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Management of ErbB2-positive breast cancer: insights from preclinical and clinical studies with lapatinib.

Vogel C, Chan A, Gril B, Kim SB, Kurebayashi J, Liu L, Lu YS, Moon H - Jpn. J. Clin. Oncol. (2010)

Bottom Line: Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer.Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases.Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center at Deerfield Beach, University of Miami Miller School of Medicine, 1192 East Newport Center Drive, Deerfield Beach, FL 33442, USA. drcvogel@aol.com

ABSTRACT
The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.

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Molecular crosstalk between the ER and ErbB1/ErbB2 cellular signaling pathways in endocrine-resistant ErbB2-positive breast cancer cells. Estrogen bound to the ER activates estrogen-regulated genes via a classical signaling pathway. ErbB1/ErbB2 stimulation by growth factors results in activation of the PI3K/Akt and MAPK signaling pathways, leading to tumor cell growth. Long-term tamoxifen therapy may promote endocrine resistance via bidirectional crosstalk between the ER and growth factor receptor (i.e. IGF-1R or ErbB1/ErbB2) signaling pathway components. Bidirectional activation of these pathways promotes ER phosphorylation and ER target gene transcription as well as ErbB1/ErbB2/MAPK-mediated signaling and IGF-1R-mediated PI3K/Akt growth signaling pathways. Modulation of these pathways by combined use of lapatinib and anti-estrogen therapy (e.g. letrozole) may overcome endocrine resistance. CBP, cAMP response element binding protein (CREB)-binding protein; ER, estrogen receptor; ErbB1, human epidermal growth factor receptor 1; ErbB2, human epidermal growth factor receptor 2; mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; P, phosphate; p90RSK, p90 ribosomal S6 kinase; p160, p160 steroid receptor co-activator protein(s); PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RAF, murine leukemia viral oncogene homologue 1; SOS, son-of-seven less guanine nucleotide exchange factor. Figure adapted from the publication by Johnston (64) (Fig. 1) with permission from the American Association for Cancer Research.
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HYQ084F5: Molecular crosstalk between the ER and ErbB1/ErbB2 cellular signaling pathways in endocrine-resistant ErbB2-positive breast cancer cells. Estrogen bound to the ER activates estrogen-regulated genes via a classical signaling pathway. ErbB1/ErbB2 stimulation by growth factors results in activation of the PI3K/Akt and MAPK signaling pathways, leading to tumor cell growth. Long-term tamoxifen therapy may promote endocrine resistance via bidirectional crosstalk between the ER and growth factor receptor (i.e. IGF-1R or ErbB1/ErbB2) signaling pathway components. Bidirectional activation of these pathways promotes ER phosphorylation and ER target gene transcription as well as ErbB1/ErbB2/MAPK-mediated signaling and IGF-1R-mediated PI3K/Akt growth signaling pathways. Modulation of these pathways by combined use of lapatinib and anti-estrogen therapy (e.g. letrozole) may overcome endocrine resistance. CBP, cAMP response element binding protein (CREB)-binding protein; ER, estrogen receptor; ErbB1, human epidermal growth factor receptor 1; ErbB2, human epidermal growth factor receptor 2; mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; P, phosphate; p90RSK, p90 ribosomal S6 kinase; p160, p160 steroid receptor co-activator protein(s); PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RAF, murine leukemia viral oncogene homologue 1; SOS, son-of-seven less guanine nucleotide exchange factor. Figure adapted from the publication by Johnston (64) (Fig. 1) with permission from the American Association for Cancer Research.

Mentions: As ErbB2+ tumors have an increased resistance to endocrine therapy, compared with ErbB2-negative (ErbB2–) tumors (31,63), much attention has focused on whether anti-ErbB2 therapies might restore or enhance sensitivity to endocrine therapies. The molecular crosstalk between the estrogen receptor (ER) and the ErbB1/ErbB2 signaling pathways may contribute to endocrine resistance (64) (Fig. 5). Therefore, treatments that interfere with the ErbB1/ErbB2 signaling pathway, such as lapatinib, have the potential to modify ER and ErbB crosstalk and subsequently restore sensitivity to endocrine therapy. Results from preclinical studies support this hypothesis. Lapatinib and tamoxifen effectively inhibited the growth of tamoxifen-resistant breast cancer xenograft tumors in vivo; both the rate and volume of tumor growth were reduced with combined treatment (60). Lapatinib in combination with estrogen deprivation also effectively blocked the growth of lapatinib-resistant ErbB2+ breast cancer cell colonies (31).Figure 5.


Management of ErbB2-positive breast cancer: insights from preclinical and clinical studies with lapatinib.

Vogel C, Chan A, Gril B, Kim SB, Kurebayashi J, Liu L, Lu YS, Moon H - Jpn. J. Clin. Oncol. (2010)

Molecular crosstalk between the ER and ErbB1/ErbB2 cellular signaling pathways in endocrine-resistant ErbB2-positive breast cancer cells. Estrogen bound to the ER activates estrogen-regulated genes via a classical signaling pathway. ErbB1/ErbB2 stimulation by growth factors results in activation of the PI3K/Akt and MAPK signaling pathways, leading to tumor cell growth. Long-term tamoxifen therapy may promote endocrine resistance via bidirectional crosstalk between the ER and growth factor receptor (i.e. IGF-1R or ErbB1/ErbB2) signaling pathway components. Bidirectional activation of these pathways promotes ER phosphorylation and ER target gene transcription as well as ErbB1/ErbB2/MAPK-mediated signaling and IGF-1R-mediated PI3K/Akt growth signaling pathways. Modulation of these pathways by combined use of lapatinib and anti-estrogen therapy (e.g. letrozole) may overcome endocrine resistance. CBP, cAMP response element binding protein (CREB)-binding protein; ER, estrogen receptor; ErbB1, human epidermal growth factor receptor 1; ErbB2, human epidermal growth factor receptor 2; mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; P, phosphate; p90RSK, p90 ribosomal S6 kinase; p160, p160 steroid receptor co-activator protein(s); PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RAF, murine leukemia viral oncogene homologue 1; SOS, son-of-seven less guanine nucleotide exchange factor. Figure adapted from the publication by Johnston (64) (Fig. 1) with permission from the American Association for Cancer Research.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2964177&req=5

HYQ084F5: Molecular crosstalk between the ER and ErbB1/ErbB2 cellular signaling pathways in endocrine-resistant ErbB2-positive breast cancer cells. Estrogen bound to the ER activates estrogen-regulated genes via a classical signaling pathway. ErbB1/ErbB2 stimulation by growth factors results in activation of the PI3K/Akt and MAPK signaling pathways, leading to tumor cell growth. Long-term tamoxifen therapy may promote endocrine resistance via bidirectional crosstalk between the ER and growth factor receptor (i.e. IGF-1R or ErbB1/ErbB2) signaling pathway components. Bidirectional activation of these pathways promotes ER phosphorylation and ER target gene transcription as well as ErbB1/ErbB2/MAPK-mediated signaling and IGF-1R-mediated PI3K/Akt growth signaling pathways. Modulation of these pathways by combined use of lapatinib and anti-estrogen therapy (e.g. letrozole) may overcome endocrine resistance. CBP, cAMP response element binding protein (CREB)-binding protein; ER, estrogen receptor; ErbB1, human epidermal growth factor receptor 1; ErbB2, human epidermal growth factor receptor 2; mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; P, phosphate; p90RSK, p90 ribosomal S6 kinase; p160, p160 steroid receptor co-activator protein(s); PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RAF, murine leukemia viral oncogene homologue 1; SOS, son-of-seven less guanine nucleotide exchange factor. Figure adapted from the publication by Johnston (64) (Fig. 1) with permission from the American Association for Cancer Research.
Mentions: As ErbB2+ tumors have an increased resistance to endocrine therapy, compared with ErbB2-negative (ErbB2–) tumors (31,63), much attention has focused on whether anti-ErbB2 therapies might restore or enhance sensitivity to endocrine therapies. The molecular crosstalk between the estrogen receptor (ER) and the ErbB1/ErbB2 signaling pathways may contribute to endocrine resistance (64) (Fig. 5). Therefore, treatments that interfere with the ErbB1/ErbB2 signaling pathway, such as lapatinib, have the potential to modify ER and ErbB crosstalk and subsequently restore sensitivity to endocrine therapy. Results from preclinical studies support this hypothesis. Lapatinib and tamoxifen effectively inhibited the growth of tamoxifen-resistant breast cancer xenograft tumors in vivo; both the rate and volume of tumor growth were reduced with combined treatment (60). Lapatinib in combination with estrogen deprivation also effectively blocked the growth of lapatinib-resistant ErbB2+ breast cancer cell colonies (31).Figure 5.

Bottom Line: Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer.Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases.Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center at Deerfield Beach, University of Miami Miller School of Medicine, 1192 East Newport Center Drive, Deerfield Beach, FL 33442, USA. drcvogel@aol.com

ABSTRACT
The management of human epidermal growth factor receptor 2-positive (ErbB2+) breast cancer is challenging; patients with ErbB2+ breast tumors have more aggressive disease and a poor prognosis. The increasing incidence of breast cancer in Asia and the limitations of existing treatments pose additional challenges. In this review, we summarize the preclinical and clinical evidence that indicates how lapatinib, a novel inhibitor that targets the human epidermal growth factor receptor (ErbB1) and ErbB2 may help clinicians address four particularly challenging issues in the management of ErbB2+ breast cancer. These issues are: (i) trastuzumab therapy failure, (ii) development of central nervous system metastases, (iii) minimizing toxicity and (iv) selecting the most appropriate partners (chemotherapy and non-chemotherapy) for combination therapy with lapatinib. Lapatinib, in combination with chemotherapeutic agents, such as capecitabine, provides clinical benefits to patients with ErbB2+ breast cancer, including patients who develop progressive disease on trastuzumab. Lapatinib, in combination with non-chemotherapeutic agents, such as letrozole, may also provide a chemotherapy-free treatment option for postmenopausal patients with estrogen receptor-positive/ErbB2+ metastatic breast cancer. Encouraging results have also emerged regarding the synergistic effects of lapatinib in combination with other agents for the treatment of ErbB2+ breast cancer. Promising findings have also been reported for the use of lapatinib to prevent and treat central nervous system metastases. Collectively, these results indicate that the judicious use of lapatinib, an effective oral therapy with a manageable toxicity profile, can enhance the management of patients with ErbB2+ breast cancer.

Show MeSH
Related in: MedlinePlus