Sandrina Lambrechts1, Dominiek Smeets2, Matthieu Moisse2, Elena Ioana Braicu3, Adriaan Vanderstichele4, Hui Zhao2, Els Van Nieuwenhuysen1, Els Berns5, Jalid Sehouli3, Robert Zeillinger6, Silvia Darb-Esfahani3, Dan Cacsire Castillo-Tong5, Diether Lambrechts7, Ignace Vergote1. 1. Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. 2. Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium. 3. Department of Gynecology and Obstetrics, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. 4. Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium. 5. Erasmus MC, Cancer Institute, Department Medical Oncology, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. 6. Department of Obstetrics and Gynecology, Molecular Oncology Group, Comprehensive Cancer Center, Gynecologic Cancer Unit, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. 7. Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address: Diether.Lambrechts@vib-kuleuven.be.
Abstract
BACKGROUND: Most high-grade serous ovarian carcinoma (HGSOC) patients benefit from first-line platinum-based chemotherapy, but progressively develop resistance during subsequent lines. Re-activating BRCA1 or MDR1 mutations can underlie platinum resistance in end-stage patients. However, little is known about resistance mechanisms occurring after a single line of platinum, when patients still qualify for other treatments. METHODS: In 31 patients with primary platinum-sensitive HGSOC, we profiled tumours collected during debulking surgery before and after first-line chemotherapy using whole-exome sequencing and single nucleotide polymorphism profiling. RESULTS: Besides germline BRCA1/2 mutations, we observed frequent loss-of-heterozygosity in homologous recombination (HR) genes and mutation spectra characteristic of HR-deficiency in all tumours. At relapse, tumours differed considerably from their primary counterparts. There was, however, no evidence of events reactivating the HR pathway, also not in tumours resistant to second-line platinum. Instead, a platinum score of 13 copy number regions, among other genes including MECOM, CCNE1 and ERBB2, correlated with platinum-free interval (PFI) after first-line therapy, whereas an increase of this score in recurrent tumours predicted the change in PFI during subsequent therapy. CONCLUSIONS: Already after a single line of platinum, there is huge variability between primary and recurrent tumours, advocating that in HGSOC biopsies need to be collected at relapse to tailor treatment options to the underlying genetic profile. Nevertheless, all primary platinum-sensitive HGSOCs remained HR-deficient, irrespective of whether they became resistant to second-line platinum, further suggesting these tumours qualify for second-line Poly APD ribose polymerase (PARP) inhibitor treatment. Finally, chromosomal instability contributes to acquired resistance after a single line of platinum therapy.
BACKGROUND: Most high-grade serous ovarian carcinoma (HGSOC) patients benefit from first-line platinum-based chemotherapy, but progressively develop resistance during subsequent lines. Re-activating BRCA1 or MDR1 mutations can underlie platinum resistance in end-stage patients. However, little is known about resistance mechanisms occurring after a single line of platinum, when patients still qualify for other treatments. METHODS: In 31 patients with primary platinum-sensitive HGSOC, we profiled tumours collected during debulking surgery before and after first-line chemotherapy using whole-exome sequencing and single nucleotide polymorphism profiling. RESULTS: Besides germline BRCA1/2 mutations, we observed frequent loss-of-heterozygosity in homologous recombination (HR) genes and mutation spectra characteristic of HR-deficiency in all tumours. At relapse, tumours differed considerably from their primary counterparts. There was, however, no evidence of events reactivating the HR pathway, also not in tumours resistant to second-line platinum. Instead, a platinum score of 13 copy number regions, among other genes including MECOM, CCNE1 and ERBB2, correlated with platinum-free interval (PFI) after first-line therapy, whereas an increase of this score in recurrent tumours predicted the change in PFI during subsequent therapy. CONCLUSIONS: Already after a single line of platinum, there is huge variability between primary and recurrent tumours, advocating that in HGSOC biopsies need to be collected at relapse to tailor treatment options to the underlying genetic profile. Nevertheless, all primary platinum-sensitive HGSOCs remained HR-deficient, irrespective of whether they became resistant to second-line platinum, further suggesting these tumours qualify for second-line Poly APD ribose polymerase (PARP) inhibitor treatment. Finally, chromosomal instability contributes to acquired resistance after a single line of platinum therapy.
Authors: Julia Jabs; Franziska M Zickgraf; Jeongbin Park; Steve Wagner; Xiaoqi Jiang; Katharina Jechow; Kortine Kleinheinz; Umut H Toprak; Marc A Schneider; Michael Meister; Saskia Spaich; Marc Sütterlin; Matthias Schlesner; Andreas Trumpp; Martin Sprick; Roland Eils; Christian Conrad Journal: Mol Syst Biol Date: 2017-11-27 Impact factor: 11.429
Authors: Siel Olbrecht; Pieter Busschaert; Junbin Qian; Adriaan Vanderstichele; Liselore Loverix; Toon Van Gorp; Els Van Nieuwenhuysen; Sileny Han; Annick Van den Broeck; An Coosemans; Anne-Sophie Van Rompuy; Diether Lambrechts; Ignace Vergote Journal: Genome Med Date: 2021-07-09 Impact factor: 11.117