The predictive role of phosphatase and tensin homolog (PTEN) loss, phosphoinositol-3 (PI3) kinase (PIK3CA) mutation, and PI3K pathway activation in sensitivity to trastuzumab in HER2-positive breast cancer: a meta-analysis

Abstract

Objective:

Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be related to trastuzumab resistance in in vitro studies; however, this issue in clinical studies is controversial. Therefore, we conducted a meta-analysis to assess the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in HER2-positive breast cancer patients.

Methods:

A computerized search was performed through the PubMed database, the online proceedings of the American Society of Clinical Oncology Annual Meetings, the San Antonio Breast Cancer Symposium and the International St. Gallen Breast Cancer Conference. Ten eligible studies including 1889 cases were identified.

Results:

In HER2-positive locally advanced breast cancer patients, neither PTEN loss, PIK3CA mutation nor PI3K activation was associated with the response rate of trastuzumab-based neoadjuvant treatment (PTEN loss: RR = 0.687, 95% CI: 0.439–1.074, P = 0.099; PIK3CA mutation: RR = 1.114, 95% CI: 0.453–2.735, P = 0.814; PI3K activation: RR = 0.787, 95% CI: 0.417–1.484, P = 0.459; RR = 0.772, 95% CI: 0.387–1.539, P = 0.462). In HER2-positive early stage breast cancer patients, PTEN loss was not associated with the disease-free survival (DFS) rate of trastuzumab-based adjuvant treatment (HR = 1.096, 95% CI: 0.706–1.700, P = 0.684). In HER2-positive recurrent or metastatic breast cancer patients, PTEN loss was significantly correlated with poorer efficacy of trastuzumab-based salvage treatment (RR = 0.682, 95% CI: 0.550–0.846, P = 0.000).

Conclusions:

In HER2-positive recurrent or metastatic breast cancer patients PTEN loss might indicate resistance to trastuzumab-based salvage treatment. Due to the small sample size and the considerable heterogeneity in the chemotherapy treatment regimens, further research is needed to clarify the association between PTEN loss, PIK3CA mutation and the efficacy of trastuzumab-based treatment in neoadjuvant and adjuvant settings.

Keywords::

• Breast cancer·
• Meta-analysis
• PI3K activation·
• PIK3CA mutation·
• PTEN loss·
• Trastuzumab

Transparency

Declaration of funding

The authors received no external funding sources for this study.

Author contributions: J.L. is responsible for all of the following: (1) the conception and design of the study, and acquisition, analysis and interpretation of data, (2) revising the article, (3) final approval of the version to be submitted. Y.W., Y.L., Y.D. and W.Y. have contributed to the following: (1) acquisition, analysis and interpretation of data, (2) drafting and revising the article.

Declaration of financial/other relationships

Y.W., Y.L., Y.D., W.Y. and J.L. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.