Cryoablation for Breast Cancer – Evidence to date

Cryoablation, the use of extreme cold to destroy tumors by freezing, is emerging as an innovative treatment for breast cancer.*  Breast cancer is a disease that impacts approximately one in eight women in their lifetime. Current standards of breast cancer treatment can involve surgery, radiation, chemotherapy, hormone therapy, and targeted therapy. 

As a minimally invasive treatment compared to surgery, during a cryoablation procedure a thin needle-like cryoprobe is inserted into a tumor under imaging guidance. The cryoprobe creates an ultra-cold and lethal ice ball around the target tissue. It is an alternative treatment approach that has been applied to the treatment of cancer since the mid-19th century. Cryoablation has growing and well-documented efficacy in the treatment of kidney cancer, lung cancer, and bone cancer. 

Approved for use in Europe and several other countries, cryoablation for breast cancer has been used for over two decades. It is considered a well-tolerated outpatient procedure. 

In the United States, cryoablation for breast cancer is currently being investigated in several landmark clinical studies. While FDA clearance exists for cryoablation of various benign and malignant tumors, including fibroadenoma (benign breast tumor), there is yet to be a specific FDA indication for the treatment of breast cancer. 

In this article, we will share some of the latest evidence available for the use of cryoablation in breast cancer treatment. 

Use of Cryoablation for Breast Cancer

The trend in surgical treatment for benign and malignant breast tumors is toward less-invasive techniques. Total mastectomy is still performed in some patients. However, breast-conserving surgery followed by radiation therapy has been established as an oncologically safe approach for patients with early breast cancer. Multidisciplinary treatment, including systemic therapy, has also contributed to the trend toward minimally invasive local treatment.

The most common application of cryoablation is to ablate solid tumors found in the lung, liver, breast, kidney, and prostate. Cryoablation is considered a safe and effective procedure with advantages over alternative treatment including:

• Minimal scarring as only a small incision is made and usually only closed with a steri-strip.
• Size and shape of the breast are maintained.
• Can be performed in an office-based setting under local anesthesia without the need for hospitalization or general anesthesia, a great benefit for patients at high risk for surgery.
• Lower cost secondary to an office-based setting versus an operating room and overnight hospital stays.
• Anesthetic effect of cold augments the local anesthesia.
• Possibility to treat multiple lesions in the same session
• Repeatable procedure in case of local relapse or incomplete ablation.
• Acts in synergy with adjuvant and systemic therapies, i.e., chemotherapy, radiation, hormone therapy, immunotherapy
• Can create a cryo-immune response via tumor lysates and be considered a weak form of in situ cancer vaccination.
• High local control

Growing Experience Treating Fibroadenomas with Cryoablation

Cryoablation for the treatment of fibroadenomas is becoming a well-established procedure and has received FDA and CE clearance

Approximately 500,000 women today undergo surgical resection of FAs each year. Treatment results include a ~ 90% volume reduction with more than 80% of fibroadenomas non-palpable a year after treatment. (1,2,3)

Typical fibroadenoma (FA) changes following cryoablation

Fig 1. Ultrasound image of FA (arrow) pre- and 6, 12, 18, and 36 months post-cryoablation. Sheth, M., Lodhi, U., Chen, B., Park, Y., & McElligott, S. (2019). Initial Institutional Experience With Cryoablation Therapy for Breast Fibroadenomas: Technique, Molecular Science, and Post‐Therapy Imaging Follow‐up. Journal of Ultrasound in Medicine, 38(10), 2769-2776.

The American Society of Breast Surgeons (ASBrS) Oct. 2018 Guidelines found cryoablation of fibroadenomas to be similar in efficacy and safety to open surgical excision. According to the guidelines of ASBrS, lesions less than 4 cm in largest diameter can be treated with cryoablation.

IceCure’s liquid nitrogen cryoablation system, ProSense™, has been used for treating fibroadenomas successfully since 2012.

Cryoablation for Breast Cancer: Clinical Trials

There is increasing interest among breast surgeons, breast radiologists, and interventional radiologists in the use of cryoablation for breast cancer. The number of clinical publications and studies on this topic continues to grow. Several landmark studies have helped to pave the way for clinical trials for cryoablation of early stage, low-risk breast cancer. Each study has built upon the existing body of scientific evidence supporting the efficacy of cryoablation for breast cancer.

ACOSOG trial (2008) (completed in 2013)

The ACOSOG multicenter phase II clinical trial showed cryoablation was highly effective for treating tumors <1 cm. In this study, patients underwent surgical resection of the primary tumor within 28 days of the cryoablation. Results showed that when multifocal disease outside of the targeted cryoablation zone was not defined as ablation failure, 92% of the lesions were completely ablated (100% of the lesions <1 cm; 8% Ipsilateral breast tumor recurrence (IBTR). 

FROST – Freezing Instead of Removal of Small Tumors (2013) (Unknown Status)

The FROST trial aimed to investigate the use of cryoablation in place of surgical excision for patients aged 50 and above with early stage, invasive breast cancer. Criteria for Inclusion in the FROST trial were a primary invasive breast carcinoma ≤1.5 cm in diameter, hormone receptor-positive, Her2 negative, with <25% intraductal component. The primary goal was to evaluate successful tumor ablation, defined as absence of residual viable invasive or in situ carcinoma at 6-months post-cryoablation biopsy. Patients underwent US-guided cryoablation followed by adjuvant hormonal therapy and serial imaging exams. 

ICE3 trial (2014 – Completed in 2024)

The ICE3 trial was the largest multi-center clinical trial investigating the safety and efficacy of liquid-nitrogen- based cryoablation system for up to 1.5 cm (about 0.59 in), low-risk, early-stage malignant breast tumors without subsequent excision.The ICE3 trial was designed to explore the potential for cryoablation to safely and effectively treat women aged 60 and over with early-stage breast cancer, allowing them to avoid the associated risks of surgery, such as the need for general anesthesia, infection, and risk of re-excision. 

Patients, at 19 different U.S. medical centers, were treated with a cryoablation freeze-thaw-freeze cycle for 9, 8, 9 minutes, respectively, using the ProSense™ Cryoablation System.   

After five years of follow-up, among the 124 patients who received only endocrine hormone therapy post-cryoablation, 96.3% of the women remained free from breast cancer (IBTR rate of 3.7%). This rate is comparable with the recurrence rates observed in studies of surgical excision followed by adjuvant therapy.   

In the final analysis of the 5-year study, no significant adverse effects or complications were reported.  In terms of quality of life, patients experienced significant improvements. Their distress levels were reduced at six months compared to baseline. Both patients and physicians reported 100% satisfaction with the cosmetic results, at the five-year assessment. 

fig 2. ICE3 case report #3: After 8 months necrotic tissue completely covering lesion

Investigator Initiated Studies Exploring Breast Cancer Cryoablation

A number of articles and abstracts have been published that explore the suitability for cryoablation in patients that fall outside the ICE3 inclusion criteria. These publications suggest that there might be an even wider role for cryoablation in breast cancer treatment in the future.  

Acceptance and results of cryoablation for the treatment of early breast cancer in non-surgical patients – Grana-Lopez et al (2024)  

Recently published in the British Journal of Radiology, this study evaluated the acceptance and efficacy of percutaneous cryoablation for patients with early-stage breast cancer, who opted out of surgery. Conducted between 2020 and 2023, the study reviewed 66 tumors in 63 non-surgical patients with a median age of 88. The treatment’s intention was curative in tumors up to 25mm and local control in larger tumors. Of the 45 patients offered cryoablation, 95.6% accepted. No major complications were seen. Complete tumor necrosis with no residual disease was observed in 81.3% of cases followed for at least 6 months.  For Luminal tumors ≤ 25 mm (treated with curative intention), the complete ablation rate was 100%, after a median follow-up of 16 months. 

The findings suggest that most patients with early breast cancer who choose not to have surgery will accept cryoablation. It also suggests that cryoablation is a safe and effective alternative for managing early-stage breast cancer in patients who opt out of surgery. The procedure was well-tolerated, with excellent outcomes in local control, particularly for small Luminal tumors. These results indicate that ,cryoablation could offer a valuable option for this patient group, providing effective cancer control while avoiding the risks of surgery. 

Cryoablation of Primary Breast Cancer in Patients Ineligible for Clinical Trials: A Multi-institutional Study – Oueidat el al (2024) 

Published in the American Journal of Roentgenology, this study assessed cryoablation in breast cancer patients who were ineligible for prospective cryoablation clinical trials, such as FROST or ICE3. Patients may have been excluded due to unfavorable tumor or patient characteristics (e.g. age <50 years, tumor size >1.5 cm). Involving 112 women with unifocal breast cancer (with a median age of 71 years), the study demonstrated a high technical success rate of 98.2%. Cryoablation was found to be safe, with only minor adverse events reported. During a median 2-year follow-up, 6.36% of patients experienced true ipsilateral breast tumor recurrence (IBTR). The procedure was particularly effective for localized control, providing a minimally invasive alternative for patients who are poor surgical candidates.  

CT-Guided Percutaneous Cryoablation of Breast Cancer: A Single-Center Experience – Vogl et al (2024) 

This independent study was conducted by Professor Thomas J. Vogl in Germany and published in the leading journal “Cancers.’ The study was a retrospective evaluation of the safety and efficacy of liquid-nitrogen based CT-guided cryoablation for breast cancer patients. Patients who had previously undergone other types of treatment and experienced recurrence or patients with metastasis were included in the study.  

Patients were treated in outpatient settings with curative intention for non-metastatic patients, while patients with metastases were treated to achieve local tumor control. The patient population (n=45, with 56 tumors) with a mean age of 55.6 ± 12.5 years (range, 31.3–86.0 years) was very heterogeneous. Eleven study patients had recurrent breast tumors, and 21 patients had metastatic disease. Ten of the tumors were above 2 cm in diameter and 46 were equal to or less than 2 cm in diameter (82.1%). Patients were observed at 3, 6, 9, and 12 months, and biannually thereafter. There were four cases of local tumor progression, representing a rate of 8.9%. No complications were observed in any of the 56 ablations and initial complete ablation was achieved in 100% of cases. There were four cases of local tumor progression, representing a rate of 8.9%. 

The study concluded that cryoablation is a safe and effective local treatment for breast cancer, with a low complication rate and a high complete ablation rate, which can be performed as an outpatient procedure. Further evidence is still needed, with a more homogenous group of patients. 

The treatment of Breast Cancer with Percutaneous Thermal Ablation – Results of the THERMAC Trial – Wooldrik, et al (2024) 

This independent trial from the Netherlands was presented at the 2024 European Society of Breast Imaging Conference in 2024 and compared the safety and the efficacy of breast cancer treatment in terms of complete ablation with radiofrequency, microwave, and cryoablation. With a 94% complete rate of ablation and no adverse events, cryoablation was determined to be the safest and most effective among the methods used in the trial. In comparison, for patients in the same study who underwent radiofrequency there was a complete ablation rate of 33% and 50% experienced mild to moderate adverse events. For patients in the same study treated with microwave, there was a complete ablation rate of 73% and 40% experienced mild to moderate adverse events. 

Assessing the outcome of cryoablation treatment on different molecular subtype of low-grade breast cancer” – Di Naro et al (2023)  

In this independent study presented at the 2023 European Society of Breast Imaging Conference, leading Italian breast radiologist, Dr. Frederica Di Naro, investigated the impact of cryoablation on breast tumor size reduction for biopsy-confirmed malignant lesions on patients who were deemed inoperable by a multidisciplinary group and underwent endocrine therapy.  

The median age of the 28 study patients was 73.4 years old, with half of the women having Luminal-A tumors and the other half having Luminal-B tumors. Patients were monitored by ultrasound at 1, 3, and 6 months and Contrast Enhanced Mammography and a core-needle biopsy at 1-year post cryoablation.  

Among the patients in the Luminal-A group, there was an absence of residual malignant cells in all biopsy samples and a disappearance of lesions. This led the study to conclude that Luminal-A, which is the most common subtype of breast cancer representing between 50%-60% of all breast cancers5, is a predictive factor for the complete effectiveness of treatment.  

Percutaneous ultrasound-guided cryoablation for early-stage primary breast cancer: a follow-up study in Japan – Kawamoto et al (2024) 

In an independent study from Japan, 18 patients with a mean age of 59.0 ± 9.0 years, mean tumor size of 9.8 ± 2.3 mm, ER + , PR + (17/18), HER2-, Ki67 < 20% (15/18), underwent percutaneous cryoablation followed by radiation and endocrine therapies for breast cancer. Patients were followed for a total of 5 years, with mean follow-up time of 44.3 months .Local control (by imaging: mammography, ultrasound, and MRI), safety, patient quality of life (QoL), satisfaction and cosmetic outcomes were followed  at baseline, 1, 6, 12-, 24-, 36-, and 60-months post cryoablation. No residual cancer was detected during the follow-up (mean 44.3 months (range 18-68 months) in all patients, and no serious adverse events were reported (there was only one non-serious minor adverse event). Cosmetic results were excellent, with no nipple position distortion, breast deformity, or asymmetry observed. The study revealed notable enhancements in both patient satisfaction and health-related quality of life across the five years. 

The study concluded that cryoablation for early-stage breast cancer is an effective and safe treatment with excellent cosmetic outcomes and improved quality of life.  

New hope for breast cancer patients

With promising results and the potential for more accessible and less invasive treatment options, cryoablation treatment offers new hope for appropriately selected low risk breast cancer patients. 

The results of the ICE3 clinical trial on cryoablation of small, low-risk breast cancers present a promising new minimally invasive choice in breast cancer treatment.

The ProSense™ Cryoablation System is considered an optimal solution for treating a selected group of early stage, low risk breast cancer patients. In Europe and many other countries, cryoablation is approved for breast cancer treatment. 

While the US still awaits FDA marketing clearance for the breast cancer cryoablation, ASBrS guidelines recommend participation in breast cryoablation registries and clinical trials to continue evaluating the use of percutaneous ablative technology.

Learn more

To receive a demo or to learn more about the ProSense™ liquid nitrogen cryoablation system, visit here. 

References:

1. Niu L. et al. Cryosurgery for breast fibroadenomas. Gland Surg. 2012 Aug; 1(2): 128–131.
2. Littrup P. J. et al. Cryotherapy for breast fibroadenomas. Radiology. 2005 Jan;234(1):63-72.
3. Golatta M. et al. Ultrasound-guided cryoablation of breast fibroadenoma: a pilot trial. Arch Gynecol Obstet. 2015 Jun;291(6):1355-60.
4. Fine, R.E. et al. Cryoablation without excision for low-risk early-stage breast cancer: 3-year interim analysis of ipsilateral breast tumor recurrence in the ICE3 Trial. Ann Surg Oncol. 2021 Aug; 28(10): 5525-5534
5. Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol. 2014 Aug 10;5(3):412-24. doi: 10.5306/wjco.v5.i3.412. PMID: 25114856; PMCID: PMC4127612. 

* IceCure Medical, LTD’s cryoablation systems are not currently cleared for breast cancer treatment in the United States. Please check that the clinical indications discussed in this article have regulatory clearance for you use in your country.

Updated October 28, 2024