LORETTA (JCOG1505) Trial: A Single-Arm Study of Tamoxifen Alone Without Surgery for Low-Risk, ER-Positive/HER2-Negative DCIS of the Breast

The incidence of ductal carcinoma in situ (DCIS) has risen significantly due to increased breast cancer screening. The standard treatment for DCIS remains surgical resection. While a 2024 prospective study on nonsurgical management of low-grade DCIS reported positive outcomes, the short observation period limits its acceptance as a recommended treatment option.

The LORETTA (JCOG1505) trial is a single-arm confirmatory study evaluating the efficacy of tamoxifen monotherapy without surgery in estrogen receptor (ER)-positive, low-risk DCIS. Conducted at 1 of the Japan Clinical Oncology Group institutions, the study enrolled female patients aged ≥40 years with low-risk DCIS, defined as nuclear grade (NG) 1 or 2 without comedo necrosis, ER-positive/HER2-negative disease confirmed on core biopsy, and no microinvasive or invasive cancer. Tumor size was limited to ≤25 mm, with no evidence of invasive cancer on mammography (MMG), ultrasound (US), or MRI. All patients received tamoxifen 20 mg/day without surgery. The primary endpoint was the 5-year cumulative incidence proportion of ipsilateral invasive cancer (CIPIC). Secondary endpoints included contralateral breast disease–free survival (BDFS), overall survival (OS), surgical proportion and timing, and safety. The analysis was powered to detect a 5-year CIPIC threshold of 7% and an expected 2.5% with a 1-sided α of 2.5% and 95% power. Efficacy was confirmed if the upper limit of the 95% CI for CIPIC did not exceed 7%.

Between July 2017 and January 2024, 344 patients were enrolled. In January 2025, the Data and Safety Monitoring Committee recommended early termination after interim analysis indicated that the 5-year CIPIC exceeded the predefined threshold of 7%. Median follow-up was 36 months (range, 0-80.4). Patient characteristics included a median age of 53 years (range, 40-85); performance status (PS) of 0 in 340 patients and PS of 1 in 1 patient; NG1 in 234 patients and NG2 in 107 patients; and premenopausal status in 162 patients and postmenopausal status in 173 patients. Among the 341 patients, 18 developed ipsilateral invasive cancer, resulting in a 5-year CIPIC of 9.8% (95% CI, 5.2%-16.1%). Subgroup analysis revealed a significant association between imaging-defined tumor diameter and invasive cancer occurrence: MMG (P=.0278), US (P=.0433), and MRI (P=.053). No significant associations were observed for NG, HER2 status, progesterone receptor, or age. Contralateral BDFS was 97.5%, with 4 events observed. Five-year OS was 98.8%, with 2 unrelated deaths. The surgical proportion was 9.7% (33/341), with a 5-year surgery-free survival rate of 82%. Grade ≥3 adverse events (AEs) were reported, with the most common being elevated aspartate aminotransferase (2.1%) and alanine aminotransferase (2.7%). Tamoxifen discontinuation by related AEs occurred in 26 cases.

The primary endpoint of the LORETTA trial was not met, as the 5-year CIPIC exceeded the predefined threshold of 7%. However, the incidence of ipsilateral invasive breast cancer and the surgical proportion remained low at 5 years. Tamoxifen monotherapy without surgery may represent a treatment option for carefully selected patients with low-risk, ER-positive/HER2-negative DCIS.

Source: Iwata H, Kanbayashi C, Toyama T, et al. The single-arm confirmatory trial of tamoxifen alone without surgery for low-risk DCIS of the breast with ER-positive HER2-negative (LORETTA trial: JCOG1505). Presented at: San Antonio Breast Cancer Symposium 2025. December 11, 2025; San Antonio, TX. Presentation GS2-09.