Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

The optimal preemptive dose of gabapentin following gynecologic surgery.

BACKGROUND: Gabapentin decreases acute nociceptive pain in animal and human studies when given before surgical incision. Various doses of gabapentin have been used (300-1,200 mg) to measure this preemptive effect. Here, we evaluated the optimal dose of gabapentin for reducing fentanyl consumption and the adverse effects of gabapentin following gynecologic surgery. METHODS: We recruited 100 patients who underwent laparotomy for gynecologic surgery. Patients were randomly divided into 4 groups and received a placebo (control), gabapentin 300 mg (G 300), gabapentin 600 mg (G 600), or gabapentin 1,200 mg (G 1200) 2 h before surgery. Postoperatively, patients received fentanyl via an intravenous patient controlled analgesia device. The cumulative fentanyl doses were recorded 2, 6, 12, 24 h, and 48 h postoperatively, and the sedation scale was recorded in the post anesthetic care unit (PACU). RESULTS: The postoperative fentanyl requirement was lower with gabapentin treatment, but there was no significant differences for the different doses. PACU sedation scores were not different in any group. CONCLUSIONS: Gabapentin has a preemptive effect in gynecologic surgery, but there were no additional fentanyl-sparing benefits at doses above 300 mg. Thus, 300 mg is an optimal dose for decreasing fentanyl consumption following gynecologic surgery.