Clinical Benefit of Lapatinib-Based Therapy in Patients with Human Epidermal Growth Factor Receptor 2–Positive Breast Tumors Coexpressing the Truncated p95HER2 Receptor

Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
Clinical Cancer Research (Impact Factor: 8.72). 05/2010; 16(9):2688-95. DOI: 10.1158/1078-0432.CCR-09-3407
Source: PubMed


A subgroup of human epidermal growth factor receptor 2 (HER2)-overexpressing breast tumors coexpresses p95HER2, a truncated HER2 receptor that retains a highly functional HER2 kinase domain but lacks the extracellular domain and results in intrinsic trastuzumab resistance. We hypothesized that lapatinib, a HER2 tyrosine kinase inhibitor, would be active in these tumors. We have studied the correlation between p95HER2 expression and response to lapatinib, both in preclinical models and in the clinical setting.
Two different p95HER2 animal models were used for preclinical studies. Expression of p95HER2 was analyzed in HER2-overexpressing breast primary tumors from a first-line lapatinib monotherapy study (EGF20009) and a second-line lapatinib in combination with capecitabine study (EGF100151). p95HER2 expression was correlated with overall response rate (complete + partial response), clinical benefit rate (complete response + partial response + stable disease > or =24 wk), and progression-free survival using logistic regression and Cox proportional hazard models.
Lapatinib inhibited tumor growth and the HER2 downstream signaling of p95HER2-expressing tumors. A total of 68 and 156 tumors from studies EGF20009 and EGF100151 were evaluable, respectively, for p95HER2 detection. The percentage of p95HER2-positive patients was 20.5% in the EGF20009 study and 28.5% in the EGF100151 study. In both studies, there was no statistically significant difference in progression-free survival, clinical benefit rate, and overall response rate between p95HER2-positive and p95HER2-negative tumors.
Lapatinib as a monotherapy or in combination with capecitabine seems to be equally effective in patients with p95HER2-positive and p95HER2-negative HER2-positive breast tumors.

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Available from: Joaquín Arribas,
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    • "Based on available evidences, it is suggested that CTF-expressing breast cancer patients are more likely to experience metastasis and have a poorer prognosis compared with patients expressing wild type HER2 (Molina et al., 2002). In 1998, Christianson et al. showed that CTF-611/CTF-648 expressing breast tumors are associated with lymph node metastasis (Christianson et al., 1998), and resisting to trastuzumab, but respond to lapatinib (Scaltriti et al., 2010). Effectiveness of lapatinib on these tumors is due to its inhibitory role on tyrosine kinase activity which can also inhibit the activity of the CTFs (Pedersen et al., 2009). "
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    ABSTRACT: HER2 overexpression has been observed in 20-30% of breast cancer cases. In addition to main products of HER2 gene, there are other variations, of which, the most important one is Δ16HER2. In principle, although HER2 overexpression is the first step for carcinogenesis, it is not sufficient, and the main reason responsible for breast tumorigenesis is Δ16HER2. This onco-protein, which lacks exon 16, can form stable homodimers remaining active constitutively. Like Δ16HER2, 611-CTF, a specific HER2 carboxy-terminal fragment, expresses a constitutively active homodimers. Therefore, targeting of Δ16HER2 and 611-CTF is the most promising strategy for treating HER2+ breast cancer. Along with inhibitors of HER2 gene products, miRNAs are also novel candidates for treatment of breast malignancy. Several drugs, working against different domains of the HER2 receptor, have been presented for treatment of HER2 positive breast cancers and they can increase mortality in patients.
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    • "General mechanisms of resistance to HER2-targeted therapies occur at three levels.22 The first includes mechanisms intrinsic to the target, such as molecular changes in the target receptor;23 the expression of p95HER2, which is a truncated HER2 receptor;24,25 and HER2 gene amplification.26 Resistance involving parallel signaling pathways bypassing HER2 inhibition, such as increased activation of HER3,27–31 aberrant activation of pathways downstream of the receptor,32–34 and compensatory crosstalk with other pathways, might also occur.23,35–38 "
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    ABSTRACT: Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancers; HER2 overexpression is indicative of poor prognosis. Trastuzumab, an anti-HER2 monoclonal antibody, has led to improved outcomes in patients with HER2-positive breast cancer, including improved overall survival in adjuvant and first-line settings. However, a large proportion of patients with breast cancer have intrinsic resistance to HER2-targeted therapies, and nearly all become resistant to therapy after initial response. Elucidation of underlying mechanisms contributing to HER2 resistance has led to development of novel therapeutic strategies, including those targeting HER2 and downstream pathways, heat shock protein 90, telomerase, and vascular endothelial growth factor inhibitors. Numerous clinical trials are ongoing or completed, including phase 3 data for the mammalian target of rapamycin inhibitor everolimus in patients with HER2-resistant breast cancer. This review considers the molecular mechanisms associated with HER2 resistance and evaluates the evidence for use of evolving strategies in patients with HER2-resistant breast cancer.
    Breast cancer 07/2014; 8(1):109-18. DOI:10.4137/BCBCR.S9453
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    • "When given in combination with capecitabine, this agent significantly improves time to progression [8]. Combined with paclitaxel, lapatinib is active as first-line treatment [9]. Unfortunately, some patients are constitutively resistant to lapatinib treatment, and, even in responders, the disease often progresses because of the selection of tumor cells that have acquired resistance to the drug. "
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    ABSTRACT: Introduction Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which Src overexpression sustains this resistance, we tested a panel of breast cancer cell lines either sensitive or resistant to lapatinib. Methods To determine the role of Src in lapatinib resistance, we evaluated the effects of Src inhibition/silencing in vitro on survival, migration, and invasion of lapatinib-resistant cells. In vivo experiments were performed in JIMT-1 lapatinib-resistant cells orthotopically implanted in nude mice. We used artificial metastasis assays to evaluate the effect of Src inhibition on the invasiveness of lapatinib-resistant cells. Src-dependent signal transduction was investigated with Western blot and ELISA analyses. Results Src activation was higher in lapatinib-resistant than in lapatinib-sensitive cells. The selective small-molecule Src inhibitor saracatinib combined with lapatinib synergistically inhibited the proliferation, migration, and invasion of lapatinib-resistant cells. Saracatinib combined with lapatinib significantly prolonged survival of JIMT-1-xenografted mice compared with saracatinib alone, and impaired the formation of lung metastases. Unexpectedly, in lapatinib-resistant cells, Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than with HER2. Moreover, EGFR targeting and lapatinib synergistically inhibited survival, migration, and invasion of resistant cells, thereby counteracting Src-mediated resistance. These findings demonstrate that Src activation in lapatinib-resistant cells depends on EGFR-dependent rather than on HER2-dependent signaling. Conclusions Complete pharmacologic EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer.
    Breast cancer research: BCR 05/2014; 16(3):R45. DOI:10.1186/bcr3650 · 5.49 Impact Factor
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