scholarly journals Clinicopathologic significance of nuclear HER4 and phospho-YAP(S127) in human breast cancers and matching brain metastases

2020 ◽  
Vol 12 ◽  
pp. 175883592094625
Author(s):  
Priyakshi Kalita-de Croft ◽  
Malcolm Lim ◽  
Haarika Chittoory ◽  
Xavier M. de Luca ◽  
Jamie R. Kutasovic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Hippo Pathway ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Hazard Ratio ◽  
Breast Cancers ◽  
Cell Nuclei ◽  
Er Status

Background: Human epidermal growth factor receptor-4 (HER4) and yes-associated protein-1 (YAP) are candidate therapeutic targets in oncology. YAP’s transcriptional coactivation function is modulated by the HER4 intracellular domain (HER4-ICD) in vitro, but the clinical relevance of this has not been established. This study investigated the potential for targeting the HER4-YAP pathway in brain metastatic breast cancer. Methods: We performed immuno-phenotypic profiling of pathway markers in a consecutive breast cancer series with 25 years of clinical follow up ( n = 371), and patient-matched breast and metastatic brain tumours ( n = 91; 30 pairs). Results: Membrane localisation of phospho-HER4 [pHER4(Y1162)] was infrequent in primary breast cancer, but very frequent in brain metastases (5.9% versus 75% positive), where it was usually co-expressed with pHER3(Y1289) ( p < 0.05). The presence of YAP in tumour cell nuclei was associated directly with nuclear pERK5(T218/Y210) ( p = 0.003). However, relationships with disease-specific survival depended on oestrogen receptor (ER) status. Nuclear pYAP(S127) was associated with smaller, good prognostic ER+ breast tumours (log-rank hazard-ratio 0.53; p = 9.6E−03), but larger, poor prognostic triple-negative cancers (log-rank hazard-ratio 2.78; p = 1.7E−02), particularly when co-expressed with nuclear HER4-ICD ( p = 0.02). This phenotype was associated with stemness and mitotic instability markers (vimentin, SOX9, ID1, SPAG5, TTK, geminin; p < 0.05). YAP expression in brain metastases was higher than matched primary tumours; specifically, nuclear pYAP(S127) in ER-negative cases ( p < 0.05). Nuclear YAP was detected in ~70% of ER-negative, HER4-activated brain metastases. Discussion: Our findings suggest that the canonical-mechanism where Hippo pathway-mediated phosphorylation of YAP ostensibly excludes it from the nucleus is dysfunctional in breast cancer. The data are consistent with pYAP(S127) having independent transcriptional functions, which may include transducing neuregulin signals in brain metastases. Consistent with mechanistic studies implicating it as an ER co-factor, nuclear pYAP(S127) associations with breast cancer clinical outcomes were dependent on ER status. Conclusion: Preclinical studies investigating HER4 and nuclear YAP combination therapy strategies are warranted.

scholarly journals CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

2018 ◽  
Vol 10 ◽  
pp. 175883591881834 ◽  
Author(s):  
Adriana Matutino ◽  
Carla Amaro ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Breast Cancers ◽  
Cyclin Dependent Kinase ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

scholarly journals HER2 antibody-drug conjugate controls growth of breast cancer brain metastases in hematogenous xenograft models, with heterogeneous blood–tumor barrier penetration unlinked to a passive marker

2020 ◽  
Vol 22 (11) ◽  
pp. 1625-1636 ◽  
Author(s):  
Brunilde Gril ◽  
Debbie Wei ◽  
Alexandra S Zimmer ◽  
Christina Robinson ◽  
Imran Khan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Statistical Significance ◽  
Growth Factor Receptor ◽  
Antibody Drug Conjugate ◽  
Brain Penetration ◽  
Her2 Breast Cancer ◽  
Antibody Drug

Abstract Background Brain metastases of HER2+ breast cancer persist as a clinical challenge. Many therapeutics directed at human epidermal growth factor receptor 2 (HER2) are antibodies or antibody-drug conjugates (ADCs), and their permeability through the blood–tumor barrier (BTB) is poorly understood. We investigated the efficacy of a biparatopic anti-HER2 antibody-tubulysin conjugate (bHER2-ATC) in preclinical models of brain metastases. Methods The compound was evaluated in 2 hematogenous HER2+ brain metastasis mouse models, SUM190-BR and JIMT-1-BR. Endpoints included metastasis count, compound brain penetration, cancer cell proliferation, and apoptosis. Results Biparatopic HER2-ATC 3 mg/kg prevented metastasis outgrowth in the JIMT-1-BR model. At 1 mg/kg bHER2-ATC, a 70% and 92% reduction in large and micrometastases was observed. For the SUM190-BR model, an 85% and 53% reduction, respectively, in large and micrometastases was observed at 3 mg/kg, without statistical significance. Proliferation was reduced in both models at the highest dose. At the endpoint, bHER2-ATC uptake covered a median of 4–6% and 7–17% of metastasis area in the JIMT-1-BR and SUM190-BR models, respectively. Maximal compound uptake in the models was 19% and 86% in JIMT-1-BR and SUM190-BR, respectively. Multiple lesions in both models demonstrated ADC uptake in the absence or low diffusion of Texas Red Dextran, a marker of paracellular permeability. Using in vitro BTB assays, the ADC was endocytosed into brain endothelial cells, identifying a potentially new mechanism of antibody permeability. Conclusions Biparatopic HER2-ATC significantly prevented JIMT-1-BR brain metastasis outgrowth and showed activity in the SUM190-BR model. The bHER2-ATC penetration into metastases that are impermeable to fluorescent dye suggested an endocytic mechanism of brain penetration.

scholarly journals The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1894 ◽  
Author(s):  
Irene De Santo ◽  
Amelia McCartney ◽  
Ilenia Migliaccio ◽  
Angelo Di Leo ◽  
Luca Malorni
Keyword(s):  
Breast Cancer ◽  
Endocrine Resistance ◽  
Metastatic Breast ◽  
Predictive Biomarker ◽  
Clinical Findings ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Er Positive ◽  
Esr1 Mutations

Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field.

scholarly journals Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Gabriel L. Fiszman ◽  
María A. Jasnis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Alternative Pathways ◽  
Downstream Signaling ◽  
Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.

1996 ◽  
Vol 14 (3) ◽  
pp. 737-744 ◽  
Author(s):  
J Baselga ◽  
D Tripathy ◽  
J Mendelsohn ◽  
S Baughman ◽  
C C Benz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Metastatic Breast Cancer ◽  
Growth Factor ◽  
Human Cancer ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Maintenance Phase ◽  
Breast Cancers ◽  
Prior Therapy

PURPOSE Breast cancer frequently overexpresses the product of the HER2 proto-oncogene, a 185-kd growth factor receptor (p185HER2). The recombinant humanized monoclonal antibody (rhuMAb) HER2 has high affinity for p185HER2 and inhibits the growth of breast cancer cells that overexpress HER2. We evaluated the efficacy and toxicity of weekly intravenous administration of rhuMAb HER2 in patients with HER2-overexpressing metastatic breast cancer. PATIENTS AND METHODS We treated 46 patients with metastatic breast carcinomas that overexpressed HER2. Patients received a loading dose of 250 mg of intravenous rhuMAb HER2, then 10 weekly doses of 100 mg each. Patients with no disease progression at the completion of this treatment period were offered a maintenance phase of 100 mg/wk. RESULTS Study patients had extensive metastatic disease, and most had received extensive prior anticancer therapy. Adequate pharmacokinetic levels of rhuMAb HER2 were obtained in 90% of the patients. Toxicity was minimal and no antibodies against rhuMAb HER2 were detected in any patients. Objective responses were seen in five of 43 assessable patients, and included one complete remission and four partial remissions (overall response rate, 11.6%; 95% confidence interval, 4.36 to 25.9). Responses were observed in liver, mediastinum, lymph nodes, and chest wall lesions. Minor responses, seen in two patients, and stable disease, which occurred in 14 patients, lasted for a median of 5.1 months. CONCLUSION rhuMAb HER2 is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers that had received extensive prior therapy. This is evidence that targeting growth factor receptors can cause regression of human cancer and justifies further evaluation of this agent.

scholarly journals Current and Future Management of HER2-Positive Metastatic Breast Cancer

2021 ◽  
pp. OP.21.00172
Author(s):  
Olga Martínez-Sáez ◽  
Aleix Prat
Keyword(s):  
Breast Cancer ◽  
Early Stage ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Standard Of Care ◽  
Trastuzumab Emtansine ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Line Setting ◽  
Future Management

Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 20% of breast cancers, conferring an aggressive tumor behavior but also an opportunity for targeted therapies. In the advanced setting, the prognosis of patients suffering from this disease has greatly improved after the introduction of new anti-HER2 drugs beyond trastuzumab. For most patients, a taxane combined with trastuzumab and pertuzumab in the first-line setting, followed by trastuzumab-emtansine in second line, should be considered the standard of care today. However, chemo-free anti-HER2 strategies in hormone receptor-positive, HER2-positive breast cancer could also be considered in selected patients. In the third-line setting and beyond, several emerging anti-HER2 therapies are becoming available, including tucatinib, fam-trastuzumab deruxtecan-nxki (DS-8201a), neratinib, and margetuximab-cmkb. In addition, new compounds and combinations are showing promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, active drugs such as pertuzumab and trastuzumab-emtansine are moving to early-stage, many biomarkers, including quantification of HER2 itself, are being explored to improve patient selection, and patient populations with specific needs are emerging, such as those with brain metastasis. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer.

scholarly journals Evaluation of Sirt1 And Foxo’s In Primary Tumor And Distant Organ Metastasis Invaded By Benign And Highly Metastatic Breast Carcinoma Cells Under In Vitro And In Vivo Conditions.

2021 ◽  
Author(s):  
Sayra Dilmac ◽  
Nilay Kuscu ◽  
Ayse Caner ◽  
Sendegul Yildirim ◽  
Burcak Yoldas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Signal Pathways ◽  
Breast Cancers ◽  
Primary Tumors ◽  
Metastatic Breast Carcinoma ◽  
Liver Tissues

Abstract Breast cancer is the second most common cancer in women. In malignant breast cancers, tumor cells have the potential to metastasize to distant organs through the lymphatic system and blood circulation. The aim of this study is to evaluate the expression of SIRT1 and FoxO proteins in metastatic and nonmetastatic breast cancer cells and distant organs metastasis. In our study, SIRT1, p53, p21, and FoxO proteins have been evaluated in metastatic 4TLM and non-metastatic 67NR cell lines by immunocytochemistry in vitro and also in mice breast cancer model in vivo. Cells were orthotopically injected to mammary fat pads of 8-10 weeks old Balb/c female mice. Primary tumor, lung and liver tissues were removed and expressions of these proteins were evaluated by immunohistochemistry, western blot and RT-PCR. In addition, signal pathways that are related to SIRT and FoxO proteins were examined by using IPA core analysis. TCGA database was browsed for investigation of different genes.In primary tumors, SIRT1, p21, p53, E2F1 and FoxO expressions were higher in 67NR compared to 4TLM. In metastatic lung and liver tissues, the expression levels of SIRT1, FoxO1, FoxO3a and FoxO4 proteins were increased in 4TLM compared to 67NR. IPA and TCGA analysis have also revealed that SIRT1 and FoxO proteins are lower in primary tumors, but increased in metastatic stages. In conclusion, in primary tumors SIRT1 and FoxO expressions were decreased in 4TLM compared to 67NR. Moreover, SIRT1 and FoxO, especially expressed in metastatic cells. High level of FoxO expressions in metastatic stages in TNBC patients also supports its association with metastasis. Our findings suggest that SIRT1 and FoxO’s have crucial role in tumor progression metastatic process in breast cancer.

scholarly journals Subtype switching in breast cancer brain metastases: a multicenter analysis

2020 ◽  
Vol 22 (8) ◽  
pp. 1173-1181 ◽  
Author(s):  
Alexander F C Hulsbergen ◽  
An Claes ◽  
Vasileios K Kavouridis ◽  
Ali Ansaripour ◽  
Claudine Nogarede ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Growth Factor Receptor ◽  
Hazard Ratio ◽  
Receptor Expression ◽  
Her2 Status ◽  
Primary Tumors ◽  
Pathology Reports ◽  
Breast Cancer Brain Metastases ◽  
Extracranial Metastases

Abstract Background Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM. Methods BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed. Results In BM from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen, 25.2% for progesterone, and 10.4% for HER2. Because estrogen and progesterone were considered together for hormonal status, 50 (22.8%) patients switched subtype as a result; 20 of these switches were HER2 based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+ patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by estrogen loss (hazard ratio = 1.80, P = 0.03). Patients gaining HER2 status (n = 8) showed a nonsignificant tendency toward improved survival (hazard ratio = 0.64, P = 0.17). Conclusions In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice.

scholarly journals Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Konstantinos V. Floros ◽  
Sheeba Jacob ◽  
Richard Kurupi ◽  
Carter K. Fairchild ◽  
Bin Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Myeloid Cell ◽  
Cdk Inhibitors ◽  
The Novel ◽  
Breast Cancers ◽  
Cancer Models ◽  
Epidermal Growth

AbstractHuman epidermal growth factor receptor 2 gene (HER2) is focally amplified in approximately 20% of breast cancers. HER2 inhibitors alone are not effective, and sensitizing agents will be necessary to move away from a reliance on heavily toxic chemotherapeutics. We recently demonstrated that the efficacy of HER2 inhibitors is mitigated by uniformly low levels of the myeloid cell leukemia 1 (MCL-1) endogenous inhibitor, NOXA. Emerging clinical data have demonstrated that clinically advanced cyclin-dependent kinase (CDK) inhibitors are effective MCL-1 inhibitors in patients, and, importantly, well tolerated. We, therefore, tested whether the CDK inhibitor, dinaciclib, could block MCL-1 in preclinical HER2-amplified breast cancer models and therefore sensitize these cancers to dual HER2/EGFR inhibitors neratinib and lapatinib, as well as to the novel selective HER2 inhibitor tucatinib. Indeed, we found dinaciclib suppresses MCL-1 RNA and is highly effective at sensitizing HER2 inhibitors both in vitro and in vivo. This combination was tolerable in vivo. Mechanistically, liberating the effector BCL-2 protein, BAK, from MCL-1 results in robust apoptosis. Thus, clinically advanced CDK inhibitors may effectively combine with HER2 inhibitors and present a chemotherapy-free therapeutic strategy in HER2-amplified breast cancer, which can be tested immediately in the clinic.

scholarly journals Difference in Risk Factors for Breast Cancer by ER Status in an Indigenous African Population

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
M. Galukande ◽  
H. Wabinga ◽  
F. Mirembe ◽  
C. Karamagi ◽  
A. Asea
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Contraceptive Use ◽  
Growth Factor Receptor ◽  
Gene Profiling ◽  
Sub Saharan Africa ◽  
Breast Cancers ◽  
Ethical Approval ◽  
Sub Saharan ◽  
Er Status

Introduction. Breast cancer is the commonest cancer among women globally. In Uganda, it is on the rise, projected at a 4.5% annual ASR increase (age standardized incidence rate). The reasons for this steep increase are not fully established. In the recent past, gene profiling in tumor tissues suggests that breast cancers are divided into subtypes dependent on the presence or absence of oestrogen receptor, progesterone, and human epidermal growth factor receptor 2 (HER 2). These subtypes do have distinctive clinical outcomes and perhaps risk factors from past studies. There is paucity of data on hormonal receptor status and the traditionally known risk factors in sub-Saharan Africa. The purpose of this study therefore was to establish the differences between ER status and the traditionally known risk factors for breast cancer in Uganda. Methods. An observational analytical hospital, based study, carried out at Makerere University, College of Health Sciences. Formalin fixed and paraffin imbedded sections were prepared for haemotoxylin and eosin (H&E) stains and immunohistochemistry (IHC). Ethical approval was obtained. Results. A total of 113 women were recruited. Mean age was 45 years (SD14). There were no significant differences in selected risk factors (setting, age, contraceptive use, parity, breast feeding, or menarche) by ER status although ER negative tumors had significantly higher grade tumors (by a factor of two) compared to ER positive tumors. Conclusion. There were no significant differences among risk factors by ER status contrary to what several other studies suggest. The manifestation of breast cancer in Africa warrants further extensive inquiry.

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