CYP19A1 polymorphisms and clinical outcomes in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1–98 trial

Abstract

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.

CYP1A2 – a novel genetic marker for early aromatase inhibitor response in the treatment of breast cancer patients

“…However, genotypes, haplotypes, and diplotypes of CYP19A1 SNPs rs4646, rs10046, Aro1, and Aro2 were not significantly associated with a risk of early breast cancer events in the AI-treated patients. These results are in line with the recent study by of Leyland-Jones et al [ 11 ] that investigated CYP19A1 tumor genotype data in relation to endocrine treatment response in the BIG 1–98 trial, but in contrast to a previous study on genomic CYP19A1 genotypes regarding the risk of recurrence in AI-treated patients [ 13 ]. In the recent abstract by Umamasheran et al, an increased risk for breast cancer recurrence was observed among 191 Indian letrozole-treated T/T carriers of rs4646 [ 13 ].…”

“…However, endocrine resistance is a major obstacle to optimal treatment effect [ 4 ]. Several genetic markers for tamoxifen response have been proposed, although no consensus has yet been reached [ 5 – 11 ]. For AIs, data on genetic markers are sparse [ 10 – 13 ].…”

“…Only a few studies have investigated the association between polymorphisms in Cytochrome P450 (CYP) CYP19A1 (aromatase) and disease-free survival in breast cancer [ 10 , 18 , 19 ]. There are currently only a few studies published with a proposed polymorphism for predicting AI response in the adjuvant setting, and these have contradictory results [ 11 , 13 ]. Some studies have investigated the impact of CYP19A1 polymorphisms on treatment response in the metastatic- [ 20 ] and in the neoadjuvant settings [ 21 , 22 ].…”

Elevated Aromatase (CYP19A1) Expression Is Associated with a Poor Survival of Patients with Estrogen Receptor Positive Breast Cancer

“…Another CYP19A1 haplotype was associated with a poor OS, DFS, and metastasis-free survival (MFS) in premenopausal, ER-positive breast cancer patients [ 35 ]. In contrast, two other large studies found no evidence for an association of rs10046 and OS, DFS, and MFS in unselected breast cancer patients [ 36 , 37 ].…”

“Just Wear Dark Underpants Mainly”: Learning from Adolescents' and Young Adults' Experiences with Early Discontinuation of the Contraceptive Implant

“…Future research for better personalized prediction of side effects, for example, on the basis of biomarkers, which are being investigated for drugs such as depot medroxyprogresterone 17 or tamoxifen, 18 could decrease the number of patients who require early removal for side effects. Until then, however, counseling should stress that there is no way to predict who will develop intolerable side effects, but that patients are welcome to return for implant removal if this happens to them.…”