Components of the phosphatidylinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway are deregulated in many human cancers, with about 30% of breast cancers harboring PIK3CA gene mutations. Emerging research shows that these mutations may render estrogen receptor alpha-positive tumors less sensitive to endocrine agents, and HER2-positive tumors less responsive to anti-HER2 therapy. The good news is that compounds in development appear to overcome these effects, as reported at the 2013 San Antonio Breast Cancer Symposium for the following four studies.
1. An in vitro combinatorial drug screen showed that the pairing of a PI3K inhibitor (the pan inhibitor GDC-0941, or the alpha-specific inhibitor BYL-719) with a CDK4/6 inhibitor (LEE-011) was synergistic in PI3K inhibitor–resistant cell lines and a PIK3CA-mutated breast cancer model with de novo resistance to PI3K inhibitors. In the upfront setting, the combination led to tumor regression in this mouse model study from Massachusetts General Hospital.1
2. In a phase I study from Washington University, St. Louis, the pan-PI3K inhibitor BKM120 plus fulvestrant (Faslodex) produced partial response or disease stabilization for over 6 months in 10 of 18 patients with metastatic estrogen receptor–positive breast cancer.2 The results of this trial led to the ongoing phase III trials of this combination for patients with estrogen receptor–positive breast cancer who had disease progression on an aromatase inhibitor.
3. To overcome resistance that develops to everolimus (Afinitor), researchers from the University of California, Los Angeles, administered BKM120 as a single agent or with fulvestrant in a mouse model of everolimus resistance and achieved strong tumor growth inhibition with either treatment.3
4. The combination of the alpha-specific PI3K inhibitor GDC-0032 combined with fulvestrant yielded a 73% response rate in an international phase Ib study.4 ■
References
1. Vora SR, King N, Costa C, et al: Overcoming resistance to PI3K inhibitors in PIK3CA mutant breast cancer using CDK4/5 inhibition: Results from a combinatorial drug screen. 2013 San Antonio Breast Cancer Symposium. Abstract S4-04. Presented December 12, 2013.
2. Ma CX, Wang J, Luo J, et al: A phase I study of BKM120 and fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract PD1-4. Presented December 12, 2013.
3. O’Brien NA, Tong L, Ayala R, et al: Targeting PI3K overcomes in vivo resistance to everolimus in estrogen receptor (ER+) breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract PD1-5. Presented December 11, 2013.
4. Juric D, Saura C, Cervantes A, et al: Ph1b study of the PI3K inhibitor CDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract PD1-3. Presented December 11, 2013.
