Polymorphism at 19q13.41 predicts breast cancer survival specifically after endocrine therapy
Polymorphism at 19q13.41 predicts breast cancer survival specifically after endocrine therapy
Purpose: Although most patients with estrogen receptor (ER)–positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies.
Experimental Design: We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy patients, evaluating 486,478 single-nucleotide polymorphisms (SNP). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totaling 5,011 patients, with 3,485 receiving endocrine therapy.
Results: A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine-treated patients [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.37–2.07; P = 6.34 × 10?7] and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment, indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI, 1.30–3.60; P interaction = 0.003) and HR = 7.77 (95% CI, 0.93–64.71) for the homozygous genotype carriers. A biologic rationale is suggested by in silico functional analyses.
Conclusions: Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment.
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Khan, S.
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Fagerholm, R.
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Rafiq, S.
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Tapper, W.
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Aittomaki, K.
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Liu, J.
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Blomqvist, C.
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Eccles, D.
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Nevanlinna, H.
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Khan, S.
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Fagerholm, R.
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Rafiq, S.
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Tapper, W.
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Aittomaki, K.
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Liu, J.
516e902e-000e-4f9c-b9bc-bac18b1f5ade
Blomqvist, C.
61aa59a2-9f7b-4f93-9984-8196c9a59384
Eccles, D.
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Nevanlinna, H.
188d5d63-7183-49de-8721-242adee86703
Khan, S., Fagerholm, R., Rafiq, S., Tapper, W., Aittomaki, K., Liu, J., Blomqvist, C., Eccles, D. and Nevanlinna, H.
(2015)
Polymorphism at 19q13.41 predicts breast cancer survival specifically after endocrine therapy.
Clinical Cancer Research, .
(doi:10.1158/1078-0432.CCR-15-0296).
(PMID:25964295)
Abstract
Purpose: Although most patients with estrogen receptor (ER)–positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies.
Experimental Design: We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy patients, evaluating 486,478 single-nucleotide polymorphisms (SNP). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totaling 5,011 patients, with 3,485 receiving endocrine therapy.
Results: A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine-treated patients [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.37–2.07; P = 6.34 × 10?7] and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment, indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI, 1.30–3.60; P interaction = 0.003) and HR = 7.77 (95% CI, 0.93–64.71) for the homozygous genotype carriers. A biologic rationale is suggested by in silico functional analyses.
Conclusions: Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment.
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Accepted/In Press date: 30 April 2015
e-pub ahead of print date: 11 May 2015
Organisations:
Cancer Sciences
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Local EPrints ID: 380554
URI: http://eprints.soton.ac.uk/id/eprint/380554
ISSN: 1078-0432
PURE UUID: 9f0b6f13-4f93-48a8-aa80-0ed37876d80d
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Date deposited: 18 Aug 2015 08:06
Last modified: 15 Mar 2024 03:02
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Author:
S. Khan
Author:
R. Fagerholm
Author:
S. Rafiq
Author:
K. Aittomaki
Author:
J. Liu
Author:
C. Blomqvist
Author:
H. Nevanlinna
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