BACKGROUND: High grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet. METHODS: Ninety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients. RESULTS: A high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1-100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%. CONCLUSIONS: A multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.
BACKGROUND: High grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet. METHODS: Ninety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients. RESULTS: A high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1-100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%. CONCLUSIONS: A multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.
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Authors: Kathryn Alsop; Sian Fereday; Cliff Meldrum; Anna deFazio; Catherine Emmanuel; Joshy George; Alexander Dobrovic; Michael J Birrer; Penelope M Webb; Colin Stewart; Michael Friedlander; Stephen Fox; David Bowtell; Gillian Mitchell Journal: J Clin Oncol Date: 2012-06-18 Impact factor: 44.544
Authors: David D Bowtell; Steffen Böhm; Ahmed A Ahmed; Paul-Joseph Aspuria; Robert C Bast; Valerie Beral; Jonathan S Berek; Michael J Birrer; Sarah Blagden; Michael A Bookman; James D Brenton; Katherine B Chiappinelli; Filipe Correia Martins; George Coukos; Ronny Drapkin; Richard Edmondson; Christina Fotopoulou; Hani Gabra; Jérôme Galon; Charlie Gourley; Valerie Heong; David G Huntsman; Marcin Iwanicki; Beth Y Karlan; Allyson Kaye; Ernst Lengyel; Douglas A Levine; Karen H Lu; Iain A McNeish; Usha Menon; Steven A Narod; Brad H Nelson; Kenneth P Nephew; Paul Pharoah; Daniel J Powell; Pilar Ramos; Iris L Romero; Clare L Scott; Anil K Sood; Euan A Stronach; Frances R Balkwill Journal: Nat Rev Cancer Date: 2015-11 Impact factor: 60.716
Authors: L Paz-Ares; E-H Tan; K O'Byrne; L Zhang; V Hirsh; M Boyer; J C-H Yang; T Mok; K H Lee; S Lu; Y Shi; D H Lee; J Laskin; D-W Kim; S A Laurie; K Kölbeck; J Fan; N Dodd; A Märten; K Park Journal: Ann Oncol Date: 2017-02-01 Impact factor: 32.976
Authors: Erik N Bergstrom; Mi Ni Huang; Uma Mahto; Mark Barnes; Michael R Stratton; Steven G Rozen; Ludmil B Alexandrov Journal: BMC Genomics Date: 2019-08-30 Impact factor: 3.969
Authors: Chey Loveday; Kevin Litchfield; Paula Z Proszek; Alex J Cornish; Flavia Santo; Max Levy; Geoff Macintyre; Amy Holryod; Peter Broderick; Darshna Dudakia; Barbara Benton; Maise Al Bakir; Crispin Hiley; Emily Grist; Charles Swanton; Robert Huddart; Tom Powles; Simon Chowdhury; Janet Shipley; Simon O'Connor; James D Brenton; Alison Reid; David Gonzalez de Castro; Richard S Houlston; Clare Turnbull Journal: Nat Commun Date: 2020-05-04 Impact factor: 14.919