Trastuzumab-reactive antibodies (TR-abs) in serum and trastuzumab (Tzb) benefit prediction in patients with HER2-overexpressing breast cancer.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 77-77 ◽  
Author(s):  
Paula Raffin Pohlmann ◽  
Todd W. Miller ◽  
David L Blum ◽  
Dipti Pareh ◽  
Heping Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Transgenic Mice ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Breast Cancer Cell Lines ◽  
Therapeutic Antibodies ◽  
Stage Iv Breast Cancer ◽  
Pharmacologically Active

77 Background: Trastuzumab (Tzb) is a humanized monoclonal antibody (MAb) approved for treatment of HER2-overexpressing breast cancer. Unfortunately not all patients benefit from it and lack of response cannot be predicted. We detected TR-abs in serum of mice and patients treated with Tzb. We hypothesized that TR-abs would associate with response to therapy. Methods: Direct/competition ELISA, dot blot, and mass spectrometry were used to detect and characterize TR-abs in sera from Tzb treated FVBMMTV/HER2transgenic mice, from hybridoma MAbs stemming from transgenic mice responding favorably to Tzb (992-18 mMAb), and in sera of 22 patients with metastatic breast cancer enrolled in a phase I clinical trial. WST-1 viability assay was used to assess biological activity of 992-18 on SKBR3 or BT474 human breast cancer cell lines. Results: From 12 mice bearing HER2-overexpressing tumors and treated with Tzb, 5 responded to therapy and 7 exhibited progressive disease (PD). All 5 responders had elevated TR-abs, whereas TR-abs were low/undetectable with PD (p=0.002; Mann-Whitney two-tailed). This was confirmed in a second cohort of 16 mice, in which TR-abs were undetectable prior to treatment, but gradually detected with Tzb therapy and tumor regression. TR-MAb 992-18 directly targeted also SKBR3 and BT474 in cell-based ELISAs and immunofluorescence assays. Treatment with 992-18 reduced BT474 and SKBR3 cell viability in comparison to isotype-matched control Ab (p<0.0001). In sera from patients with metastatic breast cancer, higher concentrations of TR-abs were significantly associated with lower risk of disease progression (p=0.023, Cox regression, univariate analysis). Conclusions: Low serum TR-abs are associated with poor response to Tzb in mice and with shorter progression free survival in women with HER2 overexpressing stage IV breast cancer. In addition, TR-abs (e.g. 992-18) produced in response to therapy may be pharmacologically active. Results support prospective evaluation of patients undergoing treatment with therapeutic antibodies to determine if this non-invasive immunoassay detecting anti-therapeutic antibodies would predict benefit to therapy.

scholarly journals PIK3CA and MAP3K1 alterations imply luminal A status and are associated with clinical benefit from pan-PI3K inhibitor buparlisib and letrozole in ER+ metastatic breast cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Mellissa J. Nixon ◽  
Luigi Formisano ◽  
Ingrid A. Mayer ◽  
M. Valeria Estrada ◽  
Paula I. González-Ericsson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Benefit ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Pi3k Inhibitor ◽  
Breast Cancer Cell Lines ◽  
Luminal A ◽  
Pik3ca Mutations ◽  
Pi3k Inhibitors

Abstract Clinical trials have demonstrated the efficacy of combining phosphoinositide 3-kinase (PI3K) inhibitors with endocrine therapies in hormone therapy-refractory breast cancer. However, biomarkers of PI3K pathway dependence in ER+ breast cancer have not been fully established. Hotspot mutations in the alpha isoform of PI3K (PIK3CA) are frequent in ER+ disease and may identify tumors that respond to PI3K inhibitors. It is unclear whether PIK3CA mutations are the only biomarker to suggest pathway dependence and response to therapy. We performed correlative molecular characterization of primary and metastatic tissue from patients enrolled in a phase Ib study combining buparlisib (NVP-BKM-120), a pan-PI3K inhibitor, with letrozole in ER+, human epidermal growth factor-2 (HER2)-negative, metastatic breast cancer. Activating mutations in PIK3CA and inactivating MAP3K1 mutations marked tumors from patients with clinical benefit (≥6 months of stable disease). Patients harboring mutations in both genes exhibited the greatest likelihood of clinical benefit. In ER+ breast cancer cell lines, siRNA-mediated knockdown of MAP3K1 did not affect the response to buparlisib. In a subset of patients treated with buparlisib or the PI3Kα inhibitor alpelisib each with letrozole where PAM50 analysis was performed, nearly all tumors from patients with clinical benefit had a luminal A subtype. Mutations in MAP3K1 in ER+ breast cancer may be associated with clinical benefit from combined inhibition of PI3K and ER, but we could not ascribe direct biological function therein, suggesting they may be a surrogate for luminal A status. We posit that luminal A tumors may be a target population for this therapeutic combination.

Complications associated with erythropoietin stimulating agents (ESAs) in patients with metastatic breast cancer: A surveillance, epidemiology, and end results (SEER)–Medicare study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1034-1034
Author(s):  
M. Chavez-Macgregor ◽  
S. Fang ◽  
T. P. Srokowski ◽  
G. N. Hortobagyi ◽  
S. H. Giordano
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Median Number ◽  
Adverse Outcomes ◽  
Dose Effect ◽  
Curative Intent ◽  
Stage Iv Breast Cancer

1034 Background: Results of recent clinical trials suggest that the use of ESAs is associated with adverse outcomes. ESAs increase the risk for thrombotic events and have the potential of decreasing survival. Guidelines recommend the use of ESAs in patients with chemotherapy-induced anemia being treated with non curative intent. In this population-based study, we sought to evaluate the thromboembolic effects associated with the use of ESAs in patients receiving chemotherapy for metastatic breast cancer. Methods: Retrospective cohort study using the SEER-Medicare linked database. Patients with stage IV breast cancer diagnosed from 1995–2002, who were 66 and older, were treated with chemotherapy, and had full coverage of Medicare A and B were identified. Patients with end stage renal disease were excluded. ICD-9 and HCPCS codes were used to identify the use of ESAs, chemotherapy, comorbidities, and complications of therapy. Analyses were conduced using descriptive statistics, logistic regression, and Cox proportional hazard models. Results: 1411 women were included, 519 (36.8%) received ESAs and 892 (63.2%) did not; median age was 73 and 74 years old respectively. Median time from diagnosis to first ESA dose was 6 months, median number of ESAs doses was 8.5. In univariate analysis, patients receiving ESAs had higher rates of MI/CAD (38% vs 32.9% p = 0.051), thrombosis (32.4% vs 23.2% p = 0.0002), phlebitis (21.4% vs 12.6% p < 0.0001), and transfusion (37.76% vs 19.4% p < 0.0001), with no difference in the rate of stroke or pulmonary embolism. Multivariate analysis showed HR for MI/CAD 1.29 (1.01–1.66); thrombosis 1.5 (1.116–1.93), phlebitis 1.79 (1.32–2.43), and transfusion 2.65 (2.05–3.43). Significant dose effect was evident for the thrombosis and phlebitis outcomes for patients receiving more than 5 ESAs doses. Conclusions: The use of ESAs in patients with metastatic breast cancer increases the risk of thrombosis and phlebitis, with evidence of a dose-dependent effect. Patients receiving ESAs were more likely to have blood transfusions. These data support current practice of using ESAs for minimum necessary time to reduce risk of complications. No significant financial relationships to disclose.

scholarly journals Metastatic Breast Cancer with Extensive Osseous Metastasis Presenting with Symptomatic Immune Thrombocytopenic Purpura and Anemia: A Case Report and Review of the Literature

2015 ◽  
Vol 8 (2) ◽  
pp. 256-263 ◽  
Author(s):  
Jiaxin Niu ◽  
Teresa Goldin ◽  
Maurie Markman ◽  
Madappa N. Kundranda
Keyword(s):  
Breast Cancer ◽  
Platelet Count ◽  
Metastatic Breast Cancer ◽  
Immune Thrombocytopenic Purpura ◽  
English Literature ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Severe Thrombocytopenia ◽  
Thrombocytopenic Purpura ◽  
Immune Mediated

Background: Immune thrombocytopenic purpura (ITP) is a rare acquired bleeding disorder with an estimated incidence of 1 in 10,000 people in the general population. The association of ITP with breast cancer is an even rarer entity with very limited reports in the English literature. Case Presentation: We report a case of a 51-year-old female with no significant past medical history who presented with sudden onset of malaise, syncope, gingival bleed and epistaxis. She was found to have severe thrombocytopenia (platelet count 6,000/μl) and anemia (hemoglobin 7.2 g/dl). Her workup led to the diagnosis of metastatic ductal breast cancer with extensive bone metastasis. Bone marrow biopsy demonstrated myelophthisis which was initially thought to be consistent with her presentation of thrombocytopenia and anemia. Therefore, the patient was started on hormonal therapy for the treatment of her metastatic breast cancer. After 3 months of therapy, she did not improve and developed severe mucosal bleeding. Her clinical presentation was suspicious for ITP and immune-mediated anemia, and hence she was started on steroids and intravenous immunoglobulin. The patient had a dramatic response to therapy with normalization of her platelet count and hemoglobin within 2 weeks. Conclusion: To our knowledge, this is the first reported case of metastatic breast cancer presenting with symptomatic ITP and anemia, and both symptoms are postulated to be immune-mediated.

Is It The Time That We Can Depend on Bioscore as a New Staging System in Non-Metastatic Breast Cancer to Predict the Disease-Free Survival?

2021 ◽  
Author(s):  
Rehab Farouk Mohamed ◽  
Donia Hussein Abd El Hameed ◽  
Mohamed Alaa Eldeen Hassan
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Prognostic Value ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Free Survival ◽  
Disease Free

Abstract Purpose: Novel molecular characterization of breast cancer with cellular markers has allowed a new classification that offers prognostic value. This study investigates the prognostic value of the Bioscore among non-metastatic breast cancer patients with respect to disease free survival (DFS).Methods: This study included 317 patients with non-metastatic surgically treated breast cancer; they were identified in the period from January 2015 to December 2018 at Clinical Oncology Department of Assiut University Hospital. Many variables were used; pathologic stage (PS), T stage (T), nodal stage (N), grade (G), estrogen receptor (ER), progesterone receptors (PR), and human epidermal growth factor receptor (HER2) status. Univariate & two multivariate analyses were performed to identify which of these variables are associated with disease-free survival (DFS). Results: The only significant factors in the Univariate analysis were PS3, T2, T3, T4, N3, G2, G3, ER -ve, PR -ve, and HER2 –ve. The factors which were significant in the first multivariate analysis; PS3, G3, ER –ve, and in the second one were; T2, T4, N3, G3, and ER –ve. Two sets of models were built to determine the utility of combining variables. Models incorporating G and E status had the highest C-index (0.72) for T+N + G + ER in comparison with (0.69) for (PS+ G + ER) and the lowest AIC (953.01) for T + N + G + E and (966.9) for PS + G + E. Conclusions: This study confirms the prognostic significance of bioscore in non-metastatic breast cancer in concerning DFS.

scholarly journals Neutrophil-lymphocyte ratio in metastatic breast cancer is not an independent predictor of survival, but depends on other variables

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Alejandra Ivars Rubio ◽  
Juan Carlos Yufera ◽  
Pilar de la Morena ◽  
Ana Fernández Sánchez ◽  
Esther Navarro Manzano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Metastatic Breast Cancer ◽  
Performance Status ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Prognostic Impact ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio

AbstractThe prognostic impact of neutrophil-lymphocyte ratio (NLR) in metastatic breast cancer (MBC) has been previously evaluated in early and metastatic mixed breast cancer cohorts or without considering other relevant prognostic factors. Our aim was to determine whether NLR prognostic and predictive value in MBC was dependent on other clinical variables. We studied a consecutive retrospective cohort of patients with MBC from a single centre, with any type of first line systemic treatment. The association of NLR at diagnosis of metastasis with progression free survival (PFS) and overall survival (OS) was evaluated using Cox univariate and multivariate proportional hazard models. In the full cohort, that included 263 MBC patients, a higher than the median (>2.32) NLR was significantly associated with OS in the univariate analysis (HR 1.36, 95% CI 1.00–1.83), but the association was non-significant (HR 1.12, 95% CI 0.80–1.56) when other clinical covariates (performance status, stage at diagnosis, CNS involvement, visceral disease and visceral crisis) were included in the multivariate analysis. No significant association was observed for PFS. In conclusion, MBC patients with higher baseline NLR had worse overall survival, but the prognostic impact of NLR is likely derived from its association with other relevant clinical prognostic factors.

scholarly journals Impact of systemic therapy on circulating leukocyte populations in patients with metastatic breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anna-Maria Larsson ◽  
Anna Roxå ◽  
Karin Leandersson ◽  
Caroline Bergenfelz
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Natural Killer ◽  
Endocrine Therapy ◽  
Immune Cells ◽  
Systemic Therapy ◽  
Immune Cell ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Cell Populations

Abstract Tumors affect the immune system, locally and systemically. The frequencies of specific circulating immune cell populations correlate with disease progression as well as prognosis of the patients. Although largely neglected, conventional antitumoral therapies often possess immunomodulatory properties and affect the levels of specific immune cell populations. Most information, however, derive from animal or in vitro studies. As this could impact prognosis as well as response to therapy, further studies of the effects of treatment on circulating immune cells in patients are warranted. In this pilot study, we evaluated a wide panel of circulating immune cells over time (up to six months) in ten patients with metastatic breast cancer receiving standard antitumoral regimens. Overall, endocrine therapy tends to enrich for natural killer (NK) and natural killer T (NKT) cells in the circulation, whereas both chemotherapy and endocrine therapy reduce the levels of circulating monocytic myeloid-derived suppressor cells (Mo-MDSCs). This indicates that the systemic immunosuppressive profile observed in patients tends to revert over the course of systemic therapy and holds promise for future combination treatment with standard antitumoral agents and immunotherapy.

scholarly journals Local Resection of Primary Tumor in Upfront Stage IV Breast Cancer

Breast Care ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. 411-417 ◽  
Author(s):  
Thomas Kolben ◽  
Theresa M. Kolben ◽  
Isabelle Himsl ◽  
Tom Degenhardt ◽  
Jutta Engel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Univariate Analysis ◽  
Metastatic Breast ◽  
Local Therapy ◽  
Stage Iv ◽  
Organ System ◽  
Asymptomatic Patients ◽  
Local Surgery ◽  
Stage Iv Breast Cancer

Background: This study aimed to identify the association of local surgery of the primary tumor in metastatic breast cancer (MBC) patients with overall survival (OS) and prognostic factors. Patients and Methods: Patients with primary MBC (1990-2006) were included in our retrospective analysis (n = 236). 83.1% had surgery for the primary tumor. OS was evaluated using Kaplan-Meier estimates. Predictive factors for OS were determined. Results: Median follow-up was 123 months for all patients still alive at the time of analysis. In univariate analysis, patients with surgery of the primary tumor had significantly prolonged OS (28.9 vs. 23.9 months). Within the surgery group, patients with MBC limited to 1 organ system had a better outcome (39.3 vs. 24.9 months), as did asymptomatic patients. Independent risk factors for shorter OS were hormone receptor negativity, symptoms, and involvement of ≥ 1 organ system. Conclusion: Patient selection for local therapy was confounded by a more favorable profile and a lesser tumor burden before surgery, which might implicate a bias. Nevertheless, our univariate results indicate that local surgery of the primary tumor in MBC patients could be considered as part of the therapeutic regimen in selected patients. However, larger patient numbers are needed to prove these findings in the multivariate model.

Suppressions of metastatic breast cancer invasion and metastasis to brain/cross talk HER2/ERK1/2/MMP-9 signaling pathway

2018 ◽  
Vol 6 (4) ◽  
pp. 349-361
Author(s):  
Yu-Chun Lin ◽  
Dong-Qing Chin
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Signaling Pathway ◽  
Metastatic Breast ◽  
Cancer Invasion ◽  
Breast Cancer Cell Lines ◽  
Breast Cancers ◽  
Invasion And Metastasis ◽  
Matrigel Invasion ◽  
Breast Cancer Invasion

Understanding the molecular pathways that contribute to the development of metastatic breast cancer invasion and metastasis to brain is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER2/ERK1/2/MMP-9 signaling pathway in breast cancer. We performed Global exon array to study the expression of ERK1/2/MMP-9 signaling pathway in metastatic breast cancer to brain, compared its expression in primary breast cancer and breast cancers metastatic to other organs, and validated the findings by RT-PCR. Immunohistochemistry was performed to study the expression and localization of ERK1/2/MMP-9 proteins in primary and metastatic breast cancer tissues and breast cancer cell lines. We performed matrigel invasion, transendothelial migration and membrane potential assays in established lines of normal breast cells.

scholarly journals Gene Expression Signatures in Circulating Tumor Cells Correlate with Response to Therapy in Metastatic Breast Cancer

2017 ◽  
Vol 63 (10) ◽  
pp. 1585-1593 ◽  
Author(s):  
Maren Bredemeier ◽  
Philippos Edimiris ◽  
Pawel Mach ◽  
Mikael Kubista ◽  
Robert Sjöback ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Metastatic Breast Cancer ◽  
Disease Progression ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Clinical Staging ◽  
Significant Differential Expression

Abstract BACKGROUND Circulating tumor cells (CTCs) are thought to be an ideal surrogate marker to monitor disease progression in metastatic breast cancer (MBC). We investigated the prediction of treatment response in CTCs of MBC patients on the basis of the expression of 46 genes. METHODS From 45 MBC patients and 20 healthy donors (HD), 2 × 5 mL of blood was collected at the time of disease progression (TP0) and at 2 consecutive clinical staging time points (TP1 and TP2) to proceed with the AdnaTest EMT-2/StemCellSelectTM (QIAGEN). Patients were grouped into (a) responder (R) and non-responder (NR) at TP1 and (b) overall responder (OR) and overall non-responder (ONR) at TP2. A 46-gene PCR assay was used for preamplification and high-throughput gene expression profiling. Data were analyzed by use of GenEx (MultiD) and SAS. RESULTS The CTC positivity was defined by the four-gene signature (EPCAM, KRT19, MUC1, ERBB2 positivity). Fourteen genes were identified as significantly differentially expressed between CTC+ and CTC− patients (KRT19, FLT1, EGFR, EPCAM, GZMM, PGR, CD24, KIT, PLAU, ALDH1A1, CTSD, MKI67, TWIST1, and ERBB2). KRT19 was highly expressed in CTC+ patients and ADAM17 in the NR at TP1. A significant differential expression of 4 genes (KRT19, EPCAM, CDH1, and SCGB2A2) was observed between OR and ONR when stratifying the samples into CTC+ or CTC−. CONCLUSIONS ADAM17 could be a key marker in distinguishing R from NR, and KRT19 was powerful in identifying CTCs.

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