scholarly journals Adjuvant application of trastuzumab in HER2 positive breast cancer and impact on time to relapse

2020 ◽  
Vol 26 (1) ◽  
pp. 10-15 ◽  
Author(s):  
Nikolina Dukic ◽  
Zdenka Gojkovic ◽  
Jelena Vladicic-Masic ◽  
Srdjan Masic ◽  
Nenad Lalovic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Human Monoclonal Antibody ◽  
Control Group ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Significant Difference ◽  
Time To Relapse ◽  
Positive Breast Cancer

Background: Of all breast cancers 20-25% are HER2 positive. Overexpression of HER2 protein on the surface of the malignant cell leads to excessive cell proliferation through different signaling pathways. Trastuzumab is a human monoclonal antibody that binds to domain IV of HER2 receptor and blocks signaling pathway for proliferation. The result is an improved prognosis for HER 2 positive breast cancer patients, even when compared to patients with other types of breast cancers. Methods: The study presents 74 women patients with early HER2 positive breast cancer who were previously operated (either radicaly or using breast conserving surgery), and received adjuvant chemo- and radiotherapy. Fourty four patients received adjuvant trastuzumab for one year, and 30 patients did not (control group). Observed time to relapse of the disease was 60 months. Results: There was a significant difference in survival in favor of the group that received trastuzumab (p<0.001). Application of trastuzumab also delayed relapse of the disease by 51.7%. No significant difference was observed between estrogen receptor positive and estrogen receptor negative cancers., In the control group there was a significant difference in relapse free survival in favor of estrogen and progesteron receptor positive tumors (p<0.001). Conclusion: Survival of patients with a HER2 positive breast cancer whose prognosis was initially worse compared to HER2 negative patients, significantly improved after administration of trastuzumab.

Influence of Anthropometric Characteristics in Patients With Her2-Positive Breast Cancer on Initial Plasma Concentrations of Trastuzumab

2017 ◽  
Vol 51 (11) ◽  
pp. 976-980 ◽  
Author(s):  
Jonathan González García ◽  
Fernando Gutiérrez Nicolás ◽  
Gloria Julia Nazco Casariego ◽  
José Norberto Batista López ◽  
Isaac Ceballos Lenza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Standard Dose ◽  
Plasma Concentrations ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Initial Plasma ◽  
Anthropometric Characteristics ◽  
Secondary Objective ◽  
Positive Breast Cancer

Background: Plasma concentrations of trastuzumab <20 µg/mL in patients with gastric cancer are associated with reduced progression-free and overall survival. In breast cancer treatment, this relationship has not yet been studied, but a suboptimal pharmacodynamic exposure to trastuzumab could be a reason for therapeutic failure of treatment of HER2-positive breast cancer. Objective: The objective of the present study was to determine the proportion of nonmetastatic HER2-positive breast cancers that do not reach a minimum plasma concentration ( Cmin) of 20 µg/mL after first drug administration, established as therapeutically effective in clinical trials. The secondary objective was to identify the physiological and anthropometric characteristics that determine interindividual pharmacokinetic variability. Methods: Serum concentrations of trastuzumab were assessed by ELISA on day 1 of the second cycle before administration of the second dose ( Cmin). Results: Of 19 patients included, 9 (47.4%) had a mean Cmin of 19.0 µg/mL (±12.1) after the first administration. Body mass index (BMI) and weight was the main variable that determined the achievement of therapeutic levels after the first administration. Thus, the proportion of patients reaching the target concentration was 89% when BMI was ≤30 kg/m2 but only 11% when BMI was >30 kg/m2 ( P < 0.01). Conclusions: The standard dose of 600 mg subcutaneous trastuzumab did not ensure adequate pharmacodynamic exposure from the first administration in 52% of patients, with weight and BMI being related to the plasma levels obtained.

scholarly journals Epigenetic downregulation of HER2 during EMT leads to tumor resistance to HER2-targeted therapies in breast cancer

2020 ◽  
Author(s):  
Babak Nami ◽  
Avrin Ghanaeian ◽  
Zhixiang Wang
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Gene Silencing ◽  
Receptor Tyrosine Kinase ◽  
Breast Cancer Cells ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

ABSTRACTHER2 receptor tyrosine kinase (encoded by ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (known as HER2-positive breast cancers). Overexpression of HER2 causes overactivation of downstream receptor tyrosine kinase pathways including PI3K/Akt and MAPK pathways and is a poor prognosis factor in breast cancer. Tyrosine kinase inhibitor lapatinib and anti-HER2 monoclonal antibodies trastuzumab and pertuzumab are FDA-approved HER2-targeted drugs for treatment of HER2-positive breast cancers. However, development of de novo resistance to HER2 blockade occurs in majority of patients after treatment started. Resistance to HER2 targeting therapies partially due to the loss of HER2 expression on their tumor cells during the treatment. But little is known about the exact mechanism of loss of HER2 on originally HER2-positive tumor cells. Downregulation of extracellular HER2 by metalloproteinases during epithelial-mesenchymal transition (EMT) in trastuzumab-resistant/lapatinib-sensitive cells has been shown by limited studies, however, the mechanism of ERBB2 gene silencing during EMT and in the mesenchymal-like cells derived from trastuzumab-resistant/lapatinib-resistant HER2-positive breast tumors was entirely unknown. In this study, hypothesized that EMT abrogates HER2 expression by chromatin-based epigenetic silencing of ERBB2 gene as a mechanism of acquired resistance to HER2-targeted therapies. we found that HER2 expression is positively and negatively correlated with the expression of epithelial and mesenchymal phenotype marker genes respectively in breast cancer tumors. We also found that chromatin of ERBB2 gene in HER2-high epithelial-like breast cancer cells is active, while, the chromatin is inactive in HER2-low mesenchymal-like cells. HER2-low breast cancer cell line also revealed less promoter-enhancer interaction and small chromatin loops compared to the HER2-high cell lines. The lower HER2 expression, the higher EMT phenotype, and inactivated chromatin all were found correlated with a lower response to lapatinib. The higher EMT phenotype was found correlated with a lower response to lapatinib. We also found that induction of EMT of HER2-positive breast cancer BT474 cells results in downregulated HER2 expression and lower binding rate of trastuzumab to the cells. These results show that the downregulation of HER2 in mesenchymal-like cells in the culture of HER2-positive breast cancer cell lines was due to ERBB2 gene silencing by epigenetic reprogramming of the cells during EMT. These results indicate that ERBB2 gene silencing by epigenetic regulation during EMT is the main mechanism of resistance of HER2-positive breast cancer cells to trastuzumab and lapatinib.

scholarly journals 1H-NMR Plasma Lipoproteins Profile Analysis Reveals Lipid Metabolism Alterations in HER2-Positive Breast Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5845
Author(s):  
Giuseppe Corona ◽  
Emanuela Di Gregorio ◽  
Alessia Vignoli ◽  
Elena Muraro ◽  
Agostino Steffan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cancer Patients ◽  
1H Nmr ◽  
Plasma Lipoproteins ◽  
Control Group ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

The lipid tumour demand may shape the host metabolism adapting the circulating lipids composition to its growth and progression needs. This study aims to exploit the straightforward 1H-NMR lipoproteins analysis to investigate the alterations of the circulating lipoproteins’ fractions in HER2-positive breast cancer and their modulations induced by treatments. The baseline 1H-NMR plasma lipoproteins profiles were measured in 43 HER2-positive breast cancer patients and compared with those of 28 healthy women. In a subset of 32 patients, longitudinal measurements were also performed along neoadjuvant chemotherapy, after surgery, adjuvant treatment, and during the two-year follow-up. Differences between groups were assessed by multivariate PLS-DA and by univariate analyses. The diagnostic power of lipoproteins subfractions was assessed by ROC curve, while lipoproteins time changes along interventions were investigated by ANOVA analysis. The PLS-DA model distinguished HER2-positive breast cancer patients from the control group with a sensitivity of 96.4% and specificity of 90.7%, mainly due to the differential levels of VLDLs subfractions that were significantly higher in the patients' group. Neoadjuvant chemotherapy-induced a significant drop in the HDLs after the first three months of treatment and a specific decrease in the HDL-3 and HDL-4 subfractions were found significantly associated with the pathological complete response achievement. These results indicate that HER2-positive breast cancer is characterized by a significant host lipid mobilization that could be useful for diagnostic purposes. Moreover, the lipoproteins profiles alterations induced by the therapeutic interventions could predict the clinical outcome supporting the application of 1H-NMR lipoproteins profiles analysis for longitudinal monitoring of HER2-positive breast cancer in large clinical studies.

scholarly journals Nanotechnology approaches to addressing HER2-positive breast cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Bryan E. White ◽  
Molly K. White ◽  
Het Adhvaryu ◽  
Issam Makhoul ◽  
Zeid A. Nima ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
The United States ◽  
Breast Cancers ◽  
Specific Design ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Epidermal Growth ◽  
Growth Promoting ◽  
Positive Breast Cancer

Abstract Breast cancer is a major cause of cancer-associated deaths in the United States. It was estimated that 12% of women in the U.S. will develop invasive breast cancer in their lifetime. The human epidermal growth factor receptor (HER2/neu) is a growth-promoting protein that is overexpressed in 15–20% of breast cancers (HER2-positive breast cancer). HER2-positive breast cancer generally grows and spreads more quickly than other breast cancers, but it can be targeted therapeutically. Targeting drugs have been developed with a specific design to stop the growth and even the spread of cancer. These drugs include trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla, or TDM-1), fam-trastuzumab deruxtecan, lapatinib, neratinib and tucatinib. However, the need for better targeted therapy and efficacy still exists. Nanotechnology could have major advantages in terms of detection, targeting, drug delivery, and destruction of cancer cells and tumors. Although a great deal of progress has been accomplished major challenges still need to be addressed. In this review, we examine the major areas of research in the area of nanotechnology and HER2-positive breast cancer.

scholarly journals Comparative Efficacy and Tolerability of Neoadjuvant Immunotherapy Regimens for Patients with HER2-Positive Breast Cancer: A Network Meta-Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Di Wu ◽  
Tiejun Chen ◽  
Han Jiang ◽  
Chongyang Duan ◽  
Xinjian Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Meta Analysis ◽  
Random Effect ◽  
Poor Performance Status ◽  
Her2 Positive ◽  
Treatment Regimens ◽  
Her2 Positive Breast Cancer ◽  
Neoadjuvant Immunotherapy ◽  
Significant Difference ◽  
Positive Breast Cancer

This network meta-analysis addresses the need for evidence-based best-practice treatment regimens for HER2-positive breast cancer. We compared the relative efficacy and tolerability of currently available HER2-positive neoadjuvant immunotherapy regimens based on systematic searches of available randomized controlled trials (RCTs) data. Based on intention-to-treat principle, pathological complete response (pCR), overall serious adverse events (SAEs), and breast-conserving surgery (BCS) rate were analyzed using random-effect, Bayesian network meta-analysis, and standard pairwise meta-analysis. 16 RCTs (3868 patients) were included. Analyzed treatment regimens were as follows: chemotherapy+trastuzumab+pertuzumab (CTP), trastuzumab emtansine+pertuzumab (MP), chemotherapy+trastuzumab (CT), chemotherapy+pertuzumab (CP), trastuzumab+pertuzumab (TP), chemotherapy+trastuzumab+lapatinib (CTL), and chemotherapy+lapatinib (CL), and chemotherapy (C) alone. We found that, for the chance of achieving pCR, CTP was ranked first (SUCRA: 97%), followed by CTL, MP, and CT (SUCRA: 80%, 75%, and 55%, resp.). MP provided the safest regimen (SUCRA: 97%), then TP, C, and TPC (SUCRA: 82%, 76%, and 47%, resp.). CTL proved the most toxic therapy (SUCRA: 7%). No significant difference between neoadjuvant regimens was identified for BCS. Hormone receptor status did not impact ORs for pCR in any regimen. In conclusion, our findings support CTP as the optimum neoadjuvant regimen for HER2-positive breast cancer, with the best pCR and acceptable toxicity compared with CT. MP provides a therapeutic option for patients with poor performance status.

scholarly journals Multi-omics analyses identify HSD17B4 methylation-silencing as a predictive and response marker of HER2-positive breast cancer to HER2-directed therapy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Satoshi Yamashita ◽  
Naoko Hattori ◽  
Satoshi Fujii ◽  
Takeshi Yamaguchi ◽  
Masato Takahashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Good Survival ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Validation Set ◽  
Positive Breast Cancer

Abstract HER2-positive breast cancers that achieve pathological complete response (pCR) after HER2-directed therapy consistently have good survival. We previously identified HSD17B4 methylation as a marker for pCR by methylation screening. Here, we aimed to identify a new marker by conducting a multi-omics analysis of materials prepared by laser capture microdissection, and adding 71 new samples. In the screening set (n = 36), mutations, methylation, and expression were analyzed by targeted sequencing, Infinium 450 K, and expression microarray, respectively, and 15 genes were identified as differentially expressed and eight genomic regions as differentially methylated between cancer samples with and without pCR. In a validation set (n = 47), one gene showed differential expression, and one region had differential methylation. Further, in the re-validation set (n = 55), all new samples, only HSD17B4 methylation was significantly different. The HSD17B4 methylation was at the transcriptional start site of its major variant, and was associated with its silencing. HSD17B4 was highly expressed in the vast majority of human cancers, and its methylation was present only in breast cancers and one lymphoblastic leukemia cell line. A combination of estrogen receptor-negative status and HSD17B4 methylation showed a positive predictive value of 80.0%. During HER2-directed neoadjuvant therapy, HSD17B4 methylation was the most reliable marker to monitor response to the therapy. These results showed that HSD17B4 methylation is a candidate predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.

Sign in / Sign up

Export Citation Format

Share Document