Active monitoring appears to be a safe strategy for the management of some patients with low-risk ductal carcinoma in situ (DCIS), proving noninferior to guideline-concordant management of this patient population (ie, surgery with or without radiation therapy). After 2 years, the rate of invasive ipsilateral breast cancer was similar in women randomly assigned to active monitoring vs guideline-concordant management, according to results of the COMET trial, presented at the 2024 San Antonio Breast Cancer Symposium.1 The study was published simultaneously in JAMA to coincide with the presentation.2 No differences were observed between treatment arms in the development of invasive ipsilateral breast cancer in subgroups, including invasive breast cancer tumor size, nodal status, or highest grade.
After 2 years of follow-up, 19 patients in the active monitoring group and 27 patients in the guideline-concordant care arm were diagnosed with invasive ipsilateral breast cancer. The 2-year cumulative rate of invasive ipsilateral breast cancer was 4.2% in the active monitoring arm and 5.9% in the guideline-concordant arm. These results met the standard for noninferiority.
Background
“There are more than 50,000 new cases of DCIS in the U.S. each year, and treatment is surgery, often combined with radiation therapy for 98% of patients with this diagnosis. But DCIS does not always progress to invasive breast cancer. Current treatment strategies undoubtedly lead to the overtreatment of women whose tumors are at low risk of progression and can result in chronic pain, altered body image, reduced quality of life, and other side effects that may be avoidable,” explained lead author E. Shelley Hwang, MD, MPH, the Mary and Deryl Hart Distinguished Professor of Surgery, Vice-Chair of Research in the Department of Surgery, and Professor of Radiology at Duke University School of Medicine.
E. Shelley Hwang, MD, MPH
In the COMET trial, Dr. Hwang and her co-investigators explored whether a strategy of active monitoring was as effective as upfront treatment in patients with low-risk DCIS. Active monitoring is a strategy borrowed from prostate cancer, where men with prostate cancer and a Gleason score of 6 or lower have the option to be closely surveilled and treated only upon signs of disease progression. In COMET, patients were randomly assigned to active monitoring, and surgery was performed only if invasive cancer developed, she explained. The 2-year interval, although too short to establish with certainty which strategy was better, was selected to assuage concerns that active monitoring could miss invasive cancers. These results are promising, but longer follow-up is needed to determine whether active monitoring can become a standard of care, Dr. Hwang added.
Study Details
The multicenter, randomized COMET trial is the first large randomized clinical trial in the United States to evaluate different management strategies for DCIS. COMET enrolled nearly 1,000 patients (aged 40 and older), at more than 80 sites in the United States, with a new diagnosis of low-risk DCIS (ie, grade 1 or 2, hormone receptor–positive, HER2-negative DCIS with no evidence of invasive breast cancer). Patients were randomly assigned 1:1 to active monitoring (n = 473) or guideline-concordant care (n = 484).
Active monitoring consisted of yearly bilateral mammograms interspersed with mammograms every 6 months for the DCIS-affected breast for 5 years. After that, participants underwent yearly bilateral mammograms. Surgery was recommended at any sign of invasive disease progression. Guideline-concordant management entailed surgery with or without radiation therapy. All patients could have endocrine therapy if desired.
“Clearly, the study couldn’t be blinded because patients would know if they were having surgery. Although it was a randomized trial, the study probably attracted patients who hoped to avoid surgery. This confirmed that there is a lot of interest in de-escalating therapy,” Dr. Hwang noted.
A total of 46% of patients assigned guideline-concordant care declined surgery, so the investigators performed a separate per protocol analysis of 673 randomly assigned patients who adhered to their assigned treatment. In that analysis, the 2-year rate of invasive ipsilateral breast cancer was 3.1% in the active monitoring group and 8.7% in the guideline-concordant group, for an absolute difference of 5.6% favoring active monitoring.
Patients assigned to active monitoring received slightly more endocrine therapy: 71.3% vs 65.5% of the guideline-concordant arm. The 2-year rate of ipsilateral invasive breast cancer among patients who received endocrine therapy was 3.2% in the active monitoring group and 7.2% in the guideline-concordant group.
As might be expected, the rates of radiotherapy and surgery were higher in the guideline-concordant group: radiation was given to 7.4% of the active monitoring group and 26.6% of the guideline-concordant group. Lumpectomy was performed in 13.2% and 48.2%, respectively. Mastectomy was performed in 3.7% and 5.5%, respectively.
“These early results are an important first step that in the future should help patients and their providers make informed decisions about DCIS treatment. Omission of surgery has been highly controversial, with both patients and their doctors fearing that it might result in an unacceptably high rate of patients who develop invasive cancer. Our findings are reassuring, and longer follow-up with a planned analysis at 5, 7, and 10 years should determine whether these results are durable. If so, I believe the results will be practice-changing,” she stated.
Dr. Hwang emphasized that the results are not generalizable to all patients with DCIS; they apply only to those who meet the low-risk criteria used to select patients for the trial. Research is ongoing to identify a biomarker to predict which patients are at lowest risk for developing invasive disease progression and would thus be candidates for active monitoring.
Quality of Life
A separate analysis of patient-reported outcomes in the COMET trial found that health-related quality of life, anxiety, depression, worries about DCIS, and symptom trajectories were comparable in both arms of the study over 2 years of follow-up.3 The investigators evaluated emotional, social, and physical well-being domains, as well as the ability to function using well-validated instruments. Patients completed these surveys at baseline, 6 months, 1 year, and after 2 years. The survey completion rate was greater than 83% for each timepoint, which was called “remarkable.”
Ann Partridge, MD, MPH, FASCO
Although responses were comparable in both treatment arms, patients assigned to guideline-concordant care reported transient arm movement problems and breast pain at 6 months and 1 year. “These results suggest that in the short term, active monitoring is a reasonable approach to management of low-risk DCIS. If longer-term follow-up supports the safety of active management from a cancer outcomes standpoint, this approach could be considered an option for women with DCIS,” stated lead author Ann Partridge, MD, MPH, FASCO, Interim Chair of the Department of Medical Oncology at Dana-Farber Cancer Institute and Professor at Harvard Medical School, Boston.
“These early results are encouraging and suggest that both strategies are options for DCIS. But it is also critical that we understand how women feel when they are living with this ‘watch and wait’ approach and see how it impacts their overall quality of life.”
Expert Point of View
“These 2-year data from the COMET trial are truly provocative,” said San Antonio Breast Cancer Symposium Program Co-Director Virginia Kaklamani, MD, leader of the Breast Cancer Program at UT Health Center San Antonio MD Anderson Cancer Center. “This study adds to the growing interest in de-escalation of therapy.”
Dr. Kaklamani continued: “In clinical practice, we do active monitoring of older patients with DCIS and other comorbidities. We put them on endocrine therapy and follow them, and the probability is they will die of other causes. This approach started during COVID but has gained traction. We select patients carefully for active monitoring. Only a minority of patients can be managed like this,” she emphasized.
Virginia Kaklamani, MD
Formal discussant of the COMET trial, Puneet Singh, MD, MS, FACS, a breast surgeon at MD Anderson Cancer Center, said the results of this noninferiority trial support de-escalation of therapy, with no significant negative impact of active monitoring evident at 2 years in this low-risk group of patients with DCIS. Like other experts who spoke at the meeting, Dr. Singh noted that longer follow-up is needed before this strategy can become standard of care.
“The fact that 48% of those allocated to guideline-concordant management refused surgery indicates patients’ interest in de-escalation of therapy,” Dr. Singh said.
DISCLOSURE: Dr. Hwang has served as a consultant for Merck; an advisory board member for Clinetic, Exai Bio, and Havah Therapeutics; and has received research support from the Patient-Centered Outcomes Research Institute (PCORI), National Institutes of Health (NIH), U.S. Department of Defense, and Breast Cancer Research Foundation (BRCF). Dr. Partridge receives royalties from Wolters Kluwer for authorship of UpToDate and has received research support from PCORI, NIH, BCRF, Susan G. Komen, and the American Cancer Society. Dr. Kaklamani has served as a speaker for AstraZeneca, Daiichi Sankyo, Gilead Sciences, and Novartis; has served as a consultant to AstraZeneca, Celldex Therapeutics, Genentech, Lilly, Menarini, and Novartis; and has received research funding from Eisai. Dr. Singh reported a financial relationship with Physicians Education Research.
REFERENCES
1. Hwang ES: 2024 San Antonio Breast Cancer Symposium. Abstract GS2-05. Presented December 12, 2024.
2. Partridge A: 2024 San Antonio Breast Cancer Symposium. Abstract GS2-06. Presented December 12, 2024.
3. Hwang ES, et al: JAMA. December 12, 2024 (early release online).
