SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.
Preinvasive breast lesions such as Ductal Carcinoma In Situ (DCIS) and Lobular Carcinoma In Situ (LCIS) are well recognized precursors to invasive disease, yet clinicians currently lack precise tools to predict which patients will ultimately progress. Identifying individuals at highest risk is essential for guiding management, balancing the benefits of early intervention against the harms of overtreatment.
Epidemiologic data suggest that approximately 20–40% of untreated DCIS lesions eventually evolve into invasive breast cancer, while women diagnosed with LCIS have a 7–12-fold higher risk of developing invasive malignancy in either breast over time. Both entities also confer elevated risk for contralateral breast cancer. In this context, genomic risk stratification offers an opportunity to personalize surveillance and preventive strategies.
Understanding PRS313
The 313-SNP breast cancer Polygenic Risk Score (PRS313) quantifies an individual’s inherited susceptibility to breast cancer by integrating the effects of 313 Single Nucleotide Polymorphisms (SNPs) known to influence disease risk. Each variant contributes modestly on its own, but together they generate a composite score that captures the polygenic architecture of breast cancer predisposition.
Using DNA derived from blood or saliva, PRS313 calculates a weighted sum of risk alleles to estimate lifetime breast cancer risk. This score can stratify women into distinct risk quartiles, offering refined insight beyond traditional factors such as family history, breast density, and age. Importantly, PRS313 has been validated in population studies as a predictor of primary breast cancer risk. Recent research now explores its ability to forecast subsequent disease after an initial diagnosis of in situ carcinoma.
Study Overview
Investigators from the ICICLE (Investigate the genetiCs of In situ Carcinoma of the ductaL subtypE) and GLACIER (Genetics of LobulAr Carcinoma In situ in EuRope) studies conducted a retrospective analysis to evaluate whether PRS313 could predict subsequent breast cancer events following DCIS or LCIS.
The study included 2,169 women with DCIS and 185 with LCIS, each followed for a median of 11 years. Cox regression models assessed associations between PRS313 and several outcomes: any subsequent in situ or invasive breast cancer (including distant metastasis), ipsilateral breast disease, invasive ipsilateral disease, and contralateral breast cancer. For DCIS, results were analyzed by PRS313 quartiles; for LCIS, risk was modeled as a continuous variable.
Key Findings
Analysis revealed a significant association between increasing PRS313 and contralateral breast cancer after DCIS (hazard ratio [HR], 1.30; 95% CI, 1.08–1.56). Women in the highest PRS313 quartile were roughly twice as likely to develop contralateral disease compared with those in the lowest quartile. However, PRS313 was not significantly associated with ipsilateral recurrence in DCIS.
In contrast, among women with LCIS, higher PRS313 correlated strongly with ipsilateral breast cancer risk (HR, 2.16; 95% CI, 1.22–3.81). The association was even more pronounced among participants with a family history of breast cancer, where PRS313 increases translated to more than a threefold elevation in ipsilateral disease risk, rising to nearly fourfold when women who had undergone mastectomy or radiotherapy were excluded.
Lead investigator comments emphasized that while LCIS is often managed conservatively, these findings suggest that patients with a strong family history and high PRS313 may derive benefit from additional risk-reducing interventions, such as endocrine therapy or intensified surveillance.
Clinical Implications
This study provides compelling evidence that polygenic risk assessment can refine prognostication in women with in situ breast cancer, distinguishing those most likely to develop future disease. The results support integrating PRS313 into post-diagnosis risk discussions to help patients make informed decisions regarding surgery, chemoprevention, and long-term follow-up intensity.
“By combining genomic data with clinicopathologic features,” the authors noted, “clinicians can deliver more individualized care, moving beyond histologic appearance, to a truly personalized estimate of recurrence risk.”
Study Limitations
The researchers acknowledged several limitations. PRS313 was originally designed to predict invasive breast cancer risk rather than in situ disease specifically, and relevant genetic variants unique to DCIS or LCIS may remain undiscovered. Additionally, the relatively small LCIS cohort limited statistical power and generalizability across ancestries. Ongoing validation in larger and more diverse populations will be necessary before broad clinical implementation.
Conclusion
The ICICLE and GLACIER analyses underscore the potential of PRS313 as a predictive biomarker for future breast cancer events, particularly contralateral disease after DCIS and ipsilateral disease after LCIS. Incorporating polygenic risk profiling into the management of in situ breast lesions could help identify patients who warrant closer monitoring or preventive therapy, while sparing others from unnecessary intervention.
As genomic medicine advances, tools like PRS313 may become integral to personalized breast cancer prevention and survivorship care, aligning treatment intensity with each woman’s unique genetic risk landscape.
Breast Cancer Polygenic Risk Score Associated with Outcomes after In Situ Breast Disease. Timbres J, Kohut K, Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev OF1–OF10. https://doi.org/10.1158/1055-9965.EPI-25-0529. Published: 01 October 2025.
