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Breast Cancer Res Treat. 2018 Feb;167(3):731-740. doi: 10.1007/s10549-017-4533-9. Epub 2017 Nov 7.

Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer.

Author information

1
Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA. rimawi@bcm.edu.
2
Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine and Baylor St. Luke's Medical Center, BCM 600, One Baylor Plaza, Houston, TX, 77030, USA.
3
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Vanderbilt University, Nashville, TN, USA.
5
University of Alabama at Birmingham, Birmingham, AL, USA.
6
University of Chicago, Chicago, IL, USA.
7
Mayo Clinic, Rochester, MN, USA.
8
Houston Methodist Hospital, Houston, TX, USA.
9
Dana-Farber Cancer Institute, Boston, MA, USA.
10
Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
11
University of Pennsylvania, Philadelphia, PA, USA.

Abstract

PURPOSE:

Aberrant activation of the PI3K pathway has been implicated in resistance to HER2-targeted therapy, but results of clinical trials are confounded by the co-administration of chemotherapy. We investigated the effect of perturbations of this pathway in breast cancers from patients treated with neoadjuvant anti-HER2-targeted therapy without chemotherapy.

PATIENTS AND METHODS:

Baseline tumor samples from patients with HER2-positive breast cancer enrolled in TBCRC006 (NCT00548184), a 12-week neoadjuvant clinical trial with lapatinib plus trastuzumab [plus endocrine therapy for estrogen receptor (ER)-positive tumors], were assessed for PTEN status by immunohistochemistry and PIK3CA mutations by sequencing. Results were correlated with pathologic complete response (pCR).

RESULTS:

Of 64 evaluable patients, PTEN immunohistochemistry and PIK3CA mutation analysis were performed for 59 and 46 patients, respectively. PTEN status (dichotomized by H-score median) was correlated with pCR (32% in high PTEN vs. 9% in low PTEN, p = 0.04). PIK3CA mutations were identified in 14/46 tumors at baseline (30%) and did not correlate with ER or PTEN status. One patient whose tumor harbored a PIK3CA mutation achieved pCR (p = 0.14). When considered together (43 cases), 1/25 cases (4%) with a PIK3CA mutation and/or low PTEN expression levels had a pCR compared to 7/18 cases (39%) with wild-type PI3KCA and high PTEN expression levels (p = 0.006).

CONCLUSION:

PI3K pathway activation is associated with resistance to lapatinib and trastuzumab in breast cancers, without chemotherapy. Further studies are warranted to investigate how to use these biomarkers to identify upfront patients who may respond to anti-HER2 alone, without chemotherapy.

KEYWORDS:

HER2-positive breast cancer; Lapatinib; PIK3CA mutations; PTEN levels; Trastuzumab; pCR

PMID:
29110152
PMCID:
PMC5821069
[Available on 2019-02-01]
DOI:
10.1007/s10549-017-4533-9
[Indexed for MEDLINE]

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