Authors
Norah Lynn Henry
University of Michigan Medical Center, Ann Arbor, MI
Norah Lynn Henry , Todd C. Skaar , Jessica Dantzer , Lang Li , Anne T Nguyen , James M. Rae , Zeruesenay Desta , Steffi Oesterreich , Santosh Philips , Janet S Carpenter , Anna Maria Storniolo , Vered Stearns , Daniel F. Hayes , David A. Flockhart
Organizations
University of Michigan Medical Center, Ann Arbor, MI, Indiana University School of Medicine, Indianapolis, IN, University of Michigan, Ann Arbor, MI, University of Pittsburgh Cancer Institute, Pittsburgh, PA, Indiana University School of Nursing, Indianapolis, IN, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD
Background: Discontinuation of adjuvant AI therapy due to intolerable symptoms occurs in up to 30% of patients. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity.
Methods: We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane (exe) versus letrozole (let). Using multiple genetic models, we evaluated potential associations between 136 single nucleotide polymorphisms (SNP) in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling, and discontinuation of AI therapy because of toxicity. To account for multiple comparisons, statistical significance was defined as p<0.0003.
Results: Of the 467 enrolled patients who had available germ line DNA, 152 (33%) discontinued AI therapy because of toxicity. After adjusting for multiple covariates, multivariable analyses revealed that two inherited genetic variants in
ESR1, which encodes
estrogen receptor (ER) alpha, and one in
CYP19A1 were associated with increased risk of discontinuation of AI therapy because of toxicity (Table). A variant in
NCOR1 (ER co-repressor) was associated with decreased risk of discontinuation of letrozole because of toxicity.
Conclusions: Variants in genes involved in estrogen metabolism and signaling may be associated with toxicity of AI therapy.
Statistical model |
Gene |
SNP |
AI |
HR (95% CI) |
p value |
Recessive |
CYP19A1 |
rs28566535 |
Either |
8.2 (2.7-24.9) |
<0.0002 |
|
|
|
Exe |
8.1 (1.6-41) |
0.012 |
|
|
|
Let |
7.5 (1.5-38.1) |
0.016 |
|
ESR1 |
rs9322335 |
Either |
4.2 (2-8.6) |
<0.0001 |
|
|
|
Exe |
10.5 (2.9-38.7) |
<0.0004 |
|
|
|
Let |
3.3 (1.2-9.1) |
0.018 |
|
ESR1 |
rs9322336 |
Either |
3.7 (1.8-7.4) |
<0.0004 |
|
|
|
Exe |
7.2 (2.7-19.5) |
0.0001 |
|
|
|
Let |
3 (1-8.8) |
0.050 |
Additive |
NCOR1 |
rs1065822 |
Either |
0.7 (0.5-0.9) |
0.015 |
|
|
|
Exe |
1.1 (0.7-1.6) |
0.77 |
|
|
|
Let |
0.3 (0.2-0.6) |
<0.0002 |