Research Papers:

Genomic loss of heterozygosity and survival in the REAL3 trial

Elizabeth C. Smyth, Catherine Cafferkey, Andrea Loehr, Tom Waddell, Ruwaida Begum, Clare Peckitt, Thomas C. Harding, Minh Nguyen, Alicia F. Okines, Mitch Raponi, Sheela Rao, David Watkins, Naureen Starling, Gary W. Middleton, Jonathan Wadsley, Wasat Mansoor, Tom Crosby, Andrew Wotherspoon, Ian Chau and David Cunningham _

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Oncotarget. 2018; 9:36654-36665. https://doi.org/10.18632/oncotarget.26336

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Elizabeth C. Smyth1,2,*, Catherine Cafferkey1,*, Andrea Loehr3, Tom Waddell1,4, Ruwaida Begum1, Clare Peckitt5, Thomas C. Harding3, Minh Nguyen3, Alicia F. Okines1, Mitch Raponi3, Sheela Rao1, David Watkins1, Naureen Starling1, Gary W. Middleton6, Jonathan Wadsley7, Wasat Mansoor4, Tom Crosby8, Andrew Wotherspoon9, Ian Chau1 and David Cunningham1

1Department of Gastrointestinal Oncology and Lymphoma, Royal Marsden Hospital, London & Sutton, United Kingdom

2Current affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom

3Clovis Oncology, San Francisco, CA, United States of America

4Current affiliation: Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom

5Department of Clinical Research & Development, Royal Marsden Hospital, London & Sutton, United Kingdom

6Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom

7Department of Medical Oncology, Weston Park Hospital, Sheffield, United Kingdom

8Department of Clinical Oncology, Velindre Hospital, Cardiff, Wales, United Kingdom

9Department of Histopathology, Royal Marsden Hospital, London & Surrey, United Kingdom

*These authors have contributed equally to this work

Correspondence to:

David Cunningham, email: [email protected]

Keywords: gastric cancer; oesophageal cancer; chemotherapy; homologous recombination deficiency; loss of heterozygosity

Received: August 01, 2018    Accepted: October 06, 2018    Published: November 30, 2018


Background: Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy.

Methods: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes.

Results: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 – 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low.

Conclusion: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature’s predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.

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