Accuracy of Negative ctDNA Testing for Lobular Carcinoma Over 2 Years
A negative ctDNA test in lobular carcinoma has excellent negative predictive value, with approximately 90-97% overall survival at 12 months and serially negative tests strongly associated with superior clinical outcomes, though the specific 2-year accuracy data for lobular carcinoma remains limited. 1, 2
Evidence for ctDNA Testing in Lobular Carcinoma
Negative Predictive Value and Survival Outcomes
A negative ctDNA result is associated with 97% overall survival at 6 months and remains high at approximately 90% at 12-month follow-up in patients with metastatic invasive lobular carcinoma (mILC). 1
Serial postoperative ctDNA assessment has strong prognostic value, with patients who have serially negative ctDNA tests demonstrating superior clinical outcomes and providing reassurance during long-term follow-up. 2
In a study of 156 breast cancer patients monitored for up to 12 years, ctDNA negativity was strongly associated with shorter relapse-free survival (P < .0001) and overall survival (P < .0001). 2
Sensitivity and Detection Capabilities
Personalized tumor-informed ctDNA assays (Signatera) demonstrated 88.2% patient-level sensitivity (30 of 34 patients) for detecting relapse ahead of clinical or radiologic findings in breast cancer patients. 2
The median lead time for detecting relapse before clinical presentation was 10.5 months (range 0-38 months), providing a substantial window for potential therapeutic intervention. 2
In patients with mILC specifically, 92% (11 of 12) of patients showing either ctDNA decrease or no change while on treatment demonstrated clinical benefit from their prescribed regimen. 1
Important Caveats and Limitations
Hormone Receptor Status Matters
All four patients who had false-negative ctDNA tests before relapse had hormone receptor-positive (HR+) disease, suggesting that HR+ lobular carcinoma may require more cautious interpretation of negative results. 2
Five of 122 non-relapsed patients (all HR+) had occasional positive tests, indicating that decisions about treatment management in HR+ disease might require serial monitoring despite ctDNA-positive results rather than relying on a single test. 2
Triple-negative breast cancer patients showed more reliable ctDNA detection, with all relapsing patients (7/23) having ctDNA-positive tests within a median of 8 months, while all 16 non-relapsed triple-negative patients remained ctDNA-negative during median 58-month follow-up. 2
Technical Considerations for Interpretation
Negative test results should be reported as "ctDNA not detected" rather than using terms like "wildtype," "negative," or "absence of mutation(s)" when tumor fraction estimation is not included in the test. 3
Each report should include a disclaimer that the presence of mutations below the limit of detection (LOD) cannot be excluded. 3
The analytical sensitivity depends on various factors including number of molecules assayed, library conversion rate, sequencing depth, and the specific LOD of the test used. 3
Clinical Application for 2-Year Monitoring
Serial Testing Strategy
Serial ctDNA monitoring is more informative than single time-point testing, particularly for HR+ lobular carcinoma where occasional false-positive results may occur. 2
A total of 355 plasma samples were analyzed from 66 patients with mILC, demonstrating the feasibility of serial ctDNA testing for personalized surveillance and real-time therapeutic monitoring. 1
The positive predictive value of ctDNA testing increases exponentially with each consecutive positive result, suggesting that serial monitoring improves accuracy. 1
Practical Monitoring Approach
For patients with serially negative ctDNA tests over 2 years, the prognosis is excellent and provides strong reassurance, though this does not eliminate the need for standard clinical surveillance. 2
On-treatment ctDNA dynamics correlate well with clinical response as assessed by imaging, making serial testing valuable for treatment monitoring. 1
Patients should understand that while negative ctDNA has high negative predictive value, it does not guarantee absence of disease, particularly in HR+ lobular carcinoma where biology may result in lower ctDNA shedding. 2, 3
Key Pitfalls to Avoid
Do not rely on a single negative ctDNA test to definitively rule out disease, especially in HR+ lobular carcinoma—serial monitoring is essential. 2
Do not assume all breast cancer subtypes behave identically with ctDNA testing; triple-negative disease shows more reliable detection patterns than HR+ disease. 2
Do not interpret negative ctDNA as eliminating the need for standard clinical surveillance, as mutations below the LOD cannot be excluded and some tumors may shed minimal ctDNA. 3
Recognize that low or undetectable ctDNA levels may occur even in patients with high disease burden due to impairments in vascularization or other biological factors. 3