Chemoprevention of experimental estrogen receptor-negative breast cancer

This prospective, short-term biomarker modulation study evaluated dasatinib, a Src-family tyrosine kinase inhibitor, as a candidate chemopreventive agent for women at increased risk for estrogen receptor (ER)-negative breast cancer. Recognizing that existing risk-reducing therapies such as selective ER modulators and aromatase inhibitors primarily reduce ER-positive disease, the investigators sought new agents with favorable toxicity profiles that could potentially lower the risk of ER-negative tumors. The study enrolled women with a prior unilateral stage I-II ER-negative breast cancer who had completed all adjuvant therapies and had no active disease. Participants underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker assessment, then were randomized to either no treatment (control) or dasatinib at 40 mg/day or 80 mg/day for three months, after which FNA and serum collection were repeated.

Planned tissue biomarkers included cytology and the proliferation marker Ki-67 measured on breast FNA specimens. Serum biomarkers focused on the insulin-like growth factor (IGF) axis: IGF-1 and IGF-binding proteins 1 and 3. The primary objective was to evaluate changes in Ki-67, with secondary objectives addressing cytologic changes and shifts in IGF-related serum biomarkers. Toxicity and tolerability were also assessed to determine whether dasatinib could be administered safely in a prevention setting.

Twenty-three patients initiated their assigned treatment regimens, and adherence was high: 20 of 23 (86.9%) completed assigned dosing. Dasatinib demonstrated an acceptable short-term safety profile in this cohort, with no drug-related grade 3 or 4 adverse events reported. However, the study faced a critical limitation in biospecimen adequacy: only a single participant provided paired adequate FNA samples, preventing the planned assessment of Ki-67 and cytologic changes. Consequently, the trial could not meet its primary endpoint. Analysis of serum biomarkers revealed no significant changes among the three study arms across IGF-1, IGF-binding protein 1, and IGF-binding protein 3.

Although dasatinib was tolerated without severe adverse events, the inability to obtain sufficient paired tissue samples curtailed the study's ability to determine whether Src inhibition modulates tissue proliferation or cytology in high-risk, ER-negative breast tissue. The absence of serum biomarker shifts suggests that short-term dasatinib at the tested doses does not substantially alter systemic IGF-related markers in this population, but the small sample size and tissue-sampling challenges limit the strength of these conclusions.

The investigators conclude that while dasatinib is feasible and well tolerated in a short-course prevention context, larger studies with improved tissue acquisition strategies are necessary to evaluate the effectiveness of Src inhibitors for ER-negative breast cancer prevention. Future prevention trials should emphasize robust biospecimen collection methods, potentially longer treatment durations or alternative biomarker panels, and larger sample sizes to detect meaningful biological modulation and to clarify whether Src inhibition can play a role in reducing ER-negative breast cancer risk.