Predicting Risk After DCIS–LCIS With a Polygenic Risk Score: Who Needs Closer Follow-Up?
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Why does it matter?
In the past, breast cancer risk was largely explained through family history and inherited mutations such as BRCA1/2 . Today, however, we know that women with these high-risk mutations represent only 5–10% of all patients. In the much larger remaining group, risk is generally determined by the combined effects of many small-effect genetic variants .
This is where the Polygenic Risk Score (PRS) comes in. Calculated from a blood sample, it converts the combined effects of hundreds of small genetic differences associated with breast cancer into a numerical value, enabling individualized estimates of cancer risk.
In recent years, a test called PRS313 has shown promise for predicting breast cancer risk in the general population. Now, a King’s College London team has examined this score in women diagnosed with in situ breast disease — ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS) . The most difficult question with these early-stage lesions is: “What is the risk of recurrence or progression to invasive (conventional) cancer?”
Treatment decisions today generally depend on pathological findings (such as lesion size, grade, and margins). Yet these criteria do not accurately predict future risk for every patient. Here, PRS313 , a polygenic risk score (PRS) stands out as a potentially powerful way to address this gap: risk can now be read not only under the microscope but also at the DNA level.
Cancer Epidemiology, Biomarkers & Prevention published this study on 1 October 2025. It suggests that genetic information may predict future breast disease after DCIS or LCIS. If confirmed, polygenic scores could open a new era in navigating the fine line between overtreatment and undertreatment in breast cancer.
What Is PRS313, and How Does It Differ From Other Genetic Tests?
Most current breast cancer genetic tests examine genes such as BRCA1, BRCA2 or PALB2 for major changes (mutations) in a single gene . These mutations are generally “high-penetrance”—strong-effect genes whose carriers face a very high lifetime cancer risk.
Most people do not carry these mutations. Yet many women develop breast cancer because risk depends not only on “one faulty gene,” but on hundreds of small genetic differences combined . Each has a tiny effect alone, but together they make a meaningful difference.
The Polygenic Risk Score (PRS) measures precisely this: the combined effects of hundreds or thousands of small DNA variants, converted into a numerical risk score .
PRS313 is a specific test examining 313 genetic variants (SNPs – single-nucleotide polymorphisms) associated with breast cancer. Each slightly affects risk. Computer algorithms assign each variant a small “weight” to calculate an overall risk score . Higher scores mean a greater likelihood of developing breast cancer.
The score reflects inherited genetics and is measured from a blood sample . It does not search for a new mutation but assesses the cumulative effects of existing small variations. While inherited-mutation tests ask “Is there a faulty gene?”, PRS asks: “How much does my genetic makeup increase or decrease my cancer risk compared with the general population?”
Clinically, the aim is risk stratification . For example:
- High PRS: Consider more frequent screening (e.g., annual MRI), chemoprevention (such as tamoxifen/aromatase inhibitors), or more proactive treatment.
- Low PRS: Consider less frequent follow-up or avoiding overtreatment.
PRS313 may help predict future tumor risk after early-stage in situ lesions such as DCIS or LCIS, identifying patients at high risk of another tumor. Treatment decisions can then be based on individual risk profiles rather than the same approach for everyone.
Study Design: Who Was Followed, and for How Long?
Researchers examined two UK patient groups: ICICLE (focused on DCIS) and GLACIER (focused on LCIS). A total of 2169 DCIS and 185 LCIS patients were followed for a median 11 years .
Treatment reflected real-world practice: almost all DCIS patients underwent breast-conserving surgery or mastectomy (± radiotherapy). LCIS treatment relied more on surgery; 78% underwent lumpectomy, with radiotherapy less common.
| Outcome Measured | DCIS | LCIS |
|---|---|---|
| Within 10 years, new breast disease (in situ or invasive) | %16.3 | %17.5 |
| Invasive ipsilateral (same-breast) disease | %4 | %5 |
Note: Ipsilateral = same breast; contralateral = opposite breast.
Main Findings: Different Risk Patterns in DCIS and LCIS
🟦 DCIS
- In the highest PRS quartile (top 25%) contralateral (opposite-breast) disease risk increased approximately 2-fold .
- Ipsilateral (same-breast) disease showed no clear association. Possible explanation: Surgery and/or radiotherapy already reduce same-breast recurrence.
🟧 LCIS
- As the continuous PRS313 score increased, ipsilateral (in situ + invasive) disease risk increased >2-fold .
- A family history + high PRS increased ipsilateral any-disease or invasive-disease risk by >3-fold .
- No mastectomy/RT + high PRS increased ipsilateral risk >4-fold .
- Contralateral (opposite-breast) disease showed no significant association.
Clinical Interpretation: What Could This Change in Practice?
- LCIS + high PRS (+ family history): Annual MRI + mammography as more intensive screening, chemoprevention and, in selected cases, more proactive local strategies may be considered.
- LCIS + low PRS: Avoiding overtreatment and keeping follow-up frequency reasonable may be considered.
- DCIS + high PRS: Contralateral risk counseling gains a numerical basis; endocrine treatment may be supported.
- Low PRS (DCIS/LCIS): De-escalation (less frequent follow-up, fewer interventions) gains scientific rationale.
A Practical Framework
- Baseline clinical profile: Age, family history, breast density, comorbidities, previous treatment (surgery/RT), and pathology.
- Genetic stratification: Measure PRS313; interpret alongside an inherited-mutation panel (BRCA1/2, etc.) if possible.
- Risk classification: Based on PRS, low–intermediate–high categories (quartiles or thresholds).
- Management decision:
- High risk: Intensive screening, chemoprevention, greater consideration of endocrine therapy in DCIS; a more proactive LCIS approach.
- Low risk: De-escalation; less frequent follow-up and/or eligibility for active-surveillance trial protocols.
- Counseling and education: Patient-friendly explanation of numerical risk; emphasize lifestyle (weight management, physical activity, alcohol reduction, smoking cessation).
Limitations and Looking Ahead
- The study is retrospective; particularly the LCIS sampleis relatively small. Generalizability may therefore be limited.
- PRS313 was primarily developed to predict invasive disease risk ; additional variants associated with in situ disease may not be included.
- Prospective validation, clinical utility, and cost-effectiveness data are needed.
Typical Clinical Situations for Considering PRS313
- LCIS: With or without family history; cases where limited local treatment is planned.
- DCIS: Cases needing consideration of endocrine therapy and/or contralateral risk counseling.
- Active-surveillance candidates: Identifying candidates for de-escalation/surveillance strategies in low-risk DCIS.
Key Data at a Glance
- Follow-up: median 11 years (ICICLE + GLACIER)
- New disease risk within 10 years: DCIS 16.3%, LCIS 17.5%
- Invasive ipsilateral risk: DCIS 4%, LCIS 5%
- DCIS: Highest PRS quartile → contralateral risk ≈2-fold increase
- LCIS: Increasing continuous PRS → ipsilateral risk >2-fold increase
- LCIS: Family history + high PRS → >3-fold increase (ipsilateral/invasive)
- LCIS: No RT/mastectomy + high PRS → >4-fold ipsilateral increase
Frequently Asked Question: “What Does a Low PRS Offer Patients?”
Low PRSprovides concrete support for less frequent follow-up and avoiding overtreatment . This approach may reduce unnecessary procedures and costs. High PRS , by contrast, supports intensifying monitoring and preventive measures. In summary: When assessed alongside the clinical picture, PRS acts as a balancing compass .
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