A1 Refereed original research article in a scientific journal
A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients
Authors: Tumiati M, Hietanen S, Hynninen J, Pietilä E, Färkkilä A, Kaipio K, Roering P, Huhtinen K, Alkodsi A, Li Y, Lehtonen R, Erkan EP, Tuominen MM, Lehti K, Hautaniemi SK, Grénman S, Vähärautio A, Carpén O, Kauppi L
Publication year: 2018
Journal: Clinical Cancer Research
Journal name in source: Clinical cancer research : an official journal of the American Association for Cancer Research
Journal acronym: Clin Cancer Res
Volume: 24
Issue: 18
First page : 4482
Last page: 4493
Number of pages: 12
ISSN: 1078-0432
DOI: https://doi.org/10.1158/1078-0432.CCR-17-3770
.Purpose: Homologous recombination deficiency (HRD) correlates
with platinum sensitivity in patients with ovarian cancer, which
clinically is the most useful predictor of sensitivity to PARPi. To
date, there are no reliable diagnostic tools to anticipate response to
platinum-based chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments.Experimental Design:
We obtained a functional HR score by quantifying homologous
recombination (HR) repair after ionizing radiation-induced DNA damage in
primary ovarian cancer samples (n = 32). Samples clustered in 3
categories: HR-deficient, HR-low, and HR-proficient. We analyzed the HR
score association with platinum sensitivity and treatment response,
platinum-free interval (PFI) and overall survival (OS), and compared it
with other clinical parameters. In parallel, we performed DNA-sequencing
of HR genes to assess if functional HRD can be predicted by currently
offered genetic screening.Results: Low HR scores predicted primary platinum sensitivity with high statistical significance (P
= 0.0103), associated with longer PFI (HR-deficient vs. HR-proficient:
531 vs. 53 days), and significantly correlated with improved OS (HR
score <35 vs. ≥35, hazard ratio = 0.08, P = 0.0116). At the
genomic level, we identified a few unclear mutations in HR genes and the
mutational signature associated with HRD, but, overall, genetic
screening failed to predict functional HRD.Conclusions: We developed an ex vivo
assay that detects tumor functional HRD and an HR score able to predict
platinum sensitivity, which holds the clinically relevant potential to
become the routine companion diagnostic in the management of patients
with ovarian cancer.
