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

Mothaffar F. Rimawi, Carmine de Angelis, Alejandro Contreras, Fresia Pareja, Felipe C. Geyer, Kathleen A. Burke, Sabrina Herrera, Tao Wang, Ingrid A. Mayer, Andres Forero, Rita Nanda, Matthew P. Goetz, Jenny C. Chang, Ian E. Krop, Antonio C. Wolff, Anne C. Pavlick, Suzanne A.W. Fuqua, Carolina Gutierrez, Susan G. Hilsenbeck, Marilyn M. LiBritta Weigelt, Jorge S. Reis-Filho, C. Kent Osborne, Rachel Schiff

Research output: Contribution to journalArticle

24 Scopus citations

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-adminis-tration 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 (dichoto-mized 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.

Original languageEnglish (US)
Pages (from-to)731-740
Number of pages10
JournalBreast Cancer Research and Treatment
Volume167
Issue number3
DOIs
StatePublished - Nov 7 2018

Keywords

  • HER2-positive breast cancer
  • Lapatinib
  • PCR
  • PIK3CA mutations
  • PTEN levels
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Rimawi, M. F., de Angelis, C., Contreras, A., Pareja, F., Geyer, F. C., Burke, K. A., Herrera, S., Wang, T., Mayer, I. A., Forero, A., Nanda, R., Goetz, M. P., Chang, J. C., Krop, I. E., Wolff, A. C., Pavlick, A. C., Fuqua, S. A. W., Gutierrez, C., Hilsenbeck, S. G., ... Schiff, R. (2018). Low PETN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Research and Treatment, 167(3), 731-740. https://doi.org/10.1007/s10549-017-4533-9