Over the last several decades, the widespread implementation and uptake of screening mammography has contributed to earlier diagnosis of breast cancer and improvements in breast cancer mortality. However, the screening has led to a significant rise in the detection of ductal carcinoma in situ (DCIS), which is a pre-cancer of the breast. Much like invasive breast cancer, DCIS is a heterogeneous diagnosis and has a variable risk of progression to invasive cancer. Although DCIS can lead to invasive disease in some women, it may remain dormant in others; thus, in these cases, standard therapy leads to potential overtreatment.1
At present, outside of a framework of a clinical trial, DCIS is treated primarily with surgical resection, with almost one-third of women undergoing mastectomy.2 In addition, more than 30 percent of women with estrogen receptor (ER)-positive DCIS receive adjuvant endocrine therapy.3 Adjuvant endocrine therapy has proven to decrease local recurrence after surgical resection. Furthermore, endocrine therapy is a powerful tool for both the prevention and treatment of ER-positive invasive cancer. However, its effectiveness as the sole treatment modality in DCIS in the absence of surgery is unknown.
Promising results from CALGB study
The Alliance for Clinical Trials in Oncology—a coordinated network of 10,000 cancer specialists across various health care settings in the U.S. and Canada—develops and conducts clinical trials. Cancer and Leukemia Group B (CALGB) is now part of the Alliance and CALGB 40903 was a phase II single-arm study of neoadjuvant endocrine therapy in postmenopausal women with ER-positive DCIS.4
Although DCIS can lead to invasive disease in some women, it may remain dormant in others; thus, in these cases, standard therapy leads to potential overtreatment.
Women received six months of oral letrozole (2.5 mg/day) before surgery and underwent bilateral breast magnetic resonance imaging (MRI) at baseline, three months, and six months. Patients who showed disease progression on the three-month MRI proceeded to surgery. If they had stable disease or partial response, then they completed another three months of letrozole (six months total) and had a six-month MRI followed by surgery. The surgeon and patient chose the type of operation. Bilateral mammograms also were obtained at baseline and at six months.
The study included 79 patients. Initial baseline mammogram demonstrated the extent of DCIS ranged from 15 to 59 mm. Comparison of baseline with six-month mammogram showed a median 5 mm reduction of DCIS size. Similarly, the median reduction in DCIS volume on MRI was 61 percent at three months and 72 percent at six months. At six months, nearly one-third of study participants had a complete radiographic response and nearly half the women had a partial radiographic response to preoperative letrozole. Only three patients had surgery at three months because of concern about disease progression.
Ultimately, 88 percent of women went on to have surgery at the end of the six-month period, and 85 percent had residual DCIS on final pathology. However, DCIS size on pathology was significantly smaller (median 12 mm) than the original radiographic measurements (median 30 mm). Ten percent of women were upgraded to invasive cancer on final pathology—all early-stage and node-negative. All three important biomarkers of the DCIS—ER, progesterone receptor (PR), and Ki-67 (a tumor proliferation marker)—significantly decreased after letrozole therapy, highlighting its biologic effectiveness. Most notably, 15 percent of patients had no residual DCIS at surgery; among grade 1 DCIS who underwent surgery, 75 percent had no residual disease.
TABLE 1. INTERNATIONAL CLINICAL TRIALS OF ACTIVE SURVEILLANCE FOR LOW-RISK DCIS
This trial is the first known to have assessed the effects of endocrine therapy on unresected DCIS and demonstrates an impressive response to six months of letrozole. It also is timely with respect to the pandemic-related restrictions on elective surgery. In fact, the Society of Surgical Oncology and American Society of Breast Surgeons recommendation for management of ER-positive DCIS during the pandemic supported primary endocrine therapy for up to six months based on the findings from CALGB 40903.5,6
COMET trial now enrolling patients
Building upon these results, the COMET (Comparison of Operation to Monitoring, with or without Endocrine Therapy) Study is enrolling patients at Alliance sites with newly diagnosed low-risk DCIS and comparing outcomes for observation and surgical resection.7 Internationally, the concept of surveillance as an alternative to surgery in DCIS is being studied in four large clinical trials (see Table 1). All of these studies have active imaging surveillance as their main intervention in the surveillance group, and two have either an option or mandate for endocrine therapy.
Comparison of baseline and six-month mammogram showed a median 5 mm reduction of DCIS size. Similarly, the median reduction in DCIS volume on MRI was 61 percent at three months and 72 percent at six months.
The provocative results of the CALGB 40903 study and the ongoing trials of de-escalating treatment of DCIS are actively studying a potential paradigm shift in the management of women with low-risk DCIS, similar to the active surveillance approach that has been adopted for early-stage prostate cancer. In the era of shared decision-making, which seeks to balance the risks and benefits of treatment according to patient preferences, this evolving body of work around nonoperative management of DCIS could be adopted into practice as results from the ongoing trials emerge.8
For more information on CALGB 40903 or the COMET Trial, contact E. Shelley Hwang, MD, MPH, FACS, at email@example.com or on Twitter @DrShelleyHwang.
- Ryser MD, Weaver DL, Zhao F, et al. Cancer outcomes in DCIS patients without locoregional treatment. J Natl Cancer Inst. 2019;111(9):952-960.
- Worni M, Akushevich I, Greenup R, et al. Trends in treatment patterns and outcomes for ductal carcinoma in situ. J Natl Cancer Inst. 2015;107(12):djv263.
- Sagara Y, Freedman RA, Wong SM, et al. Trends in adjuvant therapies after breast-conserving surgery for hormone receptor-positive ductal carcinoma in situ: Findings from the National Cancer Database, 2004–2013. Breast Cancer Res Treat. 2017;166(2):583-592.
- Hwang ES, Hyslop T, Hendrix LH, et al. Phase II Single-Arm Study of Preoperative Letrozole for Estrogen Receptor-Positive Postmenopausal Ductal Carcinoma In Situ: CALGB 40903 (Alliance). J Clin Oncol. 2020;38(12):1284-1292.
- Society of Surgical Oncology. Resource for management options of breast cancer during COVID-19. Available at: www.surgonc.org/wp-content/uploads/2020/03/Breast-Resource-during-COVID-19-3.30.20.pdf. Accessed December 20, 2020.
- Dietz JR, Moran MS, Isakoff SJ, et al. Recommendations for prioritization, treatment, and triage of breast cancer patients during the COVID-19 pandemic. The COVID-19 Pandemic Breast Cancer Consortium. Breast Cancer Res Treat. 2020;181(3):487-497.
- Youngwirth L, Boughey J, Hwang ES. Surgery versus monitoring and endocrine therapy for low-risk DCIS: The COMET Trial. Bull Am Coll Surg. 2017;102(1):62-63. Available at: https://bulletin.facs.org/2017/01/surgery-versus-monitoring-and-endocrine-therapy-for-low-risk-dcis-the-comet-trial/. Accessed January 6, 2021.
- Kanbayashi C, Thompson AM, Hwang E-SS, et al. The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA). J Clin Oncol. 2019;37(Suppl_15):TPS603.