Human Epidermal Growth Factor Receptor Type Research Articles

Sociodemographic and Clinical-pathological Study of Molecular Subtitles of Breast Carcinoma in a Reference Unit of Maranhão.

To evaluate the distribution of the main sociodemographic and clinical-pathological characteristics in women with breast cancer according to the molecular profile by immunohistochemistry. A cross-sectional, retrospective, analytical and quantitative study was performed, with an analysis of 137 medical records from January 2015 to December 2018 of women attending the High Complexity in Oncology Unit of the city of Imperatriz, state of Maranhão, Brazil. The immunohistochemical profile of tumors based on the estrogen and progesterone receptor, Human Epidermal growth factor Receptor-type 2 (HER2) overexpression and Ki67 cell proliferation index was defined, from which six molecular subtypes were determined: luminal A, luminal B-HER2 negative, luminal B-HER2 positive, triple negative, overexpression of HER2 and inconclusive. A total of 52.6% of the patients were postmenopausal, mean age 52.1 years old, brown (56.2%), had a schooling level < 9 years (40%), staging > IIB (52.6%) and 23.4% had metastasis. Invasive ductal carcinoma accounted for 84.7%, tumor size was 2 to 5 cm (48.9%), with lymph node involvement (56.2%), axillary lymphadenectomy in 67.2%, and mastectomy in 73.7% of the patients. The most frequent molecular subtype was the luminal B-HER2 negative (36.5%), and the luminal A subtype showed characteristics of better prognosis when compared with the others. It was concluded that in the association of molecular subtypes with sociodemographic and clinical-pathological characteristics, there were no statistically significant results obtained, except for complementary therapy, referring to hormone therapy, and there was a high index of metastasis at diagnosis, which was a worrying factor and indicative of failures in the screening and early diagnosis of this population.

Ectopic breast tissue carcinoma - a case report

Background: Ectopic breast cancer is a rare entity and an important diagnostic and treatment challenge. Case Presentation: 46-year-old female with previous history of resection of ectopic axillary breast tissue who was referred to our Institution after a second resection following an increase in left axillary volume. Histology reported a ductal ectopic breast tissue carcinoma that invaded the deep layer of the dermis and was positive for estrogen and progesterone receptors and Human Epidermal growth factor Receptor-type 2. After being referred to our Institution, surgical margin re-excision and sentinel node biopsy were performed. The patient initiated hormone therapy and underwent adjuvant radiotherapy to the breast and axilla (50 Gy/25 fractions, in daily 2 Gy fractions with a 3D conformal radiation therapy technique) and boost with bolus to the axilla (to complete 60 Gy). She remains in follow-up, with no recurrence to date. Conclusion: A high index of suspicion is required for the timely diagnosis of this rare condition. Since there are no specific guidelines, treatment remains a challenge.

Biomarkers for predicting response to tyrosine kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells.

The epidermal growth factor receptor (EGFR) family is reportedly overexpressed in bladder cancer, and tyrosine kinase inhibitors (TKIs) have been suggested as treatment. Gefitinib (Iressa®) is a selective inhibitor of the EGFR and lapatinib is a dual inhibitor of both the EGFR and HER2 (human EGFR type 2 receptor). Both compounds compete with the binding of ATP to the tyrosine kinase domain of the respective receptors to inhibit receptor autophosphorylation causing suppression of signal transduction. Unfortunately, resistance to these inhibitors is a major clinical issue. The purpose of the present study was to use protein array analysis to compare the signaling pathway(s) induced by gefitinib and lapatinib, in UM-UC-5 (drug-sensitive) and UM-UC-14 (drug-resistant) bladder cancer cells and to identify molecular markers that may be useful predictors of their efficacy. The results revealed that phosphorylation of EGFR, HER3, Met and ERK1/2 was markedly overexpressed in the sensitive cell line (UM-UC-5) and was strongly inhibited by the TKIs. Other notable differences included decreased phosphorylation of RSK, GSK3, AMPK, Akt and c-Jun by TKIs in the sensitive cells. In contrast, phosphorylated p53 was highly expressed in the resistant cell line (UM-UC-14) and TKIs had no effect in the resistant cells. Overall results suggest that phosphorylated HER3, ERK1/2 and p53 may be used as biomarkers to determine the sensitivity of bladder cancers to TKIs. In particular, a combination of these markers may be more likely to predict the sensitivity to TKIs.

Use of Pertuzumab for the Treatment of HER2-Positive Metastatic Breast Cancer

Targeting the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors has proven to be effective as a therapeutic strategy for HER type 2 (HER2)-positive breast cancer. Since resistance to trastuzumab occurs relatively frequently, particularly in the metastatic setting, novel anti-HER2 targeted therapies with complementary and/or synergistic mechanisms of action have been under development. Pertuzumab, a HER2-targeted monoclonal antibody that prevents HER2 dimerisation, is the first of a class of promising targeted agents for the treatment of HER2-positive breast cancer. A review of the biomedical literature published prior to February 2013 was conducted in English using PubMed. ClinicalTrials.gov was searched for appropriate clinical trials. The search terms used included breast neoplasm, pertuzumab, dimerisation, and HER2-positive. Abstracts of studies presented at the ASCO and ESMO Annual Meetings, and San Antonio Breast Cancer Symposium were also included. Pertuzumab represents a novel anti-HER2 targeted therapy for HER2-positive breast cancers. In this article, we describe the mechanism of action of pertuzumab, as well as its drug development process and preclinical testing results. Based on the results of ancillary studies, dual inhibition using pertuzumab and trastuzumab was shown to be effective for the management of HER2-positive metastatic breast cancers pre-treated with trastuzumab-based therapy. For the first-line setting, the combination of both pertuzumab and trastuzumab with docetaxel (CLEOPATRA trial; clinical evaluation of pertuzumab and trastuzumab) has changed the paradigm of patient management. Pertuzumab provided a more comprehensive inhibition of HER2-driven signalling pathways. When administered together with trastuzumab, pertuzumab represent a significant advancement for the treatment of HER2-positive metastatic breast cancer patients.

Correlation among 16 biological factors [p53, p21waf1, MIB-1 (Ki-67), p16INK4A, cyclin D1, E-cadherin, Bcl-2, TNF-α, NF-κB, TGF-β, MMP-7, COX-2, EGFR, HER2/neu, ER, and HIF-1α] and clinical outcomes following curative chemoradiation therapy in 10 patients with esophageal squamous cell carcinoma

The expression levels of 16 proteins were analyzed to identify prognostic correlations in esophageal squamous cell carcinoma (ESCC) treated with concurrent chemoradiation therapy (CCRT). The immunohistochemical expression levels of p53, p21waf1, molecular immunology borstel-1 (MIB-1, Ki-67), p16INK4A, cyclin D1, E-cadherin, Bcl-2, tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, transforming growth factor (TGF)-β, matrix metalloproteinase (MMP)-7, cyclooxygenase (COX)-2, epidermal growth factor receptor (EGFR), human EGFR type 2 (HER2/neu), estrogen receptor (ER) and hypoxia-inducible factor (HIF)-1α were studied in 10 cases of ESCC treated with CCRT. The patients underwent CCRT between 2000 and 2010. The mean patient age was 68.1 years (range, 46-80 years). The numbers of patients in stages I, II, III and IV of the disease were 2, 2, 3 and 3, respectively. Of the tumors, 8 were positive for p53, 6 for p21waf1, 7 for MIB-1 (Ki-67), 7 for p16INK4A, 7 for cyclin D1, 8 for E-cadherin, 3 for Bcl-2, 0 for TNF-α, 5 for NF-κB, 7 for TGF-β, 9 for MMP-7, 7 for COX-2, 5 for EGFR, 1 for HER2/neu, 1 for ER and 7 for HIF-1α. The 2-year overall survival rate of patients expressing high levels of MIB-1 was 71% (±17%) compared with 0% (P=0.019) for those expressing low levels. For NF-κB, the rate was 0% for patients with high levels compared with 100% (P<0.018) for those with low levels. The 2-year local control rates of HER2/neu were 0% in patients expressing high levels and 88% (±12%) in patients expressing low levels (P=0.027). The 2-year disease-free survival rates of HER2/neu and ER were 0% for patients expressing high levels compared with 56% (±17%) for those with low levels (P=0.027). There were no significant correlations between the expression levels of the other proteins and clinical outcomes. In the present study, high levels of MIB-1 and low levels of NF-κB, HER2 and ER were shown to be good prognostic factors following definitive CCRT for ESCC.

Apoptosis-related molecular differences for response to tyrosin kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells

The epidermal growth factor receptor (EGFR) family is reportedly overexpressed in bladder cancer, and tyrosine kinaseinhibitors (TKIs) have been suggested as treatment. Gefitinib is a selective inhibitor of the EGFR and lapatinib is a dual inhibitor of both the EGFR and HER2 (human EGFR type 2 receptor). Both compounds compete with the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain of the respective receptors to inhibit receptor autophosphorylation causing suppression of signal transduction. Unfortunately, resistance to these inhibitors is a major clinical problem. To compare the apoptosis signaling pathway(s) induced by gefitinib and lapatinib, in UM-UC-5 (drug-sensitive) and UM-UC-14 (drug-resistant) bladder cancer cells and to identify molecular differences that might be useful predictors of their efficacy. Cell proliferation, cell cycle and apoptosis assay were used to detect the effect of TKIs on UM-UC-5 and UM-UC-14 cells. Molecular differences for response to TKIs were examined by protein array. TKIs strongly inhibited cell proliferation and induced cell cycle G1 arrest and apoptosis in UM-UC-5 cells. Most notable apoptosis molecular differences included decreased claspin, trail, and survivin by TKIs in the sensitive cells. In contrast, TKIs had no effect on resistant cells. Claspin, trail, and survivin might be used to determine the sensitivity of bladder cancers to TKIs.

Triple Negative Invasive Breast Carcinoma: Incidence and Clinical - Pathological Characteristics

Aim: The epidemiological behavior of malignant tumors in Costa Rica has undergone an important change during the last years; breast carcinoma has increased its incidence, occupying the second place in malignancies in women and the first one in mortality. This type of tumor can be studied by several immunohistochemistry markers, such as the expression of different hormonal receptors by neoplastic cells (estrogen receptors, progesterone receptors and Human Epidermal Growth-Factor Receptor type 2, HER2). Carcinomas which do not express any of these three receptors have a worse prognosis. Objectives for this study were to determine the main characteristics of these tumors, named triple negative carcinomas, and to define their relevance within breast carcinomas.Methodology: Data was collected from all women with breast cancer diagnosed, with immunohistochemistry studies, from January 1st, to December 31st, 2006, at the Pathology Department of the San Juan de Dios Hospital. Patient´s age, histological type and degree of differentiation, were taken into account for each case. Triple negative carcinomas were considered separately, and statistical analysis was made with Epi Info 3.3.4 software.Results: During the above mentioned period, 221 patients were diagnosed with breast cancer, 40 of them were identified as having triple negative carcinomas, which meant an incidence of 18% (C.I. 95%, 12.79 – 23.40), and had an average of 54 years old (C.I. 95%, 50 - 58 ), a median of 52 years old and a mode of 48 years old. Triple-negative cancer was more related with ductal infiltrating histological type: 67.5% (C.I. 95%, 51.73-83.26), followed by infiltrating lobular, with 12.5% (C.I. 95%, 4.18 – 26.80), medullary, with 5%, and less related are papillary type and spindle cell metaplastic carcinoma. According to the degree of differentiation, there were 23 grade-3 cases, 8 grade-2 cases, and 3 grade-1 carcinomas.Conclusion: Triple negative breast cancers are an aggressive group of tumors, which manifest at younger ages, have larger tumor size, are of higher histological grade, and mostly are infiltrating ductal carcinomas. Due to the fact that this was based only on determination of hormonal receptors and HER2, other tests might be necessary such as CK5/6 and 17 stains to check basal-like carcinoma cases. Also, this study shows a higher prevalence for infiltrating lobular carcinomas than other studies, so that other tests could be done such as e-cadherin, to verify the cases of lobular carcinomas, thereby increasing reliability of results.

Persistent expression of biologically active anti-HER2 antibody by AAVrh.10-mediated gene transfer

Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody directed against an extracellular region of the HER2 protein. We hypothesized that a single adeno-associated virus mediated genetic delivery of an anti-HER2 antibody should be effective in mediating long term production of anti-HER2 and in suppressing the growth of human tumors in a xenograft model in nude mice. The adeno-associated virus gene transfer vector AAVrh.10αHER2 was constructed based on non-human primate AAV serotype rh.10 to express the cDNAs for the heavy and light chains of monoclonal antibody 4D5, the murine precursor to trastuzumab. The data demonstrates that genetically transferred anti-HER2 selectively bound human HER2 protein and suppressed proliferation of HER2 positive tumor cell lines. A single administration of AAVrh.10αHER2 provided long term therapeutic levels of anti-HER2 antibody expression without inducing anti-idiotype response, suppressed the growth of HER2 positive tumors and increased survival of the tumor-bearing mice. In the context that trastuzumab therapy requires frequent, repeated administration, this strategy might be developed as an alternate platform for delivery anti-HER2 therapy.

Abstract 1190: Differences in responsiveness of drug-sensitive and drug-resistant human bladder cancer cells to specific EGFR inhibitors

Abstract Bladder cancer is a common genitourinary malignant disease in the USA. EGFR and/or HER2 are overexpressed in these cancers, and EGFR/HER2 inhibitors are suggested as treatment. Gefitinib (i.e., Iressa) is a selective inhibitor of the epidermal growth factor receptor (EGFR) and Lapatinib is a dual inhibitor of both the EGFR and HER2/neu (Human EGFR type 2) receptor. Both compounds compete with the binding of ATP to the tyrosine kinase domain of the respective receptors to inhibit autophosphorylation causing suppression of signal transduction. Unfortunately, resistance to these inhibitors is a problem. The purpose of this study was to compare the signaling pathway(s) induced by Gefitinib and Lapatinib, in UM-UC-5 (Gefitinib-sensitive) and UM-UC-14 (Gefitinib-resistant) bladder cancer cells and to identify molecular markers that might be useful predictors of efficacy. Each cell line was cultured to 90% confluence and then incubated 24 h in serum-free media. They were treated, respectively, with 2.5 μM Gefitinib or Lapatinib for 24 h and harvested. Cell lysates were subjected to Proteome Profiler™ Arrays (R&amp;D, Minneapolis, MN) including RTK, phospho-MAP kinase, phospho-kinase, and apoptosis arrays. Results indicate that Gefitinib and Lapatinib had differential effects on proteins known to play a role in apoptosis. Iressa appeared to decrease anti-apoptotic Bcl2, whereas Lapatinib increased pro-apoptotic Bax expression. Lapatinib, but not Iressa, also suppressed anti-apoptotic clusterin. Both agents decreased anti-apoptotic claspin, survivin, and XIAP expression but the effect of Lapatinib was 2- to 8-fold greater than Iressa. Notably, in the drug-resistant UM-UC-14 cells, Iressa had little affect whereas Lapatinib induced pro-apoptotic BAD and inhibited expression of anti-apoptotic Bcl2, Bcl-XL, and clusterin. Perhaps the most notable difference between these two drugs, was the effectiveness of Lapatinib in suppressing EGFR/HER2 expression in both cell lines. In the sensitive line, Lapatinib suppressed EGFR/HER2 expression 2-3 fold more than did Iressa and was almost as effective in the resistant line, whereas Iressa had no effect on UM-UC-14 cells. In contrast, Iressa was at least 8-fold more effective than Lapatinib in suppressing ERK1/2 expression in drug-sensitive cell lines but neither compound affected ERKs in resistant cells. Overall, the effect of these compounds on MAP kinase signaling appeared to be similar in sensitive cells; however, Lapatinib was able to suppress some MAP kinase signaling in the resistant line. Other notable differences included increased phosphorylation of p53, p27 and p70S6 kinase only by Lapatinib and decreased phosphorylation of eNOS only by Iressa in sensitive cells. Overall results suggest that human bladder cancer cells display some similarity but also marked heterogeneity in response to “specific” EGFR inhibitors ex vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1190.

In Vivo Imaging of Xenograft Tumors Using an Epidermal Growth Factor Receptor-Specific Affibody Molecule Labeled with a Near-infrared Fluorophore

Overexpression of epidermal growth factor receptor (EGFR) is associated with many types of cancers. It is of great interest to noninvasively image the EGFR expression in vivo. In this study, we labeled an EGFR-specific Affibody molecule (Eaff) with a near-infrared (NIR) dye IRDye800CW maleimide and tested the binding of this labeled molecule (Eaff800) in cell culture and xenograft mouse tumor models. Unlike EGF, Eaff did not activate the EGFR signaling pathway. Results showed that Eaff800 was bound and taken up specifically by EGFR-overexpressing A431 cells. When Eaff800 was intravenously injected into nude mice bearing A431 xenograft tumors, the tumor could be identified 1 hour after injection and it became most prominent after 1 day. Images of dissected tissue sections demonstrated that the accumulation of Eaff800 was highest in the liver, followed by the tumor and kidney. Moreover, in combination with a human EGFR type 2 (HER2)-specific probe Haff682, Eaff800 could be used to distinguish between EGFR- and HER2-overexpressing tumors. Interestingly, the organ distribution pattern and the clearance rate of Eaff800 were different from those of Haff682. In conclusion, Eaff molecule labeled with a NIR fluorophore is a promising molecular imaging agent for EGFR-overexpressing tumors.

Management of HER2-positive breast cancer in Asia: consensus statement from the Asian Oncology Summit 2009

Patients with breast cancer positive for human epidermal growth-factor receptor type 2 (HER2) are an important subgroup for consideration in the Asian context. Rationally designed, anti-HER2 targeted agents that can substantially improve treatment outcomes have become commercially available, but are still too costly for some groups in developed countries and for underdeveloped and developing nations. This review discusses the available evidence for optimum management of HER2-positive early and advanced breast cancer, and how this evidence can be applied to Asian countries with different levels of health-care resources and economic development--using framework provided by the Breast Health Global Initiative. We provide a brief overview of HER2 testing and discuss management of early and advanced HER2-positive breast cancer, and formulate a consensus statement for the management of breast cancer in the context of basic, limited, enhanced, and maximum health-care resource availability.

Targeted Antireceptor Therapy with Monoclonal Antibodies Leads to the Formation of Inactivated Tetrameric Forms of ErbB Receptors

mAbs capable of disabling heterodimeric kinase complexes of the epidermal growth factor receptor (EGFR) and human EGFR type 2/neu have therapeutic relevance to various human cancers. In this study, we demonstrate that in addition to the dimer, EGFR and human EGFR type 2 can associate as homo- and heterotetramers. EGF-induced phosphorylation of the tetramers was significantly lower than that of the dimers, indicating that the tetrameric receptor complexes have impaired signaling activity. Targeting v-erb-b2 erythroblastic leukemia viral oncogene homolog (erbB) receptors with mAbs promoted erbB tetrameric assembly, suggesting that a component of the antitumor activity may be mediated by the ability of Abs to shift the equilibrium from active dimeric to impaired tetrameric receptor complex states. This study suggests a novel therapeutic approach to disable signaling of erbB and potentially other receptors in tumors by biologic agents capable of inducing receptor tetramerization.

Molecular Determinants of the Response of Glioblastomas to EGFR Kinase Inhibitors

The epidermal growth factor receptor (EGFR) is frequently amplified, overexpressed, or mutated in glioblastomas, but only 10 to 20 percent of patients have a response to EGFR kinase inhibitors. The mechanism of responsiveness of glioblastomas to these inhibitors is unknown. We sequenced kinase domains in the EGFR and human EGFR type 2 (Her2/neu) genes and analyzed the expression of EGFR, EGFR deletion mutant variant III (EGFRvIII), and the tumor-suppressor protein PTEN in recurrent malignant gliomas from patients who had received EGFR kinase inhibitors. We determined the molecular correlates of clinical response, validated them in an independent data set, and identified effects of the molecular abnormalities in vitro. Of 49 patients with recurrent malignant glioma who were treated with EGFR kinase inhibitors, 9 had tumor shrinkage of at least 25 percent. Pretreatment tissue was available for molecular analysis from 26 patients, 7 of whom had had a response and 19 of whom had rapid progression during therapy. No mutations in EGFR or Her2/neu kinase domains were detected in the tumors. Coexpression of EGFRvIII and PTEN was significantly associated with a clinical response (P<0.001; odds ratio, 51; 95 percent confidence interval, 4 to 669). These findings were validated in 33 patients who received similar treatment for glioblastoma at a different institution (P=0.001; odds ratio, 40; 95 percent confidence interval, 3 to 468). In vitro, coexpression of EGFRvIII and PTEN sensitized glioblastoma cells to erlotinib. Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.