A cheerful version of the enigmatic Mona Lisa’s smile 

James Fleck & Gustavo Gössling: Anticancerweb 5 (01), 2019

In the world, luminal breast carcinoma, Her 2-negative represents the most prevalent molecular subtype. Palliative systemic treatment is based on menopausal status. Patients with luminal breast carcinoma, Her 2-negative, diagnosed as advanced postmenopausal disease, are usually treated with aromatase inhibitors (anastrazole or letrozole). Recently, has been suggested a therapeutic superiority with the use of fulvestrant. Binding to estrogen receptor monomers, fulvestrant inhibits dimerization, being followed by an accelerated estrogen receptor degradation. This concept has been used to overcome breast cancer hormonal treatment resistance. Alternatively, a synergistic effect has been observed on the association of letrozole with ribociclib. In breast cancer cells, the use of ribociclin causes a complementary CDK4/6 (cyclin D-cyclin-dependent kinase 4/6-retinoblastoma) blockage, disrupting the sequential transduction signaling pathway, leading to a decrease on celular proliferation. This synergistic effect could be further improved by combining ribociclib with fulvestrant, which has emerged as the alternative hypothesis of the MONALEESA III TRIAL.

In June, 2018 the Journal of Clinical Oncology published the results of MONALEESA III TRIAL on the palliative treatment of 726 postmenopausal women with advanced estrogen receptor positive, Her2-negative breast cancer. Patients were randomly assigned in a proportion 2:1 to the test arm (fulvestrant + ribociclib) or to the control arm (fulvestrant + placebo). The addition of ribociclib resulted in a 42% reduction in the risk of disease progression. The median progression-free survival (PFS) was 20.5 months in the test arm (combined treatment) versus 12.8 months in the control arm (p<0.001). The result was consistent, being observed both in first-line (HR 0.577 95% CI 0.415 – 0.802) and second-line (HR 0.565 95% CI 0.428 – 0.724) treatments. However, the data were still immature for overall survival evaluation. There was an increase in toxicity associated with the addition of the CDK4/6 inhibitor, predominantly neutropenia, leucopenia and gastrointestinal manifestations. There was some concern related to the prolongation of the QT interval in the electrocardiogram (ECG) reported in 5.6 % of the patients. Despite the ECG diagnosis of polymorphic ventricular tachycardia with a Framingham-corrected QT greater than 480 ms, no symptoms were observed.

Considering the important benefit on DFS and the relative low toxicity, the combination of fulvestrant and ribociclib might represent a new standard in the first and second-line palliative treatment of patients with ER-positive Her2-negative advanced breast cancer. Hopefully, in a near future, a more mature data extending the benefit to overall survival could be observed under the critical and enigmatic smile of Mona Lisa. 

Reference:

Dennis J. Slamon, Patrick Neven, Stephen Chia, et al: Phase III Randomized Study of Ribociclib and Fulvestranto in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: MONALEESA-3, J Clin Oncol36, 2018