Results from CALGB 40903, a phase II multicenter trial, have provided new insights into how genomic characteristics influence aromatase inhibitor therapy response in ductal carcinoma in situ (DCIS). The study evaluated postmenopausal patients with estrogen receptor-positive DCIS treated with letrozole for six months prior to surgery.
The research team analyzed 29 patients who completed the treatment protocol, including five who achieved pathologic complete response (pCR). Using RNA sequencing and DNA analysis, researchers examined genomic alterations and expression patterns associated with treatment response.
Molecular Subtyping and Response Patterns
PAM50 analysis revealed that 19 pre-treatment samples were classified as luminal A subtype, all of which responded positively to letrozole treatment. The remaining samples, classified as luminal B, HER2, basal, and normal-like subtypes, showed varied responses with six categorized as non-responders.
Treatment-induced changes were observed in eight cases, with five luminal A tumors shifting to normal-like classification post-treatment. This shift may reflect reduced estrogen-related gene expression following hormone deprivation or decreased DCIS epithelial presence in post-treatment specimens.
Gene Expression and Treatment Response
The study identified several key markers associated with treatment response:
- High levels of ESR1 and estrogen-related genes (PGR, NAT1, BCL2) correlated with positive response
- ERBB2 expression showed a trend toward non-response
- Proliferation-associated genes significantly decreased after treatment
- KRT5 and MMP7 showed elevated expression post-treatment, suggesting potential cellular selection
Clinical Implications
The findings demonstrate that DCIS response to hormone therapy closely mirrors patterns observed in invasive breast cancer. The strong association between luminal A subtype and positive treatment response suggests that genomic subtyping could help identify patients most likely to benefit from aromatase inhibitor therapy.
Treatment Effectiveness Metrics
Response assessment was based on:
- Post-treatment KI67 levels (threshold of 10%)
- Pathologic complete response
- Changes in MRI enhancement volume
The study establishes that intact estrogen signaling pathways are crucial determinants of treatment effectiveness, potentially helping guide future therapeutic strategies for DCIS management.
