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Impact of pre-neoadjuvant radioactive iodine seed marking on pathologic complete response and survival in early-stage breast cancer patients
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Yihao Geng1, Qi Zhang1, Zhao Bi1, Zhiqiang Shi1, Qiuchen Zhao2, Xiaowei Qi3, Rongrong Zhao1, Yongsheng Wang1, Pengfei Qiu1
Cancer Biology & Medicine | 2026, 23(1) : 78 - 85
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Cancer Biology & Medicine | 2026, 23(1): 78-85
• Letter •
Impact of pre-neoadjuvant radioactive iodine seed marking on pathologic complete response and survival in early-stage breast cancer patients
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Yihao Geng1, Qi Zhang1, Zhao Bi1, Zhiqiang Shi1, Qiuchen Zhao2, Xiaowei Qi3, Rongrong Zhao1, Yongsheng Wang1, Pengfei Qiu1
Affiliations
  • 1Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
  • 2Cancer Research UK Cambridge Centre and Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK
  • 3Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China
About Author:

Author contributions

Conceived and designed the analysis: Pengfei Qiu, Yongsheng Wang, Rongrong Zhao, Xiaowei Qi.

Collected the data: Yihao Geng, Qi Zhang, Zhiqiang Shi.

Analyzed the data: Qi Zhang, Qiuchen Zhao.

Wrote the paper: Yihao Geng, Zhao Bi.

Published: 2026-01-15 doi: 10.20892/j.issn.2095-3941.2025.0578
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Yihao Geng, Qi Zhang, Zhao Bi, Zhiqiang Shi, Qiuchen Zhao, Xiaowei Qi, Rongrong Zhao, Yongsheng Wang, Pengfei Qiu. Impact of pre-neoadjuvant radioactive iodine seed marking on pathologic complete response and survival in early-stage breast cancer patients[J]. Cancer Biology & Medicine, 2026 , 23 (1) : 78 -85 . DOI: 10.20892/j.issn.2095-3941.2025.0578
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Neoadjuvant therapy (NAT) has become the standard treatment for patients with locally advanced breast cancer and stage II–III HER2-positive (HER2+) or triple-negative breast cancer (TNBC)1,2. It is essential to accurately mark the primary breast tumor and positive axillary lymph nodes (ALNs) prior to NAT to ensure precise surgical excision, guide axillary downstaging, and guarantee reliable lesion retrieval for pathologic evaluation3. The false-negative rate of sentinel lymph node biopsy (SLNB) after NAT can be reduced to < 10% by applying modalities, such as the identification of ≥ 3 sentinel lymph nodes (SLNs) with dual-mapping techniques or removal of the marked lymph node with target axillary dissection (TAD) according to the ASCO, NCCN, and CBCS guidelines3–5. However, there is a lack of consensus regarding the optimal methods and materials for accurate marking6,7. Conventional techniques include clip placement, guidewire localization, and carbon or ink tattooing, whereas wireless technologies, such as Magseed®, radiofrequency identification tags, SAVI SCOUT®, and radioactive iodine-125 (125I) seeds, have also been adopted. Traditional marking techniques have a localization failure rate of approximately 10%. In contrast, the use of 125I seeds (with a radiation dose of 0.1–0.3 mCi) has significantly improved localization accuracy8,9. Nevertheless, owing to radioactive properties, concerns have been raised regarding the potential impact of 125I seed marking on assessing the pathologic complete response (pCR) after NAT10. Moreover, whether the influence of 125I seed marking on pCR could lead to suboptimal adjuvant treatment decisions and potentially compromise long-term oncologic outcomes has not been established. To investigate the potential impact of 125I seed placement on the pCR rate and long-term outcomes in breast cancer patients receiving NAT, we conducted a retrospective cohort study utilizing propensity score matching (PSM).
Clinicopathologic characteristics
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A total of 1594 breast cancer patients who received NAT followed by surgery between January 2017 and December 2024 were eligible for this study. A total of 1103 patients with complete clinicopathologic and follow-up data were included after applying inclusion and exclusion criteria (see Supplementary methods for details), as follows: 216 patients (19.6%) underwent 125I seed marking; 887 patients (80.4%) did not undergo 125I seed marking. This study was approved by the Ethics Committee of Shandong Cancer Hospital (Approval No. SDZLEC2025-477-01). The study flowchart, study population, NAT regimens, surgical procedures, pathologic evaluation, follow-up care, and statistical analysis methods are detailed in the Supplementary material.
125I seed marking protocol
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Preoperative axillary ultrasound (US) was performed by two radiologists with 12 and 8 years of experience in breast US, respectively. Following whole-breast US, the same radiologists routinely assessed axillary US and documented any suspicious sonographic features involving the ALNs. If multiple suspicious ALNs were identified, the largest node was selected for US-guided fine-needle aspiration (FNA) biopsy based on the shared decisions of the radiologists and patients. Repeated negative pressure aspiration was performed targeting the abnormal regions of the ALN and the collected specimens were subsequently subjected to cytologic evaluation. 125I seeds were simultaneously marked in the FNA-positive ALNs. ALNs were retrieved intraoperatively using gamma probe. The 125I seed implantation process and the parameters set are shown in Figure 1A and 1B.
Logistic regression analyses of pCR and cohort construction via PSM
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Univariate logistic regression analysis of pCR showed that the Ki-67 index (P = 0.001), pathologic subtype (P < 0.001), initial clinical T stage [cT] (P = 0.011), and 125I seed marked (P < 0.001) were significantly associated with pCR. Multivariate logistic regression analysis demonstrated that all four variables were independent predictors of total pCR (tpCR), which was defined as ypT0/is ypN0 (i.e., no residual invasive carcinoma in both the breast and ALNs). The Ki-67 index (OR = 2.35, 95% CI = 1.60–3.44, P < 0.001), pathologic subtype (OR = 1.88, 95% CI = 1.57–2.26, P < 0.001), cT (OR = 0.79, 95% CI = 0.63–0.98, P < 0.015), and 125I seed marking (OR = 1.66, 95% CI = 1.19–2.32, P = 0.003) are displayed in Table S1. To minimize bias and balance confounding factors between the groups, PSM was performed on the enrolled patients at a 2:1 ratio. The matching variables included age, menopausal status, histologic findings, Ki-67 index, clinical T/N stage, and pathologic subtype. After matching, 648 patients were included in the final analysis, including 432 in group A (no 125I seed marking) and 216 in group B (125I seed-marked). The demographic and clinicopathologic characteristics before and after PSM are summarized in Table 1.
pCR outcomes with 125I seed marking in the matched cohort
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Breast pCR (bpCR) was defined as no histologic evidence of invasive tumor cells in the breast with or without ductal carcinoma in situ (ypT0/is). Axillary pCR (apCR) is defined as the absence of micro- and macro-metastases in ALNs (ypN0). Patients with 125I seed marking in the matched cohort had significantly higher rates of bpCR, apCR, and tpCR. (tpCR: 55% vs. 46%, P = 0.030; bpCR: 63% vs. 53%, P = 0.016; apCR: 71% vs. 60%, P = 0.009; Figure 1C). Subgroup analysis based on pathologic subtype revealed that among the HR+/HER2−subgroup, the 125I seed-marked group had a significantly higher tpCR rate than group A (tpCR: 26% vs. 8%, P = 0.028; Figure 1D). By contrast, no significant differences were detected in tpCR, bpCR, and apCR rates (tpCR: 60% vs. 57%; bpCR: 70% vs. 62%; apCR: 77% vs. 73%, P > 0.05; Figure 1E) in HER2+ patients. The 125I seed-marked group in TNBC patients had significantly higher tpCR and bpCR rates compared to group A (tpCR: 59% vs. 39%, P = 0.033; bpCR: 66% vs. 48%, P = 0.021; Figure 1F). These findings suggested that 125I seed marking may enhance pCR following NAT in patients with breast cancer.
Correlation between 125I seed marking and long-term prognosis
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As of the final follow-up in December 2024, the median duration of follow-up was 36.7 months. A total of 50 recurrence/metastasis events were recorded [50/648 (7.7%)]: 8 in the 125I seed-marked group (3 local/axillary recurrences and 5 distant metastases); and 42 in the unmarked group (13 local/axillary recurrences and 29 distant metastases). The invasive disease-free survival (iDFS) was defined as the interval between the first postoperative day and the first occurrence of local recurrence or distant metastasis. Kaplan–Meier survival analysis showed that the 125I seed-marked group had a significantly higher 3-year iDFS compared to patients without 125I seed marking (96% vs. 90%, P = 0.02; Figure 1G). The survival curves for each subtype are provided in the Figures S2 and S3.
Kaplan–Meier survival analysis stratified by 125I seed-marked status was performed among patients with pCR. The analysis demonstrated that in both group A and B, patients achieving pCR had significantly better iDFS and lower risk of recurrence compared to those without pCR (group A: 96% vs. 85%, P = 0.021; group B: 99% vs. 83%, P = 0.003). Patients who achieved pCR exhibited similarly favorable prognosis, irrespective of 125I seed marked status (99% vs. 96%, P = 0.875; Figure 1H).
Discussion
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Recent studies have reported that there were no significant differences in recurrence rates and survival outcomes between TAD and SLNB groups9,11,12. 125I seeds have been increasingly utilized due to enhanced accessibility and cost-effectiveness. In the current study, the 125I seed-marked group exhibited significantly higher tpCR, bpCR, and apCR rates (P < 0.05) compared to the group that did not undergo 125I seed marking. Notably, this benefit was more pronounced among patients with TNBC. These findings suggested that radioactive seed marking may enhance pCR following NAT in patients with breast cancer.
In the era of molecular subtype-guided precision therapy, the pCR after NAT serves as a crucial prognostic indicator for patients with breast cancer13. Adjuvant escalation strategies can improve overall survival for patients who do not achieve pCR14,15. Consequently, accurate assessment of the treatment response following NAT is essential. A key concern is whether pCR associated with 125I seed marking reflects genuine therapeutic response or artifact of local radiation exposure. Low-dose rate brachytherapy using 125I seed has long served as a radical treatment modality for malignant tumors16. Although the therapeutic dose is significantly higher than the pre-NAT marked dose (0.1–0.3 mCi) the potential impact of these low doses on pCR and subsequent adjuvant treatment strategies remains an open question with little published evidence linking marking dose to therapeutic efficacy. In the current study, none of the patients who achieved pCR received subsequent adjuvant intensification therapy. Notably, the results herein indicated that patients who underwent 125I seed marking and achieved pCR had comparable iDFS to patients who achieved pCR without 125I seed marking (99% vs. 96%, P = 0.875), suggesting that pCR induced by 125I seed marking may carry biological significance equivalent to that achieved with NAT alone. This finding addresses the concern regarding the prognostic validity of pCR in the context of seed marking17. Furthermore, the current study revealed that the iDFS in the 125I seed-marked group was significantly superior to that in the group without 125I seed marking (P = 0.018), indicating that the increased pCR rate associated with radioactive seed marking may translate into improved survival outcomes. These results suggested that radioactive seed marking may have unique clinical value in facilitating surgical de-escalation as well as improving long-term prognosis.
This study had several limitations. First, the potential for selection bias cannot be entirely eliminated despite the use of PSM. Second, the relatively short follow-up (median follow-up time = 36.7 months) constitutes another limitation of this study. Third, the findings lack multicenter external data validation, and the precise radiobiologic and immunologic mechanisms are incompletely understood because the precise radiobiologic effects of 125I seed marking have not been fully elucidated. Furthermore, there is a need for further in-depth research on the mechanism underlying 125I action. Future multi-center, large-sample, prospective randomized controlled studies are required to validate this conclusion.
In conclusion, this study demonstrated that pre-neoadjuvant radioactive 125I seed marking (0.1–0.3 mCi) significantly increased the pCR rates in breast cancer patients undergoing NAT, with the greatest benefit occurring in patients with TNBC. The observed improvement in pCR was associated with a measurable benefit in iDFS, indicating that the increased pCR conferred a meaningful clinical advantage.
Funding
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  • This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82573747, 82172873, W2421095, and 82503888), National Science and Technology Major Project (Grant No. 2025ZD0543900), Natural Science Foundation of Shandong Province (Grant Nos. ZR2024LMB011 and ZR2024QH058), Taishan Scholars Program of Shandong Province (Grant No. tsqn202211337), and Collaborative Academic Innovation Project of Shandong Cancer Hospital (Grant No. GF003).
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Appendix
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Year 2026 volume 23 Issue 1
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Article Info
doi: 10.20892/j.issn.2095-3941.2025.0578
  • Receive Date：2025-09-23
  • Online Date：2026-11-07
  • Published：2026-01-15
Article Data
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History
  • Received：2025-09-23
  • Accepted：2025-11-19
Funding
This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82573747, 82172873, W2421095, and 82503888), National Science and Technology Major Project (Grant No. 2025ZD0543900), Natural Science Foundation of Shandong Province (Grant Nos. ZR2024LMB011 and ZR2024QH058), Taishan Scholars Program of Shandong Province (Grant No. tsqn202211337), and Collaborative Academic Innovation Project of Shandong Cancer Hospital (Grant No. GF003).
Affiliations
    1Breast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China
    2Cancer Research UK Cambridge Centre and Department of Oncology, University of Cambridge, Cambridge CB2 0XZ, UK
    3Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing 400038, China

Corresponding:

Correspondence to: Rongrong Zhao, Yongsheng Wang and Pengfei Qiu, E-mail: , and
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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