Abstract 2591
Background
Hypertension is one of the major side effect of VEGF-pathway inhibitors. There are no validated biomarkers to predict which cancer patients will develop hypertension. This study aimed to identify genetic predictors of hypertension induced by VEGF-pathway inhibitors.
Methods
A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) (PMID 30385613) and genotyped for 1,040 germline variants in 56 genes. The most statistically significant variant from the discovery set (chi-squared test) was tested in a validation set (cause-specific Cox model) consisting of 1,041 cancer patients treated with bevacizumab (10-15 mg/kg every two-three weeks) and genotyped using GWAS microarray platforms. For both studies, grade ≥2 hypertension (CTCAE v. 3.0) was used as the endpoint. Genetic associations were adjusted for age and sex.
Results
In the discovery set, the most statistically significant variant associated with hypertension in sorafenib-treated patients was rs444904 (G>A, P = 0.006). The A allele of rs444904 (minor allele frequency, MAF 0.14) increased the risk of hypertension. In the validation set, the A allele of rs427554 (G>A, in complete linkage disequilibrium with rs444904) increased the risk of hypertension in bevacizumab-treated patients (P = 0.008, MAF 0.11). rs444904 and rs427554 are intronic variants in PIK3R5. PIK3R5 encodes the regulatory subunit of PI3Kγ, which, when activated by VEGF, leads to nitric oxide (NO) production and vasodilation. These variants have been associated with decreased expression of PIK3R5 in blood (PMID 25954001), consistent with their effect in increasing the risk of hypertension.
Conclusions
Common genetic variants that could reduce PIK3R5 activity increase the risk of sorafenib- and bevacizumab-induced hypertension. In patients treated with these drugs, reduced activity or expression of PIK3R5 may lead to a reduction in NO production, resulting in vasoconstriction and hypertension. This study, for the first time, provides evidence for new predictive genetic markers of drug-induced hypertension that should be further evaluated for other VEGF-pathway inhibitors.
Clinical trial identification
TARGET CALGB 80303 NCT00088894 CALGB 40503 NCT00601900 CALGB 40502 NCT00785291 CALGB 90401 NCT00110214.
Editorial acknowledgement
Legal entity responsible for the study
Federico Innocenti.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5579 - Quality of informed consent in clinical trials patients
Presenter: Gianluca Catania
Session: Poster Display session 3
Resources:
Abstract
5147 - Patient's rights: Where do we stand?
Presenter: Maja Kozuh
Session: Poster Display session 3
Resources:
Abstract
1279 - The oncology nurse coordinator’s role in a digestive oncology department: Impact on patient and hospital
Presenter: Fouad Awada
Session: Poster Display session 3
Resources:
Abstract
1670 - Nursing model for a breast cancer unit at the Catalan Institute of Oncology
Presenter: Ana Rodriguez-ortega
Session: Poster Display session 3
Resources:
Abstract
3936 - Role of cancer nurse in the prevention and control of acute deterioration for oncohematologic patient
Presenter: Raquel Azor Portolés
Session: Poster Display session 3
Resources:
Abstract
2789 - Standardized nursing care in the department of radiotherapy of a network of cancer centres
Presenter: José Delgado
Session: Poster Display session 3
Resources:
Abstract
4482 - Exploring anxiety, depression and quality of life of ambulatory cancer patients during chemotherapy.
Presenter: Theodoula Adamakidou
Session: Poster Display session 3
Resources:
Abstract
3075 - Implementing a Cancer Survivorship Program for Individuals with Recurrent Breast Cancer
Presenter: Darcy Burbage
Session: Poster Display session 3
Resources:
Abstract
3869 - The perceptions of parents/guardians regarding their child/adolescent’s experience of reflexology or non-specific foot massage The perceptions of parents/guardians regarding their child/adolescents experience of reflexology or non-specific foot massage
Presenter: Patricia Fox
Session: Poster Display session 3
Resources:
Abstract
4064 - Quality of life in survivors of adult haematological malignancies
Presenter: Anita Immanuel
Session: Poster Display session 3
Resources:
Abstract