Genetic heterogeneity after first-line chemotherapy in high-grade serous ovarian cancer

Publication date: January 2016
Source:European Journal of Cancer, Volume 53
Author(s): Sandrina Lambrechts, Dominiek Smeets, Matthieu Moisse, Elena Ioana Braicu, Adriaan Vanderstichele, Hui Zhao, Els Van Nieuwenhuysen, Els Berns, Jalid Sehouli, Robert Zeillinger, Silvia Darb-Esfahani, Dan Cacsire Castillo-Tong, Diether Lambrechts, Ignace Vergote
BackgroundMost 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.MethodsIn 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.ResultsBesides 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.ConclusionsAlready 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.



from Cancer via ola Kala on Inoreader http://ift.tt/1Y9mQ90
via IFTTT