PI3K pathway activation results in low efficacy of both trastuzumab and lapatinib

BMC Cancer

Research Article

Zhimin Shao¹  Biyun Wang²  Leiping Wang²  Xichun Hu²  Jian Zhang²  Si Sun²  Qunling Zhang²  Haiyi Guo²  Zhen Jia²  Zhonghua Wang² 

[1] Department of Breast Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China;Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China;

关键词: Trastuzumab;    Capecitabine;    Lapatinib;    PI3K Pathway;    PIK3CA Mutation;   

DOI  :  10.1186/1471-2407-11-248

 received in 2011-03-16, accepted in 2011-06-15,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundHuman epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive (refered to HER2-overexpressing) breast cancer which are dependent on or "addictive" to the Phosphatidylinositol-3-kinase (PI3K) pathway. HER2-related target drugs trastuzumab and lapatinib have been the foundation of treatment of HER2--positive breast cancer. This study was designed to explore the relationship between PI3K pathway activation and the sensitivity to lapatinib in HER2--positive metastatic breast cancer patients pretreated with anthracyclins, taxanes and trastuzumab.MethodsSixty-seven HER2-positive metastatic breast cancer patients were recruited into a global lapatinib Expanded Access Program and 57 patients have primary tumor specimens available for determination of PI3K pathway status. PTEN status was determined by immunohistochemical staining and PIK3CA mutations were detected via PCR sequencing. All patients were treated with lapatinib 1250 mg/day continuously and capecitabine 1000 mg/m2 twice daily on a 2-week-on and 1-week-off schedule until disease progression, death, withdrawal of informed consent, or intolerable toxicity.ResultsPIK3CA mutations and PTEN loss were detected in 12.3% (7/57) and 31.6% (18/57) of the patients, respectively. Twenty-two patients with PI3K pathway activation (defined as PIK3CA mutation and/or PTEN expression loss) had a lower clinical benefit rate (36.4% versus 68.6%, P = 0.017) and a lower overall response rate (9.1% versus 31.4%, P = 0.05), when compared with the 35 patients with no activation. A retrospective analysis of first trastuzumab-containing regimen treatment data showed that PI3K pathway activation correlated with a shorter median progression-free survival (4.5 versus 9.0 months, P = 0.013).ConclusionsPIK3CA mutations occur more frequently in elder patients for HER2-positive breast cancer. PIK3CA mutations and PTEN loss are not mutually exclusive. PI3K pathway activation resulting from PTEN loss or PIK3CA mutations may lead to drug resistance to lapatinib and trastuzumab (http://ClinicalTrials.gov number, NCT00338247).

【 授权许可】

Unknown   
© Wang et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.