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Genomic loss of heterozygosity and survival in the REAL3 trial


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The cover for issue 94 of Oncotarget features Figure 6, "Progression free survival in LOH-high and LOH-low groups with operated patients censored at time of potentially curative surgery," by Smyth, et al.

Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing assay. A cut-off of 21% genomic LOH defined an LOH-high subgroup who had median overall survival of 18.3 months versus 11m for the LOH-low group.

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.

Dr. David Cunningham from the Department of Gastrointestinal Oncology and Lymphoma, at the Royal Marsden Hospital, in London & Sutton, United Kingdom said, "Homologous recombination is a complex process requiring the coordinated function of a number of genes products in order to repair double-stranded breaks in DNA."

Figure 6: Progression free survival in LOH-high and LOH-low groups with operated patients censored at time of potentially curative surgery.

Targeting HRD in BRCA mutant tumours using a synthetically lethal approach with poly ADP ribose polymerase inhibitors has resulted in beneficial effects for patients in ovarian, breast and prostate cancer.

However, HRD may also be present in tumours without BRCA mutations; similar to BRCA mutant tumours these cancers are often platinum sensitive and may also respond to other DNA damage targeting drugs.

Determination of HRD using LOH may have clinical implications; in the ARIEL2 Part 1 trial of previously treated ovarian cancer, BRCA wild-type patients with high levels of LOH treated with the PARP inhibitor rucaparib were more likely to respond to rucaparib therapy and had longer progression free survival compared to rucaparib-treated patients who were not LOH-high.

In order to examine this hypothesis we assessed genomic LOH in tumour samples from patients treated with epirubicin, oxaliplatin and capecitabine plus or minus panitumumab in the REAL3 Trial, and correlated LOH with survival in this patient cohort.

The Cunningham research team concluded, "As immuno-oncology therapy moves to the fore, tumours with high levels of genomic scar which elicit robust immune responses may also be candidates for immune checkpoint therapy, and it is possible that combining PARP inhibition and checkpoint inhibitor therapy could provide long term benefits for selected patients."

Full text - https://doi.org/10.18632/oncotarget.26336

Correspondence to - David Cunningham - david.cunningham@rmh.nhs.uk

Keywords - gastric cancer, oesophageal cancer, chemotherapy, homologous recombination deficiency, loss of heterozygosity



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