What is the next step in managing a patient with invasive lobular carcinoma on letrozole with a negative Signatera test?

Management of Invasive Lobular Carcinoma on Letrozole with Negative Signatera Test

Continue letrozole therapy and implement routine surveillance with clinical examinations every 3-4 months for the first 2 years, then every 6 months for years 3-5, plus annual bilateral mammography with consideration of supplemental ultrasound given the infiltrative growth pattern of lobular carcinoma. 1, 2

Interpretation of Negative Signatera Result

• A negative circulating tumor DNA (ctDNA) test indicates no detectable molecular residual disease, suggesting excellent disease control on current endocrine therapy 1
• This finding supports continuation of the current treatment strategy rather than escalation or modification 1

Continuation of Letrozole Therapy

• For hormone receptor-positive invasive lobular carcinoma, extended adjuvant aromatase inhibitor therapy beyond 5 years improves disease-free survival 1
• The MA.17R trial demonstrated benefit of letrozole for 5 additional years in women who had already received 4.5-6 years of AI therapy 1
• Invasive lobular carcinoma responds particularly well to adjuvant hormonal therapy compared to invasive ductal carcinoma, with improvement in survival in patients receiving hormonal therapy 3
• ILC demonstrates an 86% hormone receptor positivity rate and shows better response to adjuvant hormonal therapy than ductal carcinoma 3

Surveillance Strategy Specific to ILC

Clinical Monitoring

• Clinical examinations every 3-4 months for the first 2 years, every 6 months for years 3-5, and annually thereafter 2
• Regular assessment of bone density for patients on aromatase inhibitors due to accelerated bone loss risk 1
• Annual gynecologic examination is not required for aromatase inhibitor therapy (only for tamoxifen) 2

Imaging Surveillance

• Annual bilateral mammography is mandatory 2
• Supplemental ultrasound should be strongly considered for invasive lobular carcinoma follow-up because ILC has an infiltrating growth pattern that decreases detectability on mammography alone 2, 4
• Digital breast tomosynthesis (DBT) improves conspicuity of ILC with sensitivity of 80-88%, which is superior to digital mammography alone 4
• Screening ultrasound identifies additional ILCs even after DBT, with supplemental cancer detection rate of 0-1.2 ILC per 1000 examinations 4
• MRI has 93% sensitivity for ILC and may be considered in high-risk surveillance scenarios 4

Critical Pitfalls to Avoid

• Do not discontinue letrozole based solely on negative ctDNA testing - the standard duration of extended AI therapy should be completed as ILC demonstrates indolent but progressive characteristics with nearly linear survival curves that can cross those of ductal carcinoma after approximately 10 years 3
• Do not rely on mammography alone for surveillance - ILC's infiltrative growth pattern makes it less conspicuous on standard imaging, requiring supplemental modalities 4
• Do not assume excellent short-term control means cure - ILC exhibits indolent but progressive behavioral characteristics with worse long-term outcomes after 10 years despite initially favorable prognosis 3

Monitoring for Treatment Toxicity

• Calcium and vitamin D supplementation is recommended to mitigate bone loss from aromatase inhibitor therapy 1
• Regular bone density assessment should be performed 2
• Monitor for aromatase inhibitor-associated musculoskeletal symptoms 1

When to Consider Treatment Modification

• Evidence of disease progression on clinical examination or imaging would warrant reassessment 1
• Development of endocrine resistance (rapidly progressive disease, visceral crisis) would indicate need for chemotherapy 1
• Intolerable toxicity from letrozole would warrant switch to alternative endocrine agent (exemestane, fulvestrant) 1