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Genetics and Genomics

A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO

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Abstract

Introduction

Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility.

Methods

We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations.

Results

BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI: 0.73–0.84 and 0.70, 95% CI: 0.60–0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94]).

Discussion

The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.

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Fig. 1: Hypothetical family.
Fig. 2: Estimated risk of Pancreatic cancer.

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Data availability

Data are available, through a collaborative agreement, upon request. BRCAPANCPRO is part of the R package BayesMendel and freely available for research use.

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Acknowledgements

Deepest gratitude to the patients and families who participated in research studies contributing to this work.

Funding

This work was supported by the Lustgarten Foundation and NCI RO1CA154823 (to APK), U01CA247283 (to APK), NCI P50 CA62924 (to APK), P30CA006973 (to Nelson), P30CA006516 (to Glimcher), R01 CA132829 (to SS), R01CA097075 (to GMP), Rolfe Pancreatic Cancer Foundation (to GMP), and the Sol Goldman Pancreatic Cancer Research Center.

Author information

Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, MD, USA

    Amanda L. Blackford, Erica J. Childs, Nancy Porter, Michael G. Goggins, Ralph H. Hruban & Alison P. Klein

  2. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

    Gloria M. Petersen & Kari G. Rabe

  3. Divison of General Surgery, University of Toronto, Toronto, ON, Canada

    Steven Gallinger & Ayelet Borgida

  4. Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA, USA

    Sapna Syngal

  5. Gastroenterology Division, Brigham and Women’s Hospital, Boston, MA, USA

    Sapna Syngal

  6. Department of Oncology, Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA

    Michele L. Cote & Ann G. Schwartz

  7. The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University, Baltimore, MD, USA

    Michael G. Goggins, Ralph H. Hruban & Alison P. Klein

  8. Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA, USA

    Giovanni Parmigiani

Authors
  1. Amanda L. Blackford
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  2. Erica J. Childs
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  3. Nancy Porter
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  4. Gloria M. Petersen
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  14. Alison P. Klein
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Contributions

ALB—study design, statistical analysis, drafting and revision of manuscript. EJC—statistical analysis, revision of manuscript. NP—data collection, statistical analysis, revision of manuscript. GMP, KGR, SG, AB, SS, MLC, AGS, MGG, RHH—data collection, revision of manuscript. GP—study design, supervision of data analysis, data collection, revision of manuscript, APK—study design, supervision of data analysis, data collection, provision of funding, drafting and revision of manuscript.

Corresponding author

Correspondence to Alison P. Klein.

Ethics declarations

Ethics approval and consent to participate

The Johns Hopkins IRB approved this study. Cohort and registry data participants at Johns Hopkins and participating sites provided informed consent at the enrolling site. The study was performed in accordance with the Declaration of Helsinki.

Consent to publish

Not applicable as no individual-level information is shared.

Competing interests

APK has previously consulted for MERCK and SS has consulted for Myriad Genetics.

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Blackford, A.L., Childs, E.J., Porter, N. et al. A risk prediction tool for individuals with a family history of breast, ovarian, or pancreatic cancer: BRCAPANCPRO. Br J Cancer 125, 1712–1717 (2021). https://doi.org/10.1038/s41416-021-01580-x

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