Polygenic risk score shows promise in predicting future breast cancer events

A retrospective analysis shows the potential of the 313-SNP breast cancer (BC) polygenic risk score (PRS₃₁₃) blood test to predict future in situ or invasive breast disease in women diagnosed with ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS).

DCIS and LCIS are pre-invasive breast lesions associated with an elevated risk of contralateral BC. [NPJ Breast Cancer 2020;6:60] “It is therefore important that we find ways to predict which women with DCIS and LCIS are most likely to develop invasive BC in the future so they can be given the most appropriate treatment and avoid unnecessary treatment,” noted senior author Dr Elinor Sawyer from King’s College London, UK, in a press release.

The researchers used datasets from the ICICLE* and GLACIER** studies to evaluate the ability of PRS₃₁₃ to predict the odds of developing contralateral or ipsilateral BC after DCIS or LCIS diagnosis (n=2,169 [DCIS] and 185 [LCIS]). Median follow-up was 11 years. [Cancer Epidemiol Biomarkers Prev 2025:doi:10.1158/1055-9965.EPI-25-0529]

DCIS

Compared with the lowest PRS₃₁₃ quartile, the highest quartile was associated with an increased risk of developing contralateral disease after adjusting for potential confounders*** (hazard ratio [HR], 2.03).

Multivariate analysis showed an association between continuous PRS₃₁₃ and worse disease-free survival (DFS) after DCIS, which remained unchanged after adjusting for confounders (HR, 1.13). This outcome was primarily driven by an association with contralateral BC relapse (HR, 1.30).

LCIS

Continuous PRS₃₁₃ was tied to worse DFS after LCIS (HR, 1.43), but this association became less pronounced after adjusting for family history of BC and age at first diagnosis (HR, 1.39).

There was an increased risk of recurrence-free survival (RFS) after LCIS with increasing PRS₃₁₃ on both univariate and multivariate analyses (HRs, 2.15 and 2.16). The risk was greater when looking at invasive RFS after LCIS (HR, 2.50).

Family history may play a role

On multivariate analysis, family history of BC was associated with worse DFS after DCIS, specifically with ipsilateral recurrence (HR, 1.71).

Among participants with LCIS who had a family history of BC, increasing PRS₃₁₃ was associated with an increased risk of any ipsilateral (HR, 3.12) and ipsilateral invasive diseases, specifically after LCIS (HR, 3.31). The risk was greater after excluding those who had undergone mastectomy or radiotherapy (HR, 4.19).

These results could be due to the presence of variants in the CHEK2 gene within PRS₃₁₃, which is associated with the CHEK2 c.1100delC variant – a founder mutation reported to be strongly associated with LCIS and invasive lobular carcinoma. [Cancer Epidemiol Biomarkers Prev 2019;28:1162-1168; J Clin Oncol 2021;39:3918-3926]

“LCIS is not always surgically removed or treated with hormone therapies, as it is considered lower risk than DCIS. However, these results indicate that those with a family history may benefit from such additional treatments, which could reduce their risk of further cancer,” noted study lead author Dr Jasmine Timbres, also from King’s College London.

Results may inform clinical decisions

Taken together, the findings underscore the ability of PRS₃₁₃ to inform clinical decisions regarding surveillance, risk-reduction treatments, and personalized care in individuals who have in situ BC, which could improve outcomes and optimize healthcare resource utilization, the investigators noted.

“In clinical practice, PRS₃₁₃  could be valuable in identifying patients at higher risk for second primaries in either breast following in situ disease. These individuals may benefit from risk-reduction therapies such as tamoxifen or an aromatase inhibitor, as most lesions express oestrogen receptors and PRS₃₁₃  could help determine the optimal duration for annual surveillance,” they said.

“The associations found in this study could be useful in helping women decide their treatment options after a diagnosis of DCIS or LCIS,” noted Timbres. “By looking at the full picture, rather than just how cells look under a microscope, we can give women more accurate information about their personal risk of recurrence. This could help them make more informed choices about their treatment options and what’s right for them.”

“Although more work still needs to be done to confirm the results of this study in other groups of patients or assess additional genetic changes, the results are promising and have the potential to influence treatment decisions,” Sawyer said.