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Clinical Trial
. 2011 Jun 15:11:248.
doi: 10.1186/1471-2407-11-248.

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

Leiping Wang  1 , Qunling Zhang, Jian Zhang, Si Sun, Haiyi Guo, Zhen Jia, Biyun Wang, Zhimin Shao, Zhonghua Wang, Xichun Hu
Affiliations
Clinical Trial

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

Leiping Wang et al. BMC Cancer. .

Abstract

Background: 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. 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.

Methods: Sixty-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.

Results: PIK3CA 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).

Conclusions: PIK3CA 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.

Trial registration: ClinicalTrials.gov NCT00338247.

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Figures

Figure 1
Figure 1
PTEN gene mutations. Sample 38, 46, 65, 68 have exon 20 missense mutations, H1047R (a); sample 2 has exon 9 missense mutation, E542K (b); sample 11 has exon 9 missense mutation, L540F (c); sample 54 has exon 20 missense mutation, T1052A (d).
Figure 2
Figure 2
PTEN expression. PTEN negative (IRS 0-3, a); Weak Positive (IRS 4-6, b); Positive (IRS 7-9, c); and Strong Positive (IRS 10-12, d).
Figure 3
Figure 3
Overall response rate (ORR) and clinical benefit rate (CBR) grouped by the status of PI3K pathway activation. The ORR was marginally significant between pathway activation group and wild type group; the CBR was statistically significant between pathway activation and wild type groups.
Figure 4
Figure 4
Progression-free survival with objective response, clinical benefit, and PI3K pathway activation. The difference in PFS between patients with response (CR+PR) and those without response (a); the difference in PFS between patients with clinical benefit (CR+PR+SD > 6 months) and those without benefit (b); the difference in PFS between patients with pathway activation and those with no activation (c), and pathway activation status with efficacy of the first Trastuzumab-containing regimen (d).
See this image and copyright information in PMC

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