Bi-weekly very-high-dose lapatinib: an easy-to-use active option in HER-2-positive breast cancer patients with meningeal carcinomatosis
The erbb2 gene, which encodes the growth factor receptor HER2, is amplied and overexpressed in 1525 % of breast cancers, associated with poorer prognosis before the use of HER2 targeting agents. In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and do...
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| Veröffentlicht in: | Breast cancer research and treatment 2016-05, Vol.157 (1), p.191-192 |
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| creator | Lavaud, P. Rousseau, B. Ajgal, Z. Arrondeau, J. Huillard, O. Alexandre, J. Hulin, A. Goldwasser, F. |
| description | The erbb2 gene, which encodes the growth factor receptor HER2, is amplied and overexpressed in 1525 % of breast cancers, associated with poorer prognosis before the use of HER2 targeting agents. In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel signicantly improved the median overall survival to 56.5 months [1]. Prolonged survival combined with high neurotropism of HER2-amplied tumors results in increasing incidence of leptomeningeal metastases. Due to very limited options, this situation represents an emerging issue. The prognosis of breast cancer patients with meningeal carcinomatosis is very poor with a reported median survival of 4.5 months with high-dose intrathecal methotrexate [2]. Of crucial importance, comparison of HER2 statuses in cerebrospinal uid-derived tumor cells from patients with metastatic breast cancer with leptomeningeal carcinomatosis and corresponding archival primary tumors revealed a very concordance rate [3]. Furthermore, because of the high molecular weight of trastuzumab and pertuzumab, unable to cross the bloodbrain barrier, leptomeninges may be a sanctuary for cancer cells to monoclonal antibodies. Consequently, meningeal metastases may result from a pharmacokinetic limitation to treatment delivery rather than from a molecular resistance to HER2 blockade. The pulsatile administration of high doses of tyrosine kinase inhibitors is a potential way to obtain a very high plasma maximal concentration, resulting in active concentrations in the leptomeninges [4]. Lapatinib, a reversible dual tyrosine kinase inhibitor of EGFR and HER2, is active in patients with HER2-positive metastatic breast cancer. Because it has a small molecular weight and is lipophilic, we hypothesized that very high doses of lapatinib may circumvent the sanctuary effect in case of HER2-positive breast cancer with leptomeningeal metastases. |
| doi_str_mv | 10.1007/s10549-016-3798-8 |
| format | Article |
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In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel signicantly improved the median overall survival to 56.5 months [1]. Prolonged survival combined with high neurotropism of HER2-amplied tumors results in increasing incidence of leptomeningeal metastases. Due to very limited options, this situation represents an emerging issue. The prognosis of breast cancer patients with meningeal carcinomatosis is very poor with a reported median survival of 4.5 months with high-dose intrathecal methotrexate [2]. Of crucial importance, comparison of HER2 statuses in cerebrospinal uid-derived tumor cells from patients with metastatic breast cancer with leptomeningeal carcinomatosis and corresponding archival primary tumors revealed a very concordance rate [3]. Furthermore, because of the high molecular weight of trastuzumab and pertuzumab, unable to cross the bloodbrain barrier, leptomeninges may be a sanctuary for cancer cells to monoclonal antibodies. Consequently, meningeal metastases may result from a pharmacokinetic limitation to treatment delivery rather than from a molecular resistance to HER2 blockade. The pulsatile administration of high doses of tyrosine kinase inhibitors is a potential way to obtain a very high plasma maximal concentration, resulting in active concentrations in the leptomeninges [4]. Lapatinib, a reversible dual tyrosine kinase inhibitor of EGFR and HER2, is active in patients with HER2-positive metastatic breast cancer. 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In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel signicantly improved the median overall survival to 56.5 months [1]. Prolonged survival combined with high neurotropism of HER2-amplied tumors results in increasing incidence of leptomeningeal metastases. Due to very limited options, this situation represents an emerging issue. The prognosis of breast cancer patients with meningeal carcinomatosis is very poor with a reported median survival of 4.5 months with high-dose intrathecal methotrexate [2]. Of crucial importance, comparison of HER2 statuses in cerebrospinal uid-derived tumor cells from patients with metastatic breast cancer with leptomeningeal carcinomatosis and corresponding archival primary tumors revealed a very concordance rate [3]. Furthermore, because of the high molecular weight of trastuzumab and pertuzumab, unable to cross the bloodbrain barrier, leptomeninges may be a sanctuary for cancer cells to monoclonal antibodies. Consequently, meningeal metastases may result from a pharmacokinetic limitation to treatment delivery rather than from a molecular resistance to HER2 blockade. The pulsatile administration of high doses of tyrosine kinase inhibitors is a potential way to obtain a very high plasma maximal concentration, resulting in active concentrations in the leptomeninges [4]. Lapatinib, a reversible dual tyrosine kinase inhibitor of EGFR and HER2, is active in patients with HER2-positive metastatic breast cancer. 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Academic</collection><jtitle>Breast cancer research and treatment</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lavaud, P.</au><au>Rousseau, B.</au><au>Ajgal, Z.</au><au>Arrondeau, J.</au><au>Huillard, O.</au><au>Alexandre, J.</au><au>Hulin, A.</au><au>Goldwasser, F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bi-weekly very-high-dose lapatinib: an easy-to-use active option in HER-2-positive breast cancer patients with meningeal carcinomatosis</atitle><jtitle>Breast cancer research and treatment</jtitle><stitle>Breast Cancer Res Treat</stitle><addtitle>Breast Cancer Res Treat</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>157</volume><issue>1</issue><spage>191</spage><epage>192</epage><pages>191-192</pages><issn>0167-6806</issn><eissn>1573-7217</eissn><coden>BCTRD6</coden><abstract>The erbb2 gene, which encodes the growth factor receptor HER2, is amplied and overexpressed in 1525 % of breast cancers, associated with poorer prognosis before the use of HER2 targeting agents. In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel signicantly improved the median overall survival to 56.5 months [1]. Prolonged survival combined with high neurotropism of HER2-amplied tumors results in increasing incidence of leptomeningeal metastases. Due to very limited options, this situation represents an emerging issue. The prognosis of breast cancer patients with meningeal carcinomatosis is very poor with a reported median survival of 4.5 months with high-dose intrathecal methotrexate [2]. Of crucial importance, comparison of HER2 statuses in cerebrospinal uid-derived tumor cells from patients with metastatic breast cancer with leptomeningeal carcinomatosis and corresponding archival primary tumors revealed a very concordance rate [3]. Furthermore, because of the high molecular weight of trastuzumab and pertuzumab, unable to cross the bloodbrain barrier, leptomeninges may be a sanctuary for cancer cells to monoclonal antibodies. Consequently, meningeal metastases may result from a pharmacokinetic limitation to treatment delivery rather than from a molecular resistance to HER2 blockade. The pulsatile administration of high doses of tyrosine kinase inhibitors is a potential way to obtain a very high plasma maximal concentration, resulting in active concentrations in the leptomeninges [4]. Lapatinib, a reversible dual tyrosine kinase inhibitor of EGFR and HER2, is active in patients with HER2-positive metastatic breast cancer. Because it has a small molecular weight and is lipophilic, we hypothesized that very high doses of lapatinib may circumvent the sanctuary effect in case of HER2-positive breast cancer with leptomeningeal metastases.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>27106482</pmid><doi>10.1007/s10549-016-3798-8</doi><tpages>2</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Breast cancer research and treatment, 2016-05, Vol.157 (1), p.191-192 |
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| source | MEDLINE; SpringerNature Journals |
| subjects | Aged Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - blood Antineoplastic Agents - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Bone Neoplasms - drug therapy Bone Neoplasms - secondary Breast cancer Breast Neoplasms - pathology Brief Report Cancer patients Cancer research Cancer therapies Care and treatment Diarrhea - chemically induced Dosage and administration Female Gene expression Humans Liver Neoplasms - drug therapy Liver Neoplasms - secondary Magnetic Resonance Imaging Medicine Medicine & Public Health Meningeal Carcinomatosis - diagnostic imaging Meningeal Carcinomatosis - drug therapy Meningeal Carcinomatosis - secondary Metastasis Oncology Quinazolines - administration & dosage Quinazolines - adverse effects Quinazolines - blood Quinazolines - therapeutic use Receptor, ErbB-2 - metabolism Trastuzumab - therapeutic use Treatment Outcome |
| title | Bi-weekly very-high-dose lapatinib: an easy-to-use active option in HER-2-positive breast cancer patients with meningeal carcinomatosis |
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