Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy

Johnston, Stephen; Trudeau, Maureen; Kaufman, Bella; Boussen, Hamouda; Blackwell, Kimberley; LoRusso, Patricia; Lombardi, Donald P.; Ahmed, Slim Ben; Citrin, Dennis L.; DeSilvio, Michelle; Harris, Jennifer L.; Westlund, Ron E.; Salazar, Vanessa; Zaks, Tal; Spector, Neil L.

doi:10.1200/jco.2007.13.9949

Cited by 175 publications

(98 citation statements)

References 40 publications

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“…In first-line patients with trastuzumabnaïve, HER2-positive advanced or MBC, lapatinib monotherapy resulted in 24% ORR . Lapatinib combination therapy has promising efficacy as treatment for HER2-positive advanced or MBC, including treatment-naïve MBC (Geyer et al, 2006;Di Leo et al, 2008;O'Shaughnessy et al, 2008;Johnston et al, 2008a, b). The outcome of this study complements the efficacy reported earlier for lapatinib and confirms that lapatinib offers a beneficial therapeutic option to patients with HER2-overexpressing BC, including those with brain metastases.…”

Section: Discussionsupporting

confidence: 78%

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

et al. 2009

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BACKGROUND: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies. METHODS: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab. RESULTS: For HER2-positive tumours (n ¼ 100), objective response rate was 19.0% (95% confidence interval (CI): 11.8 -28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9 -34.7). One out of 22 HER2-negative tumour was documented as complete response (n ¼ 22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P ¼ 0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib. CONCLUSION: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

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Section: Discussionsupporting

confidence: 78%

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

et al. 2009

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“…In fact, lapatinib was recently shown to restore endocrine sensitivity in breast cancer cells with acquired resistance because of modest adaptive upregulation of HER2 (Leary et al, 2010). Moreover, lack of p53 and phosphorylated HER3 have been associated with better lapatinib responses in HER2-overexpressing patients; HER2-overexpressing tumors also exhibit increased expression of heregulin/ neuregulin (Johnston et al, 2008). Our results for the first time link BTG2-dependent effects on cell transformation to ErbB receptor signaling, and raise the possibility that inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.…”

Section: Discussionmentioning

confidence: 99%

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

et al. 2011

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The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

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“…HER2 overexpression/amplification is widely accepted as a lapatinib therapy response predictor based on the results of several clinical studies 15,85,86 . Coexpression of pHER2 and pHER3 in IBC seems to predict a favorable response to lapatinib even more accurately 87 . On the other hand, HER1 did not predict lapatinib response in various studies 15,40,85,88 .…”

Section: The Her Familymentioning

confidence: 99%

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

Bouchalová¹,

Cizkova²,

Cwiertka³

et al. 2010

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Background. Breast cancer treatment trends are currently based on tailored therapies using tumor and patient biomarkers. Lapatinib is the first dual inhibitor of HER1 (EGFR, ErbB1) and HER2 (ErbB2, Neu) tyrosine kinases to be used in clinical practice. However, only HER2 is currently used for therapy indications and new predictors for the treatment with lapatinib are sought.Methods and results. This minireview focuses on lapatinib and its role in breast cancer treatment. Preclinical and clinical studies as well as pharmacological characteristics are briefly reviewed while the focus is on efficacy assessment including predictive factors for therapy outcome.Conclusion. Lapatinib (Tykerb/Tyverb) was Food and Drug Administration (FDA) approved in 2007 for use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who had received previous treatment (including anthracycline, taxane and trastuzumab containing regimens) and in 2010 for use in combination with letrozole for postmenopausal women with hormonal receptor positive and HER2-positive metastatic breast cancer. In contrast to trastuzumab (Herceptin), lapatinib is orally administered and it targets both HER2 and HER1 receptors. As a synthetic and oral tyrosine kinase inhibitor (TKI), it is convenient, cheaper and easier to produce than monoclonal antibodies. The recommended dosage is not dependent on body weight either. Lapatinib plasma level measurement could be an approach to tailored therapy for further optimizing the dose and prolonging this efficient therapy. New lapatinib response predictors are being evaluated. At this time, only HER2

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Phase II Study of Predictive Biomarker Profiles for Response Targeting Human Epidermal Growth Factor Receptor 2 (HER-2) in Advanced Inflammatory Breast Cancer With Lapatinib Monotherapy

Cited by 175 publications

References 40 publications

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Lapatinib monotherapy in patients with relapsed, advanced, or metastatic breast cancer: efficacy, safety, and biomarker results from Japanese patients phase II studies

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

Lapatinib in Breast Cancer - The Predictive Significance of Her1 (Egfr), Her2, Pten and Pik3ca Genes and Lapatinib Plasma Level Assessment

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