We’re delighted to be at ESMO2018. In all, our teams will present seven abstracts and posters. Pictured at the poster announcing some results of the Cancer Trial Ireland sponsored trial PantHER is Dr Sinead Toomey, Translational oncology lecturer and research scientist based in RCSI, Dublin.
Monitoring the effect of PI3K inhibition on HER2 therapy resistant breast cancer using serial analysis of PIK3CA mutant tumour DNA in plasma
Keegan1, S. Toomey2, A. Farrelly2, A. Carr2, G. Calzaferri3, J. Walshe4, G. Gullo4, J.P. Crown4, K. Egan5, A. Hernando6, A. Teiserskiene6, L. Grogan7, O.S. Breathnach7, P.G. Morris5, B. Hennessy8
1Department of Molecular Oncology, RCSI Beaumont Hospital, Dublin, Ireland, 2Oncology Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland, 3Department of Medical Oncology, Cancer Clinical Research Trust, Dublin, Ireland, 4Medical Oncology, St Vincent’s University Hospital, Dublin, Ireland, 5Cancer Clinical Trials and Research Unit, Beaumont Hospital, Dublin, Ireland, 6Breast DSSG, Cancer Trials Ireland, Dublin, Ireland, 7Medical Oncology, Beaumont Hospital, Dublin, Ireland, 8Cancer Clinical Trials and Research Unit and Cancer Trials Ireland, RCSI Beaumont Hospital, Dublin, Ireland
Background:
PIK3CA is mutated in up to 20% of HER2 positive breast cancers, contributes to HER-2 therapy resistance and may be predictive of response to PI3K inhibitor therapy. PIK3CA mutations in breast cancer occur primarily at hotspots E545K at exon 9 and H1047R at exon 20. Copanlisib (C) is a pan-class I PI3K inhibitor that shows particular activity against PI3Ka, the isoform encoded by the PIK3CA gene. The aim of this study was to assess PIK3CA mutation status in matched tumour and plasma samples pre copanlisib treatment and to monitor PIK3CA mutation concentration changes in plasma over the course of PI3K inhibition therapy.
Methods:
For 12 patients with advanced HER2 positive, breast cancer treated on a clinical trial of copanlisib and trastuzumab, we prospectively examined serial plasma samples to quantify the PIK3CA hotspot mutations in circulating tumour DNA by droplet digital PCR (ddPCR). Samples were taken pre-treatment, then every two weeks on treatment and immediately after radiological disease progression. Archival formalin fixed paraffin embedded (FFPE) primary tumour tissue were examined using Mass ArrayVR to detect PIK3CA mutation.
Results:
PIK3CA mutations were detected in 6/12 (50%) archival FFPE primary tumours; either an exon 9 (n¼2) or exon 20 (n¼4), all of which were also oestrogen receptor positive and had at least one prior line of anti Her2 therapy in the advanced cancer setting.
There were 106 plasma samples included in the mutation analysis. PIK3CAmutation (H1047R or E545K)>500copies/mL were detected in 66% (70/106) of the samples. Of the six tumour samples that had no PIK3CAmutation detected, three had>500copies/mL (range: 0-25,500copies/mL) of mutated PIK3CA detected in serial plasma samples. Variations in plasma DNA mutation levels over time were found in all 12 patients.
Conclusions:
Our data demonstrate that PIK3CA mutation is detectable in the plasma of a large proportion of a cohort of patients with HER2 therapy resistant advanced breast cancer, is potentially a more meaningful representation of current mutation status than archival primary tumour tissue given discordance and levels of mutation fluctuate with PI3K inhibition combined with trastuzumab.
Legal entity responsible for the study:
Cancer Trials Ireland.
Funding:
Bayer Pharmaceuticals.
Disclosure: B. Hennessy: Research funding: Bayer Pharmaceuticals. All other authors have declared no conflicts of interest.