Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer

Geyer, Charles E.; Forster, John; Lindquist, Deborah; Chan, Stephen Y.; Romieu, C; Pieńkowski, Tadeusz; Jagiełło-Gruszfeld, Agnieszka; Crown, John; Chan, Arlene; Kaufman, Bella; Skarlos, Dimosthenis; Campone, Mario; Davidson, N.; Berger, Mark S.; Oliva, Cristina; Rubin, Stephen D.; Stein, Steven; Cameron, David

doi:10.1056/nejmoa064320

Cited by 3,128 publications

(2,083 citation statements)

References 16 publications

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“…Although a definitive safety profile for lapatinib must await the completion of several randomized phase III trials in breast cancer, it seems likely that the frequency of cardiac dysfunction will be low. Indeed, in a recent randomized trial in metastatic breast cancer, lapatinib was associated with only a 2.5% incidence of asymptomatic decreased LVEF 33 . How can this be reconciled with the more prominent cardiotoxicity of trastuzumab?…”

Section: Box 1 | Haematological Cancers: Good Targets For Tyrosine Kimentioning

confidence: 99%

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

2007

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Section: Box 1 | Haematological Cancers: Good Targets For Tyrosine Kimentioning

confidence: 99%

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

2007

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“…Similarly, data suggest that lapatinib has a more‐favorable cardiac risk profile than trastuzumab7, 47 and the combination of both does not appear to be more cardiotoxic than the use of trastuzumab alone 6. Trials of ado‐trastuzumab suggest low rates of cardiotoxicity during follow‐up to date 9…”

Section: The Cardiac Risks Of Her2 Targeted Therapiesmentioning

confidence: 99%

“…Lapatinib is an oral small molecule that inhibits the tyrosine kinases of HER2 and epidermal growth factor receptor type 1 (HER1). Clinical studies have not demonstrated significant cardiotoxicity associated with use of lapatinib 7, 47…”

Section: Pathophysiologymentioning

confidence: 99%

“…Development of the monoclonal antibody that targets the extracellular domain of HER2, trastuzumab, revolutionized the care of these patients, leading to large improvements in disease‐free and overall survival 5. In addition, development of newer anti‐HER2 therapies has led to further improvements in cancer outcomes for this population 6, 7, 8, 9…”

Section: Introductionmentioning

confidence: 99%

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Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

Florido

Smith

Cuomo

et al. 2017

JAHA

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“…In the clinic, lapatinib is active and improves time to disease progression in patients with advanced disease who have progressed to trastuzumab (Geyer et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

et al. 2008

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Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially nonoverlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo-(HER2/HER2) and hetero-(HER2/EGFR and HER2/HER3) dimers. Lapatinibinduced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

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Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer

Abstract: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).

Cited by 3,128 publications

References 16 publications

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition

Cardiotoxicity From Human Epidermal Growth Factor Receptor‐2 (HER2) Targeted Therapies

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

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