Research Article: Validation of a genetic risk score for Arkansas women of color

Date Published: October 3, 2018

Publisher: Public Library of Science

Author(s): Athena Starlard-Davenport, Richard Allman, Gillian S. Dite, John L. Hopper, Erika Spaeth Tuff, Stewart Macleod, Susan Kadlubar, Michael Preston, Ronda Henry-Tillman, Amanda Ewart Toland.


African American women in the state of Arkansas have high breast cancer mortality rates. Breast cancer risk assessment tools developed for African American underestimate breast cancer risk. Combining African American breast cancer associated single-nucleotide polymorphisms (SNPs) into breast cancer risk algorithms may improve individualized estimates of a woman’s risk of developing breast cancer and enable improved recommendation of screening and chemoprevention for women at high risk. The goal of this study was to confirm with an independent dataset consisting of Arkansas women of color, whether a genetic risk score derived from common breast cancer susceptibility SNPs can be combined with a clinical risk estimate provided by the Breast Cancer Risk Assessment Tool (BCRAT) to produce a more accurate individualized breast cancer risk estimate. A population-based cohort of African American women representative of Arkansas consisted of 319 cases and 559 controls for this study. Five-year and lifetime risks from the BCRAT were measured and combined with a risk score based on 75 independent susceptibility SNPs in African American women. We used the odds ratio (OR) per adjusted standard deviation to evaluate the improvement in risk estimates produced by combining the polygenic risk score (PRS) with 5-year and lifetime risk scores estimated using BCRAT. For 5-year risk OR per standard deviation increased from 1.84 to 2.08 with the addition of the polygenic risk score and from 1.79 to 2.07 for the lifetime risk score. Reclassification analysis indicated that 13% of cases had their 5-year risk increased above the 1.66% guideline threshold (NRI = 0.020 (95% CI -0.040, 0.080)) and 6.3% of cases had their lifetime risk increased above the 20% guideline threshold by the addition of the polygenic risk score (NRI = 0.034 (95% CI 0.000, 0.070)). Our data confirmed that discriminatory accuracy of BCRAT is improved for African American women in Arkansas with the inclusion of specific SNP breast cancer risk alleles.

Partial Text

Racial disparities among women of color is evident. African American women have higher mortality rates, poorer breast cancer survival rates, and are more likely to develop early onset basal-like breast tumors that are non-responsive to hormone receptor therapy compared with European American women [1–3]. In the state of Arkansas breast cancer incidence rates have dramatically decreased due to state-funded breast and cervical cancer screening and diagnostic services for eligible Arkansas women. However, mortality rates due to breast cancer among African American Arkansas women are amongst the highest in the nation [1]. Breast cancer risk assessment tools, such as the BCRAT (also known as the Gail model) were developed by scientists at the National Cancer Institute to estimate a woman’s risk of developing invasive breast cancer within the next 5 years and within her lifetime (up to age 90). The BCRAT considers race/ethnicity, age, breast cancer risk factors that influence estrogen production (such as menopausal status, body weight, parity, age at menarche, age at the time of the birth of a first child and), number of past breast biopsies, and first-degree and second-degree family history of breast cancer. Women with a 5-year risk of 1.67 percent or higher are classified as “high-risk.” The BCRAT has been shown to be well calibrated for predicting breast cancer risk for European American women but unfortunately not for African American women [4, 5]. Modification of the BCRAT based on data of African American women from the Women’s Contraceptive and Reproductive Experiences study also underestimated breast cancer risk in African American women [6–8].

Table 1 shows the characteristics of the study participants and the questionnaire variables used in the calculation of the BCRAT risk score. For cases, the mean age at diagnosis was 54.6 years (standard deviation [SD] = 10.4), and for controls, the mean age at interview was 53.3 years (SD = 9.8). The mean BCRAT 5-year risk of breast cancer was 1.80% (SD 1.10%) for cases and 1.20% (SD 0.50%) for controls. The mean BCRAT lifetime risk of breast cancer was 10.4% (SD 5.20%) for cases and 8.0% (SD 2.70%) for controls. The mean SNP-based risk score was 1.02 (SD 0.43) for cases and 0.89 (SD 0.38) for controls. S1 Table shows, for each of the 75 SNPS, the per-allele OR and 95% CI in this study as well as the previously published per-allele OR and 95% CI.

Genome-wide association studies conducted mainly in European or Asian populations have identified an increasing number of genetic susceptibility loci for breast cancer. In addition to the observation that SNPs are associated with increased risk of developing breast cancer, several studies have investigated the possibility of combining the SNP-based risk scores with conventional breast cancer risk prediction tools, particularly for women of European descent [13–16, 32] but also recently for women of African ancestry and Hispanic ancestry [33]. Using the same SNPs validated in a recent comprehensive panel for African Americans [25], this study’s smaller, independent cohort of African American women in Arkansas confirms the added value of SNP to breast cancer risk assessment among the African American population. Importantly, for European ancestry women, the combined SNP-based and risk prediction tool scores are now among the strongest known measures for differentiating women with and without breast cancer [32]. Given the disparity in stage at breast cancer diagnosis between African American women and other US populations, identification and testing the validity of a breast cancer risk assessment tool that may increase screening and prevention awareness in African American women is needed and SNP-based risk assessment may enable the medical community to better identify those women that would benefit from increased screening, screening adherence or risk reducing medication.

In conclusion, our results indicate that discriminatory accuracy of BCRAT is improved for African American women in Arkansas with the inclusion of African American specific SNP breast cancer risk alleles. We anticipate that the SNP-based risk score will further improve when genome-wide association studies use Phase I data sets that are relevant to the African American population, and when fine mapping studies have been conducted within that population.




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