Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations.

Although endocrine therapy is successfully used to treat patients with estrogen receptor (ER) positive breast cancer, a substantial proportion of this population will relapse. Several mechanisms of acquired resistance have been described including activation of the mTOR pathway, increased activity of CDK4 and activating mutations in ER. Using a patient derived xenograft model harboring a common activating ER ligand binding domain mutation (D538G), we evaluated several combinatorial strategies using the selective estrogen receptor degrader (SERD) fulvestrant in combination with chromatin modifying agents, and CDK4/6 and mTOR inhibitors. In this model, fulvestrant binds WT and MT ER, reduces ER protein levels, and downregulated ER target gene expression. Addition of JQ1 or vorinostat to fulvestrant resulted in tumor regression (41% and 22% regression, respectively) though no efficacy was seen when either agent was given alone. Interestingly, although the CDK4/6 inhibitor palbociclib and mTOR inhibitor everolimus were efficacious as monotherapies, long-term delayed tumor growth was only observed when co-administered with fulvestrant. This observation was consistent with a greater inhibition of compensatory signaling when palbociclib and everolimus were co-dosed with fulvestrant. The addition of fulvestrant to JQ1, vorinostat, everolimus and palbociclib also significantly reduced lung metastatic burden as compared to monotherapy. The combination potential of fulvestrant with palbociclib or everolimus were confirmed in an MCF7 CRISPR model harboring the Y537S ER activating mutation. Taken together, these data suggest that fulvestrant may have an important role in the treatment of ER positive breast cancer with acquired ER mutations.

Outcome of Arthroscopic Treatment of Posterior Impingement of the Ankle.

BACKGROUND: Open and arthroscopic techniques have been utilized in the treatment of posterior impingement of the ankle and hindfoot. Because posterior impingement occurs more frequently in patients who repetitively plantarflex the ankle, this population may especially benefit from a procedure that reduces pain and results in maximal range of motion (ROM). The purpose of this study was to assess the outcome of hindfoot endoscopy in patients with posterior ankle impingement through a higher level of function outcome measures and physical examination parameters, focused on analysis of ROM. METHODS: Twenty patients were followed prospectively at a minimum 1-year follow-up (mean 38.2 months). Nineteen of 20 patients were competitive athletes. Patients completed a minimum of 3 months of nonoperative treatment. Diagnoses included os trigonum, tibial exostosis, talar exostosis, loose body or fracture nonunion, and ganglion cyst removal. Patients underwent arthroscopic treatment utilizing a posterior approach; all relevant pathology was addressed. RESULTS: At the most recent follow-up, visual analog scale pain and American Orthopaedic Foot & Ankle Society hindfoot scores showed significant improvement (P < .01) pre- to postoperatively; Tegner score remained unchanged (P = .888). Three patients were professional athletes; all returned to their previous level of professional activity. ROM variables between affected and unaffected sides reached statistical similarity at the most recent follow-up. Only ankle plantarflexion reached statistical significance when compared pre- to postoperatively. Fifteen percent of patients reported postoperative neuritis. CONCLUSIONS: Posterior ankle arthroscopy allowed for maintenance or restoration of anatomic ROM of the ankle and hindfoot, ability to return to at least previous level of activity, and improvement in objective assessment of pain relief and higher level of function parameters. Complications associated with this procedure were minimal. LEVEL OF EVIDENCE: Level IV, retrospective case series.