Highlights
- •Substantial genetic heterogeneity underlies high-grade serous ovarian carcinoma (HGSOC) collected before and after platinum.
- •Biopsies collected at relapse are therefore needed to tailor treatment options to the underlying genetic profile.
- •Platinum-sensitive HGSOCs remain homologous recombination-deficient after first-line platinum, irrespective of their response.
- •Therefore, these tumours also qualify for second-line PARP inhibitors.
- •Chromosomal instability of specific regions contributes to acquired resistance to platinum.
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.
Keywords
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Article info
Publication history
Published online: December 13, 2015
Accepted:
November 2,
2015
Received:
September 29,
2015
Identification
Copyright
© 2015 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
