Molecular targeted therapy in recurrent glioblastoma: current challenges and future directions

Introduction: The survival of patients with glioblastoma (GBM), which is the most common primary brain malignancy, remains poor with current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes. Areas covered: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) initiate key signaling pathways in GBM; however, trials with anti-EGFR agents have failed to show improved outcomes. Bevacizumab, a monoclonal antibody targeting VEGF, remains the only FDA-approved molecular drug in GBM; yet its use has only improved progression-free survival without any improvement in overall survival. We review the evidence supporting the continued evaluation of targeted molecular therapies in recurrent GBM. In addition, newer potential therapies targeting other signaling pathways, heat shock proteins and proteosomes, as well as the concept of targeting glioma stem cells are discussed. Expert opinion: The complex genetic origin of GBM makes it challenging to identify molecular subsets that may benefit from specific targeted therapies. Pathway inhibition, via multisite kinase inhibitors or a carefully selected combination of molecular drugs with or without cytotoxic agents, is currently undergoing evaluation in clinical trials and may improve outcomes in these patients.     

Targeted therapy of hepatocellular cancer

Importance of the field: Hepatocellular cancer (HCC) is the fifth most common malignancy worldwide and third leading cause of cancer death. HCC is highly resistant to conventional systemic therapies, and prognosis for advanced HCC patients remains poor. However, identification of signaling pathways responsible for HCC growth and progression such as RAS/RAF/MEK/ERK or PI3K/AKT/mTOR has determined crucial molecular targets and led to development of novel promising targeted therapies.

Areas covered in this review: This article presents molecular mechanisms responsible for development and progression of HCC and strategies aimed to block important molecules involved in signal transduction. It also reviews the clinical studies evaluating efficacy and safety of novel targeted approaches for treatment of this malignancy.

What the reader will gain: Inhibition of molecular targets (ligands, membrane receptors and receptor-associated kinases) represents a promising strategy for treatment of HCC; in the case of sorafenib, this has already been demonstrated to significantly improve survival of advanced HCC patients. This article reviews novel therapeutic approaches that are based on combinations of different targeted agents with or without classic cytotoxic drugs.

Take home message: Despite significant progress, advanced HCC remains an incurable disease, and the overall efficacy of recently approved targeted therapy (sorafenib) remains moderate. It is to be hoped that several ongoing clinical trials evaluating novel targeted approaches for treatment of HCC will lead to further improvement in the management of advanced disease.     

Protein kinase inhibitors against malignant lymphoma

Introduction: Tyrosine kinases (TKs) are intimately involved in multiple signal transduction pathways regulating survival, activation, proliferation and differentiation of lymphoid cells. Deregulation or overexpression of specific oncogenic TKs is implicated in maintaining the malignant phenotype in B-lineage lymphoid malignancies. Several novel targeted TK inhibitors (TKIs) have recently emerged as active in the treatment of relapsed or refractory B-cell lymphomas that inhibit critical signaling pathways, promote apoptotic mechanisms or modulate the tumor microenvironment.

Areas covered: In this review, the authors summarize the clinical outcomes of newer TKIs in various B-cell lymphomas from published and ongoing clinical studies and abstracts from major cancer and hematology conferences.

Expert opinion: Multiple clinical trials have demonstrated that robust antitumor activity can be obtained with TKIs directed toward specific oncogenic TKs that are genetically deregulated in various subtypes of B-cell lymphomas. Clinical success of targeting TKIs is dependent upon on identifying reliable molecular and clinical markers associated with select cohorts of patients. Further understanding of the signaling pathways should stimulate the identification of novel molecular targets and expand the development of new therapeutic options and individualized therapies.     

Novel molecular targets for the therapy of urothelial carcinoma

Introduction: First-line platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma; however, long-term outcomes including disease-specific and overall survival remain suboptimal. In addition, approximately 40 – 50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy. Improvements in our understanding of the molecular mechanisms of urothelial tumorigenesis have led to first-generation clinical trials evaluating novel agents targeting molecular pathways. These are particularly relevant in regard to subpopulations. Novel trial designs warrant consideration to accelerate accrual.

Areas covered: In this review, novel molecular targets for the therapy of urothelial carcinoma, as well as recently completed and ongoing clinical trials utilizing novel targeted agents, are discussed. A Medline search with key words, abstracts reported at national conferences on urothelial carcinoma and NCI clinical trial identifiers was used for this review.

Expert opinion: Improved understanding of molecular biology has identified a number of new molecular targets, but there is a seeming absence of one dominant molecular driver for urothelial cancer. An adaptive and biomarker-derived strategy may be warranted. Clinical trials utilizing targeted agents are ongoing and results are awaited.     

Emerging biological therapies for the treatment of myelodysplastic syndromes

Introduction: No drug has resulted in a survival advantage in patients with lower-risk myelodysplastic syndromes (MDS). While hypomethylating agents (HMA) have revolutionized treatment options for patients with higher-risk MDS, the prognosis remains dismal after HMA treatment failure. Novel effective therapies are urgently needed especially after HMA failure.

Areas covered: This review covers the current approach to disease prognostication and risk-adaptive therapy, as well as novel therapeutic approaches. We discuss the recent advancements in the understanding of MDS disease biology as a basis of targeted drug development. Several classes of novel agents are reviewed including drugs targeting dysregulated epigenetic control mechanisms, signaling pathways, abnormal splicing, as well as agents that target the immune system and the MDS bone marrow niche.

Expert opinion: Significant advancements in the understanding of the underlying biology of MDS are only starting to be translated into novel treatment options for MDS. Epigenetic therapy has shown significant clinical activity with HMA but the results of clinical trials combining HMAs with histone deacetylase inhibitors (HDACi) have been disappointing to date. Similarly, targeting several aberrant pathways in MDS has not resulted in significant improvements in therapy. Future therapies will focus both on synergic combination of existing drugs as well as novel agents targeting dysregulated immune responses and abnormal RNA splicing in MDS.     

Current investigational drugs in psoriasis

Introduction : The advent of biologic therapies has revolutionized the treatment of psoriasis. Increased understanding of immunogenetic pathways has allowed for the development of more selective targeted biologic therapies. Multiple new treatments are currently in development for the treatment of psoriasis. Preliminary data for many of these agents, particularly with regard to agents targeting the IL-23/Th17 pathway, are promising. Proven long-term safety, however, is an absolute necessity with newly developed drugs, and should, therefore, still be considered second-line agents to current established treatments with long-term safety data.

Areas covered : This review details the mechanisms of action of drugs currently in development or in clinical trials for the treatment of psoriasis, using clinical trial registries and associated publications. Readers will gain a comprehensive overview about the mechanism of action of emerging treatments targeting various immune pathways deeply involved in psoriasis. Pathogenesis, clinical efficacy and safety data for these treatments are discussed where available.

Expert opinion : Psoriasis remains a heavily undertreated systemic immune-mediated disease despite increased understanding of immunopathogenesis of the disease and advent of a multitude of novel therapeutic agents with potentially improved bioavailability and safety profiles. Limitations, however, remain in the realm of topical agents for treatment of mild to moderate psoriasis, which has seen little progress over the years. A concerted effort will need to be made among researchers, clinicians and patient advocacy groups to ensure new therapeutic agents are developed and gain proper exposure.     

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib

Importance of the field: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC.

Areas covered in this review: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor.

What the reader will gain: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC.

Take home message: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.     

Selective genetic analysis of myoma pseudocapsule and potential biological impact on uterine fibroid medical therapy

Introduction: Tumor-associated angiogenesis is one of the essential hallmarks underlying cancer development and metastasis. Anti-angiogenic agents accordingly aim to restrain cancer progression by blocking the formation of new vessels, improving the delivery of chemotherapeutic agents to the tumor site and reducing the shedding of metastatic cells into the circulation. This review article addresses some key issues in the use of angiogenesis inhibitors in cancer.

Areas covered: The authors review the complex interactions between cell signaling pathways involved in tumor angiogenesis, and focus in particular on the molecular mechanisms that may induce resistance to angiogenesis inhibitors. They will also discuss some novel therapeutic strategies evolving within anti-angiogenic therapy such as the targeting of VEGFR-3, endothelial integrins and hepatocyte growth factor-MET signaling.

Expert opinion: Although anti-angiogenic therapy is targeted at the non-malignant part of the tumor, the intricate network of growth promoting signaling pathways and in particular the redundancy when single pathways are targeted in endothelial cells represents a major therapeutic obstacle. A key challenge will be to develop more efficient inhibitors, combined with an individualized approach based on each tumor's own endothelial signaling profile. Furthermore, reliable biomarkers which pinpoint those patients that will benefit from anti-angiogenic therapy need to be identified.     

Tyrosine kinase inhibitors to treat liver cancer

Importance of the field: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Although patients with early-stage disease have a good prognosis, there has been no effective therapy available for those with advanced disease. Despite the death risk of patients with advanced HCC being reduced with sorafenib therapy, many patients eventually turn out to be refractory to this therapy. Thus, treatment of HCC remains an urgent health concern.

Areas covered in this review: Recent improvement in understanding the pathophysiology of HCC at the molecular level has fostered the development of molecular targeted therapies that specifically block the disrupted pathways.

What the reader will gain: This review summarizes the preclinical and clinical data from 2004 to 2009 on the efficacy and safety of the emerging drug for the treatment of HCC, including small molecule inhibitors (erlotinib, sunitinib, sorafenib, vandetanib, cediranib, brivanib and dovitinib) and the rationale for combination therapies for patients with advanced HCC.

Take home message: Understanding the mechanisms of action, safety and efficacy of these new agents and new methods of combining these drugs may help prolong overall survival of patients with HCC and reduce disease recurrence after surgery or ablative therapies.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.     

TRAIL receptor signaling and therapeutics

Importance of the field: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, which can induce apoptotic cell death in a variety of tumor cells by engaging specific death receptors, TRAIL-R1 and TRAIL-R2, while having low toxicity towards normal cells. There is interest in cancer therapy inducing cell death by activation of the death-receptor-mediated apoptotic pathway while avoiding decoy-receptor-mediated neutralization of the signal. This has led to the development of a number of receptor-specific TRAIL-variants and agonistic antibodies. Some of these soluble recombinant TRAIL and agonist antibodies targeting TRAIL-R1 and/or TRAIL-R2 are progressing in clinical trials. In addition, TRAIL-resistant tumors can be sensitized to TRAIL by a combination of TRAIL or agonistic antibodies with chemotherapeutic agents, targeted small molecules or irradiation.

Areas covered in this review: Recent advances in developing TRAIL or its agonist receptor antibodies in cancer therapy. We also discuss combination therapies in overcoming TRAIL resistance in cancer cells.

What the reader will gain: Knowledge of current clinical trials, the promise and obstacles in the future development of therapies affecting TRAIL signaling pathways.

Take home message: Cancer therapeutics targeting the TRAIL/TRAIL receptor signaling pathway hold great promise for molecularly targeted pro-apoptotic anti-cancer therapy.     

Novel targeted treatment options for advanced cholangiocarcinoma

Introduction: Surgical resection remains the mainstay of potentially curative treatment in the early stages of cholangiocarcinoma, whereas for the advanced stage, systemic chemotherapeutics and experimental targeted therapies are the primary treatment options. The molecular heterogeneity of the tumor is based on location, liver dysfunction, and relative rarity of the disease and confers challenges for clinical trial enrollment. The advancements in the understanding of molecular pathogenesis of cholangiocarcinoma have led to the development of targeted therapies that are currently being evaluated in the clinical trials.

Areas covered: This review summarizes the current understanding and future directions of targeted therapeutic options in the management of advanced cholangiocarcinoma.

Expert opinion: Advanced cholangiocarcinoma has a dismal prognosis; improved understanding of the molecular pathogenesis and advancements in development of targeted therapy offers hope that we may improve outcomes in this rare, but highly lethal cancer. Among the newly discovered molecular alterations, targeting FGFR2 fusions, IDH1/2 mutations and HER2 receptors hold great promise for improving the future management of cholangiocarcinoma. Immunotherapy in combination with targeted agents and chemotherapy may improve outcomes. In addition, drugs targeting the MEK, EGFR, KRAS, BRAF, and ROS1 pathways and neo-angiogenesis may also provide new horizons in the management of cholangiocarcinoma.     

Emerging monoclonal antibodies for the treatment of renal cell carcinoma (RCC)

Introduction: Advanced renal cell carcinoma (RCC) was considered refractory to most cancer therapies until the 1980s, after which immune modulating agents and targeted agents were developed. Recently the rapid development of therapeutic monoclonal antibodies targeting immune checkpoint pathways has provided significant clinical benefit in patients with many distinct cancer types. Nivolumab, an anti-PD1 monoclonal antibody showed improvement in response rate and overall survival in patients with previously treated RCC and received US FDA approval in late 2015. Current efforts with anti-PD1-based therapy include combinations with ipilimumab and with VEGF pathway blockers in the hopes on building on the activity of single agent therapy.

Areas covered: We describe our current understanding of tumor immunology including the basis of the tumor-specific immune response and the adaptive mechanisms used by the tumor for immune escape. We describe the mechanisms of action as well as the therapeutic application of the antibodies, ipilimumab, nivolumab and atezolizumab in patients with RCC. We identify key areas of active research in biomarker development and combination therapies.

Expert opinion: Clinical trials and the field of RCC therapeutics are expected to move in the direction of combination therapies using immune checkpoint inhibitors, extending overall survival as a benchmark for new drug approvals, and biomarker validation for improved selection of patients for specific therapies.     

Emerging drugs for squamous cell lung cancer

Introduction: The management of advanced NSCLC has been shifted by histology-driven treatment and molecularly targeted therapy, especially in lung adenocarcinoma. However, as the second most common histology in NSCLC, the treatment options for squamous cell lung cancer (SQCLC) remain very limited.

Areas covered: The review first discusses the role of histology in management of NSCLC and new cytotoxic agents in SQCLC, and then addresses genomic characterization and potential molecular targets in SQCLC. The article then provides an overview for several major categories of novel molecularly targeted therapies and immune-based strategies with particular attention to ongoing SQCLC trials.

Expert opinion: The key challenges in drug development are to uncover novel actionable targets and to identify predictive biomarkers. Progress in genomic analysis has identified some promising targetable genes and oncogenic pathways in SQCLC with a wave of targeted agents being tested in clinical trials. Immunotherapy has also raised great interest in management of SQCLC, especially agents targeting immune check points, cytotoxic T-lymphocyte antigen-4, programmed death-1 receptor and its ligands. Better understanding of tumor biology and development of novel targeted therapies will help to facilitate more effective personalized therapy for patients with this devastating illness.     

Focal adhesion kinase inhibitors in the treatment of metastatic cancer: a patent review

Introduction: Focal adhesion kinase (FAK) plays a prominent role in integrin signaling. FAK activation increases phosphorylation of Tyr397 and other sites of the protein. FAK-dependent activation of signaling pathways implicated in controlling essential cellular functions including growth, proliferation, survival and migration. FERM (F for the 4.1 protein, ezrin, radixin and moesin) domain-enhanced p53 degradation plays a critical role in proliferation and survival. FAK, overexpressed in metastatic tumors, has emerged as an important therapeutic target for the development of selective inhibitors. FAK inhibitors achieved tumor growth inhibition and induced apoptosis. Strategies targeting FAK inhibition using novel compounds have created an exciting opportunity for anticancer therapy.

Areas covered: This review summarizes the current research with available data from early phase clinical trials and discusses the available small-molecule inhibitors of FAK from patents. The importance of inhibiting FAK activity in cancer patients is discussed.

Expert opinion: Emerging data from clinical trials with orally available small-molecule inhibitors of FAK are promising. Although this approach is appropriate as a targeted therapeutic approach against several metastatic cancer types, several compounds in research are yet to prove their preclinical efficacy. This report lays special emphasis on the available patent data of FAK inhibitors for such targeted molecular therapies. This review summarizes current knowledge about FAK inhibition in cancer therapy.     

Emerging pathways and future targets for the molecular therapy of pancreatic cancer

Introduction: Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing.

Areas covered: This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer.

Expert opinion: Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine–targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.     

Endothelin (ET), its Precursor BigET,and its Receptor,ETA

Introduction: The PI3K signaling pathway is involved in the regulation of cancer cell growth, motility, survival and metabolism. The pathway is frequently active in many different types of cancer—e.g., breast, bladder, prostate, thyroid, ovarian and NSCLC. Targetable genetic aberrations in this pathway give us many opportunities for development of targeted therapies for different types of cancer.

Areas covered: The genetic alterations in the PI3K/mammalian target of rapamycin (mTOR)/Akt pathway, as well as the drugs that target this pathway, either alone, in combination with other targeted agents or in chemotherapy. Targeted inhibitors of the PI3K pathway currently being tested in clinical trials in different types of human cancer.

Expert opinion: Small-molecule inhibitors targeting the PI3K/Akt/mTOR pathway show some success with these agents in current clinical trials. For further improvement in response, molecular correlates that can be used for patient selection, need to be determined. A more efficient and effective way to screen for patients to determine which patients are most likely to benefit from PI3K pathway inhibitors is also needed.     

JAK2 inhibitors in the treatment of myeloproliferative neoplasms

Introduction: Dysregulation of JAK-STAT signaling is a pathogenetic hallmark of myeloproliferative neoplasms (MPNs) arising from several distinct molecular aberrations, including mutations in JAK2, the thrombopoietin receptor (MPL), mutations in negative regulators of JAK-STAT signaling, such as lymphocyte-specific adapter protein (SH2B3), and epigenetic dysregulation as seen with Suppressor of Cytokine Signaling (SOCS) proteins. In addition, growth factor/cytokine stimulatory events activate JAK-STAT signaling independent of mutations.

Areas covered: The various mutations and molecular events activating JAK-STAT signaling in MPNs are reviewed. Detailed inhibitory kinase profiles of the currently developed JAK inhibitors are presented. Clinical trial results for currently developed JAK targeting agents are comprehensively summarized. The limitations of JAK-STAT targeting in MPNs, as well as potential rational combination therapies with JAK2 inhibitors, are discussed.

Expert opinion: Aberrant JAK-STAT signaling is an underlying theme in the pathogenesis of MPNs. While JAK2 inhibitors are active in JAK2V617F and wild-type JAK2 MPNs, JAK2V617F mutation-specific or JAK2-selective inhibitors may possess unique clinical attributes. Complimentary targeting of parallel pathways operating in MPNs may offer novel therapeutic approaches in combination with JAK inhibition. Understanding the intricacies of JAK-STAT pathway activation, including growth factor/cytokine-driven signaling, will open new avenues for therapeutic intervention at known and novel molecular vulnerabilities of MPNs.     

Update on emerging drug therapies for systemic lupus erythematosus

Importance of the field: Despite the improvement in survival of systemic lupus erythematosus (SLE), a cure for this chronic and disabling disease is still a myth. Refractory manifestations and treatment-related complications are still major causes for mortality and morbidity. More effective but less toxic therapies through modification of existing regimens, combination strategies or more specific targeting at the immunopathogenetic pathways are necessary.

Areas covered in this review: The availability of biotechnology has led to the emergence of targeted therapies for SLE. In the past 5 years, there have been a number of clinical trials in the pipeline that involve existing drugs or novel biological agents. This article updates different novel therapeutic approaches in SLE that have emerged since 2006.

What the readers will gain: Readers will read the latest information and critical appraisals regarding recent clinical trials in lupus. Expert opinions on future directions of SLE treatment trials are also provided.

Take home message: SLE is a clinically and immunologically heterogeneous disease. Targeted therapies are currently available but to the disappointment of the lupus community, data from many recent clinical trials are unfavorable. While flaws and limitations in the study design and outcome measures may contribute to the futility of these trials, selection of SLE subsets by serum and cellular biomarkers may identify those who will benefit from these targeted therapies.     

The potential for targeting HER2 therapeutically in esophageal cancer – a grasp at straws?

Introduction: Human EGFR-2 (HER2) has an impact on cellular proliferation and survival. HER2 overexpression has been shown to be a marker for poorer prognosis in several malignancies. Trastuzumab, a humanized mAb, is successfully used to target HER2 in breast cancer. The effect of targeting HER2 in esophageal cancer (EC) is the focus of current trials.

Areas covered: Basic knowledge, detection techniques and definitions of HER2 overexpression, as well as the molecular mechanisms underlying the effects of trastuzumab on HER2, are reviewed. An overview of research on the prognostic and predictive relevance of HER2 in EC is given, as well as an overview of current trials targeting HER2 in EC.

Expert opinion: The first aim of novel targeted therapies must be perioperative neoadjuvant and adjuvant applications, as surgery is the only option for curative treatment in patients with stage I – III EC. Regarding targeted therapies in EC, HER2 is currently the most promising target. Trials of trimodal neoadjuvant therapy regimes (neoadjuvant radiochemotherapy plus trastuzumab) are currently recruiting. However, the prognostic impact of HER2 overexpression in EC remains ambiguous. Targeting HER2 may have negative and positive impacts on survival, depending on which subgroup of EC patients is treated.