Abstract PD1-1: PI3-kinase mutations in recurrences in patients with estrogen receptor positive breast cancer
Authors: JM Dixon, L Renshaw, J Keys, A Sims, J Thomas, TR Wilson, MR Lackner
Journal: Cancer Research (2013)

Abstract INTRODUCTION Activation of the Phosphatidylinositide 3-kinase/mammalian target of rapamycin (PI3K)/mTOR pathway is thought to play a role in the development of resistance to endocrine therapy. The aim was to investigate PIK3CA mutation and PTEN status in a series of patients with estrogen receptor positive alpha (ER+) breast cancer at diagnosis and on progression, recurrence or development of a new breast cancer during or following adjuvant endocrine treatment. METHODS Formalin fixed paraffin embedded tissue was available from a series of 120 patients at diagnosis and from; local recurrences (in breast tumour recurrence, or recurrence in mastectomy scars), metastatic recurrences (nodal, or distant metastatic disease), local progression (patients treated with neoadjuvant endocrine therapy who initially responded well and then progressed), and from second breast cancers (ipsilateral second breast cancers, or contralateral new primaries). Samples were profiled with a comprehensive qPCR based mutation assay covering 17 mutational hotspots in PIK3CA, as well as having immunohistochemistry for PTEN assessment. RESULTS PIK3CA mutation status was available from 88 paired-matched samples at both diagnosis and recurrence. 38 (43%) had at least one PIK3CA mutation at diagnosis, and 37 (42%) had a mutation present in tissue taken at the time of recurrence. The most common mutations in the 176 tissues analysed in order were: H1047R (35 samples), H1047L (11 samples), E545K (19 samples), E542K (6 samples), H1047R (3 samples), C420R (4 samples), 542K (1 sample). Three cancers had 2 mutations. PTEN protein status by immunohistochemistry at diagnosis was: null = 1, 1-100 = 7, 101-200 = 24, &amp;gt;200 = 14. At recurrence the PTEN status was null = 6, 1-100 = 5, 101-200 = 13, &amp;gt;200 = 32. The change in PIK3CA mutation status in different groups is outlined in Table 1. Table 1.EventNumberPIK3CA gainPIK3CA lossChange in PIK3CA mutation status%Local progression28011 (3.6%)Metastatic recurrences19112 (10.5%)Local recurrence30303 (10%)Contralateral new primary6235 (83%)Ipsilateral 2nd tumour5213 (60%)Total8814814 Few patients changed their PIK3CA mutation status on development of local recurrence, metastatic disease or progression on hormone treatment. Frequent changes in PIK3CA mutation status were seen in patients who developed a new cancer in the treated or in the contralateral breast. There was an increase in PTEN null cases (from 2.2% to 10.7%) and PTEN over-expression &amp;gt;200 (from 30.4% to 57%) from the first to the second samples. CONCLUSION • The acquisition of mutations in PIK3CA does not appear to be responsible for the development of endocrine resistance. • PIK3CA mutation status does not change in the majority of patients on progression or development of recurrence on or after endocrine therapy. PIK3CA mutation status at diagnosis can thus be used to determine whether a PI3-Kinase inhibitor might be suitable for treatment in patients with metastatic disease. • Patients who develop new breast cancers frequently develop cancers with a different PIK3CA mutation status. • These are the most comprehensive currently available data correlating PIK3CA status and endocrine resistance. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-1.