Endocrine therapy of short duration prevents local and contralateral recurrence of ductal carcinoma in situ of the breast: A multicenter retrospective cohort study in China

To the Editor: De-escalating the treatment of ductal carcinoma in situ (DCIS) of the breast has been investigated in recent years. A 5-year adjuvant endocrine therapy (AET) regimen is the recommended treatment for hormone receptor-positive DCIS. Selective estrogen receptor modulators (such as the commonly used tamoxifen and toremifene) and aromatase inhibitors (AIs) are the currently used AET drugs. However, long-term AET is accompanied by severe side effects such as menopausal symptoms, endometrial carcinoma, cardiovascular events, venous thromboembolic events, osteoporosis, and joint pain that can significantly reduce patients' quality of life. It was reported that only 50% of the patients completed the recommended 5-year AET mainly because of side effects, while higher adherence rates were observed with shorter-duration regimens.[1,2] Therefore, de-escalation of AET should be considered to reduce the side effects of AET and improve adherence. The phase III TAM-01 clinical trial involving 500 patients with breast intraepithelial neoplasia showed that 5 mg/day of tamoxifen administration for 3 years was associated with improved efficacy compared to the placebo, and serious adverse events were not significantly different from that of the placebo.[3] The effect was similar to that observed with 20 mg/day tamoxifen treatment for 5 years in the NSABP B-24 subgroup analysis of hormone receptor-positive DCIS.[3] Furthermore, the 10-year results were presented indicating that tamoxifen 5 mg/day for 3 years significantly prevented recurrence after 7 years from treatment cessation without long-term adverse events.[4] Despite the strong evidence, the duration of the protective effects in a real-world setting is not known, as the treatment duration can vary among patients. In this study, we compared the efficacy of AET ≤3 years vs. >3 years in hormone receptor-positive DCIS patients based on local and contralateral recurrence rates to help determine the optimal AET duration in the real world. We collected demographic information, personal history, surgical treatment, tumor pathology, postsurgical treatment, and follow-up data from 12 centers in China (the First Hospital of China Medical University, the First Hospital of Jilin University, Jilin Cancer Hospital, Affiliated Zhongshan Hospital of Dalian University, the Second Hospital of Jilin University, the First Affiliated Hospital of Dalian Medical University, China-Japan Union Hospital affiliated to Jilin University, the Second Hospital of Dalian Medical University, the Fifth People's Hospital of Shenyang, General Hospital of Benxi Iron & Steel Industry Group of Liaoning Health Industry Group, Affiliated Hospital of Hebei Engineering University, and the Fourth People's Hospital of Shenyang) on 1354 women aged 18–85 years with a primary diagnosis of DCIS with estrogen receptor- or progesterone receptor-positive staining (≥1%), who were treated between 2004 and 2017, by mastectomy or breast-conserving surgery (BCS) and postoperative radiotherapy (RT). Exclusion criteria were microinvasion >2 mm and lymph node metastasis or distant metastasis. Patients were also excluded if they met one or more of the following criteria: (1) had other malignant tumors; (2) had received AET with drugs including but not limited to tamoxifen, toremifene, letrozole, anastrozole, or exemestane before the diagnosis of DCIS; and (3) had a serious comorbidity. This multicenter retrospective cohort study was approved by the Institutional Ethics Committee of the First Hospital of China Medical University (No. [2020]222) and was registered with clinicaltrials.gov (registration number: NCT04666805). A waiver for written, informed consent was granted because of the minimal risk to the patients in this study. The principal investigator at each institution identified qualified patients and anonymized the collected data before they were transferred to the multicenter database at the First Hospital of China Medical University. AET administration, RT fractionation, chemotherapy, and targeted therapy were in accordance with the policies of each institution and were determined from electronic medical records. Women were considered recipients of AET if they had received therapy during any one treatment course after the initial diagnosis of primary cancer. The recipients should be under a common dose (20.0 mg/day for tamoxifen, 60.0 mg/day for toremifene, 25.0 mg/day for exemestane, 1.0 mg/day for anastrozole, and 2.5 mg/day for letrozole). These events were verified based on medical records and follow-up data. The histologically confirmed breast cancer events, including both invasive breast cancer and new or recurrent DCIS, were calculated. The patients who stopped AET because of the occurrence of events were excluded from this analysis; thus, these events were excluded from the calculation. Besides, the patients whose first events were axillary or subclavian lymph node metastasis, distant metastasis, death, or other cancers were also excluded from this analysis. We excluded samples for which complete multivariate information was missing. The chi-squared test was performed to compare the distribution of these factors between groups. In the safety analysis, we excluded samples that refused to accept AET. We calculated the proportion of patients with complications related to AET and their occurrence in different groups from follow-up data. The chi-squared test was used to compare the incidence of each adverse event between groups. The proportion of patients corresponding to each reason for discontinuation was calculated. Statistical significance was set at P <0.05. Two-tailed tests were used. All data were analyzed using SPSS v23.0 (SPSS Inc, Chicago, IL, USA). A total of 1354 patients were enrolled, and all patients were followed up for a median time of 55 months (interquartile range: 39 months), and the median age of patients was 48 years (range: 21–84 years). Local and contralateral recurrence events, baseline information, tumor characteristics, and the therapeutic regimens of 1016 patients with full informations are shown in Table 1. It was indicated that only three events were observed in total. Two of them were in the AET ≤3 years group and one of them was in the AET >3 years group, and no statistical significance was demonstrated (P = 0.549). The baseline characteristics were comparable between groups except for tumor maximum diameter (P = 0.047) and human epidermal growth factor receptor (HER) 2 expression (P = 0.001). Table 1 - Main participants, events, tumor characteristics, and treatment regimen at baseline. Items Total AET ≤3 years AET >3 years P values All patients 1016 502 514 Events 0.549 Yes 3 (0.3) 2 (0.4) 1 (0.2) No 1013 (99.7) 500 (99.6) 513 (99.8) Age (years) 0.119 ≤39 136 (13.4) 72 (14.3) 64 (12.5) 40–49 429 (42.2) 193 (38.4) 236 (45.9) 50–64 333 (32.8) 176 (35.1) 157 (30.5) ≥65 118 (11.6) 61 (12.2) 57 (11.1) Maximum diameter (cm) 0.047 ≤1 234 (23.0) 101 (20.1) 133 (25.9) (1, 2] 313 (30.8) 161 (32.1) 152 (29.6) (2, 3] 232 (22.8) 109 (21.7) 123 (23.9) >3 237 (23.3) 131 (26.1) 106 (20.6) Ki-67 expression 0.486 <14 510 (50.2) 243 (48.4) 267 (51.9) 14–19 127 (12.5) 63 (12.5) 64 (12.5) ≥20 379 (37.3) 196 (39.0) 183 (35.6) HER-2 expression 0.001 +++ 210 (20.7) 125 (24.9) 85 (16.5) Not +++ 806 (79.3) 377 (75.1) 429 (83.5) Surgical method 0.304 BCS 141 (13.9) 64 (12.7) 77 (15.0) Mastectomy 875 (86.1) 438 (87.3) 437 (85.0) Chemotherapy or not 0.378 Yes 223 (21.9) 116 (23.1) 107 (20.8) No 793 (78.1) 386 (76.9) 407 (79.2) Drug – None 151 (14.8) 151 (29.8) 0 (0) Tamoxifen 508 (50.1) 206 (41.3) 302 (58.8) Toremifene 99 (9.9) 35 (7.2) 64 (12.5) AIs 258 (25.2) 110 (21.8) 148 (28.7) Data are presented as n (%). The chi-squared test was performed to compare the distribution of these factors between groups. AET: Adjuvant endocrine therapy; AIs: Aromatase inhibitors; BCS: Breast-conserving surgery; HER-2: Human epidermal growth factor receptor; –: Not applicable. Hot flashes and night sweats (n = 216, 18.72%), a thickened endometrium (n = 170, 14.73%), ostealgia (n = 84, 7.28%), and osteoporosis (n = 80, 6.93%) were the most common adverse events. In the tamoxifen and toremifene groups, hot flashes and night sweats and a thickened endometrium were the most frequently recorded side effects (hot flashes and night sweats: 151/693 [21.79%] and 20/117 [17.09%], respectively; thickened endometrium: 128/693 [18.47%] and 33/117 [28.21%], respectively). Ostealgia (57/344, 16.57%) and osteoporosis (65/344, 18.90%) were most frequently observed in the AI group. In terms of serious adverse events, there were two cases of venous thrombosis and four of endometrial cancer. Ostealgia was the only side effect that differed significantly between the AET ≤3 years and >3 years groups, not only in the total population (P = 0.029) but also in patients receiving AI (P = 0.039). More patients in the AET ≤3 years group experienced ostealgia than in the AET >3 years group in the total population (9.35% [43/460] vs. 5.91% [41/694]) and in the AI group (21.83% [31/142] vs. 12.87% [26/202]). Overall, 107 in 1154 (9.27%) patients discontinued AET because of side effects while only 5 in 1154 (0.43%) patients did so for economic reasons. Before the TAM-01 trial, 5 years of AET was recommended for women with hormone receptor-positive DCIS of the breast, the same as for patients with invasive breast cancer. In our study, local and contralateral recurrence rates did not differ significantly between the AET ≤3 years and >3 years groups, and very few recurrence rates were demonstrated in both groups. Shortening the duration of drug treatment is an important and practical factor in treatment de-escalation, which can improve AET adherence and improve patients' quality of life. Our research provides evidence supporting the clinical benefits of DCIS treatment de-escalation. In conclusion, our study provided the idea and evidence that short-term AET may be sufficient in preventing local and contralateral recurrence in patients diagnosed with hormone receptor-positive DCIS of the breast. The possibility of a 3-year regimen as the standard of care to improve patients' adherence and quality of life without negatively impacting clinical outcome warrants further exploration. Funding This research was funded by grants from the 2023 Applied Basic research project of Liaoning province (No. 2023JH2/101300048 to B. Chen) and 2021 Science and Technology project of Shenyang (No. 21-173-9-07 to G. Zhu). Conflicts of interest None.