Introduction

Although breast cancer is the world’s most prevalent cancer, survival from it has improved due to a combination of advancements in early detection and multidisciplinary treatment programs [1]. Improvement in breast imaging leads to the detection of cancers at earlier stages with better overall prognosis. Surgical resection of the primary tumor in non-metastatic breast cancer is the standard of care to obtain curative intent and locoregional control of disease [2]. Surgical options and techniques have evolved as studies showed that radical surgery did not correlate to improved survival. This paved the way for patients to have options for breast conservation, with or without oncoplastic techniques, versus mastectomy, including options such as nipple-sparing mastectomy [3, 4]. Continued efforts to de-escalate therapies aim to enhance the quality of life without the toxicity of overtreatment. Nonoperative techniques are pursued by patients not interested in an operation or those who are not acceptable surgical candidates. Cryoablation of breast tumors can be an effective and well-tolerated procedure for appropriately selected patients.

Background

Ablative therapies were developed as alternatives to surgical intervention for solid tumors. Cryoablation dates to the 1960s when a percutaneous technique using liquid nitrogen probes was developed for various types of cancers [5]. In 1985, Rand et al. reported on cryoablation of a breast tumor followed by surgical resection. Surgical pathology revealed no viable tumor cells [6].

Alternative percutaneous ablative therapies such as radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), laser thermotherapy, and microwave ablation have been studied with limited long-term follow-up. They are generally performed in the radiology department and require anesthesiology-administered sedation for pain control [7]. Cryotherapy is advantageous over thermal techniques because cold is a natural analgesic [8]. Cryoablation for breast disease is favored over alternative ablative techniques due to its ability to be performed in the office with local anesthesia and minimal discomfort.

Procedure

Cryoablation is performed with ultrasound guidance, allowing real-time visualization of probe placement, ice ball formation, and monitoring of surrounding tissues. An insulated cryoablation needle probe of 3 mm diameter is inserted along the long axis of the lesion through its geometric center [9]. Using either liquid nitrogen through closed-loop circulation, or argon gas via the Joule–Thomson effect, the process of freeze, passive thaw, and refreeze technique is completed. The duration of treatment intervals is dependent on the size of the lesion with or without margin that is to be ablated. and on the probe size and shape chosen. Fibroadenomas do not require a margin but a 1 cm margin is recommended for the treatment of cancers [10]. Ultrasound guidance allows for active monitoring of ice ball formation to ensure the probe placement is maintained centrally within the lesion during the procedure. A discrete boundary between frozen and unfrozen tissue appears as a visible hyperechoic rim [11]. The risk of skin burns can be minimized with saline hydro-dissection to maintain a safe distance between the skin and the forming ice ball. Elevation of the probe during the procedure to lift tissues off the chest wall can aid protection of the underlying musculature from damage [9].

The procedure can be performed with local anesthetic in the office setting. Patients can expect skin bruising or swelling in the initial 24 to 48 h after the procedure, with swelling and ecchymosis typically resolving over 3 weeks and any palpable change subsiding over subsequent months [12]. The scar at the puncture site is akin to a core needle biopsy scar. Minor complications such as skin blisters or alteration in pigmentation related to tape dressing may occur but could also occur with an incision site dressing after surgery. Patients can resume normal activities in 1–2 days just as they would after a core needle biopsy.

Ultrasound experience is critical to the success of the procedure. Experienced proceduralists have better accuracy of probe insertion through the center of the lesion to reduce issues with margins, and better technique can reduce the risk of skin necrosis [10].

Mechanism of Action

The pathophysiologic mechanisms of cryoablation occur through both direct and indirect cellular injury. Direct cellular injury through ice crystal formation denatures proteins and disrupts mitochondria [13••]. Reperfusion injury releases toxic free radicals, and vascular injury leads to ischemia and tissue necrosis [13••]. Osmotic shifts cause cellular dehydration and increased permeability of cell membranes. [14]. Repetitive freezing by a second freeze–thaw cycle causes further cell breakdown and increases the extent of tissue destruction [15]. Immune-mediated cytotoxicity also leads to tumor cell death [13••].

Benign Breast Disease—Fibroadenomas

Fibroadenomas are commonly diagnosed benign breast tumors frequently presenting as a palpable mass. Management of biopsy-proven fibroadenomas has historically included either excision or observation. Excision confirms final pathologic diagnosis by assessment of the entire resected mass and negates the need for continued imaging follow-up. Excision requires a surgical procedure inclusive of some type of anesthesia and a scar with variable resultant cosmesis. Conversely, observation requires continued clinical and imaging surveillance which can be both emotionally and financially burdensome to patients. Clinicians note that there can be subjective variation with follow-up ultrasound measurements based on both operator and patient positioning variables. This requires clinical judgment when interpreting the growth rate that would necessitate progression to excision.

Cryoablation was explored as an alternative to surgical excision of fibroadenomas and the success of early studies led to the subsequent approval by the FDA in 2002. Kaufman et al. treated 50 patients with biopsy-proven fibroadenomas with cryoablation [12]. Outcomes demonstrated a 100% successful procedure rate, with high patient satisfaction. At 6- and 12-month intervals, median tumor size was reduced by 65% and 92% respectively [12]. An updated series by Kaufman et al. reported on 63 patients with 78 biopsy-proven benign breast lesions, 66 of which were fibroadenomas- [14]. With a 12-month follow-up of 52 patients, lesions decreased in volume by 88.3%. Patient satisfaction was 92%, and 73% of nodules were nonpalpable at 12-month follow-up. There were no major complications. A correlation was made between the rate of resorption and tumor size: larger lesions remained palpable longer with slower resorption [14].

A Fibroadenoma Cryoablation Treatment Registry was created to assess outcomes following cryoablation of fibroadenomas in various community practices. Initial outcomes reported by Edwards et al. showed excellent patient satisfaction (92%), and side effects such as edema and swelling were managed with over-the-counter analgesics alone in 78% of patients [16]. Outcomes pooled treatment of 444 fibroadenomas across 55 sites, with a mean fibroadenoma diameter of 1.8 cm. Follow-up data was available at the 6-month interval for 249 patients, and the 12-month interval for 92 patients. Overall patient satisfaction was 91%, and palpability reduced to 35% at 12 months. Most patients with fibroadenoma < 2 cm became nonpalpable with faster resorption compared to larger diameters [17].

In a series by Littrup et al., 42 biopsy-proven fibroadenomas in 29 patients were treated with cryoablation [18]. The average pretreatment volume of 4.2 cm was reduced to 0.7 cm at 12 months. At 12-month follow-up, 89% of patients reported an acceptable reduction in palpability, either nonpalpable or substantially decreased. Similarly, Hahn et al. treated 23 patients with fibroadenomas and 91% of patients reported good or excellent satisfaction [19]. The median volume decreased by 75% in 1 year regardless of size. An update to this cohort by Golatta et al. in 2014 reported a reduction in palpability from 76% to 22%, with 100% good or excellent cosmesis and 97% patient-reported satisfaction at 1 year [20]. While the size of fibroadenomas treated was smaller than other reported studies with a mean volume of 1.2 cm, 93% were completely gone by ultrasound at 1 year.

The American Society of Breast Surgeons has published an official statement with guidelines for the use of cryoablation to treat fibroadenomas [21].

Malignant Breast Disease

Early cryoablation studies for malignant breast disease focused on feasibility and procedural success rate as determined by the histopathologic assessment of the ablated tumor after surgical excision [22,23,241]. Staren et al. described a single case report of cryoablation of two invasive lobular cancers in 1 breast which was successful [25]. Subsequent biopsy of the treated tumor was performed at 4 and 12 weeks which did not reveal residual disease. Pfleiderer et al. concluded after cryoablation of 15 patients that it is feasible without severe complications and while effective for invasive disease, ductal carcinoma in situ (DCIS) poses a problem with residual disease at the margins. Another study by Pfleiderer reported on 30 patients with 100% successful ablation of invasive disease. However, 16.7% had residual DCIS beyond the margins of the treated tumor. They suggest using multiple cryoprobes for larger tumors to ensure complete ablation of the tumor with adequate margin [22].

Table 1 Cryoablation of Breast Malignancies
Full size table

Sabel et al. had similar success rates in 29 patients, with an overall 85% complete ablation, noting 4 cases with DCIS at the margin [23]. 100% ablation was achieved if the tumor was < 1 cm. Another series of 9 patients showed 78% complete ablation, with no residual cancer in tumors ≤ 17 mm [24].

Littrup was the first to report on cryoablation without surgical resection [26]. In this feasibility study, patients with either recurrent or newly diagnosed breast cancer had the primary tumor treated with cryoablation. Multiple cryoprobes were utilized as needed to ensure a 1 cm margin of visible ice around the tumor, treating tumors up to 7 cm. To address concerns regarding DCIS at margins, additional core biopsies were taken at the edges of the formed ice ball upon completion of the final freeze cycle. Authors reported a 100% local success rate at 18 months, and no local recurrences for up to 6 years, citing the importance of preoperative planning including breast magnetic resonance imaging (MRI) [26]. Breast MRI was also utilized for post cryoablation surveillance, with images obtained at 1, 3, 6, 12, 18, and 24 months.

Several studies evaluated MRI assessment post-cryoablation and pre-resection to determine if post-procedure enhancement on MRI correlated to histopathologic findings to monitor for residual disease [27,28,29]. In two studies by Manenti et al. post-procedure enhancement on MRI correlated to histopathologic assessment in 95% of cases [27, 28]. In the first series, 14 of 15 patients had complete necrosis, and incorrect probe positioning was cited for the 1 failure, as the necrosis pattern on post-treatment MRI was not centralized around the previously enhancing tumor [27]. Similarly, Poplack et al. reported a series of 20 patients for whom the cryoablation procedure was 100% successful. 85% had complete ablation and 15% had residual disease (DCIS) at the periphery of the cryosite, and while MRI demonstrated 88% specificity it was not sensitive enough to detect residual disease [29]. A later study demonstrated that 7 of 54 patients (13%) had suspicious findings on the first post-cryoablation MRI that were resolved by the second post-cryoablation MRI [30]. In this study, all patients received adjuvant whole breast irradiation and adjuvant endocrine therapy, suggesting that if the enhancement correlated to any residual viable disease, it may have resolved due to adjuvant therapy [30].

Cazzato et al. performed cryoablation for 23 “non-surgical” patients using a combination of ultrasound and CT guidance for tumors < 3 cm and the use of multiple cryoprobes (median = 2) [31]. They found a high rate of early tumor control with follow-up MRI at 3 and 12 months but decreasing local control at 18 and 24-month follow-up [31]. Of the 5 patients that recurred, 2 were successfully re-treated by repeat cryoablation.

In a larger prospective phase 2 multicenter study, patients with unifocal disease ≤ 2 cm, with < 25% intraductal component and enhancement of tumor on pre-procedure MRI, successful ablation was confirmed pathologically in 75.9% of the 87 treated cancers [32]. When accounting for the size of the treated lesion, 100% ablation was seen in tumors < 1 cm compared with 77.4% in tumors ≥ 1 cm. All patients had MRI repeated post-ablation and pre-surgery with an 81.2% negative predictive value [32].

Early studies focused on feasibility and did not routinely report specifically on tumor receptors [22,23,24, 26, 29, 32]. All patients underwent core biopsy before cryoablation to assess hormonal receptor status before the destruction of tumor cells [22]. More recent studies have selected patients with favorable tumor characteristics. The majority of patients in the largest series by Simmons et al. were ER + /HER2 negative (86.2%). A series by Habrawi et al. used similar selection criteria and treated 12 patients with cryoablation without subsequent surgical resection [33••]. Eleven of these patients had at least a 6-month follow-up showing complete ablation by mammogram, ultrasound, and MRI. One patient had suspicious findings on MRI at 6 months and the biopsy showed fat necrosis; suspicious findings resolved by 12-month MRI.

The recent ICE3 trial (Cryoablation of Low-Risk Small Breast Cancer) has reported a 3-year interim analysis of 194 patients undergoing cryoablation without resection [34••]. This trial included patients with small (≤ 1.5 cm), ER + , HER2-negative, low to intermediate-grade, unifocal breast cancers. In breast tumor recurrence (IBTR) rate was 2.06% with a mean follow-up period of 34.8 months. Though the study limited patient selection to favorable early-stage breast cancer patients, it did not control receipt of axillary surgery, radiation therapy, or systemic therapy. Interestingly, none of the patients who experienced local recurrence received radiation therapy, and only 2 of the 5 had at least a short exposure to endocrine therapy despite all 5 having estrogen-positive disease. The 5-year analysis reported a 96.3% local recurrence free rate which is comparable to the 5-year local recurrence free rates in women treated with lumpectomy and endocrine therapy [35, 36]. FROST (Freezing Instead of Removal of Small Tumors) had similar inclusion criteria to the ICE3 trial and has closed to accrual; interim results at 1-year short-term follow-up demonstrated a 1.1% local recurrence rate [7]. Another clinical trial is currently recruiting patients: COOL-IT-PRO: Cryoablation of Breast Cancer in Non-surgical Patients [37••].

Synergy with Immunotherapy

Evidence of response in distant sites of disease after local treatment to the primary tumor is known as the abscopal effect [38]. Though first described in the 1950s in the context of radiation therapy, recent studies have shown the enhanced systemic immune response following cryoablation as a form of local treatment [39,40,41]. Cryoablation preserves tumor antigens otherwise removed during primary surgical resection and may generate a greater immune response compared to heat-based techniques because the antigens released into circulation are not damaged during the ablative process [42, 42, 43, 43, 44

Two cases of the abscopal effect following cryoablation for breast cancer have been separately reported [45, 46

The presence of tumor-infiltrating lymphocytes (TILs), including T cells, macrophages, natural killer cells, and dendritic cells, can predict response to immunotherapy and correlate to survival [43, 47]. In a mice model experiment by Khan et al., levels of TILs in distant tumors were assessed as a measure of the abscopal effect of cryoablation of breast cancer [48•]. Induced TIL response by cryoablation was greater compared to primary resection, and a higher level of TILs correlated to better overall disease control [48•].

Two clinical trials are currently recruiting patients to evaluate the combination of cryoablation and immunotherapy: A Study of Pembrolizumab and Cryoablation in People with Breast Cancer, and Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women with Triple-negative Breast Cancer [49, 50

Multidisciplinary Considerations and Challenges

Cryoablation trials for breast cancer did not uniformly control for axillary lymph node surgery, systemic therapy, or adjuvant radiation. Cryoablation could be considered an alternative to lumpectomy, but surgery is one component of the comprehensive treatment plan. De-escalating multiple aspects of the treatment plan simultaneously creates a challenge when interpreting outcomes.

Ductal Carcinoma in Situ

Most cryoablation studies excluded cancers with extensive intraductal component (EIC) and have not yet assessed the treatment of pure DCIS. EIC may correlate to the presence of residual intraductal cancer near the primary tumor, posing a risk for unresected malignancy [51]. Obtaining an adequate number of samples obtained by core needle biopsy is important to ensure extensive intraductal component is ruled out before cryoablation to optimize success [24]. Ensuring margin clearance without an excised specimen poses a challenge. Residual DCIS in the vicinity of the cryoablated tumor could be addressed by adjuvant therapies. The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial will evaluate endocrine therapy alone for low-risk DCIS without surgical resection [52•]. A clinical trial is currently recruiting patients to evaluate cryoablation for DCIS [53••].

Lymph Node Assessment

Axillary lymph node assessment is important for the pathologic staging of breast cancer and can inform adjuvant treatment decisions, impacting the radiation treatment field, chemotherapy regimen and duration, extended endocrine therapy, and/or need for ovarian suppression. If patients are undergoing cryoablation of primary breast cancer to avoid surgery, they are likely to also omit sentinel lymph node (SLN) evaluation. The extent of axillary surgery in clinically node-negative patients has not been demonstrated to influence overall survival [3, 54, 55]. Omission of SLN biopsy has been explored for clinically node-negative patients with early-stage breast cancer. Choosing Wisely guidelines published in 2016 by the Society of Surgical Oncology cautioned “not to routinely use SLN biopsy in clinically node-negative women ≥ 70 years of age with hormone receptor-positive invasive breast cancer” [56]. An evaluation of a cohort meeting this guideline noted that despite only 40% patient adherence to endocrine therapy, the incidence of breast cancer-related events was only 4% [57]. The SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound) trial concluded that omission of axillary surgery was non-inferior to SLN biopsy in patients with early-stage breast cancer and negative axillary ultrasound based on no difference in 5-year overall survival and disease-free survival [58•]. Most patients were estrogen-positive (87.8%). Axillary lymph nodes should be assessed by clinical exam and axillary ultrasound when considering candidacy for cryoablation to decrease risk of locoregional failure.

Adjuvant Systemic Therapy

Early cryoablation studies focused on feasibility and did not limit patient selection to favorable tumor biology, whereas more recent studies largely evaluated outcomes in patients with luminal A tumors. One concern with cryoablation is that the destruction of the tumor without resection eliminates the ability to know the exact tumor size with certainty. Accurate staging according to tumor size is critical in recommendations for adjuvant systemic therapies. For smaller tumors, however, evaluation of the lumpectomy specimen after large-core biopsies can make tumor measurement unreliable if little or no tumor remains [25]. In addition, tumor size measurement is well estimated on current breast imaging, and genomic profiling may be more informative of treatment recommendations. Based on selection criteria for the more recent cryoablation trials, most of these patients would not likely necessitate genomic profiling based on small tumor size and low grade. In studies where tumor receptors were reported, most patients included had estrogen-positive tumors. Not only was treatment with endocrine therapy not consistently reported, but we know adherence to endocrine therapy amongst breast cancer patients (76.3%) is problematic resulting in substandard clinical outcomes [59]. Recommendations for adjuvant systemic therapies should be based on clinical staging and tumor markers obtained at biopsy.

Adjuvant Radiation Therapy

The success of cryoablation could be owed in part to the reduction in local recurrence rates from receipt of adjuvant radiation therapy, as this variable was not controlled in recent studies. The addition of radiation therapy after lumpectomy results in a reduction in local recurrence compared to lumpectomy alone [4]. However, several studies have demonstrated low local recurrence rates with no difference in overall survival in patients with favorable early-stage breast cancer treated with lumpectomy and endocrine therapy without radiation therapy [36, 60, 61]. More recently, 10-year data demonstrated accelerated partial breast irradiation to be comparable to whole breast irradiation in terms of in breast tumor recurrence, and with better cosmesis and less toxicity [62]. Consideration of radiation may aid in achieving adequate local tumor control for patients who prefer nonoperative intervention with cryoablation.

Imaging Challenges

Comprehensive breast imaging workup is important to select appropriate candidates for cryoablation. Breast density can interfere with accurate evaluation of tumor size and margins pretreatment [24]. Breast MRI may be most helpful in evaluating pre- and post-cryoablation. The high negative predictive value of breast MRI can exclude any additional clinically relevant disease that would make someone a poor candidate for cryoablation [26]. While immediate post-cryoablation MRI was not sensitive in detecting microscopic residual disease, it may be more useful when obtained serially in the months following cryoablation [29]. Two studies evaluated persistent suspicious enhancement of MRI post-cryoablation, seen in 5% and 11.8% of patients [28, 29]. None of these patients had histopathologic evidence of residual carcinoma. False positive enhancement of fat necrosis can complicate post-cryoablation surveillance [63••].

Surveillance mammography should ideally include digital breast tomosynthesis and is suggested at 6-month intervals for 1 year, then annually [64•]. The previously seen tumor becomes more fat-replaced on mammography and decreases in size over time [63••]. Fat necrosis with or without coarse calcifications may be seen, not unlike follow-up imaging after breast conservation [64•]. Sonographically, while most treated lesions reduce in size or disappear, there is variability in the appearance of any residual necrotic change [65]. With such variability in shape and size, routine sonographic follow-up is not advised but should supplement routine mammography as needed [64•]. A suspicious finding on any imaging modality should be evaluated with a biopsy.

Current Use Of Cryoablation

Standard practice includes surgical resection in patients who are operative candidates. Breast cancer cryoablation studies were not uniformly designed with respect to subtype and did not account for variation in receipt of adjuvant treatments. The safest use appears to be in patients with low-risk early-stage disease who would otherwise be a candidate for lumpectomy and endocrine therapy without the need for axillary nodal sampling, adjuvant chemotherapy, or adjuvant radiation. The use of cryoablation in a breast cancer patient who otherwise declines all treatment can complicate imaging surveillance and monitoring for local recurrence. Patients should be adequately informed that performing cryoablation outside of a trial is not currently standard of care, as it has not yet been approved by the FDA for use in treating breast cancer. Further studies including clinical trials and registries are needed to support the ICE3 study's results while we await long-term follow-up from the FROST trial.

Conclusion

Cryoablation remains an effective and well-tolerated non-surgical option for women with benign breast fibroadenomas. Cryobalation for breast cancer has been primarily studied in small, low-risk tumors. As adjuvant therapies for breast cancer continue to de-escalate, we must be mindful that the omission of multiple aspects of current standard treatments does not negatively impact local recurrence or overall survival. Current guidelines do not support the use of cryoablation for patients who are otherwise candidates for standard treatment. There is promising evidence to support the enhancement of immunotherapy with cryoablation or as local treatment of the breast primary in the setting of metastatic disease. Cryoablation also remains a treatment option for non-operable breast cancer.