title: Spatial and temporal heterogeneity in high-grade serous ovarian cancer: a phylogenetic analysis.
abstract: BACKGROUND
  The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease.
  
  
  RESULTS
  Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22-46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66-1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy.
  
  
  CONCLUSIONS
  This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Roland F
authors.initials: RF
authors.lastname: Schwarz
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Susanna L
authors.initials: SL
authors.lastname: Cooke
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Scott
authors.initials: S
authors.lastname: Newman
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Jillian
authors.initials: J
authors.lastname: Temple
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Piskorz
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Davina
authors.initials: D
authors.lastname: Gale
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Sayal
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Muhammed
authors.initials: M
authors.lastname: Murtaza
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Baldwin
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nitzan
authors.initials: N
authors.lastname: Rosenfeld
authors.affiliation: Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom; NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Earl
authors.affiliation: University Department of Radiology, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Evis
authors.initials: E
authors.lastname: Sala
authors.affiliation: Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Jimenez-Linan
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parkinson
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom; Department of Oncology, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
mesh_terms: D000368:Aged; D000465:Algorithms; D000483:Alleles; D000077216:Carcinoma, Ovarian Epithelial; D004273:DNA, Neoplasm; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D010802:Phylogeny; D010984:Platinum / Q000627:therapeutic use*
chemical_list: D004273:DNA, Neoplasm; D010984:Platinum