Dihydropyrimidine dehydrogenase polymorphisms in patients with gastrointestinal malignancies and their impact on fluoropyrimidine tolerability: Experience from a single Italian institution

Table 1 Demographic and clinical characteristics

Characteristic	DPYD testing, n = 149	No DPYD testing, n = 151	Total, n = 300
Median age	66 (84-33)	65 (85-34)	65 (85-33)
ECOG PS
0	133 (89)	143 (95)	276 (92)
1	16 (11)	8 (5)	24 (8)
Sex
Male	79 (53)	86 (57)	165 (55)
Female	70 (47)	65 (43)	135 (45)
Type of cancer
Colon	80 (54)	87 (58)	167 (55.7)
Rectal	32 (21)	46 (30)	78 (26)
Gastric	29 (19)	16 (11)	45 (15)
Esophageal	1 (1)	0 (0)	1 (0.3)
Anal	7 (5)	1 (1)	8 (2.7)
Appendiceal	0 (0)	1 (1)	1 (0.3)
Stage of disease
Localized	104 (70)	95 (63)	199 (66.3)
Metastatic	45 (30)	56 (37)	101 (33.7)
Type of treatment
Monotherapy	23 (15)	20 (13)	43 (14)
Monotherapy + RT	20 (13)	34 (23)	54 (18)
Doublet	97 (65)	88 (58)	185 (61.7)
Triplet	9 (6)	9 (6)	18 (6)

Data are n (%). ECOG: Eastern cooperative oncology group; PS: Performance Status; RT: Radiotherapy.

Table 2 Prevalence of DPYD polymorphisms

DPYD variant	Number detected (%)
HapB3	2 (1.3)1
DPYD2A	1 (0.7)1
c.2846A>T	1 (0.7)1
DPYD13	0 (0)
DPYD6	18 (12.1)2
Wild-type	127 (85.2)
All polymorphisms	22 (14.8)
All polymorphisms except DPYD6	4 (2.7)

¹All in heterozygosity.

²All in heterozygosity except 1 in homozygosity.

Data are n (%).

Table 3 Correlation between DPYD polymorphisms and toxicity

Parameter	Cohort A, n = 149	Cohort B, n = 151	P value
Patients with any AEs ≥ G3	39 (26.17)	67 (44.37)	0.00098
Patients with FP dose reduction	33 (22.15)	69 (45.7)	0.00002
Patients with ChT delay for any grade AEs	38 (25.5)	52 (34.44)	0.09136
Patients with hematological AEs ≥ G3	26 (17.4)	29 (19.3)	0.6944
Patients with non-hematological AEs ≥ G3	5 (3.4)	20 (13.3)	0.0028

Data are n (%). AEs: Adverse events; ChT: Chemotherapy; FP: Fluoropyrimidine.

Table 4 Prevalence of DPYD polymorphisms in European populations

Polymorphism	Photo DPYD Spain[17], n = 8054	Paulsen Denmark[18], n = 4215	Pallet France[19], n = 3680	Henricks Netherland[13], n = 1103
DPYD2A	55 (0.7)	43 (1)	25 (0.67)	16 (1)
DPYD13	15 (0.2)	8 (0.2)	4 (0.1)	1 (< 1)
Hap3B	209 (2.6)	208 (4.9)	109 (2.96)	51 (5)
c.2846A>T	105 (1.3)	57 (1.4)	34 (0.92)	17 (2)
Total	384 (4.8)	316 (7.5)	172 (4.65)	85 (8)

Data are n (%).

Table 5 DPYD polymorphisms analysis in Italian cancer patients

Feature	TOSCA trial[20]	TRIBE trial[21]	IRCCS Pascale[22]
Setting	Colon cancer high-risk stage 2 or stage 3	Colo-rectal cancer stage 4	Gastrointestinal malignancies
Treatment	FOLFOX/CAPOX	FOLFOXIRI/FOLFIRI + bevacizumab	Patients candidates for fluoropyrimidines
Patients	508	439	1000
Total number of tested variants	10	3	5
Prevalence of the four recommended variants in heterozygosity	19/508 (3.7)	10/439 (2.3)1	39/1000 (3.9)
Prevalence of the four recommended variants + DPYD6 in heterozygosity	84/508 (16.5)	0/439 (0)2	180/1000 (18)
Prevalence of the four recommended variants + DPYD6 in homozygosity	5/508 (1.0)3	0/439 (0)2	5/1000 (0.5)3

¹HapB3 not analyzed.

²HapB3 and DPYD6 not analyzed.

³All DPYD6.

Data are n (%). TOSCA: A randomized trial investigating the role of oxaliplatin, fluorouracil and leucovorin calcium-4 regimen duration (3 months vs 6 months) and bevacizumab as adjuvant therapy for patients with stage 2/3 colon cancer; TRIBE: Phase 3 randomized trial of oxaliplatin, irinotecan, fluorouracil, and leucovorin calcium + bevacizumab vs irinotecan, fluorouracil, and leucovorin calcium + bevacizumab as first-line treatment for metastatic colorectal cancer. CAPOX: Capecitabine and oxaliplatin; FOLFIRI: Irinotecan, fluorouracil, and leucovorin calcium; FOLFOX: Oxaliplatin, fluorouracil, and leucovorin calcium; FOLFOXIRI: Oxaliplatin, irinotecan, fluorouracil, and leucovorin calcium; IRCCS: Scientific institute for research, hospitalization and healthcare.