Evaluation of NTRK Gene Fusion by Five Different Platforms in Triple-Negative Breast Carcinoma

Triple-negative breast carcinoma (TNBC) is an aggressive disease that has a poor prognosis since it lacks effective treatment methods. Neurotrophic tyrosine receptor kinase (NTRK) fusion genes are excellent candidates for targeted RTK inhibitor therapies and there are available targeted therapy drugs for the treatment of TRK fusion-positive tumors in a tumor agnostic pattern. Our study was designed to investigate the NTRK gene fusion status in TNBC patients and to determine whether RTK-targeted therapies are suitable for TNBC patients. A total of 305 TNBC patients were enrolled in our study. IHC was employed as a prescreening method, and IHC positive cases were further submitted for evaluation by FISH, RT-PCR, and NGS methods. NTRK IHC was evaluated successfully in 287 of the 305 cases, and there were 32 (11.15%) positive cases. FISH was carried out in the 32 IHC positive cases. There were 13 FISH-positive cases if the threshold was set as >15% of the 100 counted tumor cells having a split orange and green signal with more than one signal diameter. There were only 2 FISH-positive cases if the cutoff value was defined as >15% of the counted tumor cells having a split signal with more than two signal diameter widths. One of the FISH-positive cases had a separate NTRK3 FISH signal in 88% of the tumor cells, and its IHC result was strong nuclear staining in all the tumor cells. After evaluation of the morphology, it was re-diagnosed as secretory breast carcinoma, and the NGS result confirmed that it had a NTRK3-ETV6 fusion gene. The other FISH-positive cases were all negative for NTRK gene fusion in the NGS or RT-PCR examination. The NTRK gene fusion rate was low in our TNBC cohort. NTRK gene fusion may be a rare event in TNBC. The high false-positive rate of NTRK gene fusion detected by IHC questions its role as a prescreening method in TNBC. More data may be needed to determine a suitable threshold for NTRK FISH in TNBC in the future. More studies are needed to confirm whether RTK-targeted therapies are appropriate treatments for TNBC patients.

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Higher CD1a Levels Correlate with PD-L1 Expression and Predict Worse Overall Survival in Triple-Negative Breast Carcinoma

Breast Care ◽

10.1159/000513502 ◽

2021 ◽

pp. 1-9

Author(s):

Jian Zheng ◽

Yuntao Wei ◽

Xiaoxi Li ◽

Zhan Shen ◽

Yong Zhang ◽

...

Keyword(s):

Overall Survival ◽

Dendritic Cells ◽

Lymph Node ◽

Breast Carcinoma ◽

Triple Negative ◽

Carcinoma Tissue ◽

Kaplan Meier ◽

Immature Dendritic Cells ◽

Triple Negative Breast Carcinoma ◽

High Median

Objective: The aim of this study was to measure the expression of PD-L1, CD1a (a marker for immature dendritic cells), and CD83 (a marker for mature dendritic cells) and further examine the associations of PD-L1, CD83, and CD1a with overall survival (OS) in triple-negative breast carcinoma patients. Methods: PD-L1, CD1a, and CD83 expression in breast carcinoma tissues and CD83 expression in lymph node tissues were examined by immunohistochemistry and tissue microarray in 159 patients. Patients were classified into the low, medium, and high PD-L1, CD1a, and CD83 levels. Pearson χ2 test was used to analyze the correlations between PD-L1, CD1a, and CD83. The Kaplan-Meier method was used to calculate the OS. Multivariate analysis was used to identify determinants of 3- and 5-year OS. Results: 25.1, 25.8, and 49.1% of the patients had low, medium, and high PD-L1 levels, respectively. PD-L1 levels significantly correlated with CD1a (r = 0.30409, p < 0.001) and CD83 levels (r = 0.6146, p < 0.001) in breast carcinoma tissue, as well as CD83 levels (r = 0.17508, p = 0.027) in lymph node. The median OS was 83 months (range 12–106), and the 3- and 5-year OS rates were 94.97% (95% CI 91.57–98.37) and 86.79% (95% CI 81.53–92.06), respectively. Moreover, patients with high median CD1a levels had a significantly lower 5-year OS rate (75.6%) than those with low median CD1a levels (93.5%, p = 0.038). Conclusion: PD-L1, CD1a, and CD83 are variably expressed in triple-negative breast carcinoma tissues, and PD-L1 expression correlates with CD1a and CD83. Higher CD1a levels correlate with PD-L1 expression and predict worse OS in triple-negative breast carcinoma.

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Induction of mitochondrial apoptotic pathway in triple negative breast carcinoma cells by methylglyoxal via generation of reactive oxygen species

Molecular Carcinogenesis ◽

10.1002/mc.22665 ◽

2017 ◽

Vol 56 (9) ◽

pp. 2086-2103 ◽

Cited By ~ 10

Author(s):

Anirban Roy ◽

Manisha Ahir ◽

Saurav Bhattacharya ◽

Pravat Kumar Parida ◽

Arghya Adhikary ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Breast Carcinoma ◽

Triple Negative ◽

Reactive Oxygen ◽

Carcinoma Cells ◽

Oxygen Species ◽

Apoptotic Pathway ◽

Mitochondrial Apoptotic Pathway ◽

Breast Carcinoma Cells ◽

Triple Negative Breast Carcinoma

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Understanding the Evolutionary Games in NSCLC Microenvironment

10.1101/2020.11.30.404350 ◽

2020 ◽

Author(s):

Ranjini Bhattacharya ◽

Robert Vander Velde ◽

Viktoriya Marusyk ◽

Bina Desai ◽

Artem Kaznatcheev ◽

...

Keyword(s):

Tumor Cells ◽

Targeted Therapies ◽

Evolutionary Dynamics ◽

Fusion Gene ◽

Evolutionary Game ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Intrinsic Resistance ◽

Frequency Changes

AbstractWhile initially highly successful, targeted therapies eventually fail as populations of tumor cells evolve mechanisms of resistance, leading to resumption of tumor growth. Historically, cell-intrinsic mutational changes have been the major focus of experimental and clinical studies to decipher origins of therapy resistance. While the importance of these mutational changes is undeniable, a growing body of evidence suggests that non-cell autonomous interactions between sub-populations of tumor cells, as well as with non-tumor cells within tumor microenvironment, might have a profound impact on both short term sensitivity of cancer cells to therapies, as well as on the evolutionary dynamics of emergent resistance. In contrast to well established tools to interrogate the functional impact of cell-intrinsic mutational changes, methodologies to understand non-cell autonomous interactions are largely lacking.Evolutionary Game Theory (EGT) is one of the main frameworks to understand the dynamics that drive frequency changes in interacting competing populations with different phenotypic strategies. However, despite a few notable exceptions, the use of EGT to understand evolutionary dynamics in the context of evolving tumors has been largely confined to theoretical studies. In order to apply EGT towards advancing our understanding of evolving tumor populations, we decided to focus on the context of the emergence of resistance to targeted therapies, directed against EML4-ALK fusion gene in lung cancers, as clinical responses to ALK inhibitors represent a poster child of limitations, posed by evolving resistance. To this end, we have examined competitive dynamics between differentially labelled therapy-naïve tumor cells, cells with cell-intrinsic resistance mechanisms, and cells with cell-extrinsic resistance, mediated by paracrine action of hepatocyte growth factor (HGF), within in vitro game assays in the presence or absence of front-line ALK inhibitor alectinib. We found that producers of HGF were the fittest in every pairwise game, while also supporting the proliferation of therapy-naïve cells. Both selective advantage of these producer cells and their impact on total population growth was a linearly increasing function of the initial frequency of producers until eventually reaching a plateau. Resistant cells did not significantly interact with the other two phenotypes. These results provide insights on reconciling selection driven emergence of subpopulations with cell non-cell autonomous resistance mechanisms, with lack of evidence of clonal dominance of these subpopulations. Further, our studies elucidate mechanisms for co-existence of multiple resistance strategies within evolving tumors. This manuscript serves as a technical report and will be followed up with a research paper in a different journal.

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A STUDY ON THE HISTONE METHYLTRANSFERASE ENHANCER OF ZESTE HOMOLOG 2 EXPRESSION IN BREAST CARCINOMA

10.36106/ijsr/6014009 ◽

2020 ◽

pp. 66-68

Author(s):

Rubaiya Ahmad ◽

Syed Meraj Imam ◽

Debarshi Jana

Keyword(s):

Breast Carcinoma ◽

Breast Tumor ◽

Triple Negative ◽

Histone Methyltransferase ◽

Expression Level ◽

High Grade ◽

Over Expression ◽

Ezh2 Expression ◽

Triple Negative Breast Carcinoma ◽

Enhancer Of Zeste

The over expression of EZH2 in Breast Carcinoma. Compare EZH2 expression in different immunophenotypes of breast carcinoma(basal, luminal, triple-negative). The study EZH2 expression level in association to staging and grading of breast carcinoma Patients attending the Dept of Pathology, Sri Krishna Medical Collage Muzaffarpur, Bihar with epithelial breast tumor. We found that EZH2 in Breast Carcinoma was significantly associated with grade of the tumour. EZH2 was significantly associated with stage of the tumour. It was found that EZH2 was significantly correlated with ki67 in Breast Carcinoma patients. Triple negative Breast Carcinoma patient was significantly associated with high grade of EZH2 tumour.

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