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1098P Incidence and impact of DPD mutation on neoadjuvant chemotherapy in head and neck cancers

In Annals of Oncology
By: Turkar SW.
Contributor(s): Chougule A | Patil V | Noronha V | Joshi A | Pande N | Chandrashekharan A | Prabhash K.
Material type: materialTypeLabelArticlePublisher: 2017Description: .Subject(s): Head and neck cancers | DPD mutation | Neoadjuvant chemotherapy In: Annals of OncologySummary: Background: Dihydropyrimidine dehydrogenase (DPD) is an enzyme essential for metabolism of 5FU. The incidence of polymorphisms or mutation in variable across different ethnic populations. This study is first report highlighting the high incidence of DPYD mutation is seen in head and neck cancers in India. Methods: Consecutive patients with head and neck cancer undergoing TPF neoadjuvant chemotherapy at our centre between May 2015 - December 2016 underwent DPD mutation analysis. The haematological toxicities consisting of neutropenia and thrombocytopenia while gastrointestinal toxicities consisting of mucositis and diarrhea were considered as 5FU related toxicities for this analysis. Toxicities were graded in accordance with CTCAE (Common terminology criteria for adverse events) version 4.03. DPYD mutation analysis by Sanger sequencing on ABI 3500 platform, for the most prevalent exonic regions {Exon 13 –c1627 A>G(DPYD*5) p1543V (ATA>GTA); Exon 14 – 1845 G>T; (E615D) missense mutation, Exon 14 splice variant G>A and Exon 18 (DPYD*6) pV7321) - c2194 G>A (GTT>ATT)}. Descriptive statistics was performed using SPSS version 16 and RStudio. Proportions with 95% CI were described. Fisher's exact test was performed to see the relationship between DPD mutation status and grade 3-5 adverse events. Results: Consecutive 118 patients were included in this analysis. The median age was 45 years (IQR 37.25-54.00 years). The median cycles of TPF received were 2 (range 1-4). DPD mutation was seen in 29 patients (24.59%, 95%CI 16.94-32.23%). The mutations were seen in exon 18 in 17 patients (14.4%), exon 13 in 9 patients (7.6%) and in both exon 13 & 18 in 3 patients (2.5%). 100 patients were eligible for assessment of adverse events (84.7%). The rate of grade 3-5 haematological and gastrointestinal adverse events was 64% and 35% respectively. The rate of grade 3-5 haematological (88.5% versus 55.4%, p-0.002) and gastrointestinal adverse events (57.7% versus 27.0%) were higher in DPYD mutated cohort. Conclusions: This study signifies the importance of ethnic difference in drug polymorphism and mutations. The impact of these adverse events in DPD mutated patients justifies doing a DPD mutation prior to subjecting patient to 5FU in head and neck cancer.
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Background: Dihydropyrimidine dehydrogenase (DPD) is an enzyme essential for metabolism of 5FU. The incidence of polymorphisms or mutation in variable across different ethnic populations. This study is first report highlighting the high incidence of DPYD mutation is seen in head and neck cancers in India.

Methods: Consecutive patients with head and neck cancer undergoing TPF neoadjuvant chemotherapy at our centre between May 2015 - December 2016 underwent DPD mutation analysis. The haematological toxicities consisting of neutropenia and thrombocytopenia while gastrointestinal toxicities consisting of mucositis and diarrhea were considered as 5FU related toxicities for this analysis. Toxicities were graded in accordance with CTCAE (Common terminology criteria for adverse events) version 4.03. DPYD mutation analysis by Sanger sequencing on ABI 3500 platform, for the most prevalent exonic regions {Exon 13 –c1627 A>G(DPYD*5) p1543V (ATA>GTA); Exon 14 – 1845 G>T; (E615D) missense mutation, Exon 14 splice variant G>A and Exon 18 (DPYD*6) pV7321) - c2194 G>A (GTT>ATT)}. Descriptive statistics was performed using SPSS version 16 and RStudio. Proportions with 95% CI were described. Fisher's exact test was performed to see the relationship between DPD mutation status and grade 3-5 adverse events.

Results: Consecutive 118 patients were included in this analysis. The median age was 45 years (IQR 37.25-54.00 years). The median cycles of TPF received were 2 (range 1-4). DPD mutation was seen in 29 patients (24.59%, 95%CI 16.94-32.23%). The mutations were seen in exon 18 in 17 patients (14.4%), exon 13 in 9 patients (7.6%) and in both exon 13 & 18 in 3 patients (2.5%). 100 patients were eligible for assessment of adverse events (84.7%). The rate of grade 3-5 haematological and gastrointestinal adverse events was 64% and 35% respectively. The rate of grade 3-5 haematological (88.5% versus 55.4%, p-0.002) and gastrointestinal adverse events (57.7% versus 27.0%) were higher in DPYD mutated cohort.

Conclusions: This study signifies the importance of ethnic difference in drug polymorphism and mutations. The impact of these adverse events in DPD mutated patients justifies doing a DPD mutation prior to subjecting patient to 5FU in head and neck cancer.

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