Our study highlights the unmet clinical need to develop and test feasible interventions to improve AET adherence in HR+ breast cancer survivors to extend their long-term survival.

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Objective:To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of neratinib in human epidermal growth factor receptor (HER2)+ breast cancer (BC). Data Sources: A PubMed search was performed using the term neratinib between September 12, 2018, and November 21, 2018. References of published articles and reviews were also assessed for additional information. Study Selection and Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of neratinib were evaluated. Data Synthesis: Neratinib, an irreversible inhibitor of HER1, HER2, and HER4, is Food and Drug Administration approved for the extended adjuvant treatment of stage I-III HER2+ BC to follow trastuzumab-based therapy. A phase III study has demonstrated statistically significant improvement in 5-year disease-free survival rate (90.2 vs 87.7; hazard ratio = 0.73, 95% CI = 0.57-0.92, P = 0.0083). Its most common adverse effect is diarrhea, observed in more than 90% of patients. The incidence of grade 3/4 diarrhea (~40%) is reduced by half with loperamide prophylaxis, which is recommended for the first 8 weeks of neratinib therapy. Other common adverse reactions are nausea and fatigue. The patients need to be monitored for liver function tests and drug interactions with acid-reducing agents, CYP3A4 inhibitors/inducers, and P-glycoprotein substrates with narrow therapeutic window. Relevance to Patient Care and Clinical Practice: American Society of Clinical Oncology and National Comprehensive Cancer Network clinical guidelines suggest the use of neratinib for extended adjuvant therapy following 1-year trastuzumab in stage I to III HER2+ BC. Diarrhea remains a clinically significant but manageable adverse event. Conclusion: Neratinib significantly improves treatment outcomes and has manageable toxicity in stage I to III HER2+ BC patients.

Objective: To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib (LEE011, Kisqali) in hormone receptor–positive/human epidermal growth factor receptor-2–negative (HR+/HER2−) metastatic breast cancer. Data Sources: A PubMed search was performed using the terms ‘Ribociclib’, ‘Kisqali’, and ‘LEE011’ between May 2018 and November 2018. References of published articles and reviews were also assessed for additional information. Study Selection and Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib were evaluated. Data Synthesis: Ribociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, is Food and Drug Administration (FDA) approved in combination with endocrine therapy for treatment of HR+/HER2− advanced or metastatic breast cancer in premenopausal/perimenopausal and postmenopausal women. Three phase III trials have evaluated ribociclib in combination with endocrine therapy, including letrozole, anastrozole, tamoxifen, and fulvestrant. These studies found that ribociclib 600 mg/d, 21 days on, 7 days off, leads to a significantly greater median progression-free survival (PFS), ranging from 8 to 13 months. Ribociclib is well tolerated in elderly patients, maintains health-related quality of life, and significantly reduces pain scores. The dose-limiting toxicities found in phase I studies were neutropenia, thrombocytopenia, and QTc prolongation. Common adverse effects seen in phase III trials include neutropenia, leukopenia, nausea, diarrhea, vomiting, and fatigue. Relevance to Patient Care and Clinical Practice: Literature on the safety and efficacy of ribociclib as well as its place in therapy in comparison to other FDA-approved CDK4/6 inhibitors for breast cancer is discussed. Conclusions: Ribociclib, when added to endocrine therapy, significantly improves PFS and has manageable toxicity in premenopausal/perimenopausal and postmenopausal women with HR+/HER2− advanced breast cancer.