An Overview of riskScore

Myriad’s riskScore helps to refine a woman’s risk of breast cancer, with or without a family history of breast cancer.

Myriad’s myRisk Hereditary Cancer test includes analysis of several well-known breast cancer genes. However, 10% or fewer of breast cancers in women are hereditary.1,2,3 While hereditary breast cancers are due to a mutation in a specific gene, many other breast cancers are the result of a combination of small genetic factors, environment, lifestyle, and other unknown factors. Consequently, women without a mutation in a breast cancer susceptibility gene could still be at an increased risk for breast cancer due to these other genetic and non-genetic factors. Myriad developed riskScore, a polygenic risk score (PRS) and clinically validated precision medicine tool, to account for these factors.4 riskScore is part of the myRisk Hereditary Cancer test and predicts a woman’s 5-year and lifetime risks of developing breast cancer using clinical risk factors and genetic markers called single nucleotide polymorphisms (SNPs). SNPs are a common form of genetic variation and the breast cancer risk conferred by a single SNP is not high enough to significantly impact a woman’s risk of breast cancer. However, when the effect of multiple SNPs is combined, the risk can be large enough to significantly alter medical management.

Previously, a woman’s breast cancer risk would be estimated using various models that account for her family history and/or hormonal/reproductive factors. The Tyrer-Cuzick model accounts for a woman’s family history of breast and ovarian cancer; her age at menarche, parity, age at first childbirth, age at menopause, height, BMI, and personal history of atypical hyperplasia or LCIS.5 Myriad’s riskScore tool modifies a women’s Tyrer-Cuzick risk estimate by combining it with a weighted analysis of 86 SNPs. riskScore helps to refine a woman’s risk of breast cancer, with or without a family history of breast cancer. In doing so, riskScore can help identify which women may benefit from enhanced breast cancer screening and/or preventative measures.

Currently, there are no specific medical management guidelines for breast cancer based on riskScore. However, an estimated remaining lifetime risk at or above the 20% threshold may warrant consideration of risk-reduction strategies similar to those recommended for women with an estimated lifetime risk greater than 20% based on other risk prediction methods. NCCN recommends women with a breast cancer lifetime risk that is estimated to be 20% or greater based on models that are largely dependent on family history (e.g. Claus, BRCAPRO, Tyrer-Cuzick) consider annual screening with mammograms and breast MRIs at earlier ages.6

Currently, riskScore is only calculated for women of solely European ancestry, under the age of 85, and without a personal history of breast cancer, LCIS, hyperplasia, or a breast biopsy with unknown result. At the present time, riskScore is not calculated for women with a pathogenic mutation in a breast cancer risk gene. However, at the recent 2019 San Antonio Breast Cancer Symposium, Myriad presented data from a validation study using an 86-SNP PRS to refine the breast cancer risk estimates for women with a pathogenic mutation in the following genes: BRCA1, BRCA2, ATM, CHEK2, and PALB2.7 This study showed that the PRS was able to better refine the breast cancer risk for these mutation carriers, but it was strongest for CHEK2 mutation carriers. A comprehensive risk assessment that combines the 86-SNP PRS with other risk factors may improve the accuracy of risk estimates and facilitate medical decision-making, especially for women with pathogenic mutations in the moderate penetrance breast cancer genes. Myriad is currently researching this topic further and may incorporate PRS-based risk estimates for carriers of certain gene mutations in the future.

References
  1. Couch FJ, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3(9):1190-1196.
  2. Buys SS, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer. 2017;123(10):1721-1730.
  3. Siegel RL, et al. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
  4. Hughes, E. et al. SABCS (2017 presentation).
  5. Tyrer J, Duffy SW, & Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23(7):1111-1130.
  6. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer Screening and Diagnosis (Version 1.2019). https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf. Accessed April 27, 2020.
  7. Hughes, E. et al. SABCS (2019 presentation).

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