kilogram, with examinations every two weeks including caliper tumor measurements, complete blood counts, and serum chemistry panels. Full tumor staging with contrast-enhanced computed tomography was performed at the start, around day 28, and around day 56, and tumor volumes were measured from CT slices by a board-certified veterinary radiologist. Response was categorized using veterinary RECIST criteria, and any dog showing progressive disease was removed immediately and returned to standard care. Because the typical two-week wait before surgery would not be compromised, owners could try the drug without sacrificing the earliest opportunity for curative excision.

The results were remarkable in some patients. One dog achieved a complete response, with no tumor detectable by CT, and five achieved partial responses, giving an overall response rate of thirty percent. Five more dogs had stable disease, meaning fifty-five percent of the cohort derived clinical benefit. Some tumors responded with startling speed: two dogs’ tumors had shrunk to less than one cubic centimeter after just two weeks of treatment, and in five dogs the mean volume reduction at the first post-treatment evaluation was forty-five percent. In two responsive patients, bone window CT scans showed actual bone regrowth at the tumor site, visible at 28 and 56 days after treatment began, a sign of genuine tissue healing rather than mere tumor shrinkage. In some cases the visible portions of tumors became difficult or impossible to identify by external inspection.

Safety data were equally encouraging. No high-grade adverse events were detected in any dog, though about thirty percent of owners reported transient flatulence that resolved on its own. Bloodwork showed mostly grade 1 and grade 2 abnormalities that were typically no worse than pre-treatment values. The only two grade 3 events, elevated alkaline phosphatase in two dogs, were preceded by grade 2 liver enzyme elevations present before treatment began, suggesting preexisting liver pathology unrelated to the drug. No dog was removed from the study or had its dose modified because of side effects, and no neutropenia was observed. Notably, a prior phase I study had flagged hypertension and proteinuria in some dogs at similar doses, but the Cornell team did not observe owner-reported behaviors consistent with those conditions, though blood pressure and urinalysis were not directly monitored.

The most scientifically compelling finding emerged when tumors were stratified by BRAF mutational status. Seven dogs carried tumors harboring the BRAF p.V595E mutation, the canine equivalent of the human V600E mutation, and these responded dramatically better than BRAF wildtype tumors. Among BRAF-mutant cases, one dog had a complete response and four had partial responses, for a seventy-one percent objective response rate and a mean volume reduction of seventy-one percent in responding tumors. Wildtype tumors, by contrast, showed a mean reduction of only seven percent among responders, and total clinical benefit in that group was just eight percent. The difference was statistically significant at p equals 0.01. Because BRAF genotyping requires only simple PCR amplification and Sanger sequencing, the authors suggest it could readily be implemented by diagnostic laboratories to identify dogs most likely to benefit. The team recommends a starting dose of 0.030 milligrams per kilogram daily while cautioning that dose-response analyses were underpowered. Limitations remain, including the absence of an untreated control group, the lack of long-term recurrence and survival data, and the small cohort size, but the study establishes trametinib as a safe, orally available neoadjuvant option that can shrink tumors in about a third of dogs before surgery, and in the majority of those whose tumors are BRAF-mutant, with results visible in as little as two weeks.

Subject of Research: Clinical trial of the MEK inhibitor trametinib for treating oral squamous cell carcinoma in dogs

Article Title: Clinical application of the MEK inhibitor trametinib in dogs with oral squamous cell carcinoma

Article References: Katt, W. P., Balkman, C. E., Byron, M., Carney, P. C., Chrostek, E., Drozd, M. E., Duhamel, G. E., Fiani, N., Hume, K. R., King, A. L., Sylvester, S. R., Todd-Donato, A. B., Winokur, C. E., Wright, A. L., & Peralta, S. (2025). Clinical application of the MEK inhibitor trametinib in dogs with oral squamous cell carcinoma. Veterinary Oncology, 2(1), Article 31. https://doi.org/10.1186/s44356-025-00042-3

Image Credits: AI Generated

DOI: 10.1186/s44356-025-00042-3

Keywords: trametinib, MEK inhibitor, oral squamous cell carcinoma, canine cancer, BRAF mutation, RAS signaling, veterinary oncology, targeted therapy, clinical trial, neoadjuvant treatment, Cornell University, dog health

The core of the argument rests on three epidemiological realities. First, roughly half of all canine mammary tumors are benign, meaning that any staging protocol applied indiscriminately before a diagnosis of malignancy is confirmed will expose a large share of patients to unnecessary testing. Second, a clinically relevant proportion of malignant mammary tumors are low grade and highly unlikely to metastasize, so even among dogs with cancer, many derive little benefit from systemic imaging. Third, and perhaps most strikingly, distant metastasis at the time of initial presentation appears to be genuinely rare. In data drawn from the PennVet Shelter Canine Mammary Tumor Program, only 13 of 249 dogs screened for enrollment had detectable distant metastasis, and the median tumor size in that subgroup was 6.7 centimeters, suggesting that metastasis at staging is largely a phenomenon of advanced local disease.

Despite these numbers, recent recommendations have shifted toward more elaborate pre-surgical workups, including thoracic computed tomography, abdominal ultrasound, and sentinel lymph node mapping. The authors contend that this trend is driven partly by the availability of more sensitive imaging technology and partly by a fear of missing occult metastatic lesions, a fear that has not been critically examined against actual detection rates. The consequences are not trivial. Advanced imaging adds substantial cost, requires additional anesthesia or heavy sedation, and delays definitive surgical treatment. In some cases, the accumulated expense of staging may prevent owners from pursuing the surgery that would actually cure their dog, a paradox the authors describe as directly contrary to the goal of cancer care.

To build their case, the researchers looked closely at how human breast cancer, long the conceptual model for canine mammary tumor management, handles the same question. Human breast cancer staging begins with mammography and biopsy, and only after malignancy is confirmed do clinicians proceed to sentinel lymph node biopsy, molecular typing, and, selectively, systemic imaging. Notably, guidelines from the National Comprehensive Cancer Network have evolved over the past decade in the opposite direction from veterinary practice: women with early-stage, low-risk disease based on receptor profile and sentinel lymph node status now forgo systemic imaging altogether. The rationale is that metastasis is rare in early-stage asymptomatic patients, and false-positive imaging findings automatically trigger cascades of additional diagnostics, cost, and anxiety. The canine situation, the authors argue, shares these same mathematical and psychological dynamics, yet veterinary recommendations have moved toward more testing rather than less.

Sentinel lymph node biopsy receives particularly detailed scrutiny. In human breast cancer, the technique replaced radical axillary dissection because it accurately identifies the first lymph node to receive drainage from the tumor with far less morbidity. In dogs, the anatomy is simpler: the axillary lymphocenter typically contains only one or two nodes, and the predictable drainage pattern sends the two cranial mammary glands to the axillary node and the two caudal glands to the superficial inguinal node, with the third gland draining in either direction. Reviews of lymphographic studies show that this normal pattern persists as the predominant route in most dogs with tumors, with deviations being rare and possibly linked to high tumor grade, which promotes lymphangiogenesis, inflammation, and vascular remodeling within the tumor microenvironment.

Yet the authors identify practical obstacles that make routine sentinel node biopsy in dogs problematic. Dogs commonly present with multiple independent mammary tumors, with studies reporting that 60 to 70 percent have tumors in different glands, each with its own histology and biological behavior. The largest tumor is often, but not always, the most aggressive, so selecting a single tumor for mapping risks sampling the wrong lesion, while injecting multiple tumors yields multiple biopsied nodes and larger, more painful surgeries with higher complication rates. Furthermore, because sentinel node techniques require peritumoral or subareolar contrast injection before complete resection, dogs without a confirmed diagnosis of malignancy are routinely subjected to the procedure even when their tumors turn out to be benign or low risk. The authors also note that in dogs, unlike in women, lymph node status has weak implications for chemotherapy decisions, since dogs with high-grade tumors are likely to receive systemic therapy regardless of nodal findings, making the procedure’s main human indication largely moot.

Thoracic imaging comes under similar examination. Three-view thoracic radiographs remain a reasonably sensitive, widely available, and cost-effective method that can be performed under light sedation. Computed tomography detects more small pulmonary nodules, but the clinical significance of that sensitivity is questionable in this population. In human early-stage breast cancer, the false-positive rate for chest CT, about 10 percent, actually exceeded the overall yield of metastasis detection, roughly 2 percent, a cautionary statistic for anyone considering withholding surgery based on small CT findings. Classic necropsy work by Fidler and Brodey established that pulmonary metastasis was present in 81 percent of dogs with metastatic disease, compared with only 5 to 16 percent for abdominal organs, meaning the lungs are the primary metastatic site and abdominal spread is unlikely when thoracic imaging is negative. The authors’ own prospective trial data found that every dog later confirmed at necropsy to have pulmonary metastasis had preceding three-view radiographs documenting it.

Abdominal ultrasound fares similarly in the analysis. Because the lungs dominate the metastatic pattern, the risk of metastasis confined to abdominal organs in the face of negative thoracic radiographs is low. Ultrasound also cannot reliably distinguish benign from malignant hepatic or splenic nodules, generating false positives that invite further invasive diagnostics. A large prospective screening study in healthy middle-aged and older dogs found that physical examination plus cytology of superficial masses detected the great majority of cancers, undercutting the argument that abdominal imaging is needed to catch unrelated occult tumors. Follow-up data from the authors’ earlier cohort showed that non-mammary tumors detected during monitoring emerged a median of 500 to 600 days after the original surgery, indicating they were new developments rather than lesions that staging had missed.

Fine needle aspiration of the tumors themselves is likewise judged unreliable as a screening tool. Reported sensitivity for distinguishing benign from malignant mammary lesions ranges from 25 to 95.2 percent across studies, and even modern cytological grading systems show poor concordance with histology for low-grade tumors, precisely the category where misclassification matters most for staging decisions. Because cytologists evaluate cellular atypia without the architectural context available to surgical pathologists, and because even pathologists disagree about the benign-malignant boundary in low-grade lesions across institutions and countries, the authors decline to recommend routine cytology as a gatekeeper for staging. They do concede it retains value for identifying non-mammary masses such as lipomas or mast cell tumors.

The alternative framework the authors propose is elegantly simple: let tumor size and clinical risk factors decide. For tumors under 1 centimeter, or under 3 centimeters in WHO T1 category, no pre-surgical staging is recommended; post-operative thoracic radiographs are applied by grade, skipped for grade 1, optional for grade 2, and recommended for grade 3. Tumors larger than 3 centimeters warrant pre-surgical three-view thoracic radiographs, as do any tumors with cytologically positive local nodes or obvious malignant features such as rapid growth, ulceration, or deep fixation. Routine fine needle aspiration of palpably normal regional nodes is deemed unnecessary for small tumors, since inguinal nodes are typically removed anyway with the fifth gland, but firm or enlarged nodes should always be aspirated before surgery to adjust the operative plan. Patent blue dye is endorsed for identifying axillary nodes during removal of larger cranial tumors. Abdominal ultrasound is reserved for dogs with positive inguinal nodes, to assess iliac chains, and thoracic CT is judged not indicated in most cases. The authors acknowledge that a small number of small tumors with metastatic nodes could slip through the pre-surgical net, but argue that post-operative grade assessment catches grade 2 and 3 cases. Their closing message extends beyond mammary tumors: staging recommendations across veterinary oncology should be judged by whether results change prognosis or treatment, because diagnostic intensity that offers minimal clinical benefit while imposing financial and emotional costs may ultimately harm the very patients it aims to protect.

Subject of Research: Evidence-based revision of pre- and post-surgical staging practices for canine mammary tumors

Article Title: Considerations for revised staging practices in canine mammary tumors

Article References: Sorenmo, K. U., Cofone, M. A., Donnelly, L., Duda, L., & Stefanovski, D. (2026). Considerations for revised staging practices in canine mammary tumors. Veterinary Oncology, 3(1), Article 9. https://doi.org/10.1186/s44356-026-00061-8

Image Credits: AI Generated

DOI: 10.1186/s44356-026-00061-8

Keywords: canine mammary tumors, cancer staging, veterinary oncology, sentinel lymph node biopsy, thoracic radiographs, thoracic CT, abdominal ultrasound, fine needle aspiration, tumor grade, metastasis, risk-based staging, dog health

The controversy began in earnest during the 2010s, when grain-free formulations exploded across the American pet food market. Sales at one boutique retail chain tripled between 2011 and 2015, and by 2019 grain-free products accounted for 43 percent of all extruded diets sold there. By 2017, diets built on peas, chickpeas, lentils, sweet potatoes and tapioca made up more than half of the dog food market. When the FDA announced its investigation the following year, it triggered a wave of research across academia and industry, spanning randomized controlled trials and observational studies in both client-owned and research colony dogs. Yet although that body of work focused narrowly on dilated cardiomyopathy, many individual veterinarians began broadly advising owners to avoid grain-free diets for any cardiac concern, including murmurs and mitral valve disease, and even for breeds predisposed to heart disease, purely out of caution.

A central weakness in this literature has long been its reliance on owner-reported diet histories. Previous studies repeatedly identified owner recall of primary diet type, treats, supplements and other food items as a substantial methodological limitation, with reports of grain-free status frequently overestimated, misattributed or incomplete. The new analysis, led by researchers affiliated with the Dog Aging Project, set out to quantify exactly how inaccurate owner reporting of grain-free status actually is, and then to determine whether that inaccuracy could distort the apparent relationship between diet and heart disease in a large longitudinal cohort. The DAP follows more than 50,000 companion dogs of all breeds and ages, collecting annual data on health, lifestyle and environmental factors that influence canine longevity.

To validate owner reports, the team took advantage of a natural experiment within the survey structure. From January 2020 to June 2023, the DAP’s original diet survey asked owners a simple yes-or-no question about whether their dog’s primary diet was grain-free. In July 2023, a far more comprehensive questionnaire was introduced, asking for the full brand name and formula of the diet, along with how long it had been fed. Owners who reported feeding the same diet for at least twelve months could therefore be assessed twice: once by their own grain-free label, and once by independent verification. A coder individually checked 13,049 such responses against online ingredient lists, classifying any diet containing rice, corn, wheat, barley or oats as grain-inclusive.

The validation revealed striking misclassification. Thirty-five percent of owners reported feeding grain-free diets, yet when a grain-free claim was made, it was correct only 49 percent of the time, essentially a coin flip. By contrast, owners who reported grain-inclusive diets were far more reliable, with a negative predictive value of 92 percent, and overall accuracy across all reports was 77 percent. The researchers suspect naming conventions drive much of the error: diets with titles such as a meat-and-potato recipe, which carry no grain in the name but contain grains in the ingredient list, were frequently mislabeled as grain-free by owners who judged by packaging rather than ingredients.

Crucially, the team did not stop at documenting the error. They ran simulation studies with synthetic populations of 10,000 dogs, introducing reporting inaccuracy rates of 25, 50 and 75 percent across a range of hypothetical true effect sizes, from protective to severely harmful. The simulations demonstrated that this particular pattern of misclassification, in which grain-free diets are inconsistently reported while grain-inclusive diets are reliably reported, would attenuate true associations, pulling observed odds ratios toward 1, but would not create false associations or reverse their direction. In other words, if grain-free diets truly caused heart disease, the analysis should still have detected a harmful trend, merely a weakened one. Based on the degree of attenuation observed, the researchers estimated that their measured odds ratio of 1.05 corresponds to a true odds ratio of roughly 1.07, a negligible effect.

The longitudinal analysis itself drew on the first three years of DAP diet data, covering 47,444 dogs enrolled before the end of 2023, including 7,786 dogs whose owners completed an end-of-life survey capturing diagnoses reported after the last annual follow-up. Confounders were identified using a directed acyclic graph, a formal causal inference tool, rather than ad hoc selection. The unadjusted odds ratio for grain-free diet on new cardiac diagnoses was 0.98, with a p value of 0.56. After adjusting for breed status, sex, neuter status, body size and survey year, the adjusted odds ratio was 1.05, with a confidence interval spanning 0.91 to 1.21 and a p value of 0.52. Mixed-effects models and a diet-switching analysis produced consistent results. Across every modelling approach, grain-free diet status showed no effect on the risk of incident cardiac disease.

What did matter were other factors. Single-breed dogs were more likely than mixed-breed dogs to receive new cardiac diagnoses, with an odds ratio of 1.23, and neutered animals were diagnosed substantially more often than intact ones, with an odds ratio of 1.68, the strongest association in the model. Larger dogs showed smaller odds ratios, and diagnoses became more common in later survey years. The researchers argue that neuter status, which may reflect biological protection from sex hormones or simply longer lifespans and greater time at risk, deserves far more attention in future diet and cardiac research, noting that previous studies may have been affected by failing to account for it.

The most common diagnoses in the cohort were murmurs, accounting for 57 percent of reported cardiac conditions, followed by congestive heart failure, valve disease and arrhythmia, each around 8 to 9 percent. Because murmurs and valve disease dominate the cardiac burden in companion dogs, the findings are particularly relevant to practitioners who have been advising owners to transition dogs with valve disease away from grain-free diets as a precaution. The authors caution, however, that the study was not designed to detect effects on individual cardiac diseases, nor does it examine whether diet influences survival after a diagnosis, questions that ongoing work aims to address.

Important limitations remain. The original DAP diet survey did not capture individual ingredients, so the analysis cannot speak to specific components such as peas, lentils or potatoes, which prior research has flagged as potential concerns when fed in high proportions, possibly through impaired amino acid digestibility and taurine status. Moreover, the data collection period of 2020 to 2023 coincides with years of intense public scrutiny, during which many manufacturers may have reformulated grain-free products to remove suspect ingredients. If industry reformulation has already addressed the problem, the absence of an association in this cohort may reflect safer formulations rather than proof that all grain-free diets were always harmless. The team also notes possible recall bias regarding diet duration and the possibility that diets were reformulated between the time they were fed and the time their ingredients were verified in 2025.

Even with those caveats, the study’s strengths are considerable: prospective data collection, three years of dietary exposure, inclusion of dogs that died during the study window, confounder selection guided by formal causal tools, and consistency across multiple analytical methods. The conclusion is preliminarily reassuring for the millions of dog owners who have worried, or been warned, that grain-free kibble might be silently damaging their pet’s heart. At the population level, grain-free status appears to have no effect on new cardiac diagnoses, and the imperfections in owner reporting, while real, were of a kind that could only have masked a true effect, not invented a clean bill of health. As the researchers emphasize, considerably more research is needed to determine whether specific ingredients affect specific cardiac diseases, but the blanket avoidance of all grain-free diets now lacks support from the largest longitudinal dataset yet brought to bear on the question.

Subject of Research: The relationship between grain-free diets and new cardiac diagnoses in companion dogs, and the accuracy of owner-reported diet data, in the Dog Aging Project cohort.

Article Title: Multiple Modelling Methods Suggest That Grain‐Free Diets Are Not Predictive of New Owner‐Reported Cardiac Diagnoses Over Two Years in the Dog Aging Project, Despite Owner Misclassification of Diet

Article References: O'Brien, J., Bishop, M., Dog Aging Project Consortium, Tolbert, M. K., & Ruple, A. (2026). Multiple Modelling Methods Suggest That Grain‐Free Diets Are Not Predictive of New Owner‐Reported Cardiac Diagnoses Over Two Years in the Dog Aging Project, Despite Owner Misclassification of Diet. Veterinary Medicine and Science, 12(5), Article e71213. https://doi.org/10.1002/vms3.71213

Image Credits: AI Generated

DOI: 10.1002/vms3.71213

Keywords: grain-free diets, canine cardiac disease, Dog Aging Project, dilated cardiomyopathy, diet misclassification, owner-reported data, veterinary nutrition, longitudinal study, logistic regression, causal inference, dog health, FDA investigation