Dose modifications of ribociclib and endocrine therapy for treatment of ER+ HER2- metastatic breast cancer.

PURPOSE: Treatment for estrogen receptor positive (ER+), human epidermal receptor 2 negative (HER2-) metastatic breast cancer (MBC) has improved with the approval of CDK 4/6 inhibitors. Clinical trials with the CDK4/6 inhibitor ribociclib, suggest that 35% to 57.5% of the patients require a dose reduction during ribociclib treatment. Data on the possible consequences of dose reduction concerning efficacy is needed. METHODS: A retrospective cohort study on patients with ER+ HER2- MBC from three Danish oncology departments. Data on tolerability and progression-free survival were collected from electronic health records. RESULTS: One hundred and twenty-eight patients with ER+ HER2- MBC who initiated ribociclib treatment between 1st of January 2018 to 31st of March 2020 were included in our analysis. Of these patients, 48.4% required one or more dose reductions. Overall median PFS was 19.2 months (CI-95% 14.3-NR). Patients with one or more dose reductions did not have decreased median PFS (19.2 months, CI-95% 14.3-NR compared to 12.2 months, CI-95% 7.3-NR, p = 0.078). Frequency of adverse events were as previously reported, with grade III and IV neutropenia occurring in 45.3% and 7% of patients, respectively. Patients treated with fulvestrant versus an aromatase inhibitor and patients with lymph node involvement at baseline had lower odds of requiring a dose reduction (ORa = 0.30, CI-95% 0.12-0.73 & ORa = 0.41, CI-95% 0.18-0.89, respectively). CONCLUSION: Our results indicate that dose reduction of ribociclib is safe and do not compromise the efficacy of the treatment. Furthermore, the study supports translation of results from the MONALEESA trials to patients treated in real-world clinical settings.

Na+/H+-exchange inhibition by cariporide is compensated via Na+,HCO3--cotransport and has no net growth consequences for ErbB2-driven breast carcinomas.

Defense against intracellular acidification of breast cancer tissue depends on net acid extrusion via Na+,HCO3--cotransporter NBCn1/Slc4a7 and Na+/H+-exchanger NHE1/Slc9a1. NBCn1 is increasingly recognized as breast cancer susceptibility protein and promising therapeutic target, whereas evidence for targeting NHE1 is discordant. Currently, selective small molecule inhibitors exist against NHE1 but not NBCn1. Cellular assays-with some discrepancies-link NHE1 activity to proliferation, migration, and invasion; and disrupted NHE1 expression can reduce triple-negative breast cancer growth. Studies on human breast cancer tissue associate high NHE1 expression with reduced metastasis and-in some molecular subtypes-improved patient survival. Here, we evaluate Na+/H+-exchange and therapeutic potential of the NHE1 inhibitor cariporide/HOE-642 in murine ErbB2-driven breast cancer. Ex vivo, cariporide inhibits net acid extrusion in breast cancer tissue (IC50 = 0.18 µM) and causes small decreases in steady-state intracellular pH (pHi). In vivo, we deliver cariporide orally, by osmotic minipumps, and by intra- and peritumoral injections to address the low oral bioavailability and fast metabolism. Prolonged cariporide administration in vivo upregulates NBCn1 expression, shifts pHi regulation towards CO2/HCO3--dependent mechanisms, and shows no net effect on the growth rate of ErbB2-driven primary breast carcinomas. Cariporide also does not influence proliferation markers in breast cancer tissue. Oral, but not parenteral, cariporide elevates serum glucose by ∼1.5 mM. In conclusion, acute administration of cariporide ex vivo powerfully inhibits net acid extrusion from breast cancer tissue but lowers steady-state pHi minimally. Prolonged cariporide administration in vivo is compensated via NBCn1 and we observe no discernible effect on growth of ErbB2-driven breast carcinomas.