Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2011 Oct 21

PMID 22011930

Citations 106

Authors

Kunal S Taskar

Vinay Rudraraju

Rajendar K Mittapalli

Ramakrishna Samala

Helen R Thorsheim

Julie Lockman

Brunilde Gril

Emily Hua

Diane Palmieri

Joseph W Polli

Stephen Castellino

Stephen D Rubin

Paul R Lockman

Patricia S Steeg

Quentin R Smith

Affiliations

Soon will be listed here.

Abstract

Purpose: Lapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following (14)C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer.

Methods: Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.

Results: (14)C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7-9-fold greater than surrounding brain tissue at 2 and 12 h after oral administration. However, average lapatinib concentration in brain metastases was still only 10-20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells cultured ex vivo from treated brains.

Conclusions: Results show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.

Citing Articles

Molecular heterogeneity and MYC dysregulation in triple-negative breast cancer: genomic advances and therapeutic implications.

Priya , Kumar A, Kumar D 3 Biotech. 2025; 15(1):33.

PMID: 39777154 PMC: 11700964. DOI: 10.1007/s13205-024-04195-0.

Retrospective Analysis of Pyrotinib-Based Therapy for Metastatic Breast Cancer: Promising Efficacy in Combination with Trastuzumab.

Gu Q, Zhu M, Wang Y, Gu Y Breast Cancer (Dove Med Press). 2024; 16:253-268.

PMID: 38812479 PMC: 11135571. DOI: 10.2147/BCTT.S457845.

Brain-targeted drug delivery - nanovesicles directed to specific brain cells by brain-targeting ligands.

Moreira R, Nobrega C, de Almeida L, Mendonca L J Nanobiotechnology. 2024; 22(1):260.

PMID: 38760847 PMC: 11100082. DOI: 10.1186/s12951-024-02511-7.

Single-particle imaging of nanomedicine entering the brain.

Wei M, Qian N, Gao X, Lang X, Song D, Min W Proc Natl Acad Sci U S A. 2024; 121(5):e2309811121.

PMID: 38252832 PMC: 10835139. DOI: 10.1073/pnas.2309811121.

Breaking Barriers in Neuro-Oncology: A Scoping Literature Review on Invasive and Non-Invasive Techniques for Blood-Brain Barrier Disruption.

Pinkiewicz M, Pinkiewicz M, Walecki J, Zaczynski A, Zawadzki M Cancers (Basel). 2024; 16(1).

PMID: 38201663 PMC: 10778052. DOI: 10.3390/cancers16010236.

References

Sutherland S, Ashley S, Miles D, Chan S, Wardley A, Davidson N . Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases--the UK experience. Br J Cancer. 2010; 102(6):995-1002. PMC: 2844035. DOI: 10.1038/sj.bjc.6605586. View

Rusnak D, Affleck K, Cockerill S, Stubberfield C, Harris R, Page M . The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. Cancer Res. 2001; 61(19):7196-203. View

Wood E, Truesdale A, McDonald O, Yuan D, Hassell A, Dickerson S . A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res. 2004; 64(18):6652-9. DOI: 10.1158/0008-5472.CAN-04-1168. View

Lockman P, Mittapalli R, Taskar K, Rudraraju V, Gril B, Bohn K . Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010; 16(23):5664-78. PMC: 2999649. DOI: 10.1158/1078-0432.CCR-10-1564. View

Stemmler H, Schmitt M, Willems A, Bernhard H, Harbeck N, Heinemann V . Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood-brain barrier. Anticancer Drugs. 2006; 18(1):23-8. DOI: 10.1097/01.cad.0000236313.50833.ee. View

Clayton A, Danson S, Jolly S, Ryder W, Burt P, Stewart A . Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer. Br J Cancer. 2004; 91(4):639-43. PMC: 2364775. DOI: 10.1038/sj.bjc.6601970. View

Ryan Q, Ibrahim A, Cohen M, Johnson J, Ko C, Sridhara R . FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist. 2008; 13(10):1114-9. DOI: 10.1634/theoncologist.2008-0816. View

Hasegawa H, Ushio Y, Hayakawa T, Yamada K, Mogami H . Changes of the blood-brain barrier in experimental metastatic brain tumors. J Neurosurg. 1983; 59(2):304-10. DOI: 10.3171/jns.1983.59.2.0304. View

Pestalozzi B, Brignoli S . Trastuzumab in CSF. J Clin Oncol. 2000; 18(11):2349-51. DOI: 10.1200/JCO.2000.18.11.2349. View

10.

Gerstner E, Fine R . Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007; 25(16):2306-12. DOI: 10.1200/JCO.2006.10.0677. View

11.

Scheffler M, Di Gion P, Doroshyenko O, Wolf J, Fuhr U . Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on 4-anilinoquinazolines. Clin Pharmacokinet. 2011; 50(6):371-403. DOI: 10.2165/11587020-000000000-00000. View

12.

Metro G, Foglietta J, Russillo M, Stocchi L, Vidiri A, Giannarelli D . Clinical outcome of patients with brain metastases from HER2-positive breast cancer treated with lapatinib and capecitabine. Ann Oncol. 2010; 22(3):625-630. DOI: 10.1093/annonc/mdq434. View

13.

Hynes N, Lane H . ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005; 5(5):341-54. DOI: 10.1038/nrc1609. View

14.

Palmieri D, Bronder J, Herring J, Yoneda T, Weil R, Stark A . Her-2 overexpression increases the metastatic outgrowth of breast cancer cells in the brain. Cancer Res. 2007; 67(9):4190-8. DOI: 10.1158/0008-5472.CAN-06-3316. View

15.

Bria E, Cuppone F, Fornier M, Nistico C, Carlini P, Milella M . Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials. Breast Cancer Res Treat. 2007; 109(2):231-9. DOI: 10.1007/s10549-007-9663-z. View

16.

Kinoshita M, McDannold N, Jolesz F, Hynynen K . Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A. 2006; 103(31):11719-23. PMC: 1544236. DOI: 10.1073/pnas.0604318103. View

17.

Pestalozzi B . Correction: Meningeal carcinomatosis from breast carcinoma responsive to trastuzumab. J Clin Oncol. 2001; 19(20):4091. View

18.

Lin N, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler H . Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009; 15(4):1452-9. DOI: 10.1158/1078-0432.CCR-08-1080. View

19.

Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R . Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res. 2009; 69(17):6871-8. DOI: 10.1158/0008-5472.CAN-08-4490. View

20.

Steeg P, Camphausen K, Smith Q . Brain metastases as preventive and therapeutic targets. Nat Rev Cancer. 2011; 11(5):352-63. PMC: 7351203. DOI: 10.1038/nrc3053. View