Abstract
Five-year absolute breast cancer risk prediction models are required to comply with national guidelines regarding risk reduction regimens. Models including the Gail model are under-utilized in the general population for various reasons, including difficulty in accurately completing some clinical fields. The purpose of this study was to determine if a streamlined risk model could be designed without substantial loss in performance. Only the clinical risk factors that were easily answered by women will be retained and combined with an objective validated polygenic risk score (PRS) to ultimately improve overall compliance with professional recommendations. We first undertook a review of a series of 2,339 Caucasian, African American and Hispanic women from the USA who underwent clinical testing. We first used deidentified test request forms to identify the clinical risk factors that were best answered by women in a clinical setting and then compared the 5-year risks for the full model and the streamlined model in this clinical series. We used OPERA analysis on previously published case-control data from 11,924 Gail model samples to determine clinical risk factors to include in a streamlined model: first degree family history and age that could then be combined with the PRS. Next, to ensure that the addition of PRS to the streamlined model was indeed beneficial, we compared risk stratification using the Streamlined model with and without PRS for the existing case-control datasets comprising 1,313 cases and 10,611 controls of African-American (n = 7421), Caucasian (n = 1155) and Hispanic (n = 3348) women, using the area under the curve to determine model performance. The improvement in risk discrimination from adding the PRS risk score to the Streamlined model was 52%, 46% and 62% for African-American, Caucasian and Hispanic women, respectively, based on changes in log OPERA. There was no statistically significant difference in mean risk scores between the Gail model plus risk PRS compared to the Streamlined model plus PRS. This study demonstrates that validated PRS can be used to streamline a clinical test for primary care practice without diminishing test performance. Importantly, by eliminating risk factors that women find hard to recall or that require obtaining medical records, this model may facilitate increased clinical adoption of 5-year risk breast cancer risk prediction test in keeping with national standards and guidelines for breast cancer risk reduction.
Highlights
Apart from non-melanoma skin cancer, breast cancer is the most common form of cancer affecting women and approximately one in eight women in the United States of America (U.S A) will develop the disease in their lifetime [1]
For women who are not initially identified as at high risk based on previous personal history of breast cancer, or family history suggestive of germline pathogenic mutations, the U.S Preventative Services Task Force (USPSTF) [2], the American Society of Clinical Oncology (ASCO) [3], as well as the National Comprehensive Cancer Network (NCCN) [4], all have guidelines that these women should be screened to determine their five-year risk of developing breast cancer and offered risk-reducing medications, if appropriate
Our single nucleotide polymorphisms (SNP) were validated in African American and Hispanic women [19], population-specific SNP improvements need be made in future studies for a more robust model because the majority of the SNP panels were discovered in European ancestry populations
Summary
Apart from non-melanoma skin cancer, breast cancer is the most common form of cancer affecting women and approximately one in eight women in the United States of America (U.S A) will develop the disease in their lifetime [1]. For women who are not initially identified as at high risk based on previous personal history of breast cancer, or family history suggestive of germline pathogenic mutations, the U.S Preventative Services Task Force (USPSTF) [2], the American Society of Clinical Oncology (ASCO) [3], as well as the National Comprehensive Cancer Network (NCCN) [4], all have guidelines that these women should be screened to determine their five-year risk of developing breast cancer and offered risk-reducing medications, if appropriate. The USPSTF uses a 5-year high-risk threshold of 3% and recommends a strong grade B (‘offer or provide this service’) guidance that providers offer tamoxifen or raloxifene for women above this 3% threshold [2], while ASCO and NCCN use a lower 5-year high-risk threshold of 1.67%, and in addition to tamoxifen and raloxifene, provide the option of aromatase inhibitors [3, 4]
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