Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sunitinib malate (SUTENT) is an oral, multitargeted tyrosine kinase inhibitor that blocks several pathways central to angiogenesis and tumor cell proliferation and migration, including vascular endothelial growth factor receptors (VEGFRs) and platelet-derived growth factor receptors (PDGFRs). Sunitinib has demonstrated clinical activity as a single agent in patients with metastatic breast cancer and it is hypothesized that enhanced clinical benefit may be derived by combining sunitinib with chemotherapy or other targeted agents. The current report describes four patients with advanced/metastatic breast cancer who experienced clinically meaningful responses following treatment with sunitinib in combination with docetaxel.
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PMID:Early experience with sunitinib, combined with docetaxel, in patients with metastatic breast cancer. 1974 25

Lapatinib (Tyverb, Tykerb) is an orally active, small molecule, reversible, dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 1 (HER1) and type 2 (HER2). In the EU, lapatinib in combination with capecitabine is indicated for the treatment of women with HER2-overexpressing, advanced or metastatic breast cancer that has progressed after treatment with regimens that include anthracyclines, taxanes and, in the metastatic setting, trastuzumab. The orally administered combination of lapatinib and capecitabine was a more effective treatment than capecitabine alone, and was a generally well tolerated, conveniently administered combination for women with trastuzumab-refractory, HER2-positive advanced or metastatic breast cancer in a clinical trial. Lapatinib combined with capecitabine provides an effective therapeutic option for a group of patients who currently have few treatment choices.
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PMID:Lapatinib: a review of its use in the treatment of HER2-overexpressing, trastuzumab-refractory, advanced or metastatic breast cancer. 1979 30

HER2 is overexpressed in 20-25% of breast cancers and is associated with an aggressive phenotype and poor prognosis. Lapatinib is a dual tyrosine kinase inhibitor selective for inhibition of epidermal growth factor receptor (EGFR1/ErbB1) and HER2/ErbB2. Having more targets, probably its antitumor activity could be more efficient. Preclinical data reveal that lapatinib has activity in trastuzumab-resistant cell lines as well as synergistic activity with trastuzumab. Phase I clinical trials have also shown that lapatinib is well tolerated, with mild diarrhea and skin rush as common toxic effects and low incidence of cardiotoxicity. Lapatinib can cross the blood-brain barrier and might therefore have a role in preventing central-nervous-system progression. In a pivotal phase III trial, a combination of lapatinib and capecitabine almost doubled time to disease progression when compared to capecitabine alone (8.4 vs. 4.1 months) in women with HER2/ErbB2-positive advanced or metastatic breast cancer previously treated with anthracyclin, taxanes and trastuzumab. The overall survival was 15.6 vs. 15.4 months. Several clinical trials that explore the efficacy of lapatinib in combination with conventional chemotherapeutic agents, hormone therapy and other target therapies are ongoing in advanced breast cancer or in neo-adjuvant and adjuvant settings.
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PMID:[Lapatinib treatment-option in trastuzumab-resistant breast cancer]. 2007 9

The discovery of HER2 gene amplification and protein overexpression in approximately 15-20% of breast cancers and access to the tailored humanized antibody, trastuzumab (Herceptin), have heralded a new era in breast cancer therapy. Trastuzumab combined with chemotherapy has caused marked tumor responses and increased overall survival in patients with metastatic breast cancer, and has also increased survival in the adjuvant setting after radical surgery. However, due to many causes, trastuzumab resistance usually occurs during treatment. In this event, possible options include the replacement of trastuzumab with lapatinib, the continuation of trastuzumab after disease progression with changed chemotherapy and the suspension of the use of targeted agents. New-generation tyrosine kinase inhibitors, which have a broader target, are now considered the key to treatment for breast cancer.
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PMID:Trastuzumab and lapatinib beyond trastuzumab progression for metastatic breast cancer: strategies and pitfalls. 2013 94

Greater understanding of the underlying etiology and biology of breast cancer is enabling the clinical development of targeted therapies for metastatic breast cancer (MBC). Following the successful introduction of trastuzumab, the first human epidermal growth factor receptor (HER) biologically targeted therapy to become widely used in MBC patients, other agents have been developed. Novel agents include monoclonal antibodies such as pertuzumab, which bind to receptors on the cell surface, and tyrosine kinase inhibitors (TKIs) such as lapatinib, which target intracellular pathways such as that of the epidermal growth factor receptor. There is also growing clinical experience with antiangiogenic agents, particularly in combination with chemotherapy. These include the monoclonal antibody bevacizumab, which targets vascular endothelial growth factor receptor, and multitargeted TKIs with antiangiogenic and antiproliferative activities, such as sunitinib. Combination treatment with multiple agents targeting both the HER family and angiogenic pathways (e.g., trastuzumab plus bevacizumab) is also showing activity in the clinical setting. Despite recent advances, there are unanswered questions regarding the management of MBC with targeted agents. Future studies are necessary to determine the optimal combinations, doses, and schedules required to maximize clinical activity while minimizing toxicity. Despite the temptation to use a targeted agent in all patients, identification of patient subgroups most likely to benefit must be a key goal and will be critical to the successful future use of these treatments. The aim of this review is to summarize some of the key signaling pathways involved in tumor progression and some of the novel therapies that are in development for MBC.
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PMID:Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review. 2020 40

Metastatic breast cancer to the liver is considered incurable. Though many patients with liver metastases may enjoy response to chemo-, immuno- and hormonal therapy, those so inflicted rarely remain disease-free from the time of diagnosis for longer than 6-11 months. New laboratory and clinical research identified that cross-talk between activation of the epidermal growth factor family of tyrosine kinase transduction pathways (EGF/HER2) and estrogen receptor (ER) activation plays a role in resistance to hormonal therapy. A 59-year-old woman with a 4.5-cm invasive ductal, ER-positive/PR-negative, grade III adenocarcinoma of the breast was treated with mastectomy. Staging revealed biopsy-proven liver metastases. Surgery was immediately followed with vinorelbine, trastuzumab, tamoxifen and exemestane. The patient underwent a bone scan and PET/CT documented complete remission. She has remained in complete remission for 7 years. It is proposed that a possible mechanism for prolonged remission of stage IV breast cancer in this patient may be related to suppression of EGF/HER2 by trastuzumab, thus inhibiting cross-talk-associated tamoxifen/estrogen withdrawal resistance.
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PMID:Inhibition of HER2/estrogen receptor cross-talk, probable relation to prolonged remission of stage IV breast cancer: a case report. 2021 Feb 47

Breast cancer is the second cause of cancer mortality worldwide and there is an unmet need for novel anticancer agents. Lapatinib is a novel tyrosine kinase inhibitor for treatment of breast cancer with human epidermal growth factor receptor 2 (HER2) amplification. Given promising results in clinical studies, we investigated the survival benefits of lapatinib use in patients with HER2-overexpressing advanced or metastatic breast cancer. We searched MEDLINE, EMBASE, American Society of Clinical Oncology Meeting proceedings, San Antonio Breast Cancer Symposia proceedings, and the Cochrane Library between 2000 and 2008 for randomized controlled trials where lapatinib was used as single agent or in combination with or following other therapies. Three trials (n=704) met the inclusion criteria. Study quality was assessed by two independent reviewers and meta-analyses were conducted. Significant differences were observed between lapatinib-containing treatments to those without lapatinib in terms of survival. Pooled estimates suggested the hazard ratios of 0.61 [95% confidence interval (CI): 0.50-0.74] for progression-free survival and 0.76 (95% CI: 0.60-0.97) for overall survival. Objective response rate and clinical benefit rate also showed significant differences in favoring the use of lapatinib with odds ratios of 2.15 (95% CI: 1.48-3.11) and 2.23 (95% CI: 1.59-3.12), respectively. Heterogeneity between studies was not observed. In conclusion, addition of lapatinib to conventional anticancer treatment might offer superior survival benefit to patients with advanced metastatic HER2-overexpressing breast cancer. Further investigations on the use of lapatinib in combination with anticancer agents are warranted.
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PMID:Survival benefits from lapatinib therapy in women with HER2-overexpressing breast cancer: a systematic review. 2022 May 14

HER2 is over-expressed in approximately 25% to 30% of human metastatic breast cancers, primarily due to gene amplification. There are currently two HER2-targeted therapies approved for clinical use, the monoclonal HER2 antibody trastuzumab and the EGFR/HER2 dual tyrosine kinase inhibitor lapatinib. Although both agents show clinical benefit in a subset of patients with metastatic breast cancer, many patients with HER2-over-expressing metastatic breast tumors do not respond to these agents. Furthermore, those who do show an initial response generally demonstrate disease progression, on average in less than one year. It has become clear that HER2 expression status alone does not adequately predict response to HER2-targeted therapy. Identification and clinical validation of molecular predictors of response to trastuzumab and lapatinib is critical for further personalizing treatment and improving clinical benefit for patients whose tumors over-express HER2. In this review, we discuss published data describing potential predictors of response or resistance to trastuzumab and lapatinib. While a discussion of the preclinical work is provided, the emphasis is placed on potential predictors that have been studied in clinical specimens such as tumor tissue or serum obtained from patients treated with HER2-targeted therapy. The present analysis and synthesis of the available literature therefore contribute towards an emerging knowledgebase to personalize breast cancer treatment taking into factors including but beyond HER2 expression.
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PMID:Personalizing HER2-targeted therapy in metastatic breast cancer beyond HER2 status: what we have learned from clinical specimens. 2030 Apr 49

The treatment of metastatic breast cancer is challenging. We recently assisted in the development of targeted therapies (in combination with chemotherapy or as monotherapy) that have improved results for selected groups of patients. Lapatinib is a dual tyrosine kinase inhibitor that has shown efficacy in breast cancer. Consequently, its use has been approved, in combination with capecitabine, for the treatment of disease positive for the human epidermal growth factor receptor. Here, we present a case of complete clinical response to a combination of lapatinib and gemcitabine that was maintained for 1 year.
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PMID:One year of complete clinical response in a metastatic breast cancer patient treated with a combination of lapatinib and gemcitabine. 2040 81

Pazopanib is an oral, multi-targeted, tyrosine kinase inhibitor (TKI) that binds to the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and several other key proteins responsible for angiogenesis, tumor growth and cell survival. Pazopanib exhibited in vivo and in vitro activity against tumor growth and, in early clinical trials, was well tolerated with the main side effects being hypertension, fatigue and gastrointestinal disorders. Pazopanib showed clinical activity in several tumors including renal cell cancer (RCC), breast cancer, soft tissue sarcoma, thyroid cancer, hepatocellular cancer and cervical cancer. A phase III clinical trial in metastatic RCC patients showed a significant improvement in progression-free survival, leading to its approval in the US. In metastatic breast cancer, the combination of pazopanib with lapatinib was more effective than lapatinib alone. At the time of the current publication, pazopanib is being evaluated in more than 35 phase II and III trials.
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PMID:Pazopanib: Clinical development of a potent anti-angiogenic drug. 2045 72


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