Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR).

BACKGROUND: Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. METHODS/DESIGN: Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. DISCUSSION: This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01589367.

Lateral lymph node metastasis in papillary thyroid carcinoma: results of therapeutic lymph node dissection.

BACKGROUND: Cervical lymph node metastases are quite common in papillary thyroid cancer (PTC) and they usually spread in a contiguous fashion. However, "skip metastasis," defined as lateral lymph node metastasis without central lymph node metastasis, also occurs in patients with PTC. There is little information regarding skip metastasis in papillary thyroid microcarcinoma (PTMC). The goal of this study was to determine the prevalence and associated clinical and imaging features of skip metastasis in PTMC. METHODS: We performed a retrospective study of 245 patients with PTMC who underwent either thyroidectomy and central lymph node dissection or thyroidectomy, central lymph node dissection, and lateral lymph node dissection if preoperative ultrasonography or computed tomography suggested lateral node metastasis. Clinicopathologic results were reviewed, and the patterns of cervical lymph node metastasis were analyzed. RESULTS: Cervical lymph node metastases were present in 26.5% of cases. The frequency of lymph node metastases was 21.8% in the group that only had thyroidectomy and central lymph node dissection and 51.3% in the group that had thyroidectomy, central lymph node dissection, and lateral lymph node dissection. Younger age, larger tumor size, multiplicity, bilaterality, encapsulation, extrathyroid extension, and lymphatic invasion were associated with metastasis to nodes in the central or lateral compartment. Lateral lymph node dissection was performed in 15.9% of patients. Skip metastasis was observed in 7.7% of the cases in which combined central and lateral node dissection was performed. No features of the primary thyroid tumor could be associated with the development of skip metastasis. CONCLUSIONS: Skip metastases occur in a minority of patients with PTMC. We recommend, therefore, that preoperative studies in patients suspected of having PTMC focus not only on nodes in the central compartment but also lateral cervical nodes since the information obtained would guide the extent of surgery.