Abstract P5-15-04: Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients

Abstract Background: Bisphosphonates can delay the onset and reduce the risk of skeletal related events in patients with bone metastatic breast cancer; it can prevent and controlcancer treatment-induced bone loss. Zoledronic acid (ZOL) plus adjuvant endocrine therapy significantly improved disease free survival. The aim of the study is to evaluate the benefits of ZOL combined with adjuvant therapy in premenopausal early breast cancer patients. Patients and methods: Patients were premenopausal females who had undergone primary surgery for stage I, II ER +ve and/or PR +ve breast cancer with &amp;lt; 10 positive lymph nodes. All 300 patients were scheduled for standard tamoxifen 20mg/day for five years plus goserelin 3.6 mg every 28 days and were randomized to ZOL 4mg every 6 months for 3 years (group A) and without ZOL (group B). The primary end points were toxicity and disease-free survival (DFS), while overall survival (OS) was the secondary end point. Results: Between April 2005 and March 2012, 300 patients were enrolled, the median follow up duration was 98.4 months (range 14-120 months), adding ZOL to endocrine therapy strongly suggests improved DFS versus endocrine therapy alone (90% versus 85% for an absolute increase of 5%). There were fewer disease recurrences in the ZOL group versus no ZOL group (12% vs. 16%) with the greatest reductions in the loco-regional recurrence (3% vs. 5%), distant metastasis (6% vs. 7%) and bone metastasis (3% vs. 5%). Conclusion: ZOL with adjuvant endocrine therapy were generally well tolerated with no reports of renal failure or osteonecrosis of the jaw. So, a twice yearly ZOL enhanced the efficacy of adjuvant endocrine treatment, and this benefit is maintained for long time. Citation Format: El-Ibrashi MM, El-Sadda WM, Abdel-Halim II, Elashri MS. Zoledronic acid combined with adjuvant tamoxifen with or without ovarian function suppression in premenopausal early breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-15-04.</jats:p

Caveolin-1/PTRF upregulation constitutes a mechanism for mediating p53-induced cellular senescence: implications for evidence-based therapy of delayed wound healing in diabetes

A heightened state of oxidative stress and senescence of fibroblasts constitute potential therapeutic targets in nonhealing diabetic wounds. Here, we studied the underlying mechanism mediating diabetes-induced cellular senescence using in vitro cultured dermal fibroblasts and in vivo circular wounds. Our results demonstrated that the total antioxidant capacity and mRNA levels of thioredoxinreductase and glucose-6-phosphate dehydrogenase as well as the ratio of NADPH/NADP were decreased markedly in fibroblasts from patients with type 2 diabetes (DFs). Consistent with this shift in favor of excessive reactive oxygen species, DFs also displayed a significant increase in senescence-associated β-galactosidase activity and phospho-γ-histone H2AX (pH2AX) level. Moreover, the ability of PDGF to promote cell proliferation/migration and regulate the phosphorylation-dependent activation of Akt and ERK1/2 appears to be attenuated as a function of diabetes. Mechanistically, we found that diabetes-induced oxidative stress upregulated caveolin-1 (Cav-1) and PTRF expression, which in turn sequestered Mdm2 away from p53. This process resulted in the activation of a p53/p21-dependent pathway and the induction of premature senescence in DFs. Most of the aforementioned oxidative stress and senescence-based features observed in DFs were recapitulated in a 10-day-old diabetic wound. Intriguingly, we confirmed that the targeted depletion of Cav-1 or PTRF using siRNA- or Vivo-Morpholino antisense-based gene therapy markedly inhibited diabetes/oxidative stress-induced premature senescence and also accelerated tissue repair in this disease state. Overall, our data illuminate Cav-1/PTRF-1 as a key player of a novel signaling pathway that may link a heightened state of oxidative stress to cellular senescence and impaired wound healing in diabetes