Repurposing statins in combination therapy for effective ablation of metastatic breast cancer

Image-Guided Ablation in Breast Cancer Treatment

Background: Screening mammography makes it possible to identify small size of breast cancer (BC) and minimize surgical management. Previously we reported about a multi-center cohort study on radiofrequency ablation (RFA) in early breast cancer (ASCO2012 #1119). Although various devices and ablation procedure were attempted, 5-year’s recurrence-free survival of ipsilateral breast tumor was 96% in 425 cases of T1BC treated with RFA alone (the mean follow-up, 50 months). To validate complete pathological ablation in BC, we started a non-randomized phase II study in 2013 (UMIN000013836). Eligibility criteria: Unilateral BC patients with stage 0 (TisN0M0) or I (T1N0M0 or T1N1miM0) are eligible. Written informed consent is obtained. Tumor diameter of 2cm or less should be diagnosed by ultrasound and MR mammography. BC with diffuse calcification, extensive intraductal components, or multiple tumors is excluded. Methods: RFA is performed by Cool-tip RF ablation system (Covidien, USA). The needle electrode is inserted into the center of referent tumor under ultrasound guidance. The first ablation is started at an initial electrical power level of 5W for 1 min and the power is increased at 10W for 1 min. After then, it is increased in steps of 10W from every minute until rapid elevation of tissue impedance. The second ablation is allowed by physician’s discretion. One month later, ablated tissue is collected by core needle biopsy or vacuum-assisted breast biopsy. Cell viability is examined by central review of independent pathologists using tumor specimens stained with hematoxylin–eosin and nicotinamide adenine dinucleotide (NADH) diaphorase. In case of complete ablation, breast irradiation and adjuvant therapy will be performed. In case of incomplete ablation, partial mastectomy should be recommended. Aims: The primary endpoint is complete ablation rate. The secondary endpoints are deformity after RFA, relapse-free survival and overall survival for 10 years. Two-step design is used for statistical evaluation. Finally, 32 patients will be needed. Present accrual: As of April 2014, 16 patients were enrolled. One patient was ineligible because of macrometastasis in a sentinel node. Of 13 eligible patients who underwent pathological examination, one patient had viable cancer cells with NADH diaphorase staining. We also investigate optimal histological examination of cell viability and adequate image diagnosis after RFA. Citation Format: Shigeru Imoto, Shinji Nagamine, Shunichi Ito, Hitoshi Tsuda, Masayuki Yoshida, Mitsuhiro Tozaki, Satoshi Morita, Takayuki Ueno. Phase II study on radiofrequency ablation in stage 0 and I breast cancer without extensive intraductal components [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-3-01.

e12094 Background: We reported about a multi-center registration study on radiofrequency ablation (RFA) in early breast cancer (BC) (ASCO2012 #1119). Although various devices and ablation procedure were used, 5-year’s recurrence-free survival was 96% in 425 cases of T1BC treated with RFA alone. To validate complete pathological ablation in BC, we started a non-randomized phase II study in 2013 (UMIN000013836). Methods: Unilateral BC patients with stage 0 (TisN0M0) or I (T1N0M0 or T1N1miM0) were eligible. Tumor diameter of 2cm or less should be diagnosed by ultrasound and MR mammography. RFA was performed by Cool-tip RF ablation system (Covidien, USA). One month later, ablated tissue was collected by core needle biopsy or vacuum-assisted breast biopsy. Cell viability was determined by central review of independent pathologists using tumor specimens stained with hematoxylin–eosin and nicotinamide adenine dinucleotide (NADH) diaphorase. In case of complete ablation, breast irradiation and adjuvant therapy was planned. In case of incomplete ablation, partial mastectomy was recommended. The primary endpoint is complete ablation rate. The secondary endpoints are breast deformity after RFA, relapse-free survival and overall survival for 10 years. Two-step design consisting of 9 cases at 1st step and 20 cases at 2nd step was used for statistical evaluation. We expected complete ablation rate of 95% and 29 cases were needed to reject the null hypothesis that complete ablation rate would be less than 80% at lower threshold. Thus, 32 cases were required. Results: Thirty-six patients were enrolled between February 2013 and May 2016. The mean tumor size was 1.3 cm measured by MR mammography. Two patients were ineligible because of macrometastasis in a sentinel node. Of 34 eligible patients, one patient had viable cancer cells with NADH diaphorase staining in ablated specimens. Finally, complete ablation rate was 97%. As of January 2017, one patient, who refused adjuvant therapy and breast irradiation, had in-breast tumor recurrence adjacent to previously ablated lesion. Conclusions: Long-term follow-up should be needed, but RFA in early BC is a promising strategy instead of breast-conserving surgery. Clinical trial information: UMIN000013836.

Increased infiltration of activated tumor-infiltrating lymphocytes after high intensity focused ultrasound ablation of human breast cancer

Background: Over the past decades, breast cancer treatment has evolved from extensive disfiguring surgery to less invasive procedures. In patients with small localized tumors breast conserving therapy (BCT) has become the standard of care. However, surgery still involves risks associated with general anesthesia and complications such as bleeding, infection and suboptimal cosmetic results. Conversely, Magnetic Resonance-guided High intensity Focused Ultrasound (MR-HIFU) ablation of breast cancer is an entirely non-invasive procedure that can be performed under procedural sedation and analgesia (PSA). With MR-HIFU, a focused ultrasound beam penetrates through soft tissues and causes localized heating (55-70°C) of a target. Magnetic resonance imaging (MRI) is used for target-identification and real-time temperature-monitoring (MR thermometry). In a previous phase I study in ten breast cancer patients, tumors were deliberately partially ablated and safety and accuracy of a dedicated MR-HIFU breast system (Profound Medical) was shown.1,2 This system’s lateral sonication approach and wide aperture reduce the risk of heating heart, lungs and skin to a minimum.3 In the current study we aim to demonstrate that complete breast tumor ablation with MR-HIFU is feasible. Trial design: Single-arm phase II study in patients with primary breast cancer. We will use a dedicated MR-HIFU breast system (Profound Medical) to ablate breast tumors before BCT or mastectomy, in a treat-and-resect protocol. We will perform MRI before MR-HIFU, during the MR HIFU session and one week after to evaluate radiologic response. Primary endpoint is efficacy, assessed by percentages of necrotic and residual viable tumor. Secondary endpoint is safety, assessed by adverse events and cosmetic changes. Descriptive statistics will be used. Eligibility criteria Non-pregnant, non-lactating women ≥18 years of age, weighing < 90 kg, who have: histologically proven invasive breast cancer, cT1-2 N0-2 Mx, subtypes invasive ductal carcinoma or invasive carcinoma ‘not otherwise specified’ / ‘no special type’ a tumor in reach of the HIFU beams, diameter ≤ 3.0 cm and distance ≥1.5 cm to skin, nipple and pectoral wall WHO-Performance Score ≤2 a body size fitting in the MR bore and the ability to lie in prone position no prior treatment with neoadjuvant chemotherapy in the past 3 months no prior radiotherapy, thermal therapy or surgery in the targeted breast no contraindications to PSA, MRI or MRI contrast agents no conditions that may interfere with MR-HIFU such as a pacemaker, scar tissue, breast prosthesis or surgical clips no extensive intraductal components, determined on biopsy Additionally, patients may be excluded when the risk of adjuvant over- or undertreatment (due to performing Bloom and Richardson grading on the tumor biopsy) is considered too high. Target accrual 10 patients (present: 0, IRB approval obtained) Conclusion In this phase II trial we aim to show the feasibility of complete tumor ablation of breast cancer with a dedicated MR-HIFU breast system. This approach could lead to a non-invasive treatment alternative for selected patients with primary breast cancer. References 1Merckel 2016, Eur Radiol; 2Deckers 2015, Phys Med Biol; 3Merckel 2013, Cardiovasc Intervent Radiol; Acknowledgements Financial support of Center for Translational Molecular Medicine and Vrienden UMC Utrecht. Profound Medical provides non-financial support. Contact information Josanne de Maar, j.s.demaar@umcutrecht.nl ClinicalTrials.gov Identifier: NCT02407613 Citation Format: Josanne Sophia de Maar, Roel Deckers, Lambertus Wilhelmus Bartels, Thijs van Dalen, Joost van Gorp, Paul J van Diest, Arjen J Witkamp, H. H.B. Vaessen, Maria NicoleGerardineJohanna Aleida Braat, Chrit Moonen. Efficacy of magnetic resonance-guided high intensity focused ultrasound for the ablation of breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-07-01.

<Purpose> To evaluate therapeutic efficacy of percutaneous ultrasound (US) guided radiofrequency (RF) ablation therapy for primary breast cancer using contrast-enhanced US. <Methods and Materials> The study was approved by the institutional ethics committee, and written informed consent was obtained. Between January 2012 and April 2014, 25 patients with biopsy-confirmed T1 breast cancer underwent RF ablation therapy in one institution. We examined 25 patients with 25 T1 breast cancers by contrast-enhanced MRI/CT, and contrast-enhanced US before and after RF ablation therapy. US guided RF abltion was performed using a 17-gauge internally cooled electrode (Cool-TipTM, Valleylab, Boulder, CO, USA) under general anesthesia. After injection 0.015mL/kg body weight of Sonazoid®(perflubutane), contrast-enhanced US was performed at a low mechanical index (0.17-0.24). Therapeutic success was defined as a lack of contrast enhancement by contrast-enhanced MRI, US and non-viable cancer tissues by US guided vacuum assisted biopsy (VAB) or core needle biopsy (CNB). <Results> Contrast-enhanced US and MRI four weeks or more after RF ablation therapy showed ablation zones and adequate tumor necrosis in all 25 cancer lesions treated. Contrast-enhanced US made it possible to see that tumor vessels of treated lesions had disappeared after treatment. Contrast enhanced MRI showed a lack of stain with ring-like enhancement of ablation zone and non-viable tissues were seen by VAB and/or CNB in 25 ablation zones. <Conclusion> Contrast-enhanced US using Sonazoid® was useful modalities for evaluating the efficacy of RF ablation therapy in breast cancer lesions. Citation Format: Toshikazu Ito, Jyunji Okayama, Kumiko Uji, Masaaki Izukura. Contrast-enhanced ultrasound for evaluation of therapeutic efficacy of radiofrequency ablation for primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-02-07.

Optimizing the treatment of breast cancer remains a major topic of interest. In current clinical practice, breast-conserving therapy is the standard of care for patients with localized breast cancer. Technological developments have fueled interest in less invasive breast cancer treatment. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a completely noninvasive ablation technique. Focused beams of ultrasound are used for ablation of the target lesion without disrupting the skin and subcutaneous tissues in the beam path. MRI is an excellent imaging method for tumor targeting, treatment monitoring, and evaluation of treatment results. The combination of HIFU and MR imaging offers an opportunity for image-guided ablation of breast cancer. Previous studies of MR-HIFU in breast cancer patients reported a limited efficacy, which hampered the clinical translation of this technique. These prior studies were performed without an MR-HIFU system specifically developed for breast cancer treatment. In this article, a novel and dedicated MR-HIFU breast platform is presented. This system has been designed for safe and effective MR-HIFU ablation of breast cancer. Furthermore, both clinical and technical challenges are discussed, which have to be solved before MR-HIFU ablation of breast cancer can be implemented in routine clinical practice.

Background: NRG-BR002 randomized patients with OMBC to SOC with vs. without ablation (surgery or radiation) of all visible metastases. The phase II PFS go signal for improvement with ablation was not met. Blood for CTCs was collected from consenting patients and sent for the FDA-approved CellSearch CTC assay and High-Definition Single Cell CTC Analysis (HDSCA). The primary CTC objective was that pretreatment CTCs (PreRX CTCs) would be prognostic for PFS. Secondary objectives included baseline CTCs being predictive for the effect of RX on PFS and CTC post-treatment clearance rate correlating with PFS. Statistical Design and Methods: A secondary endpoint analysis of the prognostic effect of PreRX CTCs on PFS and the interaction between study arm and the PreRX CTCs on PFS were evaluated for both assays using multivariable Cox proportional hazards models (MVA). CellSearch CTCs were dichotomized 0 vs. ≥ 1 and HDSCA CTCs were assessed by < vs. ≥ lowest quartile (Q1). Due to small numbers of CTC+ cases, CTC clearance correlation with PFS was not able to be tested. Descriptive results are presented. Results: Of 125 phase II eligible patients, 108 (86%) consented to blood collection. Among the cohort with CTC data (n=62 for CellSearch, n=60 for HDSCA), demographic and treatment variables were balanced between study arms and similar to the trial population. Thirty-six (58%) and 26 (42%) had CellSearch CTC = 0 and ≥1, respectively. Fifteen (25%) and 45 (75%) had HDSCA CTCs < Q1 and ≥ Q1, respectively. Median follow up at the time of analysis was 48 months. PreRX CTCs (CellSearch and HDSCA) were not prognostic for PFS. In each of the analyses for PreRX CTC (0 or < Q1) being predictive for PFS, after adjusting for number of metastases (1 v >1), the interaction between study arm and CTCs had a HR > 3, reaching statistical significance for HDSCA (p=0.024; HR 5.58, 95% CI: 1.26, 24.77) and trending towards statistical significance for CellSearch (p=0.063; HR 3.39, 95% CI: 0.94, 12.25). Patients in the ablation arm, with HDSCA PreRX CTCs < Q1, experienced better PFS than those with PreRX CTCs ≥ Q1; 78% vs. 33% at 2 years, respectively, as compared to patients on the control arm (17% vs. 55%). Patients in the ablation arm, with CellSearch PreRX CTCs = 0, also experienced better PFS than those with PreRX CTCs ≥ 1; 54% vs. 27% at 2 years, respectively, as compared to patients on the control arm (35% vs. 61%). For CellSearch only, 19/62 patients (9 SOC and 10 ablation) had positive PreRX and PostRX CTC values. In the SOC arm, clearance of CTCs was seen in 6 patients (all progression-free) and no clearance in 3 (2 progressed/1 died). In the ablation arm, clearance (n=5)/decrease (n=2) of CTCs was seen in 7 patients; however, only 3 remained progression-free; and an increase was seen in 3 patients whose disease progressed. For the 9 patients across both arms with PreRX and PostRX CTCs that progressed, all 9 developed new metastatic sites. Conclusion: Lower PreRX CTCs predicted for improved PFS after ablation using the HDSCA assay. The pre-specified CTC analyses provide consistent results using two independent assays highlighting the robustness of the finding. These hypothesis-generating findings suggest that PFS is improved in CTC negative OMBC patients who are treated with ablation. This project was supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), BCRF-23-089, U01CA285013 (LBRL), and U24CA180803 (IROC) from the National Cancer Institute (NCI). Citation Format: Wendy Woodward, Jennifer Moughan, Steven Chmura, Peter Kuhn, Anthony Lucci, Virginia F Borges, Joseph K Salama, Hania Al-Hallaq, Martha M Matuszak, Michael T Milano, Nora Jaskowiak, Stephanie N Shishido, Jeremy Mason, Salyna Meas, Carol Hall, Sachin R Jhawar, Robert A Nordal, Gregory N Gan, Diane C Ling, Imran Zoberi, Sobha Kurian, Kathryn Winter, Eleftherios P Mamounas, , Julia R White. Baseline circulating tumor cells (CTCs) predict for progression-free survival (PFS) after ablation on NRG-BR002, a randomized phase II/III study of ablation vs. standard systemic therapy care (SOC) for oligometastatic breast cancer (OMBC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-01-21.

Radiofrequency ablation (RFA) is an emerging minimally invasive technique for breast cancer treatment. There are two different needle designs. One is to deploy a series of arrays to allow an even distribution of heat within the tumor. A new design is a straight needle with continuous infusion of cold saline to prevent charring and ensure continuous heat delivery. We report the first comparative study using two different needles for ablation of breast cancer. Chinese patients with breast cancer less than 2cm were prospectively recruited. Multifocal tumor was excluded. RFA was performed under general anesthesia following sentinel node biopsy. Sequential allocation was used. In the first group, tumor was ablated by using the LeVeen needle. Cool-tip needle was used in the subsequent group. The tumor was then resected. Tumor viability was assessed by nicotinamide adenine dinucleotide-diaphorase (NADH) staining. Complete ablation rate was compared. Evidence of thermal damage to the skin was also assessed. Twenty patients were recruited. Mean tumor size was 14mm. Complete ablation rate was the same (90% versus 89% for the Cool-tip and the LeVeen, respectively). Cool-tip has a shorter ablation time when compared with LeVeen (12 versus 28min), and the Cool-tip needle was found to be easier to insert. There was no visible skin burn after RFA. Cool-tip and LeVeen systems had the same efficacy in ablation of breast cancer, but Cool-tip was easier to insert and had a shorter ablation time.

Activation of Tumor-Infiltrating Antigen Presenting Cells by High Intensity Focused Ultrasound Ablation of Human Breast Cancer

Background: Radiofrequency ablation (RFA) for early-stage breast cancer with tumors ≤15 mm in diameter was approved for coverage under Japan’s national health insurance in December 2023, following favorable results from several clinical trials. Clinical RFA procedures commenced at our institution in May 2024. Small early-stage breast cancers—especially non-mass lesions—are often difficult to visualize or delineate using conventional B-mode ultrasound (US) alone. Additionally, gas formation during RFA may obscure the lesion, complicating precise localization for additional ablation. This study aimed to evaluate the clinical utility of fusion imaging combining contrast-enhanced breast magnetic resonance imaging (MRI) with US and/or contrast-enhanced US (CEUS) to improve lesion targeting and procedural accuracy during RFA. Patients and Methods: Fourteen patients with early-stage breast cancer underwent RFA guided by fusion imaging. A volume navigation system (LOGIQ E10x, GE Healthcare) was used to fuse dynamic contrast-enhanced MRI with US, aligning anatomical landmarks such as the nipple to ensure accurate lesion localization. CEUS using Sonazoid® was performed to evaluate intratumoral microvascularity. A Cool-tip needle (Medtronic, CO, USA) was inserted with a planned 1-cm safety margin around the tumor. Intratumoral impedance was measured upon insertion, and 10-20 mL of 5% glucose was injected into the retromammary space to prevent heat diffusion. Ablation was initiated at 5 W and continued until automatic roll-off occurred, due to increasing impedance. Therapeutic efficacy was assessed ≥4 weeks post-procedure using follow-up imaging and ultrasound-guided vacuum-assisted biopsy (US-VAB) of the ablation zone. Results: Patient ages ranged from 34 to 82 years (mean: 57 years), with tumor sizes from 7 to 15 mm (mean: 12.4 mm). Histopathologic findings included ductal carcinoma in situ (DCIS; n=8) and invasive ductal carcinoma (IDC; n=6). Molecular subtypes included Luminal A-like (n=4) and Luminal B-like (n=2). Tumors were located in the upper outer quadrant (n=8), upper inner quadrant (n=2), lower outer quadrant (n=2), and deep medial or axillary tail regions (n=1 each). Fusion imaging significantly improved visualization and delineation of lesions that were challenging to identify with B-mode US alone. It also enabled accurate re-localization of the original lesion during additional ablation sessions, resulting in successful complete ablation in all cases. Initial impedance ranged from 116 to 245 Ω (mean: 169 Ω), maximum ablation temperature from 83°C to 100°C (mean: 93°C), and ablation time from 14 to 32 minutes (mean: 20 minutes). One case of postoperative nipple retraction was observed; no other major complications occurred. No viable cancer cells were detected in any US-VAB specimens. Conclusion: Fusion imaging combining contrast-enhanced MRI with US/CEUS enhances the precision, safety, and efficacy of RFA for early-stage breast cancer, particularly for lesions that are poorly visualized on conventional US. Further accumulation of clinical cases is needed to standardize fusion imaging protocols and optimize outcomes. Citation Format: C. YAMANAKA, S. MATSUZAKI, Y. HAYAKAWA, H. MANABE, M. KUBOTA, T. ITO, Y. KOMOIKE. Evaluation of fusion imaging guidance in radiofrequency ablation for early-stage breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-05-07.

Minimally invasive treatments for early breast cancer have been reported. The objective of this study was to evaluate and compare two such treatments, laser ablation and photodynamic therapy (PDT), regarding their therapeutic efficacy for breast cancer. Breast tumors were induced in 12 mice models. The treatment options were classified into four groups: control group (without any treatment, A), group treated only with laser ablation (B), group treated only with PDT (C), and group treated with the combination of laser ablation followed by PDT (D). The treatment effects were compared among these groups. Among the groups, the group D underwent the most effective treatment for breast cancer. Not only were the breast cancer cells necrotized by laser ablation, but the tumor margin was also managed by PDT. The treatment method combining laser ablation and PDT showed superior results to single treatment techniques using just one of these approaches.

Radiofrequency Ablation Therapy for Small Breast Cancer

At present, no clinical guidelines have been established regarding the use of radiofrequency ablation (RFA) for early stage breast cancer. The Radiofrequency Ablation Therapy for Early Breast Cancer as Local Therapy (RAFAELO) study aimed to assess the efficacy and safety of RFA as an alternative to partial mastectomy in patients with early stage breast cancer. This study was a multicenter, single-arm, phase 3 study. Female patients with a single breast cancer classified as Tis-T1 (tumor size ≤1.5 cm), N0M0 Stage 0-I underwent treatment RFA. All patients then received radiation therapy totaling 45-60 Gy. The primary endpoint was the 5-year ipsilateral breast tumor recurrence-free survival (IBTRFS) rate. The threshold for a clinically unacceptable 5-year IBTRFS rate was set at 90% with a one-sided alpha of 5%. A total of 370 patients underwent RFA and 353 patients (median [IQR] age, 55 [47-65] years) completed the 5-year follow-up. For the primary endpoint, the IBTRFS rate at 5 years was 98.6% (90% CI 97.1-99.3%, 95% CI 96.6-99.4%). The lower limit of the 90% CI was greater than the threshold of 90%, suggesting the noninferiority of RFA to historical control partial mastectomy. During the study, two recurrences were observed in the ipsilateral breast. Skin ulceration grade ≥3 was observed in just one of the 370 patients. RFA was shown to be a safe and minimally invasive treatment for early stage breast cancer, comparable in efficacy to partial mastectomy.

Image-guided focussed ultrasound (FUS) ablation is a non-invasive procedure that has been used for treatment of benign or malignant breast tumours. Image-guidance during ablation is achieved either by using real-time ultrasound (US) or magnetic resonance imaging (MRI). The past decade phase I studies have proven MRI-guided and US-guided FUS ablation of breast cancer to be technically feasible and safe. We provide an overview of studies assessing the efficacy of FUS for breast tumour ablation as measured by percentages of complete tumour necrosis. Successful ablation ranged from 20% to 100%, depending on FUS system type, imaging technique, ablation protocol, and patient selection. Specific issues related to FUS ablation of breast cancer, such as increased treatment time for larger tumours, size of ablation margins, methods used for margin assessment and residual tumour detection after FUS ablation, and impact of FUS ablation on sentinel node procedure are presented. Finally, potential future applications of FUS for breast cancer treatment such as FUS-induced anti-tumour immune response, FUS-mediated gene transfer, and enhanced drug delivery are discussed. Currently, breast-conserving surgery remains the gold standard for breast cancer treatment.