The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS)

Abstract

Introduction: Ductal carcinoma in situ (DCIS) is a non-invasive non-obligate precursor of invasive breast cancer. With guideline concordant care (GCC), DCIS outcomes are at least as favourable as some other early stage cancer types such as prostate cancer, for which active surveillance (AS) is a standard of care option. However, AS has not yet been tested in relation to DCIS. The goal of the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial for low-risk DCIS is to gather evidence to help future patients consider the range of treatment choices for low-risk DCIS, from standard therapies to AS. The trial will determine whether there may be some women who do not substantially benefit from current GCC and who could thus be safely managed with AS. This protocol is version 5 (11 July 2018). Any future protocol amendments will be submitted to Quorum Centralised Institutional Review Board/local institutional review boards for approval via the sponsor of the study (Alliance Foundation Trials).

Methods and analysis: COMET is a phase III, randomised controlled clinical trial for patients with low-risk DCIS. The primary outcome is ipsilateral invasive breast cancer rate in women undergoing GCC compared with AS. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes. Patients randomised to the GCC group will undergo surgery as well as radiotherapy when appropriate; those in the AS group will be monitored closely with surgery only on identification of invasive breast cancer. Patients in both the GCC and AS groups will have the option of endocrine therapy. The total planned accrual goal is 1200 patients.

Ethics and dissemination: The COMET trial will be subject to biannual formal review at the Alliance Foundation Data Safety Monitoring Board meetings. Interim analyses for futility/safety will be completed annually, with reporting following Consolidated Standards of Reporting Trials (CONSORT) guidelines for non-inferiority trials.

Trial registration number: NCT02926911; Pre-results.

Keywords: active surveillance; breast cancer; clinical trial; ductal carcinoma in situ; non-invasive; surgery.

Figure 1

COMET trial schema. Patient flow for accrual and registration. Eligibility criteria for low-risk DCIS include 40 years of age or older, grade I/II DCIS without invasive breast cancer diagnosed on core, vacuum-assisted or surgical biopsy; ER(+) and/or PR(+); HER2(−); and no mass on physical examination or imaging with exception of fibroadenoma at a distinct/separate site from the site of DCIS. The primary study endpoint on which the sample size is based is rate of 2-year invasive breast cancer diagnosis among patients randomised to GCC compared with AS. ITT analyses adjusted for drop-out, non-compliance and contamination will be performed on all randomised patients including those who do and do not accept the arm to which they are randomised. Patient-reported outcome surveys will be collected from all patients who are registered for the study, including those who crossover. Mammograms will be performed q6 months for the index breast and q12 months for the contralateral breast in the AS arm and q12 months in both the index and contralateral breast in the GCC arm. No chest wall imaging will be performed if mastectomy has been performed. AS, active surveillance; COMET, Comparison of Operative versus Monitoring and Endocrine Therapy; DCIS, ductal carcinoma in situ; ER(+), oestrogen receptor positive; GCC, guideline concordant care; HER2 (−), human epidermal growth factor 2 negative; ITT, intention to treat; PR(+), progesterone receptor positive; q, every.

Figure 2

Surveillance protocol for COMET trial. Mammogram (MMG) not required if mastectomy performed. **Criteria for progression: (A) New mass/architectural distortion/density on surveillance MMG in either breast according to American College of Radiology Breast Imaging Reporting and Data System; (B) Increase in extent of calcifications ≥5 mm in at least one dimension compared with the most recent prior MMG of the index breast; (C) New suspicious findings on other radiological studies (ultrasound, MRI) in either breast. AS, active surveillance; COMET, Comparison of Operative versus Monitoring and Endocrine Therapy; DCIS, ductal carcinoma in situ; GCC, guideline concordant care; SoC, standard of care.