Abstract PO5-03-08: Detection and quantification of triple-negative breast cancer (TNBC) across ethnicities through analysis of cell-free DNA (cfDNA) methylation
Authors: Cance William , Liu Edison , Antonio Margaret , Shaver Timothy , Shih Stephannie , Chu Bong Chul , Kurtzman Kathryn , Newman Lisa 
Published: May 2024

Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype contributing to race-related outcome disparities in breast cancer. These disparities are partly explained by the higher burden of TNBC in Black women, less access to new mammography technologies, and further compounded by limited efficacy of screening mammography in early detection of TNBC (Newman L & Mitchell E, J Natl Med Assoc 2023). To better understand these disparities, we compared results from the Galleri® multi-cancer early detection (MCED) test and the tumor methylated fraction (TMeF) tumor quantification algorithm in a population of TNBC patients across different stages and self-reported ethnicities (SRE).

Methods: Within the case-control Circulating Cell-free Genome Atlas third substudy, we performed MCED testing and TMeF estimation in 507 women with breast cancer, 84 of whom had TNBC. The MCED test detects methylation patterns associated with circulating tumor DNA (ctDNA) to identify a common cancer signal and predict a cancer signal of origin. Tumor methylated fraction (TMeF) is an estimate of ctDNA abundance using machine learning models trained on whole-genome bisulfite sequencing of tumor biopsy tissue. We used SRE to compare results between non-Hispanic Black and White participants and those of other (Hispanic, Asian, Pacific Islander) or unreported ethnicities for both cancer detection by MCED test and ctDNA abundance estimation by TMeF.

Results: In Black women, 19 (49%) of 39 diagnosed breast cancers were TNBC, compared to 58 (15%) of 396 breast cancers in White women and 7 (13%) of 52 breast cancers in women of other or unreported ethnicities. The MCED test did not detect Stage I TNBC (Table 1). In patients with Stage II-IV TNBC, the MCED test successfully detected a cancer signal in 16 (94%) of 17 Black women, 31 (72%) of 43 White women, and 6 (100%) of 6 women of other or unreported ethnicities (Table 1). When we examined the TMeF in these patients using a two-way ANOVA, we found a significant difference in mean TMeF by cancer stage (p &lt; 0.001) but no significant difference in mean TMeF between SRE groups (p = 0.09) with the distribution of TMeF (Table 2). The ANOVA additionally found a significant interaction between cancer stage and SRE (p &lt; 0.001) that could represent an impact of stage on TMeF that varied by SRE or differences in cancer stage distribution by SRE.

Conclusions: In this pilot study, we observed that MCED testing was effective in detecting Stage II, III, and IV TNBC across SRE. These findings, in combination with the association of estimated ctDNA abundance with cancer stage but not patient SRE, provide hypothesis-generating evidence that analysis of methylation signals from across the genome can provide meaningful TNBC screening/detection information, independent of self-reported race/ethnicity.

Table 1. MCED cancer detection rate by stage and SRE among TNBC patients.

Table 2. Tumor methylated fraction (TMeF) by stage and SRE among TNBC patients.

Citation Format: William Cance, Edison Liu, Margaret Antonio, Timothy Shaver, Stephannie Shih, Bong Chul Chu, Kathryn Kurtzman, Lisa Newman. Detection and quantification of triple-negative breast cancer (TNBC) across ethnicities through analysis of cell-free DNA (cfDNA) methylation [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-08.