Functional hotness score based on three genes predicts long-term survival of triple-negative breast cancer independent from tumor mutational burden.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12583-e12583
Author(s):  
Eriko Katsuta ◽  
Li Yan ◽  
Mateusz Opyrchal ◽  
Pawel Kalinski ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Cancer Prognosis ◽  
Breast Cancer Patients ◽  
Term Survival ◽  
Expression Levels ◽  
Cancer Immunity ◽  
Anti Cancer

e12583 Background: Cytotoxic T-lymphocytes (CTLs) infiltration into tumor is a positive prognostic factor in breast cancer. Infiltration of CTLs are believed to be driven by mutation-induced neoantigens, thus, higher tumor mutation burden (TMB) is considered an important predictor of tumor immunogenicity and response to immunotherapy, but the association between intratumoral CTL counts and TMB in the overall cancer prognosis remains unclear. Methods: Utilizing publicly available breast cancer cohorts, we established Functional Hotness Score (FHS), based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors. The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed. Results: Breast cancer patients with high-FHS tumors demonstrated significantly better survival. FHS was lower in metastatic breast cancer. Among breast cancer subtypes, triple-negative breast cancer (TNBC) showed the highest FHS. FHS predicted patient survival not in hormone receptor (HR)-positive but in HR-negative, especially TNBCs. The high-FHS TNBCs enhanced not only CD8+ T cell infiltration, but also a broader type-1 anti-cancer immunity. The patients with the high-FHS patients showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified the unique subset of patients who did not recur over time. Conclusions: In conclusion, TNBCs with high-FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with higher anti-cancer immunity regardless of TMB, and constituting an independent prognostic marker of survival, particularly robust when combined with TMB.

Frequency distribution of SPARC in triple-negative breast cancer patients.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 37-37
Author(s):  
G. Basu ◽  
G. Van Vickle ◽  
A. Ghazalpour ◽  
R. Ashfaq ◽  
Z. Gatalica ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Frequency Distribution ◽  
Triple Negative Breast Cancer ◽  
Polyclonal Antibody ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Term Survival ◽  
Large Patient

37 Background: SPARC (secreted protein acid rich in cysteine) belongs to a group of extracellular matrix proteins and promotes adhesion of cells from the matrix. It plays an important role in tumor development in breast cancer and has a significant bearing on patient prognosis and long term survival. It is also known to predict response to nab-paclitaxel in certain tumor types including breast cancer. In 2005, FDA approved a solvent free formulation of paclitaxel for the treatment of metastatic breast cancer that utilizes albumin bound (nab) technology (nab-paclitaxel). Clinical studies have shown that nab-paclitaxel is significantly more effective than paclitaxel. Our study evaluated the frequency distribution of SPARC among triple negative breast cancer patients in which identification of a novel therapeutic target is warranted. Methods: In a total of 951 breast cancer patients, we analyzed tumor SPARC expression by immunohistochemistry (IHC) using a monoclonal (R&D Systems) and a polyclonal antibody (Exalpha Biologicals). Immunoreactivity was assessed by scoring the percentage of cells stained in each field and by the intensity of staining. A cutoff point of 2+ and >30% stained tumor cells were considered as positive. Results: From our analysis of 951 breast cancer patients profiled, a total of 165 patients (17%) were triple negative for ER, PR and HER2. Within this pathologic subtype, 29% patients stained positive with SPARC monoclonal antibody and 21% stained positive with SPARC polyclonal antibody. The correlation of SPARC tumor staining with hormone receptor status will be presented in detail. Conclusions: We conclude that SPARC over-expression is a functionally important feature of a subset of triple negative breast cancer patients. The triple negative subset of tumors generally has a more aggressive clinical course and does not benefit from conventional targeted therapies. Our study suggests that nab-paclitaxel may serve as a therapeutic agent for the subset of triple negative patients that over-express SPARC. To the best of our knowledge, this is the first study involving a large patient pool in which SPARC has been investigated in a single clinical laboratory using standardized IHC with two different SPARC antibodies.

scholarly journals Cytotoxic T-lymphocyte infiltration and chemokine predict long-term patient survival independently of tumor mutational burden in triple-negative breast cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110066
Author(s):  
Eriko Katsuta ◽  
Li Yan ◽  
Mateusz Opyrchal ◽  
Pawel Kalinski ◽  
Kazuaki Takabe
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Patient Survival ◽  
Cytotoxic T Lymphocyte ◽  
Breast Cancer Patients ◽  
Mutational Burden ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Tumor Mutational Burden ◽  
Patient Prognosis

Background: Cytotoxic T-lymphocyte (CTL) infiltration into tumor is a positive prognostic factor in breast cancer. High tumor mutational burden (TMB) is also considered as a predictor of tumor immunogenicity and response to immunotherapy. However, it is unclear whether the infiltration of functional CTL simply reflects the TMB or represents an independent prognostic value. Methods: Utilizing The Cancer Genome Atlas (TCGA) breast cancer cohort, we established the Functional Hotness Score (FHS). The associations of FHS and breast cancer patient prognosis as well as distinct immunity markers were analyzed in a total of 3011 breast cancer patients using TCGA, METABRIC and metastatic breast cancer (MBC) cohort GSE110590. Results: We established FHS, based on CD8A, GZMB and CXCL10 gene expression levels of bulk tumors, which delivered the best prognostic value among some gene combinations. Breast cancer patients with the high-FHS tumors showed significantly better survival. FHS was lower in the MBCs. Triple-negative breast cancer (TNBC) showed the highest FHS among subtypes. FHS predicted patient survival in hormone receptor (HR)-negative, especially in TNBC, but not in HR-positive breast cancer. FHS predicted patient prognosis independently in TNBC. The high-FHS TNBCs showed not only higher CD8+ T cell infiltration, but also enhanced broader type-1 anti-cancer immunity. The patients with the high-FHS tumors showed better prognosis not only in high-TMB tumors but also in low-TMB TNBCs. The combination of high-TMB with high-FHS identified a unique subset of patients who do not recur over time in TNBC. Conclusion: TNBCs with high FHS based on the expression levels of CD8A, GZMB and CXCL10 showed improved prognosis with enhanced anti-cancer immunity regardless of TMB. FHS constitutes an independent prognostic marker of survival, particularly robustly when combined with TMB in TNBC.

scholarly journals The expression and clinical significance of GADD45A in breast cancer patients

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5344 ◽  
Author(s):  
Junnan Wang ◽  
Yiran Wang ◽  
Fei Long ◽  
Fengshang Yan ◽  
Ning Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Patients ◽  
Clinical Significance ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Ki 67 ◽  
Expression Levels ◽  
Cancer Tissues

BackgroundGrowth arrest and DNA-damage-inducible protein 45 alpha (GADD45A) was previously found to be associated with risk of several kinds of human tumors. Here, we studied the expression and clinical significance of GADD45A in breast cancer.MethodsWe performed an immunohistochemical study of GADD45A protein from 419 breast cancer tissues and 116 adjacent non-neoplastic tissues.ResultsSignificantly high GADD45A expression were observed in breast cancer tissues compared with adjacent non-neoplastic tissues (P < 0.001) and were independently correlative with estrogen receptor negative (P = 0.028) and high Ki-67 index (P < 0.001). Kaplan–Meier survival analysis revealed that patients with high GADD45A expression levels had a worse long-term prognosis in triple negative breast cancer (P = 0.041), but it was not an independent prognostic factor in multivariate analysis (P = 0.058).ConclusionsGADD45A expression levels are significantly correlative with estrogen receptor status and Ki-67 index in human breast cancer. Patients with triple negative breast cancer might be stratified into high risk and low risk groups based on the GADD45A expression levels.

scholarly journals High ERK Protein Expression Levels Correlate with Shorter Survival in Triple‐Negative Breast Cancer Patients

2012 ◽  
Vol 17 (6) ◽  
pp. 766-774 ◽  
Author(s):  
Chandra Bartholomeusz ◽  
Ana M. Gonzalez‐Angulo ◽  
Ping Liu ◽  
Naoki Hayashi ◽  
Ana Lluch ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Expression Levels

Efficacy and safety of metronomic capecitabine and gefitinib in heavily pretreated metastatic triple-negative breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1071-1071
Author(s):  
Anantbhushan Ranade ◽  
Kanaka Govind Babu ◽  
Purvish M. Parikh ◽  
Jk Singh ◽  
Manisha Singh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Visceral Metastasis ◽  
Egfr Expression ◽  
Heavily Pretreated

1071 Background: Metronomic chemotherapy regimens have shown efficacy in patients with metastatic breast cancer by antiangiogenic mechanisms. When used metronomically the toxicity profile of capecitabine is low. Triple negative breast cancer is a common problem in India and developing countries. Approximately 30% of triple negative breast cancer express EGFR and its mutation. Methods: Since October 2003 to December 2011 we objectively tested response rates, clinical benefit, and safety of gefitinib and capecitabine administered with a metronomic schedule of 500 mg thrice daily in heavily pretreated metastatic breast cancer patients with gefitinib 250 mg once daily. 300 patients were screened for EGFR expression. Among 85 enrolled patients with EGFR positivity, 76 were evaluable. ECOG performance status (PS) was 0-2, median age 52 years (range 36-65), bone plus visceral metastasis in 40% of patients. Rest had only visceral metastasis. All the patients were pretreated with anthracyclines and taxanes. The combination was administered for a median duration of 32 weeks (range 12-166). Results: We observed 18 partial responses (PR: 24%), 42 (55%) stable disease (SD). Median time to progression was 53 weeks, (95% CI, range 12-166 weeks). Safety of metronomic capecitabine with gefitinib was excellent. Neither grade 2-4 haematological or clinical side effects were recorded. Only 12 patients experienced grade I (WHO) hand-foot syndrome. Conclusions: Treatment with metronomic capecitabine and gefitinib was effective and minimally toxic in heavily pretreated breast cancer patients.

scholarly journals Novel antibody–drug conjugates for triple negative breast cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592091598 ◽  
Author(s):  
Aiko Nagayama ◽  
Neelima Vidula ◽  
Leif Ellisen ◽  
Aditya Bardia
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Clinical Development ◽  
Antibody Drug Conjugate ◽  
Drug Conjugates ◽  
Anti Cancer ◽  
Late Stages ◽  
Antibody Drug

Triple negative breast cancer (TNBC) is a heterogenous subtype of breast cancer often associated with an aggressive phenotype and poor prognosis. Antibody–drug conjugate (ADC), comprising of a monoclonal antibody linked to a cytotoxic payload by a linker, is gaining increasing traction as an anti-cancer therapeutic. Emerging ADC drugs such as sacituzumab govitecan (IMMU-132) and trastuzumab deruxtecan (DS-8201a) are in late stages of clinical development for patients with metastatic breast cancer, including TNBC. In this article, we review and discuss the development and clinical application of ADCs in patients with advanced TNBC.

scholarly journals Next-Generation Multimodality of Nanomedicine Therapy: Folic Acid Conjugated Copolymer and Folate Receptor Interactions Disrupt Receptor Functionality Resulting in Dual Therapeutic Anti-Cancer Potential in Triple-Negative Breast Cancer

2020 ◽  
Author(s):  
Alexandria DeCarlo ◽  
Cecile Malardier-Jugroot ◽  
Myron R Szewczuk
Keyword(s):  
Breast Cancer ◽  
Folic Acid ◽  
Triple Negative Breast Cancer ◽  
Chemical Engineering ◽  
Triple Negative ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Expression Levels ◽  
Anti Cancer ◽  
Insight Into

The development of a highly specific drug delivery system (DDS) for anti-cancer therapeutics is an area of intense research focus. Chemical engineering of a “smart” DDS to specifically target tumor cells has gained interest, designed for safer, more efficient, and effective use of chemotherapeutics for the treatment of cancer. However, the selective targeting and choosing the critical cancer surface biomarker are essential for targeted treatments to work. The folic acid receptor alpha (FRalpha) has gained popularity as a potential target in triple-negative breast cancer (TNBC). We have previously reported on a functionalized folic acid (FA)-conjugated amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA) that has the essential features for efficient “smart” DDS. This biocompatible DDS self-assembles in a pH-dependent manner, providing stimuli-responsive, active targeting, extended-release of hydrophobic chemotherapeutic agents, and can effectively penetrate the inner core of 3-dimensional cancer spheroid models. The empty FA-DABA-SMA decreased spheroid volume, revealing a previously unknown mechanism of action. Upon further investigation, a size- and shape-dependent interaction FA-DABA-SMA with FR reduced the expression of p53, the product of the highly mutated TP53 gene, and additional oncogenic c-Myc and STAT3 proteins. Here, we investigated how this copolymer influences FR behavior and disrupting the receptor’s functions. Results indicate that FA-DABA-SMA increases FR expression levels in breast MDA MB-231 cancer cells and disrupting FR signaling by the reduction in HES1 and NOTCH1 protein expression levels. Also, FA-DABA-SMA induces apoptosis and further causes a change in the morphology of the MDA MB-231 cells, as well as significantly reduces their ability to migrate in a Scratch wound assay. Collectively, these findings provide a novel insight into the functionalized FA-DABA-SMA copolymer. The 350 kDa and 20 kDa copolymers actively target FRα to initialize internationalization. However, only the large size and sheet-shaped 350 kDa copolymers disrupt FRα signaling. The significance of these novel findings reveals the intracellular activity of the copolymer that is critically dependent on the size and structural shape. This report offers novel therapeutic insight into a dual mechanism of FA-DABA-SMA copolymer for its therapeutic potential for the treatment of cancer.

scholarly journals Long-Lasting Response after Pembrolizumab in a Patient with Metastatic Triple-Negative Breast Cancer

Breast Care ◽  
2019 ◽  
Vol 15 (4) ◽  
pp. 428-432
Author(s):  
Paloma Peinado ◽  
Carmen Ramírez ◽  
José Angel García-Sáenz ◽  
Alejandro Pascual ◽  
Jesús Fuentes-Antrás ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Therapeutic Option ◽  
Breast Cancer Patients ◽  
Term Survival ◽  
Case Presentation ◽  
Short Overall Survival ◽  
Promising Treatment

Introduction: Breast cancer is the first cause of cancer death in women. The triple-negative subtype is associated with aggressive behavior and poor prognosis. Chemotherapy is the main therapeutic option available for these patients, but it is usually associated with short overall survival. Case Presentation: We report the case of a patient diagnosed with metastatic triple-negative breast cancer with an impressive long-lasting tumor response and long-term survival after pembrolizumab monotherapy. Conclusion: Immunotherapy is emerging as a promising treatment for some breast cancer patients. Nevertheless, monotherapy studies have shown a very limited activity. Nowadays, there is no good predictor biomarker. Further investigations are needed to identify the subgroup of patients who can benefit from checkpoint inhibitor treatment.

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