CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial.
To determine whether CYP19A1 polymorphisms are associated with abnormal activity of aromatase and with musculoskeletal and bone side effects of aromatase inhibitors. DNA was isolated from tumor specimens of 4861 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Tumors were genotyped for six CYP19A1 polymorphisms using PCR-based methods. Associations with breast cancer-free interval (BCFI), distant recurrence-free interval (DRFI), musculoskeletal and bone adverse events (AEs) were assessed using Cox proportional hazards models. All statistical tests were two-sided. No association between the CYP19A1 genotypes and BCFI or DRFI was observed overall. A reduced risk of a breast cancer event for tamoxifen-treated patients with rs700518 variants was observed (BCFI CC/TC vs. TT: HR 0.53, 95 % CI 0.34-0.82, interaction P = 0.08), but not observed for letrozole-treated patients. There was an increased risk of musculoskeletal AEs for patients with rs700518 variants CC/TC versus TT (HR 1.22, 95 % CI 1.03-1.45, P = 0.02), regardless of treatment. Tamoxifen-treated patients with rs4646 variants had a reduced risk of bone AEs (AA/CA vs. CC: HR 0.76, 95 % CI 0.59-0.98), whereas an increase of minor allele (C) of rs10046 was associated with an increased risk of bone AEs (HR 1.28, 95 % CI 1.07-1.52). rs936308 variants were associated with a reduced risk of bone AEs in letrozole-treated patients (GG/GC vs. CC: HR 0.73, 95 % CI 0.54-0.99), different from in tamoxifen-treated patients (GG/GC vs. CC: HR 1.32, 95 % CI 0.92-1.90, interaction P = 0.01). CYP19A1 rs700518 variants showed associations with BCFI, DRFI, in tamoxifen treated patients and musculoskeletal AEs regardless of treatment. SNPs rs4646, rs10046, and rs936308 were associated with bone AEs.
Avera Cancer Institute, 1000 E 23rd Street, Sioux Falls, SD, 57105, USA, bleylandj@aol.com.
Brian
B
Leyland-Jones
Kathryn P
KP
Gray
Mark
M
Abramovitz
Mark
M
Bouzyk
Brandon
B
Young
Bradley
B
Long
Roswitha
R
Kammler
Patrizia
P
Dell'Orto
Maria Olivia
MO
Biasi
Beat
B
Thürlimann
Maria B
MB
Lyng
Henrik J
HJ
Ditzel
Vernon J
VJ
Harvey
Patrick
P
Neven
Isabelle
I
Treilleux
Birgitte Bruun
BB
Rasmussen
Rudolf
R
Maibach
Karen N
KN
Price
Alan S
AS
Coates
Aron
A
Goldhirsch
Olivia
O
Pagani
Giuseppe
G
Viale
James M
JM
Rae
Meredith M
MM
Regan
D000368:Aged; D000483:Alleles; D001141:Aromatase / Q000235:genetics*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D017326:Clinical Trials, Phase III as Topic; D003131:Combined Modality Therapy; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D011960:Receptors, Estrogen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D016896:Treatment Outcome; D047368:Tumor Burden
D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D001141:Aromatase; C561410:CYP19A1 protein, human