Molecular determinants of trastuzumab efficacy: What is their clinical relevance?

De, Pradip; Hasmann, Max; Leyland‐Jones, Brian

doi:10.1016/j.ctrv.2013.02.006

Cited by 52 publications

(41 citation statements)

References 72 publications

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“…Some early results have validated specific cutoff levels of expression that can be assayed in a clinical trial setting [97,108]. In contrast to reports showing resistance to trastuzumab as a single agent, early reports from the GeparQuattro and www.TheOncologist.com [109].…”

Section: Her2 Structural Alterationmentioning

confidence: 99%

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

et al. 2015

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Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually.While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer. The Oncologist 2015; 20:1058-1068Implications for Practice: This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease.

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Section: Her2 Structural Alterationmentioning

confidence: 99%

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer

et al. 2015

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“…Trastuzumab, the first-generation targeted therapy drug, is a humanized monoclonal antibody targeting the extracellular domain of HER-2 (21,22) and has the ability to downregulate the signaling pathways involving PI3K/Akt and MAPK (23,24), which in turn inhibits the proliferation of BC cells that overexpress HER2. Trastuzumab, both administered as a single agent or injected in combination with a series of chemotherapy agents (such as docetaxel or vinorelbine plus trastuzumab (25)(26)(27), showed anti-tumor effects and remarkably improved time to progression, response and survival rate (22,28,29).…”

Section: Current Targeted Therapy Drugsmentioning

confidence: 99%

Novel treatment strategies for patients with HER2‑positive breast cancer who do not benefit from current targeted therapy drugs (Review)

et al. 2018

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Abstract.Human epidermal growth factor receptor-2 positive breast cancer (HER2 + BC) is characterized by a high rate of metastasis and drug resistance. The advent of targeted therapy drugs greatly improves the prognosis of HER2 + BC patients. However, drug resistance or severe side effects have limited the application of targeted therapy drugs. To achieve more effective treatment, considerable research has concentrated on strategies to overcome drug resistance. Abemaciclib (CDK4/6 inhibitor), a new antibody-drug conjugate (ADC), src homology 2 (SH2) containing tyrosine phosphatase-1 (SHP-1) and fatty acid synthase (FASN) have been demonstrated to improve drug resistance. In addition, using an effective vector to accurately deliver drugs to tumors has shown good application prospects. Many studies have also found that natural anti-cancer substances produced effective results during in vitro and in vivo anti-HER2 + BC research. This review aimed to summarize the current status of potential clinical drugs that may benefit HER2 + BC patients in the future.

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“…Moreover, Mitra et al (2009) showed that delta16HER2-positive cells were resistant to in vitro T treatment compared to WT HER2-positive cells and, in a small cohort of HER2-overexpressing human BC cases, also observed that the aggressive features driven by delta16HER2 were mediated by activated Src, which is considered a common node of T-resistance mechanisms (Zhang et al, 2011;De et al, 2013). Indeed, in vitro treatment of delta16HER2-engineered tumor cells with dasatinib, a multi-BCR/Abl and Src family tyrosine kinase inhibitor, led to deactivation of delta16HER2 and its tumorigenic capacity (Mitra et al, 2009).…”

Section: Delta16her2 Splice Variantmentioning

confidence: 99%

“…HER2 amplification and/or overexpression occurs in 20-25% of human breast cancers (BCs) and identifies a particularly aggressive BC subtype with enhanced proliferation, metastatic potential and subsequent decreased survival Prat and Perou, 2011;Cancer Genome Atlas Network, 2012;Hurvitz et al, 2013). Based on HER2 overexpression in malignant breast tumor cells as compared to normal tissues, novel rationally designed targeted agents, such as trastuzumab (T), lapatinib and pertuzumab, have been introduced in the clinical management of BC patients (De et al, 2013;Krop, 2013). In particular, the humanized monoclonal antibody (MAb) T binds to the juxtamembrane region (subdomain IV) of HER2ECD and has been approved in combination with chemotherapy as the standard of care for HER2-positive metastatic BC, in early disease and also, very recently, in the neo-adjuvant setting De et al, 2013).…”

mentioning

confidence: 99%

“…Based on HER2 overexpression in malignant breast tumor cells as compared to normal tissues, novel rationally designed targeted agents, such as trastuzumab (T), lapatinib and pertuzumab, have been introduced in the clinical management of BC patients (De et al, 2013;Krop, 2013). In particular, the humanized monoclonal antibody (MAb) T binds to the juxtamembrane region (subdomain IV) of HER2ECD and has been approved in combination with chemotherapy as the standard of care for HER2-positive metastatic BC, in early disease and also, very recently, in the neo-adjuvant setting De et al, 2013). Although T administration induces significant clinical benefits in a consistent number of patients, tumors progress in a high percentage of cases after one year of treatment and develop de novo or acquired resistance (Rexer and Arteaga, 2012;Wong and Lee, 2012).…”

mentioning

confidence: 99%

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