Abstract OT-08-02: Comparing an operation to monitoring, with or without endocrine therapy (COMET): A prospective randomized trial for low-risk DCIS (AFT-25)
Authors: Lynch Thomas , Partridge Ann , Thompson Alastair , Frank Elizabeth , Pinto Donna , Collyar Deborah , Basila Desiree , Davies Louise , Donovan Jenny , Hyslop Terry , McCall Linda , Ryser Marc , O' Donnell Taylor , Weiss Anna , Hwang Shelley 
Published: February 2021

Background: Approximately 50,000 women in the U.S. are diagnosed with ductal carcinoma in situ (DCIS) annually. Without treatment, it is estimated that 20-30% of DCIS will lead to invasive breast cancer. Currently, more than 97% of women undergo surgery, with many also undergoing radiation. An alternative to surgery for low-risk DCIS is active monitoring (AM), an approach in which regularly scheduled mammography and physical exams are used to monitor breast changes and determine if, or when, surgery is needed. Trial design: COMET, a multicenter phase III prospective randomized trial, opened in the U.S. in June 2017 (clinicaltrials.gov reference: NCT02926911). The hypothesis is that management of low-risk DCIS using an AM approach does not yield inferior invasive breast cancer and/or quality of life outcomes compared to surgery. Eligibility criteria: Patients with a new diagnosis of unilateral, bilateral, unifocal, multifocal, or multicentric DCIS, or atypia verging on DCIS are eligible. Patients must be ≥40 years of age, have no contraindication for surgery, and pathologic confirmation of grade I/II DCIS. DCIS must be ER and/or PR≥ 10% and HER2-negative without invasion, diagnosed within 120 days of registration. Breast tissue, blood and imaging are collected at trial entry and if invasive cancer subsequently occurs, and are stored in central repositories. Specific aims: The primary aim is to assess whether the 2-yr ipsilateral invasive breast cancer rate for AM is non-inferior to surgery. Secondary aims include comparison of 2-, 5-, and 10-yr mastectomy rate, contralateral invasive breast cancer rate, overall survival and invasive breast cancer-specific survival, as well as 5- and 10-yr ipsilateral invasive breast cancer rate between groups. Patient reported outcomes (PRO) using validated tools are critical secondary endpoints, and will enable comparison of health-related quality of life and psychosocial outcomes between surgery and AM groups at prespecified time points over a period of 5 years. Statistical methods: An accrual goal of 1200 was estimated using a 2-group test of noninferiority of proportions, with the 2-yr invasive breast cancer rate in the surgery group assumed to be 0.10, including accounting for upstaging. The projected drop-out rate is 25%, for a total of 900 patients treated per allocation arm. The non-inferiority boundary was set at 0.05. Based on a 1-sided un-pooled z-test, with alpha=0.05, a sample size of n=446 per group will have 80% power to detect the specified noninferiority margin. Intention-to-treat analysis of the 2-yr invasive breast cancer rate will be conducted using all patients as randomized, and will be completed using Kaplan-Meier estimates, stratified by group, combined with Greenwood’s confidence interval. Several sensitivity analyses (per protocol, as-treated, and instrumental variable) are also planned to account for loss of follow-up, rejection of randomization allocation and withdrawals. Present and target accrual: Trial accrual as of 7/1/20 is 540 randomized patients from 84 activated Alliance for Clinical Trials in Oncology sites. Despite logistical challenges posed by the COVID-19 crisis, patients continue to be recruited to the COMET trial. Over 80% of patients have sample sets/images stored in the tissue and image repositories. This trial will provide definitive clinical, quality of life and biomarker evidence regarding the trade-offs of surgery vs AM in patients with low-risk DCIS. Support: CER-1503-29572; https://acknowledgments.alliancefound.org Contact: Thomas Lynch (Project Manager) - thomas.lynch2@duke.edu

Citation Format: Thomas Lynch, Ann Partridge, Alastair Thompson, Elizabeth Frank, Donna Pinto, Deborah Collyar, Desiree Basila, Louise Davies, Jenny Donovan, Terry Hyslop, Linda McCall, Marc Ryser, Taylor O' Donnell, Anna Weiss, Shelley Hwang. Comparing an operation to monitoring, with or without endocrine therapy (COMET): A prospective randomized trial for low-risk DCIS (AFT-25) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-08-02.