scholarly journals VISTA Is a Diagnostic Biomarker and Immunotherapy Target of Aggressive Feline Mammary Carcinoma Subtypes

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5559
Author(s):  
Andreia Gameiro ◽  
Catarina Nascimento ◽  
Jorge Correia ◽  
Fernando Ferreira
Keyword(s):  
Mammary Carcinoma ◽  
Triple Negative ◽  
Serum Levels ◽  
Luminal A ◽  
Her2 Positive ◽  
Feline Mammary Carcinoma ◽  
Tnf Α ◽  
Control Tumor ◽  
Immunotherapy Target ◽  
Tumor Expression

Feline mammary carcinoma (FMC) is a common neoplasia, showing aggressive clinicopathological features, without viable therapeutic options. The study of tumor microenvironment has gained importance, due to the ability to control tumor progression by regulating the immune response. Considering the lack of knowledge, feline serum VISTA levels from cats with mammary carcinoma were compared with healthy controls, and with serum levels of PD-1/PD-L1, CTLA-4, LAG-3, IL-6, and TNF-α. In parallel, VISTA tumor expression was evaluated in FMC samples. The obtained data revealed that serum VISTA levels were significantly higher in cats presenting HER2-positive (p = 0.0025) or triple-negative subtypes (p = 0.0019), with higher serum levels in luminal A (p = 0.0025) correlated to the presence of metastasis (p = 0.0471). Furthermore, in HER2-positive or triple-negative tumors, correlations were obtained between serum VISTA levels and the serum levels of the above-mentioned molecules. In tumors, VISTA expression revealed a stronger intensity in cancer cells, when compared to TILs (p < 0.0001). Stratifying the samples by subtypes, a higher number of VISTA-positive TILs was observed in the HER2-positive subtype, compared with triple-negative tumors (p = 0.0138). In conclusion, results support the development of therapeutic strategies for HER2-positive and triple-negative FMC subtypes, reinforcing the use of cats as a human oncology model.

scholarly journals Serum PD-1/PD-L1 Levels, Tumor Expression and PD-L1 Somatic Mutations in HER2-Positive and Triple Negative Normal-Like Feline Mammary Carcinoma Subtypes

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1386 ◽  
Author(s):  
Catarina Nascimento ◽  
Ana Catarina Urbano ◽  
Andreia Gameiro ◽  
João Ferreira ◽  
Jorge Correia ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mammary Carcinoma ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Cytotoxic T Lymphocyte ◽  
Strong Positive Correlation ◽  
Her2 Positive ◽  
Necrosis Factor Alpha ◽  
Feline Mammary Carcinoma ◽  
Tnf Α

Tumor microenvironment has gained great relevance due to its ability to regulate distinct checkpoints mediators, orchestrating tumor progression. Serum programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) levels were compared with healthy controls and with serum cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and tumor necrosis factor-alpha (TNF-α) levels in order to understand the role of PD-1/PD-L1 axis in cats with mammary carcinoma. PD-1 and PD-L1 expression was evaluated in tumor-infiltrating lymphocytes (TILs) and cancer cells, as the presence of somatic mutations. Results showed that serum PD-1 and PD-L1 levels were significantly higher in cats with HER2-positive (p = 0.017; p = 0.032) and triple negative (TN) normal-like mammary carcinomas (p = 0.004; p = 0.015), showing a strong positive correlation between serum CTLA-4 and TNF-α levels. In tumors, PD-L1 expression in cancer cells was significantly higher in HER2-positive samples than in TN normal-like tumors (p = 0.010), as the percentage of PD-L1-positive TILs (p = 0.037). PD-L1 gene sequencing identified two heterozygous mutations in exon 4 (A245T; V252M) and one in exon 5 (T267S). In summary, results support the use of spontaneous feline mammary carcinoma as a model for human breast cancer and suggest that the development of monoclonal antibodies may be a therapeutic strategy.

scholarly journals PD-1 and PD-L1 are diagnostic biomarkers and PD-L1 a promising therapeutic target in HER2-positive and triple negative normal-like feline mammary carcinoma subtypes

2020 ◽  
Author(s):  
Catarina Nascimento ◽  
Ana Catarina Urbano ◽  
Andreia Gameiro ◽  
João Ferreira ◽  
Jorge Correia ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Mammary Carcinoma ◽  
Triple Negative ◽  
Strong Positive Correlation ◽  
Her2 Positive ◽  
Diagnostic Biomarkers ◽  
Mammary Carcinomas ◽  
Tumor Subtypes ◽  
Promising Therapeutic Target ◽  
Feline Mammary Carcinoma

AbstractTumor microenvironment has gained great relevance due to its ability to regulate distinct checkpoints mediators, orchestrating tumor progression. In order to understand the role of the PD- 1/PD-L1 axis in cats with mammary carcinoma, serum PD-1 and PD-L1 levels were compared with healthy controls and with serum CTLA-4 and TNF-α levels. PD-1 and PD-L1 expression was evaluated in TILs and cancer cells, as the presence of somatic mutations. Results showed that serum PD-1 and PD-L1 levels were significantly higher in cats with HER2-positive (p=0.017; p=0.032) and triple negative (TN) normal-like mammary carcinomas (p=0.004; p=0.015). Besides, cats presenting these tumor subtypes showed a strong positive correlation between serum PD-1, PD-L1, CTLA-4 and TNF-α levels. In tumors, PD-L1 expression in cancer cells was significantly higher in HER2-positive samples than in TN normal-like tumors (p=0.010), as the percentage of PD-L1-positive TILs (p=0.038). Results from the PD-L1 gene sequencing identified two heterozygous mutations in exon 4 (A245T, 3.8%; V252M, 42.3%) and one in exon 5 (T267S, 3.8%). In summary, results support that serum PD-1 and PD-L1 levels can be used as diagnostic biomarkers of HER2-positive and TN normal-like feline mammary carcinomas and suggest that the development of monoclonal antibodies may be a good therapeutic strategy.

scholarly journals Serum and Tissue Expression Levels of Leptin and Leptin Receptor Are Putative Markers of Specific Feline Mammary Carcinoma Subtypes

2021 ◽  
Vol 8 ◽  
Author(s):  
Andreia Gameiro ◽  
Catarina Nascimento ◽  
Ana Catarina Urbano ◽  
Jorge Correia ◽  
Fernando Ferreira
Keyword(s):  
Mammary Carcinoma ◽  
Leptin Receptor ◽  
Elevated Serum ◽  
Disease Free Survival ◽  
Serum Levels ◽  
Her2 Positive ◽  
Serum Leptin ◽  
Expression Levels ◽  
Luminal B ◽  
Feline Mammary Carcinoma

Obesity is an established risk factor for breast cancer in post-menopausal women, being associated with elevated serum levels of leptin. Although overweight is a common condition in cat, the role of leptin and its receptor in feline mammary carcinoma remains unsettled. In this study, serum leptin and leptin receptor (ObR) levels were investigated in 58 cats with mammary carcinoma and compared with those of healthy animals, as were the expression levels of leptin and ObR in tumor tissues. The results showed that the Free Leptin Index is significantly decreased in cats with mammary carcinoma (p = 0.0006), particularly in those with luminal B and HER2-positive tumors, and that these animals also present significantly lower serum leptin levels (p &lt; 0.0001 and p &lt; 0.005, respectively). Interestingly, ulcerating tumors (p = 0.0005) and shorter disease-free survival (p = 0.0217) were associated to serum leptin levels above 4.17 pg/mL. In contrast, elevated serum ObR levels were found in all cats with mammary carcinoma (p &lt; 0.0001), with levels above 16.89 ng/mL being associated with smaller tumors (p = 0.0118), estrogen receptor negative status (p = 0.0291) and increased serum levels of CTLA-4 (p = 0.0056), TNF-α (p = 0.0025), PD-1 (p = 0.0023), and PD-L1 (p = 0.0002). In tumor samples, leptin is overexpressed in luminal B and triple-negative carcinomas (p = 0.0046), whereas ObR is found to be overexpressed in luminal B tumors (p = 0.0425). Altogether, our results support the hypothesis that serum levels of leptin and ObR can be used as biomarkers of specific feline mammary carcinoma subtypes, and suggests the use of leptin antagonists as a therapeutic tool, reinforcing the utility of the cat as a cancer model.

scholarly journals Emerging Biomarkers and Targeted Therapies in Feline Mammary Carcinoma

2021 ◽  
Vol 8 (8) ◽  
pp. 164
Author(s):  
Andreia Gameiro ◽  
Ana Catarina Urbano ◽  
Fernando Ferreira
Keyword(s):  
Mammary Carcinoma ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Current Knowledge ◽  
Therapeutic Options ◽  
Cancer Model ◽  
Human Breast ◽  
Her2 Positive ◽  
Prognosis Factors ◽  
Feline Mammary Carcinoma

Feline mammary carcinoma (FMC) is a common aggressive malignancy with a low survival rate that lacks viable therapeutic options beyond mastectomy. Recently, increasing efforts have been made to understand the molecular mechanisms underlying FMC development, using the knowledge gained from studies on human breast cancer to discover new diagnostic and prognostic biomarkers, thus reinforcing the utility of the cat as a cancer model. In this article, we review the current knowledge on FMC pathogenesis, biomarkers, and prognosis factors and offer new insights into novel therapeutic options for HER2-positive and triple-negative FMC subtypes.

scholarly journals Serum levels and tumour expression of leptin and leptin receptor as promising clinical biomarkers of specific feline mammary carcinoma subtypes

2020 ◽  
Author(s):  
Andreia Gameiro ◽  
Catarina Nascimento ◽  
Ana Catarina Urbano ◽  
Jorge Correia ◽  
Fernando Ferreira
Keyword(s):  
Mammary Carcinoma ◽  
Leptin Receptor ◽  
Elevated Serum ◽  
Serum Levels ◽  
Her2 Positive ◽  
Nutritional Disorder ◽  
Serum Leptin ◽  
Luminal B ◽  
Clinical Biomarkers ◽  
Feline Mammary Carcinoma

AbstractObesity is a risk factor for human breast cancer, being associated with increased serum levels of leptin. In cat, although obesity is a common nutritional disorder, the role of leptin and its receptor in mammary carcinoma is unknown. In this study, serum levels of leptin and leptin receptor (ObR) were evaluated in 58 cats with mammary carcinoma and compared with healthy controls by ELISA, as tumour expression by immunohistochemistry. Results showed that the free leptin index is decreased in cats with mammary carcinoma (p=0.0006), particularly for those with luminal B and HER2-positive disease that showed significantly lower serum leptin levels (p<0.0001 and p<0.005, respectively). Serum leptin levels above 4.17 pg/mL were associated with ulcerating tumours (p=0.0005) and shorter DFS (p=0.0217). Elevated serum ObR levels were found in all cats with mammary carcinoma (p<0.0001), with levels above 16.89 ng/mL being associated with smaller tumours (p=0.0118), ER-negative status in HER2-positive tumours (p=0.0291) and increased serum levels of CTLA-4 (p=0.0056), TNF-α (p=0.0025), PD-1 (p=0.0023) and PD-L1 (p=0.0002). In tumour samples, leptin was overexpressed in luminal B and triple-negative carcinomas (p=0.0046), whereas ObR was found overexpressed in luminal B samples (p=0.0425). Altogether, our results reinforce the importance of feline mammary carcinoma in comparative oncology.

scholarly journals Inflammatory Breast Cancer: Clinical Characteristics and Influence of Molecular Subtypes on Treatment Response

2021 ◽  
Vol 107 (1_suppl) ◽  
pp. 12-12
Author(s):  
D Aissaoui ◽  
M Bohli ◽  
R Ben Amor ◽  
J Yahyaoui ◽  
A Hamdoun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Response ◽  
Inflammatory Breast Cancer ◽  
Hormone Receptor ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B ◽  
Significant Difference

Introduction: Inflammatory Breast Cancer (IBC) is a rare and very aggressive breast cancer with poor prognosis. The prevalence is different from a country to another. In Tunisia, it is about 5 to 7% of breast cancer. The aim of this study is to describe the epidemiological and histopathological features of patients with inflammatory breast cancer and to evaluate the treatment response according to the molecular subtypes. Methods: This retrospective review identified 31 patients with no metastatic IBC treated in our radiotherapy department between December 2019 and November 2020. IBC was confirmed using the clinical criteria. Baseline clinic-pathological and treatment information was retrieved from medical records. Statistical analysis was performed with IBM SPSS V.20. Results: Median age was 51.3 years [27-68]. 48% of tumors were grade 3. The average tumor size was 36mm [10-90]. The histological type was ductal carcinoma in 97%. Vascular invasion was noted in 24 patients (77%). Thirty patients were classified as stage IIIB and one patient was IIIC. 74% were hormone receptor positive and 45% were HER2 positive. Luminal B was the predominant subtype (52%) followed by Her2 positive (32%), Luminal A (23%), and triple negative (3%) All patients had chemotherapy: neoadjuvant for 26 patients (84%) and adjuvant for 5 patients (16%). Nine patients (29%) had tumor pathological complete response (pCR). Partial response was observed in 18 patients (58%). Lymph node pCR was noted in 16% of cases (n=5). Endocrine therapy and trastuzumab were given to 76% and 45% of patients, respectively. The influence of the molecular subtype was not statistically significant on the response to neoadjuvant treatment. The highest rate of pCR were 43% for Her2positive, then 27%, 21% and 9% for Luminal B, Luminal A and Triple negative, respectively (p=0.2). Conclusion: Our study showed a high percentage of hormone receptor and Her2+ (74% and 45% respectively) in IBC. Luminal B was the most frequent subtype. Anthracycline-based chemotherapy and trastuzumab improved the pCR rate: 44% for Her2positive. Triple negative showed poorer pCR than other breast cancer subtype without a significant difference. A larger study is warranted to confirm our findings.

Trends in breast cancer mortality according to molecular subtypes: A population-based study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 572-572
Author(s):  
Yunan Han ◽  
Shuai Xu ◽  
Graham A. Colditz ◽  
Adetunji T. Toriola
Keyword(s):  
Breast Cancer ◽  
Cancer Mortality ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Breast Cancer Mortality ◽  
Treatment Strategies ◽  
Luminal A ◽  
Her2 Positive ◽  
Mortality Trends ◽  
Luminal B

572 Background: Breast cancer is the second leading cause of cancer death in U.S. women. On the molecular level, breast cancer is a heterogeneous disease. Heterogeneous expressions of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) are etiologically and clinically meaningful, as they map to distinct risk factors and different treatment strategies. Although breast cancer mortality has been declining since 1990, little is known about mortality trends according to molecular subtypes at the population level. Methods: We examined the incidence-based mortality rates and trends among women who were diagnosed with invasive breast cancer from 2010 through 2017 using the Surveillance, Epidemiology, and End Results (SEER) database. We defined incidence-based mortality using a moving 5-year calendar period starting in 2014. We further assessed mortality according to breast cancer molecular subtypes: luminal A (ER and/or PR positive, HER2 negative), luminal B (ER and/or PR positive, HER2 positive), HER2-enriched (HER2 over-expressed or amplified, ER and PR negative) and triple-negative (ER and PR negative, HER2 negative) tumors. We calculated annual percent changes (APC) in incidence-based mortality using joinpoint regression models. Results: Overall, incidence-based mortality for breast cancer significantly decreased by 1.5% annually from 2014 through 2017 (APC, -1.5%; 95% coefficient interval [CI], -2.3% to -0.7%; p<0.001). Incidence-based mortality decreased annually by 2.0% for luminal A breast cancer (APC, -2.0%; 95% CI, -3.7% to -0.3%; p<0.001), 2.1% for luminal B breast cancer (APC, -2.1%; 95% CI, -5.4% to 1.4%; p=0.1), 1.1% for triple-negative breast cancer (TNBC) (APC, -1.1%; 95% CI, -2.1% to -0.0%; p<0.001). However, incidence-based mortality for HER2-enriched breast cancer increased 2.3% annually during the study period (APC, 2.3%; 95% CI, -2.4% to 7.2%; p=0.2). Conclusions: Between 2014 and 2017, incidence-based mortality for luminal A, luminal B, and TNBC decreased among U.S. women, with a larger decrease observed for luminal tumors. However, incidence-based mortality for HER2-enriched breast cancer increased. The favorable incidence-based mortality trends for luminal tumors and TNBC are likely due to the continuing improvement in treatments and early detection. The increasing trend of incidence-based mortality for HER2-enriched breast cancer constitutes a priority for cancer control activities and further research.

scholarly journals Analysis of prolactin receptor expression in breast cancer subtypes

2020 ◽  
Vol 66 (1) ◽  
pp. 89-94
Author(s):  
T.S. Kalinina ◽  
V.V. Kononchuk ◽  
S.V. Sidorov ◽  
L.F. Gulyaeva
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Prolactin Receptor ◽  
Mrna Level ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Luminal A ◽  
Her2 Positive ◽  
Tissue Samples ◽  
Luminal B

Breast cancer (BC) is the most common cancer among women. It is known that the prolactin receptor (PRLR) may play a role in breast carcinogenesis, but the available data are often contradictory. To get a more complete picture of the relationship between the receptor and mammary gland carcinogenesis, we examined the association between changes in PRLR expression level and tumor subtype (and its main characteristics). To do this, using real-time PCR, we evaluated the level of PRLR mRNA in BC tissue samples and untransformed adjoining tissue samples (89 pairs). Since the androgen receptor (AR) has begun to be seen as a prognostic marker in breast cancer, we also evaluated the association between mRNA levels of AR and PRLR. We found a significant increase in PRLR expression in luminal subtypes; the highest level of PRLR mRNA was detected in luminal A subtype. In HER2-positive ER-, PR-negative BC, the PRLR mRNA level decreases in tumor tissues compared with untransformed tissues. High PRLR expression is also associated with smaller tumor size in luminal B HER2-negative subtype. In ER-, PR-negative tumors, PRLR expression is associated with AR expression: PRLR mRNA level is increased when AR mRNA level is reduced by more than 8 times in triple-negative tumors; in contrast, in HER2-positive subtype it decreases more significantly when AR expression is reduced by more than 3 times. A tendency towards an increase in PRLR expression with an increase in the AR mRNA level was also discovered in luminal subtypes. The level of PRLR expression depends on the age of patients. In luminal A, PRLR expression is higher in patients under 65 years. In contrast, in luminal B HER2-negative and triple-negative BC, reduced PRLR expression was observed in patients under the age of 40 years and under the age of 50 years, respectively. In this group of patients under the age of 40 years with luminal B HER2-negative BC, ER expression was also reduced (0-4 score according to the IHC assay). Thus, PRLR probably plays a different role in the development and progression of BC: in luminal A and luminal B HER2-positive subtypes PRLR may act as an oncogen, and in luminal B HER2-negative and ER-, PR-negative subtypes can play a tumor suppressor role.

scholarly journals Identification of Long Noncoding RNAs as Predictors of Survival in Triple-Negative Breast Cancer Based on Network Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Xiao-Xiao Li ◽  
Li-Juan Wang ◽  
Jie Hou ◽  
Hong-Yang Liu ◽  
Rui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Network Analysis ◽  
Molecular Mechanisms ◽  
Triple Negative ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Breast Cancers ◽  
Luminal A ◽  
Her2 Positive ◽  
Cancer Subtypes

Breast cancer is the most common cancer observed in adult females, worldwide. Due to the heterogeneity and varied molecular subtypes of breast cancer, the molecular mechanisms underlying carcinogenesis in different subtypes of breast cancer are distinct. Recently, long noncoding RNAs (lncRNAs) have been shown to be oncogenic or play important roles in cancer suppression and are used as biomarkers for diagnosis and therapy. In this study, we identified 134 lncRNAs and 6,414 coding genes were differentially expressed in triple-negative (TN), human epidermal growth factor receptor 2- (HER2-) positive, luminal A-positive, and luminal B-positive breast cancer. Of these, 37 lncRNAs were found to be dysregulated in all four subtypes of breast cancers. Subtypes of breast cancer special modules and lncRNA-mRNA interaction networks were constructed through weighted gene coexpression network analysis (WGCNA). Survival analysis of another public datasets was used to verify the identified lncRNAs exhibiting potential indicative roles in TN prognosis. Results from heat map analysis of the identified lncRNAs revealed that five blocks were significantly displayed. High expressions of lncRNAs, including LINC00911, CSMD2-AS1, LINC01192, SNHG19, DSCAM-AS1, PCAT4, ACVR28-AS1, and CNTFR-AS1, and low expressions of THAP9-AS1, MALAT1, TUG1, CAHM, FAM2011, NNT-AS1, COX10-AS1, and RPARP-AS1 were associated with low survival possibility in TN breast cancers. This study provides novel lncRNAs as potential biomarkers for the therapeutic and prognostic classification of different breast cancer subtypes.

Breast cancer in Angola, molecular subtypes: The first preliminary study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13075-e13075
Author(s):  
Lúcio Lara Santos ◽  
Fernando Miguel ◽  
Lygia Vieira Lopes ◽  
Julio Oliveira ◽  
Eduardo Ferreira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Locally Advanced ◽  
Luminal A ◽  
Her2 Positive ◽  
Luminal B ◽  
Therapeutic Decisions ◽  
Ihc Markers

e13075 Background: Women in sub-Saharan African countries, as Angola, are experiencing an increasing burden of aggressive breast cancer. Breast cancer molecular subtypes may enable more accurate diagnoses and support therapeutic decisions, however several studies have suggested that African breast cancers are predominantly hormone receptor poor. We conduct a study, to correlate the clinical pathological profiles and molecular subtypes, according its surrogate immunohistochemistry (IHC) markers, of breast cancer in Luanda, Angola. Methods: From Jan. 2011 to Dec. 30, 2014, 179 consecutive cases of microscopically confirmed invasive breast carcinoma that were evaluable for histology and IHC (ER, PR, HER2, and Ki-67) were classified. However, 21.8% (n = 39) of cases were poorly preserved, therefore it was only possible to study IHC in 140 cases. Results: All patients were female, the median age was 47 years (24-84 years). Invasive ductal carcinoma was the most common type, 91.4% (n = 128), grade 2 (moderately differentiated) was prevalent, 67.1%. Most of the tumours were locally advanced, stage III 65% (n = 91) and stage IV 3.6% (n = 5). In 140 cases studied, 53.2% (n = 74 ) of malignancies were hormone receptors positive, whence 25.7% were luminal A like, 19.3% luminal B like/ HER2 negative, 7.9% luminal B like/HER2 positive, 15.7% HER2 positive and 31,4% were triple-negative. Conclusions: Woman with breast cancer in Luanda-Angola were caracterized by advance stage and younger age at diagnosis of disease. The two predominant molecular subtypes are triple negative and luminal A like. Therefore, determining the molecular subtype using surrogate IHC markers has important treatment and prognostic implications for Angola women with breast cancer.

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