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Short-Term Biomarker Modulation Study of Dasatinib for Estrogen Receptor-Negative Breast Cancer Chemoprevention
Fatma Nihan Akkoc Mustafayev1, Diane D Liu2, Angelica M Gutierrez1
1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA.
Objective:
Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer.
Materials And Methods:
Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated.
Results:
Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups.
Conclusion:
Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention.
Insights
Dasatinib, a Src inhibitor, was evaluated for ER-negative breast cancer prevention. While well-tolerated, it showed no significant biomarker changes, and the study couldn't assess its primary objective due to insufficient tissue samples.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Prevention
Background:
- Selective estrogen receptor modulators and aromatase inhibitors are limited to ER-positive breast cancer.
- New agents are needed for ER-negative breast cancer prevention with better toxicity profiles.
- Dasatinib, a Src tyrosine kinase inhibitor, was investigated for its potential in breast cancer risk reduction.
Purpose of the Study:
- To evaluate the effect of dasatinib on breast tissue and serum biomarkers in women at high risk for contralateral breast cancer.
- To assess changes in Ki-67, cytology, and serum insulin-like growth factor (IGF) related biomarkers.
- To evaluate the safety and tolerability of dasatinib in this high-risk population.
Main Methods:
- Prospective, short-term prevention study involving women with a history of ER-negative breast cancer.
- Randomization to no treatment (control) or dasatinib (40 or 80 mg/day) for three months.
- Biomarker analysis included breast fine-needle aspiration (FNA) for cytology and Ki-67, and serum analysis for IGF-1, IGF-binding protein 1, and IGF-binding protein 3.
Main Results:
- Dasatinib was well tolerated with no grade 3 or 4 adverse events observed.
- Due to inadequate paired FNA samples, primary objective (Ki-67 changes) could not be evaluated.
- No significant changes were observed in serum biomarkers across the treatment groups.
Conclusions:
- Dasatinib was well-tolerated but did not demonstrate significant changes in the evaluated biomarkers.
- The study was unable to fulfill its primary objective due to insufficient sample adequacy.
- Larger studies are required to determine the efficacy of Src inhibitors in breast cancer prevention.
