Genetic Variants as Predictive Markers for Ototoxicity and Nephrotoxicity in Patients with Locally Advanced Head and Neck Cancer Treated with Cisplatin-Containing Chemoradiotherapy (The PRONE Study)

Abstract

Ototoxicity and nephrotoxicity are potentially irreversible side effects of chemoradiotherapy with cisplatin in locally advanced head and neck cancer (LAHNC) patients. Several predictive genetic variants have been described, but as yet none in LAHNC patients. The aim of this study is to investigate genetic variants as predictors for ototoxicity and nephrotoxicity in LAHNC patients treated with cisplatin-containing chemoradiotherapy. Our prospective cohort of 92 patients was genotyped for 10 genetic variants and evaluated for their association with cisplatin-induced ototoxicity (ACYP2, COMT, TPMT and WFS1) and nephrotoxicity (OCT2, MATE and XPD). Ototoxicity was determined by patient-reported complaints as well as tone audiometrical assessments. Nephrotoxicity was defined as a decrease of ≥25% in creatinine clearance during treatment compared to baseline. A significant association was observed between carriership of the A allele for rs1872328 in the ACYP2 gene and cisplatin-induced clinically determined ototoxicity (p = 0.019), and not for ototoxicity measured by tone audiometrical assessments (p = 0.449). Carriership of a T allele for rs316019 in the OCT2 gene was significantly associated with nephrotoxicity at any time during chemoradiotherapy (p = 0.022), but not with nephrotoxicity at the end of the chemoradiotherapy. In conclusion, we showed prospectively that in LAHNC patients genetic variants in ACYP2 are significantly associated with clinically determined ototoxicity. Validation studies are necessary to prove the added value for individualized treatments plans in these patients.

Association of Clinical Aspects and Genetic Variants with the Severity of Cisplatin-Induced Ototoxicity in Head and Neck Squamous Cell Carcinoma: A Prospective Cohort Study

“…Furthermore, other known SNVs for CDDP-induced ototoxicity unrelated to stages regarding drug absorption, distribution, metabolism, and excretion were not assessed and could be additional confounders. There is evidence supporting additional SNVs as risk factors for ototoxicity induced by CDDP related to ACYP2 [ 33 , 34 ], TPMT [ 35 ], COMT [ 35 ], and WFS1 [ 36 ] genes. ACYP2 is known to influence ATP-dependent calcium signaling, which may play a role in sensorineural hearing loss [ 33 ].…”

“…Genome-wide studies have described SNVs in acylphosphatase 2 ( ACYP2 ), involved in calcium homeostasis [ 33 , 34 , 35 ] and Mendelian deafness WFS1 genes [ 20 , 33 , 36 , 37 ], as predictors of CDDP-induced ototoxicity. Genes encoding thiopurine S- ( TPMT ) and cathecol-O methyltransferases ( COMT ) have also been described as potential risk factors [ 35 ].…”

Genome-Wide Analyses of Nephrotoxicity in Platinum-Treated Cancer Patients Identify Association with Genetic Variant in RBMS3 and Acute Kidney Injury

“…Of The patient’ clinical data were retrospectively collected from their medical files. The second cohort included cisplatin-treated adult head–neck tumor patients treated between 2013 and 2017 at the Radboud University medical center in Nijmegen, and the Erasmus University Medical Center, Rotterdam, the Netherlands, who participated in the prospective PRONE study [ 42 ]. The current study was approved by local ethical committees.…”

Development and external validation of a prediction model for tube feeding dependency for at least four weeks during chemoradiotherapy for head and neck cancer

“…Oncological treatment was previously described in detail [22,27,28]. In brief, patients treated with CRT received cisplatin (100 mg/m 2 three weekly or 40 mg/m 2 weekly) or carboplatin (1.5 AUC weekly) combined with RT.…”