Mammary Carcinoma: Insights from BRCA1 mutations

Genetic Signatures in Canine Mammary Tumors: insights from BRCA1 mutations

Mammary gland tumors (breast cancer) are considered the most prevalent cancer in intact female dogs and women^1–4. More than 50% of these tumors are classified as malignant, and distant metastasis is frequently associated with death in both species^5–7. Mammary gland tumors are one of the best studied cancers in comparative oncology largely due to similarities between dogs and humans regarding spontaneous tumor incidence, age of onset, tumor genetics, hormonal influence, biologic behavior, and the shared environmental factors ^2,8–12.

Mammary gland development is dependent on hormonal exposure to estrogen and progesterone. Consequently, continuous exposure to these hormones is one of the risk factors associated with tumor development in mammary glands^13,14. Interestingly, early ovariohysterectomy (OVH), usually recommended to be performed before the first estrus cycle in dogs in the United States, is responsible for the lower incidence of mammary neoplasia in this country compared to European and South America countries where this practice is not common¹⁵. The protective effect of OVH for mammary neoplasia development was described in female dogs spayed before the first estrus, when the risk was 0.5%, with increased risk to 8% and 26% when this procedure was performed after second and third estrus, respectively¹⁶. However, it is important to note that recent studies correlated some consequences of early sterilization, such as increased risk for other cancers development, urinary incontinence and orthopedic problems; these correlations are still under investigation^17–20. Thus, the risk of mammary tumor development is increased in non-neutered females, in small breed dogs (possible by their elevated life expectancy), and in overweight conditions^{5,13,17,21–24}. 

At the European Society of Veterinary Oncology (ESVONC) conference in Alicante, Spain, in 2023, FidoCure presented groundbreaking clinico-genomic data. This research involved an impressive cohort of 94 dogs diagnosed with mammary carcinoma, marking the largest series of sequenced cases in dogs to date. This milestone presentation signifies a significant leap forward in our understanding of mammary carcinoma in dogs. The wealth of clinico-genomic data showcased at ESVONC 2023 promises to enhance our ability to understand and manage this condition, ultimately improving the lives of affected dogs.

In this comprehensive study, we conducted a meticulous analysis of histopathology reports from a diverse cohort of dogs. Our objective was to categorize tumors into two distinct groups: those associated with a favorable prognosis and those with a less optimistic outlook. Tumors with the presence of vascular and/or lymphatic invasion, lymph node metastasis or classified as grade III by the certified pathologist were categorized as poor prognosis. Twenty dogs were classified as having good prognosis, 67 as poor prognosis and 7 were not assigned due to the lack of information in their histology reports.

For dogs with poor prognosis, 19.4% (13/67) were mixed breed dogs, 10.4% (7/67) German Shepherd, and 7.5% Chihuahua (5/67). Mixed breed dogs represented 25% (5/20) of the good prognosis groups followed by Cocker Spaniel 10% (2/20) (Figure 1). For both groups, approximately 90% were spayed, and the average age was around 10 years for both groups.

Figure 1. Common breeds of dogs with good prognosis (N=20) and poor prognosis (N=67).

The study also examined the survival outcomes. For dogs with a poor prognosis, their median survival time was 230 days, while dogs with a good prognosis had a significantly longer median survival time of 423 days (p=0.0269). Further genetic analysis was conducted to better understand the underlying factors contributing to these differences. In the poor prognosis group, a total of 180 somatic mutations were identified, averaging 2.68 mutations per dog. The most frequently mutated genes in this group were TP53 (18%), KMT2D (18%), KRAS (15%), BRCA2, CREBBP (13%), DMD (12%), and PIK3CA (9%). Conversely, in the good prognosis group, there were 37 identified somatic mutations, averaging 1.85 mutations per dog. The predominant genes affected in this group were KRAS (25%), BRCA1 (20%), PIK3CA (15%), KMT2D, TP53, and CREBBP (10%). 

In line with previous research and consistent with findings in human breast cancer, TP53 mutations were observed more frequently in aggressive forms of canine mammary carcinoma. However, in our analysis, the difference in TP53 mutation prevalence between the worse prognosis (18%) and good prognosis (10%) groups did not reach statistical significance (P=0.5070) (Figure 2). This observation suggests a nuanced relationship between TP53 mutations and prognosis in canine mammary carcinoma, warranting further investigation to elucidate the intricacies of this genetic alteration.

In contrast, our study revealed a noteworthy reduction in BRCA1 mutations within the poor prognosis group (4%) compared to the good prognosis group (20%), with statistical significance (P=0.0406) (Figure 2). This unexpected finding underscores the potential prognostic relevance of BRCA1 mutations in canine mammary carcinoma, a facet that merits deeper exploration.

Figure 2. Common somatic mutations identified in dogs with good prognosis (N=20) and poor prognosis (N=67).

The overall survival of dogs in the good prognosis group (N=20) was 423 days and for dogs in the poor prognosis group (N=67) was 230 days of survival (P=0.0269). Based on these genetic findings, targeted therapies (TT) were recommended as a treatment approach, tailored to the specific mutations detected in each dog. For dogs with a poor prognosis, the survival outcomes varied depending on the treatment approach. When treated solely with targeted therapies (TT) (N=23), dogs had a median survival time of 158 days. However, when TT was combined with chemotherapy (N=14), the median survival time improved to 284 days (p= 0.1974), although this difference was not statistically significant.

Our study contributes to the evolving understanding of genetic factors in canine mammary carcinoma and their impact on prognosis. While TP53 mutations were observed in both poor and good prognosis groups, the lack of statistical significance in their distribution hints at the complexity of this genetic alteration in determining disease outcomes. In contrast, the significant reduction in BRCA1 mutations among dogs with poor prognosis highlights the potential utility of BRCA1 mutations as a prognostic marker, a concept that has not been extensively explored in the context of this canine malignancy.

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