Impact of breast density on the efficacy of radiofrequency ablation in early-stage breast cancer

Impact of breast density on the efficacy of radiofrequency ablation in early-stage breast cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of breast density on the efficacy of radiofrequency ablation in early-stage breast cancer Manabu Futamura, Yasuko Nagao, Yukiko Takai, Yoshimi Niwa, Akira Nakakami, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6712914/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Sep, 2025 Read the published version in Breast Cancer → Version 1 posted 5 You are reading this latest preprint version Abstract Background Radiofrequency ablation (RFA) is a minimally invasive technique used to treat small breast tumors by delivering high-frequency current through a needle electrode under ultrasound guidance. In Japan, RFA became insurance-covered in 2023 as a local treatment for early-stage breast cancer. Methods We retrospectively analyzed data from patients who underwent RFA at our institution between February 2016 and March 2025. Breast density was classified into four categories based on the Breast Imaging Reporting and Data System. Associations between breast density and RFA parameters, including ablation temperature, duration, and impedance, were evaluated. Results RFA was performed on 50 breasts in 49 female patients. The mean peak ablation temperature after break was 81.0 ± 8.0 °C. A higher breast density was significantly associated with higher temperature. The mean ablation time until break was 446 ± 139 s, with a trend toward longer durations in denser breasts. The mean initial and final impedance values were 208 ± 72.3 Ω and 161 ± 66.5 Ω, respectively. Fat-rich breasts exhibited significantly higher impedance at both time points. Conclusion Fatty breast tissue was associated with higher impedance, lower peak temperatures, and shorter ablation times, potentially resulting in insufficient ablation. Breast density should be considered when planning RFA to ensure effective treatment. Radiofrequency ablation (RFA) Early breast cancer Breast density Thermal conductivity Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Multidisciplinary therapy is essential for treating breast cancer, combining local therapies such as surgery and radiation therapy with systemic therapies, including hormone therapy, chemotherapy, molecular targeted therapy, and immunotherapy. Surgical treatment plays a pivotal role in achieving local control, and the standard approach has shifted from radical mastectomy (Halsted procedure) to more conservative surgeries, such as modified radical mastectomy (Auchincloss’ method) and breast-conserving therapy involving partial mastectomy [1, 2]. The primary goal of breast oncologists is to achieve a cure while balancing between oncologic safety and aesthetic preservation. With advancements in neoadjuvant chemotherapy, particularly for breast cancer subtypes such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive tumors, more than 60% of patients can now achieve a pathological complete response [3-6]. Consequently, several clinical trials are underway to omit surgery in selected cases [7, 8]. Furthermore, in Japan, radiofrequency ablation (RFA) has emerged as a novel local treatment option for early-stage breast cancer. RFA involves the percutaneous insertion of a needle electrode into small breast tumors under ultrasound guidance, delivering high-frequency alternating current to generate Joule heat and ablate tumor tissue [9]. Initially developed as a local treatment for hepatocellular carcinoma, RFA was first reported for breast cancer treatment by Jeffery et al. in 1999 [10, 11]. Since then, phase I and II feasibility studies, primarily in Japan and Europe, have demonstrated both safety and clinical efficacy [12-21]. In Japan, the RAFAELO study, the world’s first phase III trial for RFA in breast cancer, was launched in 2017, targeting patients with solitary tumors measuring ≤ 1.5 cm. The five-year outcomes were favorable, with a 98.6% ipsilateral breast tumor recurrence-free survival rate and a local recurrence rate of only 0.57%, comparable to those of traditional breast-conserving surgery [22]. Based on these findings, regulatory approval was granted in July 2023 for the Cool-tip™ RFA system E series (Cool-tip) (Medtronic plc, MN, US) for use in RFA for early-stage breast cancer [23], and insurance coverage for RFA was introduced in December 2023. To examine the efficacy of RFA in early-stage breast cancer, we initially conducted feasibility testing through trial excisions following RFA. Subsequently, we participated in the RAFAELO and PO-RAFAELO studies conducted under patient-requested therapy [24], and we are now providing RFA as part of routine insurance-covered care. However, current knowledge regarding RFA remains limited. Therefore, in this study, we retrospectively and prospectively collected data on all RFA cases at our institution to examine the relationship between RFA treatment and breast density. Materials and Methods Study population and design In this single-institution observation study, we examined the relationship between background breast density and RFA parameters, including ablation temperature, ablation time, and impedance in patients who underwent RFA at the Department of Breast Surgery, Gifu University Hospital, between February 1, 2016 and March 31, 2025. Clinical data were retrospectively collected from electronic medical records. This study was approved by the Central Ethics Committee of Gifu University (Approval No. 2024-328). Patient selection Patients were selected according to the RAFAELO study protocol. Eligible cases included those with a solitary tumor ≤ 1.5 cm in maximum diameter, as assessed by both ultrasonography and magnetic resonance imaging (MRI). All patients treated with RFA, including those in the feasibility study with trial excision, the RAFAELO study, the PO-RAFAELO study, and those treated under the national insurance system, were included in the analysis. Radiofrequency ablation procedure Cool-tip was used for all procedures. Ablation was performed according to the guidelines for the appropriate use of RFA in early-stage breast cancer. A radiofrequency electrode needle was inserted into the tumor under general anesthesia and ultrasound guidance. The output started at 5 W and was increased to 10 W after 1 min, and then further increased by 5 or 10 W every minute thereafter. No upper limit was set for the output. If the power limit of the device was reached, ablation was continued at that output level. As ablation progressed, electrical impedance increased. When impedance exceeded a threshold, the system automatically halted output, a phenomenon referred to as a “break” or “roll-off.” After the first break, the pump was stopped and the needle tip temperature was measured. If the ablation temperature was ＜70 ℃, the ablation was considered insufficient, and an additional ablation was performed at the same site. If multiple additional ablations still failed to reach 70 °C, a decision was made to continue or discontinue the procedure based on post-ablation imaging findings. To prevent thermal injury, 5% glucose solution was injected in both the retromammary space and subcutaneous tissue. Breast density evaluation Breast density was assessed using mammograms obtained before treatment. Three board-certified radiologists independently evaluated the images using the Breast Imaging Reporting and Data System classification, which consists of four categories: Category A, almost entirely fatty; Category B, scattered areas of fibroglandular density; Category C, heterogeneously dense; and Category D, extremely dense [25]. Two radiologists performed the initial assessment, and in cases of discrepancy, a third radiologist—who was the most experienced supervisor—made the final judgment. Statistical Analysis Group comparisons based on breast density were performed using Student’s t-test. A p-value of < 0.05 was considered statistically significant. The relationship between tumor size and other variables was analyzed using the Pearson correlation coefficient. Results RFA was performed on 50 breasts in 49 female patients. The mean age was 58.5 years, and the average body mass index was 23.7 kg/m². Among the 50 treated breasts, five were from the feasibility study with trial excision, one from the RAFAELO study, 21 from the PO-RAFAELO study, and 23 were treated under national insurance coverage. Regarding histological classification, 41 cases were invasive ductal carcinoma (IDC) and nine were ductal carcinoma in situ. Among the IDC subtypes, 39 were Luminal A and two were Luminal/HER2. Breast density was categorized as follows: Category A (n = 10), Category B (n = 19), Category C (n = 16), and Category D (n = 5) (Table and Fig. 1). The mean ablation temperature measured at the tip of the electrode after break was 81.0 ± 8.0 °C (range: 68–99 °C). By breast density category, mean temperatures were as follows: Category A: 76.4 °C, Category B: 81.3 °C, Category C: 82.7 °C, and Category D: 84.0 °C. Higher breast density was associated with higher ablation temperatures. In particular, the Category C and Category D groups showed significantly higher temperatures than did the Category A group (p = 0.037 and p = 0.031, respectively) (Fig. 2a). The mean ablation duration until break was 446 ± 139 s (range: 210–720 s). By breast density: Category A: 399 s, Category B: 441 s, Category C: 470 s, and Category D: 527 s. Although the difference was not statistically significant, ablation times tended to be longer in breasts with higher density (Fig. 2b). Impedance values at the start and end of RFA were also analyzed. The mean initial impedance was 208 ± 72.3 Ω (range: 124–402 Ω). By breast density: Category A: 284 Ω, Category B: 235 Ω, Category C: 177 Ω, and Category D: 147 Ω. Higher fat content was significantly associated with higher initial impedance (Fig. 3a). The mean final impedance was 161 ± 66.5 Ω (range: 111–398 Ω). Final impedance by density group was as follows: Category A: 227 Ω, Category B: 205 Ω, Category C: 152 Ω, and Category D: 129 Ω. Similarly, final impedance was significantly higher in breasts with higher fat content (Fig. 3b). Finally, we examined the relationship between tumor size (as measured by ultrasonography and MRI) and ablation parameters. Neither peak ablation temperature nor ablation time showed a strong correlation with tumor size (Fig. 4). Discussion RFA received insurance coverage approval in Japan in 2023 and is expected to become a leading minimally invasive local treatment for breast cancer. However, current evidence remains limited, and further investigations from various perspectives are warranted. Both patient-related factors and device-specific factors, such as the Cool-tip system, likely influence the efficiency and effectiveness of RFA. During our experience performing RFA for early-stage breast cancer, we noticed that ablation temperatures and times varied from case to case. This observation led us to investigate the potential relationship between breast density and RFA parameters. Prior to the clinical application of RFA, several experimental studies examined its thermal effects in vivo . Boehm et al. performed RFA on rabbit mammary tumors implanted in fatty tissue and suggested that differences in the thermal and electrical conductivity of mammary tissue influence heat propagation during RFA [26]. Similarly, Ahmed et al. demonstrated in uniform animal tumor models that the presence of blood flow reduced the ablation area, indicating that the vascularity and conductivity of surrounding tissues could affect RFA outcomes [27]. In breast tissue, which contains a high proportion of fat, additional complexities may arise. Adipose tissue generally has low thermal and electrical conductivity, potentially causing heat to concentrate within the tumor while limiting its spread to surrounding tissue. Therefore, although the tumor core may be adequately ablated, heat distribution near the tumor margins could be uneven in fatty breast tissue [28]. The Cool-tip system features ablation tips with either 2 or 3 cm active lengths. Complete ablation of the tumor core can generally be achieved when tumors are appropriately sized to fit within this range. Previous studies have consistently reported that tumors ≤ 2 cm in diameter can be effectively ablated, and the 1.5 cm tumor size criterion adopted in the RAFAELO trial is considered appropriate for safe and effective RFA [22]. In the present study, two patients exhibited relatively low ablation temperatures (68 °C and 69° C), both in breast densities classified as Category A or B. Positioning the Cool-tip needle to traverse the entire tumor suggests that the surrounding fat tissue plausibly impacted both thermal diffusion and tissue impedance. Fortunately, both patients achieved complete ablation, as confirmed by biopsy six months post-procedure, with no local recurrence observed after a maximum follow-up of three years. Although we observed a correlation between breast density and peak ablation temperature in this study, abrupt temperature drops did not occur one centimeter above the ablation site, indicating sufficient ablation of tumor interiors. In clinical practice, we monitor ablation in real time using ultrasonography to assess treatment progress. The lower RFA temperatures observed in fatty breasts may be attributed to higher tissue impedance and shorter ablation duration, as the Cool-tip needle, positioned within fat-rich tissue, leads to earlier termination of energy delivery (break) due to higher baseline impedance. The Cool-tip system triggers a break when impedance increases by 30 Ω or 30% from the baseline value, whichever is greater. Thus, in fatty breast tissue, breakage may occur earlier due to inherently higher impedance, resulting in reduced energy delivery and consequently lower peak temperatures. Our data showed no clear correlation between tumor size and ablation temperature or duration, suggesting that adherence to appropriate patient selection criteria (i.e., tumor size ≤ 1.5 cm) leads to consistently favorable RFA outcomes. To the best of our knowledge, this is the first study to report the relationship between breast density and RFA parameters in patients with early-stage breast cancer. However, this study has several limitations. First, this was a single-center study with a relatively small sample size. Second, breast density may not directly reflect the fat content of the tissue surrounding the tumor, which may vary across different regions of the breast. Third, we did not consider the potential influence of tissue perfusion (blood flow) on ablation outcomes. Fourth, the histopathological evaluation of ablation zones was not sufficiently performed after posttreatment radiotherapy. Given the recent approval of RFA for insurance coverage in Japan, its acceptance as a local treatment option for low-invasive breast cancer is anticipated to increase. However, this study demonstrated that breast density may influence key ablation parameters such as temperature and duration, which could ultimately affect treatment efficacy and cosmetic outcomes. Continued accumulation of clinical data is essential to establish stronger evidence and further develop RFA as a Japan-originated treatment modality. In conclusion, we investigated the relationship between RFA and breast density in patients with early-stage breast cancer. In fatty breast tissue, ablation impedance was higher, peak temperatures were lower, and ablation duration tended to be shorter. These findings suggest that RFA should be performed with careful consideration of breast density, as fatty breast tissue may lead to a narrower ablation zone and potentially incomplete ablation. Declarations Acknowledgements We thank Dr. Uematsu T for his useful comments. We also thank Editage for English language editing. Author contributions MF contributed to the study conception and design. Material preparation, data collection, and data analysis were performed by MF, YNa, YT, YNi, AN, MO, YT, and JM. The first draft of the manuscript was written by MF, and all authors commented on previous versions. TK and NM supervised the study based on the data obtained. All authors read and approved the final version of the manuscript. Conflict of interest MF—remuneration: Chugai, Taiho, Nippon-Kayaku, Daiichi-Sankyo, AstraZeneca, Pfizer, Eli Lilly, Eisai. AN—remuneration: Chugai, Eisai. JM—remuneration: Chugai, Taiho, Pfizer, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly. TK—remuneration: Chugai, Nippon-Kayaku, Pfizer, Exact Science, Daiichi-Sankyo, AstraZeneca, Intutive, Covidien. NM—Grants: Asahi Kasei, Chugai, Covidien, Daiichi-Sankyo, Eisai, e-NA Biotec, EP-CRSU, JMS, Johnson & Johnson, Kaken Pharm, Kyowa Kirin, MSD, Nippon Kayaku, Ono, ShiftZero, Taiho, TERUMO, Toray Medical. remuneration: Abott, Alfresa, AMCO, Asahi Kasei, Astellas, AstraZeneca, Bayer, Bristol-Myers, Chugai, Covideien, Daiichi-Sankyo, EP Pharma, Eisai, Eli Lilly, Guardant Health Japan, Gunze Medical, Intutive, Johnson & Johnson, Kaken, Kyowa Kirin, MC Medical, MercK, MSD, Novartis, Olympus, Ono, Striker, Taiho, TAKATA, Takeda, TERUMO, Tsumura, Viartis, Yakult, ZERIA. Informed consent Formal consent was not required owing to the retrospective nature of the study. References Fisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002; 347: 1233-41. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6712914","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":466975567,"identity":"d093cc3b-94ec-4473-82cf-925460ebea41","order_by":0,"name":"Manabu 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Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Nobuhisa","middleName":"","lastName":"Matsuhashi","suffix":""}],"badges":[],"createdAt":"2025-05-21 06:00:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6712914/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6712914/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12282-025-01775-7","type":"published","date":"2025-09-22T15:57:59+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84340261,"identity":"0773fd28-6a34-47d7-a673-0fa509901c07","added_by":"auto","created_at":"2025-06-10 18:23:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":169566,"visible":true,"origin":"","legend":"\u003cp\u003eBreast density evaluated by mammography\u003c/p\u003e\n\u003cp\u003eBreast density was classified into four groups based on the Breast Imaging Reporting and Data System: Category A, almost entirely fatty (n = 10); Category B, scattered areas of fibroglandular density (n = 19); Category C, heterogeneously dense (n = 16); and Category D, extremely dense (n = 5). The area outlined by the yellow dotted line indicates early-stage breast cancer.\u003c/p\u003e","description":"","filename":"Slide1.png","url":"https://assets-eu.researchsquare.com/files/rs-6712914/v1/67c94087460efeec3c6f621f.png"},{"id":84340257,"identity":"e8b5a451-d105-4384-b5ca-21e6e6eae3fe","added_by":"auto","created_at":"2025-06-10 18:23:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37862,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between breast density and ablation temperature or time\u003c/p\u003e\n\u003cp\u003e(a) Mean ablation temperatures (℃) for each breast density category. (b) Mean ablation time (s). White numerals within the bars indicate mean values, and error bars represent standard deviations (SD).\u003c/p\u003e","description":"","filename":"Slide2.png","url":"https://assets-eu.researchsquare.com/files/rs-6712914/v1/a7a5ecc89b286f5896c11b3b.png"},{"id":84340264,"identity":"e8790298-8594-4bba-94e4-902fe1207e72","added_by":"auto","created_at":"2025-06-10 18:23:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":39024,"visible":true,"origin":"","legend":"\u003cp\u003eRelationship between breast density and tissue impedance during radiofrequency ablation (RFA)\u003c/p\u003e\n\u003cp\u003eMean impedance values at the start (a) and end (b) of RFA for each breast density group. White numerals within the bars represent mean values, and error bars indicate standard deviation (SD).\u003c/p\u003e","description":"","filename":"Slide3.png","url":"https://assets-eu.researchsquare.com/files/rs-6712914/v1/75e397c7faf2d0f99a131b54.png"},{"id":84340262,"identity":"3725a035-6d58-42b8-82b5-19814b2aac78","added_by":"auto","created_at":"2025-06-10 18:23:36","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":36497,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between tumor size and ablation temperature or time\u003c/p\u003e\n\u003cp\u003e(a) Correlation between ablation temperature and tumor size measured by ultrasonography. (b) Correlation between ablation temperature and tumor size measured by magnetic resonance imaging (MRI). (c) Correlation between ablation time and tumor size measured by ultrasonography. (d) Correlation between ablation time and tumor size measured by MRI.\u003c/p\u003e","description":"","filename":"Slide4.png","url":"https://assets-eu.researchsquare.com/files/rs-6712914/v1/44ce115113086606acf0695f.png"},{"id":92430574,"identity":"9832ce3b-cfb2-4450-bd17-660893b9314d","added_by":"auto","created_at":"2025-09-29 16:06:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":738382,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6712914/v1/dff5d4da-f44c-4521-a29e-5d206334f6d0.pdf"},{"id":84340259,"identity":"7dd2b6a8-7b47-40ec-872a-6516129bfe1b","added_by":"auto","created_at":"2025-06-10 18:23:36","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":10556,"visible":true,"origin":"","legend":"","description":"","filename":"renamedeabad.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6712914/v1/8a08c882057470e7d6736fd2.xlsx"}],"financialInterests":"","formattedTitle":"Impact of breast density on the efficacy of radiofrequency ablation in early-stage breast cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMultidisciplinary therapy is essential for treating breast cancer, combining local therapies such as surgery and radiation therapy with systemic therapies, including hormone therapy, chemotherapy, molecular targeted therapy, and immunotherapy. Surgical treatment plays a pivotal role in achieving local control, and the standard approach has shifted from radical mastectomy (Halsted procedure) to more conservative surgeries, such as modified radical mastectomy (Auchincloss\u0026rsquo; method) and breast-conserving therapy involving partial mastectomy [1, 2]. The primary goal of breast oncologists is to achieve a cure while balancing between oncologic safety and aesthetic preservation. With advancements in neoadjuvant chemotherapy, particularly for breast cancer subtypes such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive tumors, more than 60% of patients can now achieve a pathological complete response [3-6]. Consequently, several clinical trials are underway to omit surgery in selected cases [7, 8]. Furthermore, in Japan, radiofrequency ablation (RFA) has emerged as a novel local treatment option for early-stage breast cancer.\u003c/p\u003e\n\u003cp\u003eRFA involves the percutaneous insertion of a needle electrode into small breast tumors under ultrasound guidance, delivering high-frequency alternating current to generate Joule heat and ablate tumor tissue [9]. Initially developed as a local treatment for hepatocellular carcinoma, RFA was first reported for breast cancer treatment by Jeffery et al. in 1999 [10, 11]. Since then, phase I and II feasibility studies, primarily in Japan and Europe, have demonstrated both safety and clinical efficacy [12-21]. In Japan, the RAFAELO study, the world\u0026rsquo;s first phase III trial for RFA in breast cancer, was launched in 2017, targeting patients with solitary tumors measuring \u0026le; 1.5 cm. The five-year outcomes were favorable, with a 98.6% ipsilateral breast tumor recurrence-free survival rate and a local recurrence rate of only 0.57%, comparable to those of traditional breast-conserving surgery [22]. Based on these findings, regulatory approval was granted in July 2023 for the Cool-tip\u0026trade; RFA system E series (Cool-tip) (Medtronic plc, MN, US) for use in RFA for early-stage breast cancer [23], and insurance coverage for RFA was introduced in December 2023. To examine the efficacy of RFA in early-stage breast cancer, we initially conducted feasibility testing through trial excisions following RFA. Subsequently, we participated in the RAFAELO and PO-RAFAELO studies conducted under patient-requested therapy [24], and we are now providing RFA as part of routine insurance-covered care. However, current knowledge regarding RFA remains limited. Therefore, in this study, we retrospectively and prospectively collected data on all RFA cases at our institution to examine the relationship between RFA treatment and breast density.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population and design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this single-institution observation study, we examined the relationship between background breast density and RFA parameters, including ablation temperature, ablation time, and impedance in patients who underwent RFA at the Department of Breast Surgery, Gifu University Hospital, between February 1, 2016 and March 31, 2025. Clinical data were retrospectively collected from electronic medical records. This study was approved by the Central Ethics Committee of Gifu University (Approval No. 2024-328).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were selected according to the RAFAELO study protocol. Eligible cases included those with a solitary tumor \u0026le; 1.5 cm in maximum diameter, as assessed by both ultrasonography and magnetic resonance imaging (MRI). All patients treated with RFA, including those in the feasibility study with trial excision, the RAFAELO study, the PO-RAFAELO study, and those treated under the national insurance system, were included in the analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiofrequency ablation procedure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCool-tip was used for all procedures. Ablation was performed according to the guidelines for the appropriate use of RFA in early-stage breast cancer. A radiofrequency electrode needle was inserted into the tumor under general anesthesia and ultrasound guidance. The output started at 5 W and was increased to 10 W after 1 min, and then further increased by 5 or 10 W every minute thereafter. No upper limit was set for the output. If the power limit of the device was reached, ablation was continued at that output level. As ablation progressed, electrical impedance increased. When impedance exceeded a threshold, the system automatically halted output, a phenomenon referred to as a \u0026ldquo;break\u0026rdquo; or \u0026ldquo;roll-off.\u0026rdquo; After the first break, the pump was stopped and the needle tip temperature was measured. If the ablation temperature was ＜70 ℃, the ablation was considered insufficient, and an additional ablation was performed at the same site. If multiple additional ablations still failed to reach 70 \u0026deg;C, a decision was made to continue or discontinue the procedure based on post-ablation imaging findings. To prevent thermal injury, 5% glucose solution was injected in both the retromammary space and subcutaneous tissue.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBreast density evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBreast density was assessed using mammograms obtained before treatment. Three board-certified radiologists independently evaluated the images using the Breast Imaging Reporting and Data System classification, which consists of four categories: Category A, almost entirely fatty; Category B, scattered areas of fibroglandular density; Category C, heterogeneously dense; and Category D, extremely dense [25]. Two radiologists performed the initial assessment, and in cases of discrepancy, a third radiologist\u0026mdash;who was the most experienced supervisor\u0026mdash;made the final judgment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGroup comparisons based on breast density were performed using Student\u0026rsquo;s t-test. A p-value of \u0026lt; 0.05 was considered statistically significant. The relationship between tumor size and other variables was analyzed using the Pearson correlation coefficient.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eRFA was performed on 50 breasts in 49 female patients. The mean age was 58.5 years, and the average body mass index was 23.7\u0026nbsp;kg/m\u0026sup2;. Among the 50 treated breasts, five were from the feasibility study with trial excision, one from the RAFAELO study, 21 from the PO-RAFAELO study, and 23 were treated under national insurance coverage. Regarding histological classification, 41 cases were invasive ductal carcinoma (IDC) and nine were ductal carcinoma in situ. Among the IDC subtypes, 39 were Luminal A and two were Luminal/HER2. Breast density was categorized as follows: Category A (n = 10), Category B (n = 19), Category C (n = 16), and Category D (n = 5) (Table and Fig. 1).\u003c/p\u003e\n\u003cp\u003eThe mean ablation temperature measured at the tip of the electrode after break was 81.0 \u0026plusmn; 8.0 \u0026deg;C (range: 68\u0026ndash;99 \u0026deg;C). By breast density category, mean temperatures were as follows: Category A: 76.4 \u0026deg;C, Category B: 81.3 \u0026deg;C, Category C: 82.7 \u0026deg;C, and Category D: 84.0 \u0026deg;C. Higher breast density was associated with higher ablation temperatures. In particular, the Category C and Category D groups showed significantly higher temperatures than did the Category A group (p = 0.037 and p = 0.031, respectively) (Fig. 2a). The mean ablation duration until break was 446 \u0026plusmn; 139 s (range: 210\u0026ndash;720 s). By breast density: Category A: 399 s, Category B: 441 s, Category C: 470 s, and Category D: 527 s. Although the difference was not statistically significant, ablation times tended to be longer in breasts with higher density (Fig. 2b).\u003c/p\u003e\n\u003cp\u003eImpedance values at the start and end of RFA were also analyzed. The mean initial impedance was 208 \u0026plusmn; 72.3 \u0026Omega; (range: 124\u0026ndash;402 \u0026Omega;). By breast density: Category A: 284 \u0026Omega;, Category B: 235 \u0026Omega;, Category C: 177 \u0026Omega;, and Category D: 147 \u0026Omega;. Higher fat content was significantly associated with higher initial impedance (Fig. 3a). The mean final impedance was 161 \u0026plusmn; 66.5 \u0026Omega; (range: 111\u0026ndash;398 \u0026Omega;). Final impedance by density group was as follows: Category A: 227 \u0026Omega;, Category B: 205 \u0026Omega;, Category C: 152 \u0026Omega;, and Category D: 129 \u0026Omega;. Similarly, final impedance was significantly higher in breasts with higher fat content (Fig. 3b). Finally, we examined the relationship between tumor size (as measured by ultrasonography and MRI) and ablation parameters. Neither peak ablation temperature nor ablation time showed a strong correlation with tumor size (Fig. 4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eRFA received insurance coverage approval in Japan in 2023 and is expected to become a leading minimally invasive local treatment for breast cancer. However, current evidence remains limited, and further investigations from various perspectives are warranted. Both patient-related factors and device-specific factors, such as the Cool-tip system, likely influence the efficiency and effectiveness of RFA. During our experience performing RFA for early-stage breast cancer, we noticed that ablation temperatures and times varied from case to case. This observation led us to investigate the potential relationship between breast density and RFA parameters.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePrior to the clinical application of RFA, several experimental studies examined its thermal effects \u003cem\u003ein vivo\u003c/em\u003e. Boehm et al. performed RFA on rabbit mammary tumors implanted in fatty tissue and suggested that differences in the thermal and electrical conductivity of mammary tissue influence heat propagation during RFA [26]. Similarly, Ahmed et al. demonstrated in uniform animal tumor models that the presence of blood flow reduced the ablation area, indicating that the vascularity and conductivity of surrounding tissues could affect RFA outcomes [27]. In breast tissue, which contains a high proportion of fat, additional complexities may arise. Adipose tissue generally has low thermal and electrical conductivity, potentially causing heat to concentrate within the tumor while limiting its spread to surrounding tissue. Therefore, although the tumor core may be adequately ablated, heat distribution near the tumor margins could be uneven in fatty breast tissue [28]. The Cool-tip system features ablation tips with either 2 or 3 cm active lengths. Complete ablation of the tumor core can generally be achieved when tumors are appropriately sized to fit within this range. Previous studies have consistently reported that tumors \u0026le; 2 cm in diameter can be effectively ablated, and the 1.5 cm tumor size criterion adopted in the RAFAELO trial is considered appropriate for safe and effective RFA [22]. In the present study, two patients exhibited relatively low ablation temperatures (68 \u0026deg;C and 69\u0026deg; C), both in breast densities classified as Category A or B. Positioning the Cool-tip needle to traverse the entire tumor suggests that the surrounding fat tissue\u0026nbsp;plausibly impacted both thermal diffusion and tissue impedance. Fortunately, both patients achieved complete ablation, as confirmed by biopsy six months post-procedure, with no local recurrence observed after a maximum follow-up of three years.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough we observed a correlation between breast density and peak ablation temperature in this study, abrupt temperature drops did not occur one centimeter above the ablation site, indicating sufficient ablation\u0026nbsp;of tumor interiors. In clinical practice, we monitor ablation in real time using ultrasonography to assess treatment progress. The lower RFA temperatures observed in fatty breasts may be attributed to higher tissue impedance and shorter ablation duration, as the Cool-tip needle, positioned within fat-rich tissue, leads to earlier termination of energy delivery (break) due to higher baseline impedance. The Cool-tip system triggers a break when impedance increases by 30 \u0026Omega; or 30% from the baseline value, whichever is greater. Thus, in fatty breast tissue, breakage may occur earlier\u0026nbsp;due to\u0026nbsp;inherently higher impedance, resulting in reduced energy delivery and consequently lower peak temperatures.\u0026nbsp;Our data showed no clear correlation between tumor size and ablation temperature or duration, suggesting that adherence to appropriate patient selection criteria (i.e., tumor size \u0026le; 1.5 cm) leads to consistently favorable RFA outcomes.\u003c/p\u003e\n\u003cp\u003eTo the best of our knowledge, this is the first study to report the relationship between breast density and RFA parameters in patients with early-stage breast cancer. However, this study has several limitations. First, this was a single-center study with a relatively small sample size. Second, breast density may not directly reflect the fat content of the tissue surrounding the tumor, which may vary across different regions of the breast. Third, we did not consider the potential influence of tissue perfusion (blood flow) on ablation outcomes. Fourth, the histopathological evaluation of ablation zones was not sufficiently performed after posttreatment radiotherapy. Given the recent approval of RFA for insurance coverage in Japan, its acceptance as a local treatment option for low-invasive breast cancer\u0026nbsp;is anticipated to increase. However, this study demonstrated that breast density may influence key ablation parameters\u0026nbsp;such as temperature and duration, which could ultimately affect treatment efficacy and cosmetic outcomes. Continued accumulation of clinical data is essential to establish stronger evidence and\u0026nbsp;further develop RFA as a Japan-originated treatment modality.\u003c/p\u003e\n\u003cp\u003eIn conclusion, we investigated the relationship between RFA and breast density in patients with early-stage breast cancer. In fatty breast tissue, ablation impedance was higher, peak temperatures were lower, and ablation duration tended to be shorter. These findings suggest that RFA should be performed with careful consideration of breast density, as fatty breast tissue may lead to a narrower ablation zone and potentially incomplete ablation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr. Uematsu T for his useful comments. We also thank Editage for English language editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMF contributed to the study conception and design. Material preparation, data collection, and data analysis were performed by MF, YNa, YT, YNi, AN, MO, YT, and JM. The first draft of the manuscript was written by MF, and all authors commented on previous versions. TK and NM supervised the study based on the data obtained. All authors read and approved the final version of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eMF\u0026mdash;remuneration: Chugai, Taiho, Nippon-Kayaku, Daiichi-Sankyo, AstraZeneca, Pfizer, Eli Lilly, Eisai. AN\u0026mdash;remuneration: Chugai, Eisai. JM\u0026mdash;remuneration: Chugai, Taiho, Pfizer, Eisai, Daiichi-Sankyo, AstraZeneca, Eli Lilly. TK\u0026mdash;remuneration: Chugai, Nippon-Kayaku, Pfizer, Exact Science, Daiichi-Sankyo, AstraZeneca, Intutive, Covidien. NM\u0026mdash;Grants: Asahi Kasei, Chugai, Covidien, Daiichi-Sankyo, Eisai, e-NA Biotec, EP-CRSU, JMS, Johnson \u0026amp; Johnson, Kaken Pharm, Kyowa Kirin, MSD, Nippon Kayaku, Ono, ShiftZero, Taiho, TERUMO, Toray Medical. remuneration: Abott, Alfresa, AMCO, Asahi Kasei, Astellas, AstraZeneca, Bayer, Bristol-Myers, Chugai, Covideien, Daiichi-Sankyo, EP Pharma, Eisai, Eli Lilly, Guardant Health Japan, Gunze Medical, Intutive, Johnson \u0026amp; Johnson, Kaken, Kyowa Kirin, MC Medical, MercK, MSD, Novartis, Olympus, Ono, Striker, Taiho, TAKATA, Takeda, TERUMO, Tsumura, Viartis, Yakult, ZERIA.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFormal consent was not required owing to the retrospective nature of the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFisher B, Anderson S, Bryant J, Margolese RG, Deutsch M, Fisher ER, et al. 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Jpn J Radiol. 2009; 27: 197-204.\u003c/li\u003e\n\u003cli\u003eBrkljacic B, Cikara L, Ivanac G, Pustahija AH, Zic R, Stanec Z. Ultrasound-guided bipolar rediofrequency ablation of breast cancer in operable patients: a pilot study. LUltraschall in Med. 2010; 31: 156-62.\u003c/li\u003e\n\u003cli\u003eYamamoto N, Fujimoto H, Nakamura R, Arai M, Yoshii A, Kaji S,. Pilot study of radiofrequency ablation therapy without surgical bexcision for T1 breast cancer: evaluation with MRI and vacuum-assisted core needle biopsy and safety management. Breast Cancer. 2011; 18: 3-9.\u003c/li\u003e\n\u003cli\u003eNoguchi M, Motoyoshi A, Earashi M, Fujii H. Long-term outcome of breast cancer patients treated with radiofrequency ablation. EJSO. 2012; 38: 1036-42.\u003c/li\u003e\n\u003cli\u003eYoshinaga Y, Enomoto Y, Fujimitsu R, Shimakura S, Nabeshima K, Iwasaki A. Image and pathological changes after adiofrequency ablation if invasive breast cancer: A pilot study of nonsirgical therapy of early breast cancer. World J Surg. 2013; 37: 356-63.\u003c/li\u003e\n\u003cli\u003eIto T, Oura S, Nagamine S, Takahashi M, Yamamoto N, Noboru Yamamichi N. Radiofrequency ablation of breast cancer: A retrospective study. Clin Breast Cancer. 2018; 18: e495-e500.\u003c/li\u003e\n\u003cli\u003eKinoshita T, Takayama S, Takahashi M, Fujisawa T, Yamamoto N, Shien T, et al. Radiofrequency ablation without excision for breast cancer: 5-year results of ipsilateral breast tumor recurrence-free survival in the RAFAELO study (NCCH1409). J Clin Oncol. 2024; 42.\u003c/li\u003e\n\u003cli\u003eMedtronic. Cool-tip\u0026trade; RFA system E series. 2025. https://www.medtronic.com/covidien/ja-jp/products/ablation-systems/cool-tip-rf-ablation-system-e-series.html\u003c/li\u003e\n\u003cli\u003eTakayama S, Kinoshita T, Shiino S, Jimbo K, Watanabe K, Fujisawa T, et al. Patients offer radiofrequency ablation therapy for early breast cancer as local therapy (PO-RAFAELO) study under the patient-proposed health services. JMA journal. 2023; 4: 505-12.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Orsi CJ, Sickles EA, Mendelson EB, Morris EA. Breast imaging reporting and data system (BI-RADS) Atlas 5th ed Reston, VA: American College of Radiology. 2013; 5th ed. .\u003c/li\u003e\n\u003cli\u003eBoehm T, Malich A, Reichenbach JR, Fleck M, Kaiser WA. Percutaneous radiofrequency (RF) thermal ablation of rabbit Tumors Embedded in Fat. Invest Radiol 2001; 36: 480-6.\u003c/li\u003e\n\u003cli\u003eAhmed M Liu Z, Afzal KS, Weeks D, Lobo SM, Kruskal JB,. Radiofrequency ablation: Effect of surrounding tissue composition on coagulation necrosis in a canine tumor model. Radiology. 2004; 230: 761-7.\u003c/li\u003e\n\u003cli\u003eLiu MC, Ahmed M, Weinstein Y, Yi M, Mahajan, RL, Goldberg. SN. Characterization of the RF ablation-induced \u0026lsquo;oveneffect: The importance of background tissue thermal conductivity on tissue heating. International Journal of Hyperthermia. 2006; 22: 327-42.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Radiofrequency ablation (RFA), Early breast cancer, Breast density, Thermal conductivity ","lastPublishedDoi":"10.21203/rs.3.rs-6712914/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6712914/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRadiofrequency ablation (RFA) is a minimally invasive technique used to treat small breast tumors by delivering high-frequency current through a needle electrode under ultrasound guidance. In Japan, RFA became insurance-covered in 2023 as a local treatment for early-stage breast cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe retrospectively analyzed data from patients who underwent RFA at our institution between February 2016 and March 2025. Breast density was classified into four categories based on the Breast Imaging Reporting and Data System. Associations between breast density and RFA parameters, including ablation temperature, duration, and impedance, were evaluated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRFA was performed on 50 breasts in 49 female patients. The mean peak ablation temperature after break was 81.0 ± 8.0 °C. A higher breast density was significantly associated with higher temperature. The mean ablation time until break was 446 ± 139 s, with a trend toward longer durations in denser breasts. The mean initial and final impedance values were 208 ± 72.3 Ω and 161 ± 66.5 Ω, respectively. Fat-rich breasts exhibited significantly higher impedance at both time points.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFatty breast tissue was associated with higher impedance, lower peak temperatures, and shorter ablation times, potentially resulting in insufficient ablation. Breast density should be considered when planning RFA to ensure effective treatment.\u003c/p\u003e","manuscriptTitle":"Impact of breast density on the efficacy of radiofrequency ablation in early-stage breast cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 18:23:25","doi":"10.21203/rs.3.rs-6712914/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2025-06-29T01:59:33+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-06-07T04:24:11+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-05T11:19:50+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-21T10:04:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer","date":"2025-05-21T01:59:22+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"ab06b40c-f6cc-4e52-a2ae-32ded8748ea7","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-29T16:01:45+00:00","versionOfRecord":{"articleIdentity":"rs-6712914","link":"https://doi.org/10.1007/s12282-025-01775-7","journal":{"identity":"breast-cancer","isVorOnly":false,"title":"Breast Cancer"},"publishedOn":"2025-09-22 15:57:59","publishedOnDateReadable":"September 22nd, 2025"},"versionCreatedAt":"2025-06-10 18:23:25","video":"","vorDoi":"10.1007/s12282-025-01775-7","vorDoiUrl":"https://doi.org/10.1007/s12282-025-01775-7","workflowStages":[]},"version":"v1","identity":"rs-6712914","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6712914","identity":"rs-6712914","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}