Contributions
Abstract: PB1686
Type: Publication Only
Background
The therapeutic landscape for AML has changed little over the past four decades. Cytarabine, first approved in 1969, is still a standard of care treatment option for AML despite little improvement in survival rates over time. Whilst AML is a disease which can occur at any age, it predominantly affects people over the age of 65. With an increasing elderly population, the rate of incidence of AML is set to increase. Additionally, although some patients do respond to Cytarabine treatment, there is no signature or test available to determine which patients will, or will not, benefit from this type of treatment.
A DNA Damage Repair Deficiency (DDRD) score was previously developed to identify breast cancers with an intrinsic DNA double strand break (DSB) repair deficiency and therefore may respond positively to DNA damaging chemotherapeutic agents such as cyclophosphamide. This assay can be adapted to different cancer types including AML.
Aims
The objective of this study was to examine if the DDRD assay can be applied to AML samples as a potential biomarker of response and/or survival.
Methods
To test the effectiveness of DDRD score as a biomarker the DDRD calculation was applied to RNA expression data from 645 AML patients. The score was also determined for a panel AML cell lines. Cell lines defined as DDRD positive or negative were tested for sensitivity to different DNA damaging agents using clonogenic survival assays. The DNA repair capacity of these cell lines was also examined by assessing their ability to repair ionising radiation induced DSBs.
Results
Approximately 39% of the patients scored as DDRD positive. This did not significantly correlate with any risk group, cytogenetic abnormality or mutation such as FLT3 or NPM1. Survival analysis showed that the DDRD positive patients had a significantly worse survival than the DDRD negative patients (10-year survival 27% in DDRD positive patients compared to 42% in DDRD negative (p-value = 0.00047)) despite the prediction of responding better to DNA damaging agents as seen in the breast cancer studies.
The response of the cell lines to the DNA damaging agents corresponded with the patient data with DDRD positive cell lines showing less sensitivity to cytarabine as DDRD negative cell lines. The foci analysis from the IR treated cells also showed that the DDRD positive cell lines do not repair DSBs as effectively as the DDRD negative cell lines.
Conclusion
These results suggest that determining the DDRD score could effectively be used to determine which patients would benefit from treatment with DNA damaging agents. Furthermore, the poor survival rate of the DDRD positive patients indicates that cytarabine is not the optimal treatment option for these. Further analysis of this unresponsive AML sub-group could highlight therapeutic pathways to target either as single agents or in combinations with for example PARP inhibitors.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): AML, DNA Damage, DNA repair
Abstract: PB1686
Type: Publication Only
Background
The therapeutic landscape for AML has changed little over the past four decades. Cytarabine, first approved in 1969, is still a standard of care treatment option for AML despite little improvement in survival rates over time. Whilst AML is a disease which can occur at any age, it predominantly affects people over the age of 65. With an increasing elderly population, the rate of incidence of AML is set to increase. Additionally, although some patients do respond to Cytarabine treatment, there is no signature or test available to determine which patients will, or will not, benefit from this type of treatment.
A DNA Damage Repair Deficiency (DDRD) score was previously developed to identify breast cancers with an intrinsic DNA double strand break (DSB) repair deficiency and therefore may respond positively to DNA damaging chemotherapeutic agents such as cyclophosphamide. This assay can be adapted to different cancer types including AML.
Aims
The objective of this study was to examine if the DDRD assay can be applied to AML samples as a potential biomarker of response and/or survival.
Methods
To test the effectiveness of DDRD score as a biomarker the DDRD calculation was applied to RNA expression data from 645 AML patients. The score was also determined for a panel AML cell lines. Cell lines defined as DDRD positive or negative were tested for sensitivity to different DNA damaging agents using clonogenic survival assays. The DNA repair capacity of these cell lines was also examined by assessing their ability to repair ionising radiation induced DSBs.
Results
Approximately 39% of the patients scored as DDRD positive. This did not significantly correlate with any risk group, cytogenetic abnormality or mutation such as FLT3 or NPM1. Survival analysis showed that the DDRD positive patients had a significantly worse survival than the DDRD negative patients (10-year survival 27% in DDRD positive patients compared to 42% in DDRD negative (p-value = 0.00047)) despite the prediction of responding better to DNA damaging agents as seen in the breast cancer studies.
The response of the cell lines to the DNA damaging agents corresponded with the patient data with DDRD positive cell lines showing less sensitivity to cytarabine as DDRD negative cell lines. The foci analysis from the IR treated cells also showed that the DDRD positive cell lines do not repair DSBs as effectively as the DDRD negative cell lines.
Conclusion
These results suggest that determining the DDRD score could effectively be used to determine which patients would benefit from treatment with DNA damaging agents. Furthermore, the poor survival rate of the DDRD positive patients indicates that cytarabine is not the optimal treatment option for these. Further analysis of this unresponsive AML sub-group could highlight therapeutic pathways to target either as single agents or in combinations with for example PARP inhibitors.
Session topic: 3. Acute myeloid leukemia - Biology & Translational Research
Keyword(s): AML, DNA Damage, DNA repair