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Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

5045 - Monitoring the effect of PI3K inhibition on HER2 therapy resistant breast cancer using serial analysis of PIK3CA mutant tumour DNA in plasma

Date

20 Oct 2018

Session

Poster display session: Biomarkers, Gynaecological cancers, Haematological malignancies, Immunotherapy of cancer, New diagnostic tools, NSCLC - early stage, locally advanced & metastatic, SCLC, Thoracic malignancies, Translational research

Presenters

Niamh Keegan

Citation

Annals of Oncology (2018) 29 (suppl_8): viii14-viii57. 10.1093/annonc/mdy269

Authors

N. Keegan1, S. Toomey2, A. Farrelly2, A. Carr2, G. Calzaferri3, J. Walshe4, G. Gullo5, J.P. Crown6, K. Egan7, A. Hernando8, A. Teiserskiene8, L. Grogan9, O.S. Breathnach9, P.G. Morris7, B. Hennessy10

Author affiliations

  • 1 Dept Of Molecular Oncology, RCSI Beaumont Hospital, 9 - Dublin/IE
  • 2 Oncology Molecular Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, 9 - Dublin/IE
  • 3 Dept Of Medical Oncology, Cancer Clinical research Trust, 4 - Dublin/IE
  • 4 Medical Oncology, St Vincent's University Hospital, Dublin 4 - Dublin/IE
  • 5 Medical Oncology, St Vincents University Hospital, 4 - Dublin/IE
  • 6 Medical Oncology, St Vincents University Hospital, D04 Y8V0 - Dublin/IE
  • 7 Cancer Clinical Trials And Research Unit, Beaumont Hospital, Dublin 9, Ireland, Dublin 9 - Dublin/IE
  • 8 Breast Dssg, Cancer Trials Ireland, 11 - Dublin/IE
  • 9 Medical Oncology, Beaumont Hospital, 9 - Dublin/IE
  • 10 Cancer Clinical Trials And Research Unit And Cancer Trials Ireland, RCSI Beaumont Hospital, Dublin 9, Ireland, Dublin 9 - Dublin/IE
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Resources

Abstract 5045

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 PI3Kα, 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 MassArray® to detect PIK3CA mutation.

Results

PIK3CA mutations were detected in 6/12 (50%) archival FFPE primary tumours ; either an exon 9 (n = 2) or exon 20 (n = 4), 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. PIK3CA mutation (H1047R or E545K) >500copies/mL were detected in 66% (70/106) of the samples. Of the six tumour samples that had no PIK3CA mutation 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.

Clinical trial identification

Legal entity responsible for the study

Cancer Trials Ireland.

Funding

Bayer Pharmaceuticals.

Editorial Acknowledgement

Disclosure

B. Hennessy: Research funding: Bayer Pharmaceuticals. All other authors have declared no conflicts of interest.

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