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

Leiping Wang1, Qunling Zhang, Jian Zhang

  • 1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.

BMC Cancer
|June 17, 2011
PubMed
Abstract

Insights

Activation of the Phosphatidylinositol-3-kinase (PI3K) pathway, due to PTEN loss or PIK3CA mutations, is linked to reduced sensitivity to lapatinib in HER2-positive breast cancer patients. This PI3K pathway activation may cause resistance to lapatinib and trastuzumab therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacogenomics

Background:

  • HER2-positive breast cancer is dependent on the Phosphatidylinositol-3-kinase (PI3K) pathway.
  • Trastuzumab and lapatinib are standard treatments for HER2-positive breast cancer.
  • Understanding PI3K pathway activation is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To investigate the association between PI3K pathway activation and lapatinib sensitivity.
  • To explore the role of PIK3CA mutations and PTEN loss in HER2-positive metastatic breast cancer.
  • To evaluate the impact of PI3K pathway status on treatment response to lapatinib.

Main Methods:

  • Sixty-seven HER2-positive metastatic breast cancer patients were enrolled in a lapatinib Expanded Access Program.
  • Tumor specimens were analyzed for PIK3CA mutations (PCR sequencing) and PTEN status (immunohistochemistry).
  • Patients received continuous lapatinib and intermittent capecitabine until disease progression or toxicity.

Main Results:

  • PIK3CA mutations were found in 12.3% and PTEN loss in 31.6% of patients.
  • Patients with PI3K pathway activation (mutation and/or PTEN loss) showed lower clinical benefit (36.4%) and overall response rates (9.1%) compared to those without activation (68.6% and 31.4%, respectively).
  • PI3K pathway activation correlated with shorter progression-free survival in patients treated with trastuzumab-containing regimens.

Conclusions:

  • PIK3CA mutations are more frequent in older patients with HER2-positive breast cancer.
  • PIK3CA mutations and PTEN loss can co-occur.
  • Activation of the PI3K pathway, via PTEN loss or PIK3CA mutations, may confer resistance to lapatinib and trastuzumab in HER2-positive breast cancer.

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