Abstract
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).
Highlights
Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in HER2-positive breast cancer which are dependent on or “addictive” to the Phosphatidylinositol-3-kinase (PI3K) pathway
It is well known that dysregulation of PI3K pathway plays an important role in the development of malignancy, and the most common genetic alterations in this pathway are Phosphatidylinositol-3-kinase catalytic subunit (PIK3CA) mutation and PTEN loss [16,17], both of which can lead to constitutive activation of PI3K pathway and resistance to trastuzumab [7]
Patients were required to have evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST); an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; a left ventricular ejection fraction (LVEF) within the institution’s normal range; a life expectancy of at least 12 weeks; and adequate renal, hepatic, and hematologic function. patients with central nervous system (CNS) metastases were eligible if they were clinically stable for at least 3 months after discontinuation of radiation therapy. patients with preexisting heart disease or conditions that could affect gastrointestinal absorption were ineligible
Summary
Human 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. Human epidermal growth factor receptor 2 (HER2) is the most crucial ErbB receptor tyrosine kinase (RTK) family member in breast cancer with overexpression in about one fourth of patients [1]. It is well known that dysregulation of PI3K pathway plays an important role in the development of malignancy, and the most common genetic alterations in this pathway are PIK3CA mutation and PTEN loss [16,17], both of which can lead to constitutive activation of PI3K pathway and resistance to trastuzumab [7]. PI3K pathway activation resulting from PIK3CA mutation and/or PTEN loss warrants further studies
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