In an intention-to-treat (ITT) analysis of the prospective, randomised non-inferiority COMET study, the 2-year cumulative rate of invasive cancer was 5.9% for women with low-risk ductal carcinoma in situ (DCIS) randomised to guideline-concordant care and 4.2% for active monitoring. These results show that at 2 years, patients randomised to active monitoring have non-inferior invasive breast cancer risk in the affected breast compared with those randomised to guideline-concordant care.
Longer follow-up will help determine whether active monitoring offers durable safety and acceptability for patients in the management of this low-risk disease according to Dr. E. Shelley Hwang of the Duke University in Durham, NC, US, and colleagues who presented the findings at San Antonio Breast Cancer Symposium along with a simultaneous publication in the JAMA on 12 December 2024.
For breast cancer, much of the burden of overdiagnosis from mammography screening comes from the detection of DCIS, a preinvasive neoplasia that lacks the potential to spread and cause symptoms unless it undergoes progression to invasive cancer. When diagnosed, DCIS is conventionally treated with surgery, often combined with adjuvant radiation, and/or endocrine therapy. These treatments are the same as those recommended for women with low- to intermediate-risk invasive cancer.
Adverse effects of these therapies can include long-term pain, altered body image, sexual dysfunction, menopausal symptoms, or, rarely, secondary cancers. Because not all DCIS progresses to invasive cancer, there is a potential opportunity to de-escalate surgery in the management of DCIS.
The COMET is a prospective, randomised, pragmatic non-inferiority trial designed for women with newly diagnosed low-risk DCIS comparing guideline-concordant care, including surgery, with active monitoring, with surgery reserved only for disease progression to invasive cancer. The primary objective was to assess whether active monitoring was non-inferior to guideline-concordant care as defined by the invasive cancer rate in affected breasts at 2 years.
The study enrolled 995 women aged 40 years or older with a new diagnosis of hormone receptor–positive grade 1 or grade 2 DCIS without invasive cancer at 100 US Alliance Cancer Cooperative Group clinical trial sites from 2017 to 2023. Participants were randomised to receive active monitoring (follow-up every 6 months with breast imaging and physical examination; n = 484) or guideline-concordant care (surgery with or without radiation therapy; n = 473). The primary outcome was 2-year cumulative risk of ipsilateral invasive cancer diagnosis, according to planned ITT and per-protocol analyses, with a non-inferiority bound of 0.05%.
The median age of the 957 participants was 63.6 years (95% confidence interval [CI] 55.5-70.5) years in the guideline-concordant care group and 63.7 years (95% CI 60.0-71.6) in the active monitoring group. Overall, 15.7% of participants were Black and 75.0% were White. In this prespecified primary analysis, median follow-up was 36.9 months; 346 patients had surgery for DCIS, 264 in the guideline-concordant care group and 82 in the active monitoring group.
A total, 46 women were diagnosed with invasive cancer, 19 in the active monitoring group and 27 in the guideline-concordant care group. The 2-year Kaplan-Meier cumulative rate of ipsilateral invasive cancer was 4.2% in the active monitoring group versus 5.9% in the guideline-concordant care group, a difference of −1.7% (upper limit of the 95% CI 0.95%), indicating that active monitoring is not inferior to guideline concordant care. Invasive tumour characteristics did not differ significantly between groups.
The authors commented that these findings have important implications for future inclusion of active monitoring as an option for low-risk DCIS, particularly in patients who may consider endocrine therapy as part of active monitoring or who have multiple competing comorbidities.
Other ongoing studies in low-risk DCIS will also contribute to knowledge in this area. Recruitment for the LORD patient preference trial (EORTC-BCG 1401) is anticipated to be completed by 2026. The LORETTA study (JCOG 1505) completed recruitment in January 2024 as a single-group study of 360 oestrogen receptor–positive DCIS patients treated with tamoxifen for 5 years as an alternative to surgery. The LORIS prospective randomised trial conducted in the UK closed early with 188 patients, and the 10-year results are awaiting.
In an accompanied editorial article, Drs. Monica Morrow and Andrea V. Barrio of the Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center in New York, NY, US wrote that the COMET trial provides reassurance that in patients with DCIS and a limited life expectancy, surgical therapy, and possibly even endocrine therapy, can be omitted, although the more clinically relevant question is why such patients would be having mammographic screening to begin with. For the remainder, who constitute most women with DCIS, the safety of active monitoring remains in question.
The long-term risk of invasive cancer development with active monitoring is unknown at this time but, based on ECOG-ACRIN E5194 and RTOG 9804, will be at least 0.6% per year, and possibly higher given the absence of surgical excision. Women enrolling in COMET demonstrated a strong preference for active monitoring; almost half of those randomised to guideline-concordant care did not have the prescribed surgery. However, COMET participants may not be representative of the population of women with DCIS at large. Population-based studies of women with DCIS have shown that concern about recurrence, invasive or DCIS, is the most important factor in patient selection of type of surgical therapy.
Longer follow-up will also clarify the benefit of endocrine therapy in a successful active monitoring strategy. Acceptance of endocrine therapy following surgical excision of DCIS has historically been low, and adherence to 5 years of endocrine therapy is poor even in women with invasive cancer. Whether 5 years or longer of endocrine therapy is preferable to a brief outpatient surgical procedure remains to be seen. Meanwhile, adoption of active monitoring as a standard management strategy for low-risk DCIS requires longer follow-up for most patients. The initial report of COMET does not provide the safety data necessary to omit surgery as part of DCIS management according to the editorialists.
The COMET study was supported by Patient-Centered Outcomes Research Institute award and Breast Cancer Research Foundation awards. The study was sponsored by Alliance Foundation Trials.
References
- Hwang ES, Hyslop T, Lynch T, et al. for the COMET Study Investigators. Active Monitoring With or Without Endocrine Therapy for Low-Risk Ductal Carcinoma In Situ The COMET Randomized Clinical Trial. JAMA; Published online 12 December 2024. doi: 10.1001/jama.2024.26698
- Morrow M, Barrio AV. Is It Time to Abandon Surgery for Low-Risk DCIS? JAMA; Published online 12 December 2024. doi:10.1001/jama.2024.26723