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Published on: July 3, 2015
Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response
Sophie E Willis1, Claudia Winkler2, Martine P Roudier1
1Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK.
Background:
The absence of the putative DNA/RNA helicase Schlafen11 (SLFN11) is thought to cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors.
Methods:
We developed and validated a clinically applicable SLFN11 immunohistochemistry assay and retrospectively correlated SLFN11 tumour levels to patient outcome to the standard of care therapies and olaparib maintenance.
Results:
High SLFN11 associated with improved prognosis to the first-line treatment with DDAs platinum-plus-etoposide in SCLC patients, but was not strongly linked to paclitaxel-platinum response in ovarian cancer patients. Multivariate analysis of patients with relapsed platinum-sensitive ovarian cancer from the randomised, placebo-controlled Phase II olaparib maintenance Study19 showed SLFN11 tumour levels associated with sensitivity to olaparib. Study19 patients with high SLFN11 had a lower progression-free survival (PFS) hazard ratio compared to patients with low SLFN11, although both groups had the benefit of olaparib over placebo. Whilst caveated by small sample size, this trend was maintained for PFS, but not overall survival, when adjusting for BRCA status across the olaparib and placebo treatment groups, a key driver of PARP inhibitor sensitivity.
Conclusion:
We provide clinical evidence supporting the role of SLFN11 as a DDA therapy selection biomarker in SCLC and highlight the need for further clinical investigation into SLFN11 as a PARP inhibitor predictive biomarker.
Insights
Schlafen11 (SLFN11) absence may cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors. High SLFN11 levels predict better outcomes with DDAs in SCLC and sensitivity to olaparib in ovarian cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Schlafen11 (SLFN11) is a putative DNA/RNA helicase implicated in cellular responses to DNA damage.
- Its absence is hypothesized to confer resistance to DNA-damaging agents (DDAs) and poly(ADP-ribose) polymerase (PARP) inhibitors.
- Understanding SLFN11's role is crucial for predicting treatment efficacy in various cancers.
Purpose of the Study:
- To develop and validate a clinical immunohistochemistry assay for SLFN11.
- To investigate the correlation between tumor SLFN11 levels and patient outcomes.
- To assess SLFN11 as a predictive biomarker for standard-of-care therapies and olaparib maintenance treatment.
Main Methods:
- Development and validation of a clinically applicable SLFN11 immunohistochemistry assay.
- Retrospective analysis of tumor SLFN11 levels in patients treated with standard therapies.
- Correlation of SLFN11 levels with patient outcomes in small cell lung cancer (SCLC) and ovarian cancer cohorts.
- Multivariate analysis in a Phase II olaparib maintenance study (Study19) for relapsed platinum-sensitive ovarian cancer.
Main Results:
- High SLFN11 expression was associated with improved prognosis in SCLC patients treated with DDA (platinum-etoposide).
- SLFN11 levels showed a weaker association with paclitaxel-platinum response in ovarian cancer.
- In Study19, high SLFN11 tumor levels correlated with olaparib sensitivity in ovarian cancer, indicated by a lower progression-free survival hazard ratio.
- This trend persisted for PFS, but not overall survival, after adjusting for BRCA status.
Conclusions:
- Clinical evidence supports SLFN11 as a biomarker for selecting DDA therapy in SCLC.
- Further clinical investigation is warranted to establish SLFN11 as a predictive biomarker for PARP inhibitors.
- SLFN11's role in predicting response to DNA-damaging agents and PARP inhibitors requires continued research.
