BRAF mutation status and its prognostic significance in 79 canine urothelial carcinomas: A retrospective study (2006–2019)

Abstract

Urothelial carcinoma (UC) is the most common tumour of the canine urinary bladder. Recently, BRAF mutation testing emerged as a diagnostic option, but its prognostic significance is unknown. This study investigates the relationship between BRAF (variant V595E) mutation status and overall survival in UC‐bearing dogs. Seventy‐nine patients histologically diagnosed with UC of the bladder and/or urethra between 2006 and 2019 were included in this retrospective single‐centre‐study. Treatment consisted of meloxicam (n = 39, group 1 ‘Melox’), mitoxantrone and meloxicam (+/− followed by metronomic chlorambucil; n = 23, group 2 ‘Chemo’) or partial cystectomy followed by meloxicam +/− mitoxantrone (n = 17, group 3 ‘Sx’). Survival was significantly influenced by treatment (p = .0002) and tumour location (p < .001) in both uni‐ and multivariable analyses. BRAF mutation was identified in 51 tumours (=64.6%) and had no statistically significant influence on overall survival: MST for BRAF‐negative patients 359 versus 214 days for BRAF‐positive dogs (p = .055). However, in BRAF‐positive dogs, survival depended significantly on type of treatment in univariable analysis: MSTs for groups 1–3 were 151, 244 and 853 days, respectively (p = .006); In BRAF‐positive group 2 (‘Chemo’)‐patients, adjuvant metronomic chlorambucil after mitoxantrone more than doubled MST compared to patients receiving mitoxantrone alone (588 vs. 216 days; p = .030). In contrast, MSTs were not significantly different in BRAF‐negative patients among the three treatment groups (p = .069). Multivariate analysis of these data was not possible due to group size limitations. This study identified tumour location and treatment type, but not BRAF mutation status, as independent prognostic factors for overall survival.

Meloxicam in Combination with Mitoxantrone or Vinblastine as First-Line Treatment for Non-Resectable Urothelial Cell Carcinoma in Dogs

“…The median survival time (MST) of the patients treated only with meloxicam (151 days) was similar to that reported with piroxicam alone (181 days) [ 9 , 26 ]. The patients treated with meloxicam in combination with mitoxantrone, occasionally followed by metronomic chlorambucil, had slightly shorter MST (217 days) than previously reported with piroxicam in combination with mitoxantrone (291 days) [ 18 , 26 ]. The time to progression, CB, or the incidence of AEs from this combination treatment were not assessed.…”

“…Meloxicam, a selective COX-2 inhibitor, has shown anti-proliferative and pro-apoptotic effects on canine cancer cells in vitro [ 23 ] and in vivo [ 24 , 25 ]. A recent retrospective study was published evaluating meloxicam as a sole therapy or in combination with chemotherapy for the treatment of canine UCC [ 26 ]. The median survival time (MST) of the patients treated only with meloxicam (151 days) was similar to that reported with piroxicam alone (181 days) [ 9 , 26 ].…”

“…A recent retrospective study was published evaluating meloxicam as a sole therapy or in combination with chemotherapy for the treatment of canine UCC [ 26 ]. The median survival time (MST) of the patients treated only with meloxicam (151 days) was similar to that reported with piroxicam alone (181 days) [ 9 , 26 ]. The patients treated with meloxicam in combination with mitoxantrone, occasionally followed by metronomic chlorambucil, had slightly shorter MST (217 days) than previously reported with piroxicam in combination with mitoxantrone (291 days) [ 18 , 26 ].…”

Artificial Intelligence to Predict the BRAF V595E Mutation in Canine Urinary Bladder Urothelial Carcinomas

“…In order to test the options of AI to predict specific molecular alterations on routine, HE-stained tissue sections, a specific genetic mutation, and the associated disease needs to be defined first. In the field of canine cancer, the most characterised and most frequently tested somatic mutations are c-kit in mast cell tumours and BRAF in bladder and prostate cancer [3,11,12,[35][36][37]. The use of AI to predict c-kit mutation has been reported recently [38].…”

Molecular Markers in Urinary Bladder Cancer: Applications for Diagnosis, Prognosis and Therapy

“…A recent retrospective study looked at the prognostic significance of BRAF mutation in 79 canine TCCs. A total of 51 tumours (65%) were BRAF V595E -positive, and the mutation was not correlated with survival [ 62 ].…”