Background: Significant individual variation in bone loss associated with aromatase inhibitors (AIs)
emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect.
The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1)
gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive
Methods: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical
practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at
month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046,
extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at
month 12 at the lumbar spine.
Results: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten
patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for
CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an
ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared
to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without
lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total
hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of
having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04).
Conclusion: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical
and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal
breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single
CYP19A1 gene variant in a genomic context.