Dr Roy on Limitations of the Pathway Trial Evaluating PGS and Survival in Breast Cancer

Arya Mariam Roy, MBBS, fellow, Hematology/Oncology, Roswell Park Comprehensive Cancer Center, discusses limitations of the Pathway trial evaluating the association between polygenic scores (PGS) and survival outcomes in patients with breast cancer, and explains ways investigators plan to address these limitations.

Pathway was a prospective cohort study that gathered genome-wide genotype data from 3995 patients with breast cancer who were enrolled from 2006 to 2013. Investigators used data to calculate four different PGS: PGS313, PGS4k, PGS5k, and PGS6m. These PGSs were then evaluated for their association with different survival outcomes, including recurrence, contralateral second primary breast cancer, other second primary cancers, and death.

Findings, which we presented at the 2024 ASCO Annual Meeting, showed that patients who had a PGS of PGS313 were associated with a higher risk of recurrence, total breast cancer and invasive breast cancer events, and death. These outcomes were worse in patients with medium (T2) PGS313 and high (T3) PGS313 scores vs those with low (T1) PGS313 scores. However, no increased risks of these outcomes were observed among other PGS variants analyzed during the study.

Roy notes that a significant limitation of Pathway was the low enrollment of patients from minority populations. Of the patients evaluated, 7% were Black, 12% of patients were Asian, and 11% of patients were Hispanic. Roy explains that in the future, extended collaboration between institutions could help expand the minority patient population in this study, which could help identify other potential racial and ethnic disparities.

She says that another limitation of the study was the use of polygenic risk models developed from European ancestry populations. She notes that the efficacy of PGS models in patient populations with non-European ancestry has yet to be independently validated. Roy and colleagues are hope to extrapolate these data to see if we adjustments can be made to account for ancestry, she concludes.