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

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.

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

10.1101/2020.03.24.006379 ◽

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.

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Nanotechnology approaches to addressing HER2-positive breast cancer

Cancer Nanotechnology ◽

10.1186/s12645-020-00068-2 ◽

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.

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

Scientific Reports ◽

10.1038/s41598-020-72661-9 ◽

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.

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

Archive of oncology ◽

10.2298/aoo181112006d ◽

2020 ◽

Vol 26 (1) ◽

pp. 10-15 ◽

Cited By ~ 1

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.

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CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-TKI via suppressing PI3K/AKT

10.21203/rs.3.rs-30034/v1 ◽

2020 ◽

Author(s):

Hui Li ◽

Jinsong Wang ◽

Zongbi Yi ◽

Chunxiao Li ◽

Haijuan Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

High Throughput Sequencing ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Sequencing Data ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Abstract Background : While anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumor progression.Methods : To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using CRISPR/Cas9 knockout technique based on data mining across TCGA datasets and verified the candidate target in pre-clinical models and breast cancer high-throughput sequencing datasets.Results : We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitize or re-sensitize HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids (PDO) in vitro and cell-derived xenograft (CDX) or patient-derived xenograft (PDX) in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumor tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harboring a markedly shortened progression free survival (PFS) (median PFS: 4.3 months verse 6.9 months; HR 2.26 [95% CI 1.32-3.86]; P=0.0028).Conclusions : Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of HER2-positive breast cancer patients by sensitizing or re-sensitizing the tumors to anti-HER2 TKIs treatment.

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The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy

Chemotherapy Research and Practice ◽

10.1155/2012/743193 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 89

Author(s):

Zahi Mitri ◽

Tina Constantine ◽

Ruth O'Regan

Keyword(s):

Breast Cancer ◽

Cardiac Myocyte ◽

Early Stage ◽

Standard Of Care ◽

Breast Cancers ◽

Trastuzumab Resistance ◽

Her2 Receptor ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2) is overexpressed in around 20–30% of breast cancer tumors. It is associated with a more aggressive disease, higher recurrence rate, and increased mortality. Trastuzumab is a HER2 receptor blocker that has become the standard of care for the treatment of HER2 positive breast cancer. The effectiveness of Trastuzumab has been well validated in research as well as in clinical practice. The addition of Trastuzumab to standard of care chemotherapy in clinical trials has been shown to improve outcomes for early stage as well as metastatic HER2 positive breast cancer. The most clinically significant side effect of Trastuzumab is the risk of cardiac myocyte injury, leading to the development of congestive heart failure. The emergence of patterns of resistance to Trastuzumab has led to the discovery of new monoclonal antibodies and other targeted agents aimed at overcoming Trastuzumab resistance and improving survival in patients diagnosed with HER2 positive breast cancers.

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Neratinib for the treatment of early-stage, hormone receptor-positive, HER2-overexpressed breast cancer

Future Oncology ◽

10.2217/fon-2020-0046 ◽

2020 ◽

Vol 16 (17) ◽

pp. 1165-1177

Author(s):

Yolanda Jerez ◽

Blanca Herrero ◽

Marta Arregui ◽

Blanca Morón ◽

Miguel Martín ◽

...

Keyword(s):

Breast Cancer ◽

Kinase Inhibitor ◽

Early Stage ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Future Directions ◽

Her2 Positive Breast Cancer ◽

Hormone Receptor Positive ◽

Positive Breast Cancer

HER2-positive breast cancer accounts for 18–20% of all breast cancers. Despite significant advances and the currently available adjuvant treatments for management of the disease, approximately 25% of HER2-positive early-stage breast cancer patients show relapse and die. Neratinib is an irreversible tyrosine kinase inhibitor. Multiple studies have reported its significant antitumor activity in metastatic HER2-positive breast cancer. It is administered orally and has also been tested in the adjuvant setting. In this article, we present a comprehensive review of the pharmacokinetics and pharmacodynamics of neratinib as well as its clinical efficacy, with an emphasis on early HER2-positive breast cancer and suggestions for future directions for neratinib research.

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Proliferative Classification of Intracranially Injected HER2-positive Breast Cancer Cell Lines

Cancers ◽

10.3390/cancers12071811 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1811

Author(s):

Yuka Kuroiwa ◽

Jun Nakayama ◽

Chihiro Adachi ◽

Takafumi Inoue ◽

Shinya Watanabe ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Cell Lines ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer Cell ◽

The Brain ◽

Positive Breast Cancer

HER2 is overexpressed in 25–30% of breast cancers, and approximately 30% of HER2-positive breast cancers metastasize to the brain. Although the incidence of brain metastasis in HER2-positive breast cancer is high, previous studies have been mainly based on cell lines of the triple-negative subtype, and the molecular mechanisms of brain metastasis in HER2-positive breast cancer are unclear. In the present study, we performed intracranial injection using nine HER2-positive breast cancer cell lines to evaluate their proliferative activity in brain tissue. Our results show that UACC-893 and MDA-MB-453 cells rapidly proliferated in the brain parenchyma, while the other seven cell lines moderately or slowly proliferated. Among these nine cell lines, the proliferative activity in brain tissue was not correlated with either the HER2 level or the HER2 phosphorylation status. To extract signature genes associated with brain colonization, we conducted microarray analysis and found that these two cell lines shared 138 gene expression patterns. Moreover, some of these genes were correlated with poor prognosis in HER2-positive breast cancer patients. Our findings might be helpful for further studying brain metastasis in HER2-positive breast cancer.

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Expression of hormone receptors ERα, ERβ and PgR in HER2-positive breast cancers

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10525 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10525-10525

Author(s):

M. Litwiniuk ◽

V. Filas ◽

J. Moczko ◽

R. Kaleta ◽

J. Breborowicz

Keyword(s):

Breast Cancer ◽

Hormone Receptors ◽

Detection System ◽

Statistical Significance ◽

Her2 Status ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

10525 Background: HER-2/neu gene is amplified and overexpressed in 15–20% of invasive breast cancers. HER2-positive breast cancers have a worse prognosis than HER2-negative tumors and distinctive clinical features. They express hormone receptors for estrogen (ERα) and for progesterone (PgR) less frequently than HER2-negative tumors. The identification of the other human estrogen receptor, receptor beta (ERβ), raises a question of ERβ occurrence in HER2-positive breast cancer. Patients and methods: Formalin-fixed, paraffin embedded tissues from 90 patients with invasive HER2-positive breast cancer and from 99 patients with HER2-negative breast cancer were used in this study. The HER2 status was analyzed using HercepTest TM (IHC), and IHC 2+ results were confirmed with FISH test. Immunostaining for ERα, ERβ and PgR was performed using monoclonal antibodies against ERα, PgR (DakoCytomation) and against ERβ (CHEMICON). The EnVision detection system was applied. The data were analyzed using nonparametric Fisher-Freeman-Halton test; the statistical significance was considered when p < 0.5. Results: Only 33% of the HER2-positive breast cancers were ERα-positive compared with 63% in the HER2-negative group (p < 0.001). The expression of ERβ protein was observed in almost equal frequency in both groups (57% of HER2-positive breast cancers and 57.7% of HER2-negative tumors, p = 0.889). The expression of PgR was observed in 30% of HER2-positive breast cancers and in 68.7% of HER2-negative tumors (p < 0.001). Conclusion: The expression of ERβ (unlike that of ERα and PgR) was similar in HER2-positive and in HER2-negative breast cancers. Thus, ERβ may be a potential target in future endocrine therapy for women with HER2-positive breast cancers. No significant financial relationships to disclose.

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Does hormone receptor (HR) positivity affect the prognosis in breast cancers with human epidermal growth factor receptor 2 (HER2) overexpression?

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22091 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22091-e22091

Author(s):

Y. Lee ◽

J. Sohn ◽

B. Park ◽

H. Chung ◽

C. Suh ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Size ◽

Tnm Stage ◽

Adjuvant Tamoxifen ◽

Breast Cancers ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Nodal Stage ◽

N 93 ◽

Positive Breast Cancer

e22091 Background: Biologically, there is an unclear issue about the role of HR positivity in HER2 positive breast cancer. These HER2(+)/ HR(+) pts were grouped into luminal B type apart from HER2(+)/ HR(-) pts in molecular profiling. However, from the clinical point of view, these pts have been categorized and been treated as either the only HER2(+) disease regardless of HR status or vice versa. Thus, we investigated the impact of HR status on clinical outcomes in HER2-overexpressed breast cancers. Methods: We retrospectively reviewed medical charts of HER2-positive breast cancer pts who underwent curative surgical resection from 1996 to 2001 in the Severance hospital, Korea. Demographic comparisons were performed by Chi-square tests. Tumor size, nodal stage, TNM stage, HR status, and adjuvant tamoxifen use were included in the Cox proportional hazards model. Results: Among the total 174 HER2-positive pts, HR (n=93) was positive in 53.5% (n = 93) and HR-positive tumors were more likely to be premenopausal (73% v 52%; P=0.01) and well- differentiated (grade 1or 2; 77% v 62%; P=0.04). There were no significant differences according to HR status in terms of tumor size, nodal stage, TNM stage, operation methods, and chemotherapy regimen. In these HER2-positive pts, the 5-year disease free survival (DFS) was longer in HR(+) pts than in HR(-) pts (DFS; 82.9% v 61.5%; P= 0.01). In a subset analysis, the 5-year DFS of HER2(+)/ER(+) pts without adjuvant tamoxifen (n=26) was not different from that of HER2(+)/ ER(-) pts (DFS; 57.7% v 61.5%; P= 0.32). However, the 5-year DFS of HER2(+)/ ER(+) pts with adjuvant tamoxifen was significantly prolonged compared with that of HER2(+)/ ER(-) pts (DFS; 91.5% v 61.5%; P< 0.001). In a multivariate analysis of DFS, tumor size and adjuvant tamoxifen use significantly affected DFS with an adjusted hazard ratio of 2.56 (95% CI, 1.2–4.9; P= 0.01) and 6.58 (95% CI, 2.8–20.3; P< 0.001), respectively. Conclusions: In an analysis of HER2-overexpressed breast cancer, the presence of HR itself did not affect the prognosis. However, most of the survival benefit seems to be driven from adjuvant tamoxifen therapy not the HR status itself. No significant financial relationships to disclose.

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