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Breast Cancer Research and Treatment

, Volume 149, Issue 2, pp 517–523 | Cite as

A polygenic risk score for breast cancer in women receiving tamoxifen or raloxifene on NSABP P-1 and P-2

  • Celine M. Vachon
  • Daniel J. Schaid
  • James N. Ingle
  • D. Lawrence Wickerham
  • Michiaki Kubo
  • Taisei Mushiroda
  • Matthew P. Goetz
  • Erin E. Carlson
  • Soonmyung Paik
  • Norman Wolmark
  • Yusuke Nakamura
  • Liewei Wang
  • Richard Weinshilboum
  • Fergus J. Couch
Epidemiology

Abstract

Recent genetic studies have identified common variation in susceptibility loci that stratify lifetime risks of breast cancer and may inform prevention and screening strategies. However, whether these loci have similar implications for women treated with tamoxifen or raloxifene (SERMs) is unknown. We conducted a matched case–control study of 592 cases who developed breast cancer and 1,171 unaffected women from 32,859 participants on SERM therapy enrolled on NSABP P-1 and P-2 breast cancer prevention trials. We formed a quantitative polygenic risk score (PRS) using genotypes of 75 breast cancer-associated single nucleotide polymorphisms and examined the PRS as a risk factor for breast cancer among women treated with SERMs. The PRS ranged from 3.98 to 7.74, with a one-unit change associated with a 42 % increase in breast cancer (OR = 1.42; P = 0.0002). The PRS had a stronger association with breast cancer among high-risk women with no first-degree family history (OR = 1.62) compared to those with a positive family history (OR = 1.32) (P intx = 0.04). There was also suggestion that PRS was a stronger risk factor for ER-positive (OR = 1.59, P = 0.0002) than ER-negative (OR = 1.05, P = 0.84) breast cancer (P intx = 0.10). Associations did not differ by tamoxifen or raloxifene treatment, age at trial entry, 5-year predicted Gail model risk or other clinical variables. The PRS is a strong risk factor for ER-positive breast cancer in moderate to high-risk individuals treated with either tamoxifen or raloxifene for cancer prevention. These data suggest that common genetic variation informs risk of breast cancer in women receiving SERMs.

Keywords

SERMs Mammographic density Polygenic risk score Single nucleotide polymorphisms (SNPs) 

Abbreviations

AUC

Area under the curve

BCAC

Breast Cancer Association Consortium

BMI

Body mass index

DCIS

Ductal carcinoma in situ

GWAS

Genome-wide association study

LCIS

Lobular carcinoma in situ

NSABP

National Surgical Adjuvant Breast and Bowel Project

PRS

Polygenic risk score

SERMs

Selective estrogen receptor modulators

SNP

Single nucleotide polymorphism

ER

Estrogen receptor

Notes

Acknowledgments

The authors thank the women who participated in the NSABP P-1 and P-2 clinical trials and provided DNA and consent for its use in genetic studies.

Funding

This work was supported by grants from the National Cancer Institute (U10 CA12027, U10 CA69974, U10 CA37377, U10 CA69651, P50 CA116201, PGRN U19 GM61388), the Breast Cancer Research Foundation, the RIKEN Center for Integrative Medical Science, and the Biobank Japan Project which was funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Supplementary material

10549_2014_3175_MOESM1_ESM.jpg (13 kb)
Supplementary Fig. 1 Association of polygenic risk score (PRS) and breast cancer (n = 592 cases, 1,171 controls) within the National Surgical Adjuvant Breast and Bowel Project P-1 and P-2 trials.Supplementary material 1 (JPG 14 kb)
10549_2014_3175_MOESM2_ESM.doc (935 kb)
Supplementary material 2 (DOC 935 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Celine M. Vachon
    • 1
  • Daniel J. Schaid
    • 2
  • James N. Ingle
    • 3
  • D. Lawrence Wickerham
    • 4
    • 5
  • Michiaki Kubo
    • 6
  • Taisei Mushiroda
    • 6
  • Matthew P. Goetz
    • 3
  • Erin E. Carlson
    • 2
  • Soonmyung Paik
    • 4
  • Norman Wolmark
    • 4
    • 7
  • Yusuke Nakamura
    • 8
  • Liewei Wang
    • 9
  • Richard Weinshilboum
    • 9
  • Fergus J. Couch
    • 1
    • 10
  1. 1.Division of Epidemiology, Department of Health Sciences ResearchMayo ClinicRochesterUSA
  2. 2.Division of Biomedical Statistics and Informatics, Department of Health Sciences ResearchMayo ClinicRochesterUSA
  3. 3.Division of Medical Oncology, Department of OncologyMayo ClinicRochesterUSA
  4. 4.Section of Cancer Genetics and PreventionAllegheny General HospitalPittsburghUSA
  5. 5.National Surgical Adjuvant Breast and Bowel Project (NSABP)PittsburghUSA
  6. 6.RIKEN Center for Integrative Medical ScienceYokohamaJapan
  7. 7.Department of Human OncologyAllegheny General HospitalPittsburghUSA
  8. 8.Section of Hematology and Oncology, Department of MedicineUniversity of ChicagoChicagoUSA
  9. 9.Division of Clinical Pharmacology, Department of Molecular Pharmacology & Experimental TherapeuticsMayo ClinicRochesterUSA
  10. 10.Division of Experimental Pathology, Department of Laboratory Medicine and PathologyMayo ClinicRochesterUSA

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