Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Sep;23(9):1726-1737.
doi: 10.1038/s41436-021-01198-7. Epub 2021 Jun 10.

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Inge M M Lakeman #  1   2 , Alexandra J van den Broek #  3 , Juliën A M Vos  3 , Daniel R Barnes  4 , Julian Adlard  5 , Irene L Andrulis  6   7 , Adalgeir Arason  8   9 , Norbert Arnold  10   11 , Banu K Arun  12 , Judith Balmaña  13   14 , Daniel Barrowdale  4 , Javier Benitez  15   16 , Ake Borg  17 , Trinidad Caldés  18 , Maria A Caligo  19 , Wendy K Chung  20 , Kathleen B M Claes  21 ; GEMO Study Collaborators; EMBRACE Collaborators; J Margriet Collée  22 , Fergus J Couch  23 , Mary B Daly  24 , Joe Dennis  4 , Mallika Dhawan  25 , Susan M Domchek  26 , Ros Eeles  27 , Christoph Engel  28 , D Gareth Evans  29   30 , Lidia Feliubadaló  31 , Lenka Foretova  32 , Eitan Friedman  33   34 , Debra Frost  4 , Patricia A Ganz  35 , Judy Garber  36 , Simon A Gayther  37 , Anne-Marie Gerdes  38 , Andrew K Godwin  39 , David E Goldgar  40 , Eric Hahnen  41   42 , Christopher R Hake  43 , Ute Hamann  44 , Frans B L Hogervorst  45 , Maartje J Hooning  46 , John L Hopper  47 , Peter J Hulick  48   49 , Evgeny N Imyanitov  50 ; OCGN Investigators; HEBON Investigators; KconFab Investigators; Claudine Isaacs  51 , Louise Izatt  52 , Anna Jakubowska  53   54 , Paul A James  55   56 , Ramunas Janavicius  57   58 , Uffe Birk Jensen  59 , Yue Jiao  60   61   62 , Esther M John  63   64 , Vijai Joseph  65 , Beth Y Karlan  66 , Carolien M Kets  45 , Irene Konstantopoulou  67 , Ava Kwong  68   69   70 , Clémentine Legrand  71 , Goska Leslie  4 , Fabienne Lesueur  60   61   62 , Jennifer T Loud  72 , Jan Lubiński  53 , Siranoush Manoukian  73 , Lesley McGuffog  4 , Austin Miller  74 , Denise Molina Gomes  75 , Marco Montagna  76 , Emmanuelle Mouret-Fourme  77 , Katherine L Nathanson  26 , Susan L Neuhausen  78 , Heli Nevanlinna  79 , Joanne Ngeow Yuen Yie  80   81 , Edith Olah  82 , Olufunmilayo I Olopade  83 , Sue K Park  84   85   86 , Michael T Parsons  87 , Paolo Peterlongo  88 , Marion Piedmonte  74 , Paolo Radice  89 , Johanna Rantala  90 , Gad Rennert  91 , Harvey A Risch  92 , Rita K Schmutzler  41   42   93 , Priyanka Sharma  94 , Jacques Simard  95 , Christian F Singer  96 , Zsofia Stadler  97 , Dominique Stoppa-Lyonnet  77   98   99 , Christian Sutter  100 , Yen Yen Tan  101 , Manuel R Teixeira  102   103 , Soo Hwang Teo  104   105 , Alex Teulé  31 , Mads Thomassen  106 , Darcy L Thull  107 , Marc Tischkowitz  108   109 , Amanda E Toland  110 , Nadine Tung  111 , Elizabeth J van Rensburg  112 , Ana Vega  15   113   114 , Barbara Wappenschmidt  41   42 , Peter Devilee  1   115 , Christi J van Asperen  2 , Jonine L Bernstein  116 , Kenneth Offit  65   97 , Douglas F Easton  4   117 , Matti A Rookus  118 , Georgia Chenevix-Trench  87 , Antonis C Antoniou  4 , Mark Robson  97 , Marjanka K Schmidt  119   120   121
Collaborators, Affiliations

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Inge M M Lakeman et al. Genet Med. 2021 Sep.

Abstract

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

PubMed Disclaimer

Conflict of interest statement

C. Isaacs is consultant to Astra Zeneca, Novartis, Pfizer, Genentech, PUMA, Seattle Genetics, and received research support from Tesaro. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Association between the PRS and contralateral breast cancer risk for BRCA1 and BRCA2 heterozygotes.
Effect size of the association between contralateral breast cancer and the three different PRS313 after testing for covariates for the following selections: all contralateral breast cancer, invasive contralateral breast cancer only, ER-negative contralateral breast cancer, and ER-positive contralateral breast cancer. The numbers of unilateral and contralateral breast cancer cases and effect sizes are shown in Table 2 and Table S4. CBC contralateral breast cancer, ER estrogen receptor, HR hazard ratio, PRS polygenic risk score, SD standard deviation.
Fig. 2
Fig. 2. Association between categories of the PRS and contralateral breast cancer risk for BRCA1 and BRCA2 heterozygotes.
HRs and 95% CI for percentiles of the ER-negative PRS313 for BRCA1 heterozygotes and the ER-positive PRS313 for BRCA2 heterozygotes, relative to the middle quintile. The PRS percentile groups were 0–5%, 5–10%, 10–20%, 20–40%, 40–60% (reference), 60–80%, 80–90%, 90–95%, and 95–100% based on the distribution in unilateral breast cancer cases. The numbers and corresponding effect sizes are shown in Table 2. The gray line represents the distribution based on the HR of the continuous ER-negative PRS313 and ER-positive PRS313 and the distribution in unilateral breast cancer cases of BRCA1 and BRCA2 heterozygotes respectively. CI confidence interval, ER estrogen receptor, HR hazard ratio, PRS polygenic risk score.
Fig. 3
Fig. 3. Absolute contralateral breast cancer risk by PRS percentiles per age category of the first breast cancer diagnosis for BRCA1 and BRCA2 heterozygotes.
Predicted absolute contralateral breast cancer risks by percentile of the continuous ER-negative PRS313 for BRCA1 heterozygotes and ER-positive PRS313 for BRCA2 heterozygotes. The assumed contralateral breast cancer incidences were from a study that estimated breast cancer incidence in a large prospective cohort of BRCA1 and BRCA2 heterozygotes. The age categories were based on the age at diagnosis of the first primary breast tumor. Risks were calculated including the interaction between the PRS and the continuous age of first breast cancer diagnosis. The lines for different percentiles of the PRS are overlapping for the age category ≥50 year for BRCA1 heterozygotes. BC breast cancer, CBC contralateral breast cancer, PRS polygenic risk score.
See this image and copyright information in PMC

References

    1. Kuchenbaecker KB, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA. 2017;317:2402–2416. doi: 10.1001/jama.2017.7112. - DOI - PubMed
    1. Graeser MK, et al. Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J. Clin. Oncol. 2009;27:5887–5892. doi: 10.1200/JCO.2008.19.9430. - DOI - PubMed
    1. Mavaddat N, et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J. Natl. Cancer Inst. 2013;105:812–822. doi: 10.1093/jnci/djt095. - DOI - PubMed
    1. Metcalfe K, et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer. 2011;104:1384–1392. doi: 10.1038/bjc.2011.120. - DOI - PMC - PubMed
    1. Rhiem K, et al. The risk of contralateral breast cancer in patients from BRCA1/2 negative high risk families as compared to patients from BRCA1 or BRCA2 positive families: a retrospective cohort study. Breast Cancer Res. 2012;14:R156. doi: 10.1186/bcr3369. - DOI - PMC - PubMed

Publication types

Grants and funding