Citations

AbstractBackgroundContemporary guidelines for managing PTC advise an approach wherein primary tumor and regional metastases (RM) are completely resected at first surgery and radioiodine remnant ablation (RRA) is restricted to high‐risk patients, policies our group has long endorsed. To assess our therapeutic efficacy, we studied 190 children and 4242 adults consecutively treated during 1936–2015. Subjects and methodsMean follow‐up durations for children and adults were 26.9 and 15.2 years, respectively. Bilateral lobar resection was performed in 86% of children and 88% of adults, followed by RRA in 30% of children and 29% of adults; neck nodes were excised in 86% of children and 66% of adults. Tumor recurrence (TR) and cause‐specific mortality (CSM) details were taken from a computerized database.ResultsChildren, when compared to adults, had larger primary tumors which more often were grossly invasive and incompletely resected. At presentation, children, as compared to adults, had more RM and distant metastases (DM). Thirty‐year TR rates were no different in children than adults at any site. Thirty‐year CSM rates were lower in children than adults (1.1 vs. 4.9%; p = 0.01). Comparing 1936–1975 (THEN) with 1976–2015 (NOW), 30‐year CSM rates were similar in MACIS <6 children (p = 0.67) and adults (p = 0.08). However, MACIS <6 children and adults in 1976–2015 had significantly higher recurrence at local and regional, but not at distant, sites. MACIS 6+ adults, NOW, compared to THEN, had lower 30‐year CSM rates (30 vs. 47%; p < 0.001), unassociated with decreased TR at any site.ConclusionsChildren, despite presenting with more extensive PTC when compared to adults, have postoperative recurrences at similar frequency, typically coexist with DM and die of PTC less often. Since 1976, both children and adults with MACIS <6 PTC have a <1% chance at 30 years of CSM; adults with higher MACIS scores (6 or more) have a 30‐year CSM rate of 30%.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Abstract Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2− breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 &gt;10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823–32. ©2017 AACR.