In the largest patient population study to date, Mayo Clinic investigators have identified new genetic predictors of toxicity to colon cancer treatment, but the study has some caveats.
In the largest patient population study1to date, Mayo Clinic investigators have identified new genetic predictors of toxicity to colon cancer treatment, but the study has some caveats.
According to data presented at the 2015 Gastrointestinal Cancers Symposium, the novel haplotype HapB3 and the deep intronic variant c.1129-5923 C>G were shown to be moderately predictive of severe toxicity related to treatment with 5-fluorouracil (5-FU) in patients with stage III colon cancer who do not harbor the DPYD*2A, D949V, and I560S variants already associated with treatment toxicity.
“Severe adverse events (AEs) to 5-FU constitute a major dilemma in colon cancer treatment,” said Adam M. Lee, PhD, department of molecular pharmacology and experimental therapeutics, Mayo Clinic, Rochester, Minnesota.
“Our goal in this study was to assess the relationship between the DPYD HapB3 haplotype (and its individual variants), the deep intronic variant, and severe AEs common to 5-FU-based therapy,” Lee explained.
Of the approximately 275,000 patients with cancer who are treated with 5-FU in the United States each year, the National Institutes of Health (NIH) estimates that more than 8000 develop serious toxic reactions to 5-FU and that more than 1300 die each year from those toxicities.2
According to Lee, other studies have suggested potential associations between AEs and noncoding DPYD variants: a novel haplotype (HapB3) containing 3 intronic variants (c.483+18 G>A, c.680+139 G>A, and c.959-51 T>C), one synonymous variant (c.1236 G>A, E412E), and a deep intronic variant (c.1129-5923 C>G) that affects pre-messenger RNA (pre-mRNA) splicing. However, these studies included a diversity of cancer types, stages, and treatments, requiring further evaluation in a refined population.
Lee’s study involved 2134 Caucasian patients with stage 3 colon cancer who lack the DPYD*2A, D949V, and I560S variants already associated with toxicity (from the NCCTG N0147 trial). Patients received adjuvant FOLFOX (the oxaliplatin/5-FU/leucovorin combination) or FOLFIRI (the 5-FU/leucovorin/irinotecan combination) +/- cetuximab and were genotyped by multiplexed, single-base extension assays on the Sequenom MassARRAY® analysis platform. In the Mayo study, 1339 patients (62.8%) and 705 patients (33.0%) reported at least one grade 3+ (G3+) AE overall and 5-FU AE, respectively.
Subcohort analysis identified the following associations:
“Among the primary cohort,” noted Lee, “a moderate association was identified between G3+ 5-FU AEs and the deep intronic c.1129-5923 C>G variant (odds ratio [OR], 1.539; 95% confidence interval [CI], 1.001-2.367;P= .0493). However, after adjusting for multiple covariates, this association was no longer statistically significant (OR, 1.558; 95% CI, 0.976-2.488;P= .0630).”
Only the more frequent DPYD HapB3 variant c.680+139 G>A showed a significant association with G3+ overall AE rate (OR, 1.263; 95% CI, 1.016-1.572;P= .0356).In general, in the absence of DPYD*2A, D949V, and I560S, the HapB3 haplotype and the deep intronic variant have limited predictive value for severe toxicity to adjuvant 5-FU-based combination chemotherapy, but, according to Lee, the findings showed that specific variables such as sex, treatment, and KRAS status may significantly affect their predictive value.
“Significant interaction effects on G3+ 5-FU AEs were identified between DPYD variants and sex andKRAS/BRAFmutation status,” Lee explained, “with a moderate interaction effect with treatment.”