Abstract
The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.
Highlights
In a phase-II clinical study of the Src inhibitor bosutinib as monotherapy in 73 patients with previously treated advanced or metastatic breast cancer (MBC), all four responses occurred in patients with hormone receptor (HR)-positive disease.[9]
The higher than expected CBR with letrozole alone observed in this trial compared with the original first-line letrozole trial may have been due in part to the higher proportion of de novo MBC patients enrolled in this trial (37% vs 32% in Mouridsen et al).[15]
Recent phase-III trials combining first-line letrozole plus a CDK 4/ 6 inhibitor have shown CBRs of 70 to 73% with letrozole plus placebo, similar to the 66 and 71% CBRs observed with letrozole alone and with letrozole plus dasatinib in the current trial.[16,17]
Summary
Membrane-associated, non-receptor tyrosine kinase that has been implicated in the proliferation, survival, migration, and invasion of breast cancer cells, as well as the development of resistance to therapy.[1,2,3] In vitro studies have shown that Src interacts with a variety of signaling molecules including growth factor receptors, integrins, and steroid hormone receptors.[1,2,3] In breast cancer cells, membrane-associated estrogen receptor-alpha (ERα) has been shown to complex with Src and phosphatidylinositol 3-kinase (PI3K) to drive growth and endocrine therapy resistance.[4,5,6] Levels of ERα and Src are inversely correlated in primary breast cancers, and Src has been shown to increase the proteolytic degradation of Erα.[7] Combining Src inhibitors with endocrine agents can reduce the emergence of acquired endocrine resistance in preclinical studies.[1,8] Further, in a phase-II clinical study of the Src inhibitor bosutinib as monotherapy in 73 patients with previously treated advanced or metastatic breast cancer (MBC), all four responses occurred in patients with hormone receptor (HR)-positive disease.[9] Src is involved in the regulation of osteoclastmediated bone turnover,[10] and has been implicated in the survival and outgrowth of breast cancer cells in the bone marrow microenvironment.[2]
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