Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.
Background: While extended adjuvant therapy with aromatase inhibitors (AI) after initial tamoxifen has been demonstrated to improve disease-free-survival (DFS) of postmenopausal patients with hormone-receptor positive breast cancer, the optimal duration of extended AI is unknown. Moreover, it remains unclear whether patients after AI in the first 5 years benefit similarly from extended adjuvant AI therapy as patients after Tamoxifen. Methods: From February 2004 to June 2010, 3484 women with postmenopausal stage I-III hormone-receptor positive early breast cancer were randomized in 71 centers in Austria to receive either 2 years or 5 years of additional Anastrozole (1 mg daily) as extended adjuvant therapy, after initial 5 years of adjuvant endocrine treatment. Eligible patients had to be recurrence-free at 60 months of initial adjuvant therapy with Tamoxifen (Tam) or AI or Tam→AI, and younger than 80 years of age. Stratification factors were tumor stage, nodal status, initial endocrine therapy, adjuvant chemotherapy, and quantitative hormone receptors. Patients were followed-up at least annually. Primary end point of ABCSG-16 was DFS, secondary end points included overall survival (OS), fractures, contralateral breast cancer, and toxicity. Results: As of June 30, 2016, the median follow-up of the 3468 patients included in the analysis of ABCSG-16 was 105.9 months (IQR 102.2-110.3 months) after randomization (i.e. approx. 14 years after diagnosis). Median patient age was 64 years, 2507 (72%) patients had tumors smaller than 2 cm, 2301 (66%) patients were node-negative, 674 (19%) patients had high-grade tumors, 2683 (77%) patients had tumors both ER and PR positive. 2764 (80%) patients were treated with breast conserving surgery. Before randomization into ABCSG-16, 1000 (29%) patients had undergone (neo)adjuvant chemotherapy, 1774 (51%) patients had received 5 years of Tamoxifen, whereas 1688 (49%) patients had received other (AI containing) regimens in the first five years. As of June 30, 2016, 757 DFS events have been recorded, 377 (22%) in the 2-year group, and 380 (22%) in the 5-year group. There was no significant difference in DFS (HR 0.997, 95%CI 0.86-1.15, log rank p=0.982), in OS, time to secondary carcinoma and time to contralateral breast cancer. With respect to drug adherence, 81.2% of patients in the 2-year arm were taking the study drug still at 2 years, and 80.1% at 2 years in the 5-year arm. At 5 years, 65.6% of patients in the 5-year arm were still on the assigned medication. Bone fractures were more frequent in the 5-year arm (i.e. years 3 to 5 after randomization: 6% vs 4 %, HR=1.405, 95%CI 1.03-1.91, p=0.029). Conclusion: After 5 years of adjuvant endocrine therapy (Tamoxifen or AI or Sequence), 2 additional years of Anastrozole are sufficient for extended adjuvant therapy – a further extension to 5 additional years did not yield additional outcome benefit but added toxicity. Support: AstraZeneca Citation Format: Gnant M, Steger G, Greil R, Fitzal F, Mlineritsch B, Manfreda D, Tausch C, Balic M, Dubsky P, Moik M, Thaler J, Egle D, Bjelic-Radisic V, Selim U, Exner R, Singer C, Melbinger-Zeinitzer E, Haslbauer F, Stöger H, Helfgott R, Sevelda P, Trapl H, Wette V, Sölkner L, Jakesz R. A prospective randomized multi-center phase-III trial of additional 2 versus additional 5 years of anastrozole after initial 5 years of adjuvant endocrine therapy – results from 3,484 postmenopausal women in the ABCSG-16 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-01.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.