Current Status of Anti–Human Epidermal Growth Factor Receptor 2 Therapies: Predicting and Overcoming Herceptin Resistance

Human epidermal growth factor receptor 2-overexpressing (HER2+) breast cancer occurs in 20% to 25% of cases and is associated with poor prognosis. Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is a monoclonal antibody targeting the HER2 extracellular domain that has been shown to significantly reduce relapse rates. However, some patients with HER2+ tumors do not respond to Herceptin, and 60% to 85% of patients with HER2+ metastatic breast cancer acquire resistance within a short time period. In this review, we discuss proposed mechanisms of action of trastuzumab and trastuzumab resistance and various drugs that have been developed to overcome drug resistance. We introduce the basal molecular subtype as a predictor of increased risk in HER2+ breast cancer and a possible alternative cause of drug resistance.     

Patterns of Use and Tolerance of Anti–Epidermal Growth Factor Receptor Antibodies in Older Adults With Metastatic Colorectal Cancer

BackgroundLimited data are available regarding the tolerance of anti–epidermal growth factor receptor (EGFR) antibodies among elderly patients with metastatic colorectal cancer (mCRC). We retrospectively reviewed our experience of treating elderly patients with mCRC with these agents between 2004 and 2011.MethodsPatients with mCRC ≥ 65 years treated with anti-EGFR agents were included in this analysis. We recorded demographic and disease characteristics, treatment regimen and duration, KRAS status, and overall survival (OS). Toxicity evaluation included common hematologic and nonhematologic toxicities seen with these agents.ResultsOne hundred seventeen patients were included, with a median age at treatment initiation of 73 years (range, 65-86 years), 59% of male sex, 82% with colon primary tumors, and 51% with metastatic disease at presentation. Median time on anti-EGFR treatment was 2.4 months. Older age at treatment initiation was associated with use of anti-EGFR antibody as monotherapy versus combination therapy (P = .0009). Worse performance status (PS) at treatment initiation was associated with a shorter overall survival (OS) (P = .013) and shorter treatment duration (P = .01). The incidence of hematologic/nonhematologic grade ≥ 3 was 36% and 15%, respectively. No association was found between age and presence of grade ≥ 3 toxicity. Longer treatment duration and better PS at treatment initiation were the only factors associated with higher incidence of grade 3 toxicity.ConclusionOur data demonstrate that anti-EGFR antibodies can be used in older patients with mCRC, with toxicity profiles similar to those reported in large phase III studies of younger patients. Advanced age was associated with receipt of anti-EGFR agents as monotherapy but did not impact treatment outcomes in this population.     

Combined Inhibition of Vascular Endothelial Growth Factor and Epidermal Growth Factor Signaling in Non–Small-Cell Lung Cancer Therapy

Elucidation of molecular pathways that promote malignancies has led to the identification of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) as key components involved in regulation of tumor proliferation and angiogenesis, respectively. Biologic agents that target these individual pathways have proven effective in treating patients with advanced Non—Small-cell lung cancer (NSCLC), adding to previously available therapies and often with fewer side effects. However, inhibition of a single molecular pathway does not account for alternate pathways or biologic adaptations that eventually lead to resistance. Therefore, combining EGFR and VEGF inhibition is currently under investigation as a means to overcome resistance and promote synergy. Erlotinib, an anti-EGFR agent, and bevacizumab, an anti-VEGF agent, are both approved in NSCLC, demonstrating single-agent activity. The phase II trials evaluating the combination of erlotinib and bevacizumab have shown efficacy as first-line therapy or in patients with previously treated NSCLC either alone or with chemotherapy. Dual inhibition of EGFR and VEGF pathways has also been accomplished by the novel agents vandetanib and XL647, which are able to target both pathways. Vandetanib has also demonstrated activity in patients with advanced NSCLC either alone or with chemotherapy in phase I/II studies. Another novel agent, XL647, has demonstrated promising single-agent activity in patients who have been resistant to previous anti-EGFR therapy. Further evaluation of combined EGFR and VEGF inhibition is under investigation.     

Previous Bevacizumab and Efficacy of Later Anti–Epidermal Growth Factor Receptor Antibodies in Metastatic Colorectal Cancer: Results From a Large International Registry

Background

The FIRE-3 [5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus cetuximab versus FOLFIRI plus bevacizumab in first line treatment colorectal cancer (CRC)] study reported that first-line FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab resulted in similar progression-free survival (PFS) but improved overall survival (OS). A potential explanation is that the initial biologic agent administered in metastatic CRC (mCRC) affects later line efficacy of the other treatments. We sought to test this hypothesis.

RNA Interference-Mediated Gene Silencing of Vascular Endothelial Growth Factor

A ngiogenesis is a well-known process that is essential for tumor growth beyond 2 mm.[1] Although numerous growth factors are involved, vascular endothelial growth factor (VEGF), in particular VEGF-A, has been shown to play an important role in tumor angi…     

Vascular Endothelial Growth Factor Expression in Invasive Ductal Carcinoma of Breast

Objective： To detect the expression of VEGF and MVD count in invasive ductal carcinoma of breast to clarify the association of VEGF expression and MVD count with the clinicopathologic features. Methods： The expressions of VEGF, ER, PR, C-erbB-2 and MVD count in 88 cases of invasive ductal carcinoma of breast were examined by immunohistochemistry staining （SP-method）. Results： Sixty-two out of the eighty-eight specimens of breast carcinoma （70.45%） showed positive expression of VEGF. The positive rate of VEGF in cases with lymph node metastasis was higher than that without lymph node metastasis （P〈0.05）. The positive rate of VEGF in stage IIb-Ⅲ was higher than that in stage Ⅰ-Ⅱa （P〈0.05）. The positive rate of VEGF in C-erbB-2 positive group was higher than that in C-erbB-2 negative group （P〈0.05）. Higher expression of VEGF was observed in cases with higher tissue differentiation degree （P〈0.05）. Also, significant higher MVD count was observed in cases with higher tissue differentiation degree （P〈0.01）. The MVD count increased significantly with the increase of the expression of VEGF （P〈0.01）. Conclusion： The result of this study suggested that in invasive ductal carcinoma of breast, angiogenesis and metastasis were mediated mainly by VEGF. The expression of VEGF and MVD might be reference predictors for the biological behavior of breast carcinoma. The antiangiogenic therapy which used VEGF as a target would become a new method to treat patients who were C-erbB-2 positive in the future.     

Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancers Dependent on the Epidermal Growth Factor Receptor Pathway

Most advanced Non–Small-cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or L858R) initially respond to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, over time (median of 6–12 months), most tumors develop acquired resistance to EGFR TKIs. Intense research in these NSCLCs has identified two major mechanisms of resistance to gefitinib/erlotinib: secondary resistance mutations and “oncogene kinase switch" systems. The secondary T790M mutation occurs in 50% of EGFR-mutated patients with TKI resistance, and in vitro, this mutation negates the hypersensitivity of activating EGFR mutations. Sensitive detection methods have identified a proportion of TKI-naive tumors that carry T790M, and these resistant clones may be selected after exposure to gefitinib or erlotinib. Other secondary resistance mutations (D761Y, L747S, T854A) seem to be rare. The amplification of the MET oncogene is present in 20% of TKI-resistant tumors; however, in half of the cases with this “oncogene kinase switch" mechanism the T790M is coexistent. It is possible that other kinases (such as insulin-like growth factor-1 receptor [IGF-1R]) might also be selected to bypass EGFR pathways in resistant tumors. The growing preclinical data in EGFR-mutated NSCLCs with acquired resistance to gefitinib or erlotinib has spawned the initiation or conception of clinical trials testing novel EGFR inhibitors that in vitro inhibit T790M (neratinib, XL647, BIBW 2992, and PF-00299804), MET, or IGF-1R inhibitors in combination with EGFR TKIs, and heat shock protein 90 inhibitors. Ongoing preclinical and clinical research in EGFR-mutated NSCLC has the potential to significantly improve the outcomes of patients with these somatic mutations.     

Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non–Small-Cell Lung Cancer

BackgroundStandard therapy of advanced non–small-cell lung cancer harboring an activating mutation in the epidermal growth factor receptor (EGFR) gene is treatment with tyrosine kinase inhibitors (TKI). However, for rare and compound mutations of the EGFR gene, the clinical evidence of TKI therapy is still unclear.Patients and MethodsA total of 2906 lung cancer samples were analyzed for EGFR mutations during routine analysis between 2010 and 2017. The samples have been investigated by Sanger sequencing and since 2014 by next-generation sequencing.ResultsWe detected EGFR mutations in 408 specimens (14%). Among these, we found 41 samples with rare and 22 with compound mutations. In these 63 samples, 56 different rare EGFR mutations occurred. Information about the clinical outcome was available for 37. Among those with rare mutations, only one patient harboring the mutation p.G874D had disease that responded to first-generation TKI therapy. In contrast, the disease of all patients with compound mutations responded to first- or second-generation TKI therapy. Furthermore, we collected data on clinical relevance regarding TKI therapy from different databases and from an additional literature search, and only found data for 36 of the 56 detected rare mutations.ConclusionInformation about the clinical outcome of patients with rare and compound EGFR mutations remains limited. At present, second- and third-generation TKIs are available, which may represent new treatment strategies for these patients. Therefore, it is becoming increasingly important to maintain databases concerning rare EGFR mutations.     

Phase 2 Study of Dose-Dense Doxorubicin and Cyclophosphamide Followed by Eribulin Mesylate With or Without Prophylactic Growth Factor for Adjuvant Treatment of Early-Stage Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer

Background

Eribulin has significantly improved overall survival for patients with metastatic breast cancer who received ≥ 2 prior chemotherapy regimens for advanced disease. This trial assessed eribulin as adjuvant therapy for patients with early-stage breast cancer.

Management of Rash and Other Toxicities in Patients Treated with Epidermal Growth Factor Recep tor–Targeted Agents

Inhibition of the epidermal growth factor receptor (EGFR) represents one of the most important avenues for research and development in the field of cancer therapy. The EGFR is a member of the ErbB receptor tyrosine kinase (TK) family, which also includes ErbB-2 (HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). Current EGFR therapies available for use include monoclonal antibodies such as cetuximab and small-molecule EGFR TK inhibition by agents such as erlotinib. Side effects of these agents include dermatologic manifestations, without the bone marrow suppressive properties of chemotherapy. Understanding of rash and how it relates to EGFR inhibitor toxicity and, perhaps more importantly, EGFR inhibitor response, must be more clearly defined with clinical trials. The optimum management of rash in patients receiving anti-EGFR therapy remains somewhat controversial; this is secondary to imprecise classification of rash as well as the lack of clinical trials to determine the most appropriate treatment algorithm for these patients. We propose a treatment strategy to help aggressively treat dermatologic side effects, allowing patients to continue receiving therapy without dose interruption or drug discontinuation.     

Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors

Objective： To explore the role of vascular endothelial growth factor-C （VEGF-C） in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods： In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density （MVD） were assessed by image analysis. Results： VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors （P〈0.05 or P〈0.01）. In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively （P〈0.05 or P〈0.01）. VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors （P〈0.05）. VEGFR-3 positive vessels was significantly correlated with MVD（P〈0.01）. Conclusion： VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors.     

Effectiveness of Treatments for Advanced Non–Small-Cell Lung Cancer With Exon 20 Insertion Epidermal Growth Factor Receptor Mutations

BackgroundTwo main categories of epidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancer (NSCLC) patients are deletions in exon 19 and L858R in exon 21. Treatments of advanced NSCLC patients with these mutations are well documented, and clinical responses to tyrosine kinase inhibitors (TKIs) are favorable. However, effective treatments for patients with exon 20 insertion mutations are not well verified. We investigated the clinical response to various treatments (chemotherapy and TKIs) of advanced NSCLC patients with EGFR exon 20 insertions.Patients and MethodsIn this study, specimens from 3805 NSCLC patients were examined for EGFR mutations. Different first-line treatments and their effectiveness in NSCLC patients with exon 20 insertion EGFR mutations were investigated.ResultsIn the cohort of the 3805 patients, 2112 (55.5%) had EGFR mutations, including 84 patients (4.0%) with exon 20 insertion mutations. Efficacy of different first-line chemotherapy or TKIs were evaluated. Pemetrexed-containing therapies were related to better progression-free survival (6.2 vs. 2.7 months; P < .001) and overall survival (28.0 vs. 15.4 months; P = .009) than regimens without pemetrexed. Patients with exon 20 insertions had a poor response to TKIs. However, the mutation Ala763_Tyr764insPheGlnGluAla (A763_Y764 insFQEA) was related to a favorable response to TKIs.ConclusionExon 20 insertion EGFR mutations comprised a considerable group of the entire population of patients with EGFR mutations. Different first-line treatments and variants of the exon 20 insertions might be related to different outcomes in advanced NSCLC patients.     

Extending Outcomes: Epidermal Growth Factor Receptor–Targeted Monoclonal Antibodies in Non–Small-Cell Lung Cancer

The epidermal growth factor receptor (EGFR) pathway plays an important part in the formation of many epithelial malignancies and has been the target of intensive drug development. Although the small-molecule EGFR tyrosine kinase inhibitors (TKIs) have an established role as single-agent therapy in the second- or third-line treatment of patients with advanced Non—Small-cell lung cancer (NSCLC), they have failed to demonstrate any additive benefit when combined with standard cytotoxic chemotherapy. Monoclonal antibodies (MoAbs) to EGFR are a distinct class of agents that differ significantly from the TKIs in their interaction with the EGFR pathway. A number of MoAbs targeting EGFR are currently in development and their clinical usefulness in the treatment of NSCLC is discussed, with particular attention given to cetuximab.     

Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer

Angiogenesis is essential for cancer growth and progression. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The addition of bevacizumab, an antibody to vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improves survival compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are a new class of drugs that target the TK domain of the VEGF receptors. To evaluate the role of this class of agents in the treatment of NSCLC, some phase II and phase III studies using these agents alone or in combination with other agents have been completed. This review summarizes the currently available data on VEGFR TKIs in the treatment of NSCLC.     

Assessment of Folate Receptor-α and Epidermal Growth Factor Receptor Expression in Pemetrexed-Treated Non–Small-Cell Lung Cancer Patients

IntroductionFolate receptor-α regulates cellular uptake of folates and antifolates (eg, pemetrexed) and is frequently expressed in pulmonary adenocarcinoma. EGFR is an established therapeutic target in NSCLC. Therapies targeting FRA or EGFR are available. The association between FRA and EGFR expression in advanced NSCLC has not been explored. Combining therapeutic FRA antibodies with an EGFR inhibitor might be beneficial, if both of the targets are significantly coexpressed.Patients and MethodsSpecimens from 160 advanced NSCLC patients receiving pemetrexed-based chemotherapy were assessed for membranous FRA and EGFR protein expression using immunohistochemistry and the Hybrid (H)-score. EGFR (exons 18-21) and Kirsten RNA-associated rat sarcoma 2 virus (exon 2) mutations were determined. Results were correlated to patients' clinicopathological data, progression-free survival (PFS), and overall survival (OS).ResultsForty-seven patients (29%) had tumors with strong FRA and EGFR expression, but no statistically significant correlation was seen between protein levels of FRA and EGFR. High membranous FRA expression (H-score ≥ 20) was associated with prolonged PFS (5.5 vs. 3.4 months; hazard ratio [HR], 0.6060; P = .0254) and improved OS (12.1 vs. 6.4 months; HR, 0.5726; P = .0076).ConclusionSurvival times are improved in NSCLC patients whose tumors show strong membranous FRA expression. No statistical correlation between membranous FRA and EGFR expression was demonstrated in advanced NSCLC, but 47 patients (29%) had higher expression of both of the receptors and could be suitable for combined targeted therapies.