Role of Nonsurgical Management of Breast Cancer: Endocrine Therapy and Tumor Ablation

Dennis R. Holmes

The optimal surgical approach to the management of localized early-stage breast cancer is breast-conserving surgery combined with adjuvant radiotherapy and systemic therapy, or both. This approach has been supported by multiple randomized controlled trials that have demonstrated comparable breast cancer–specific and overall survival among women treated with breast-conserving therapy compared to mastectomy. However, by comparison, breast-conserving therapy is associated with less cosmetic impairment, enhanced surgical recovery, more rapid return to daily activities, improved sexual function, and an overall improvement in quality of life.

Despite the large body of data supporting primary surgical management of early-stage breast cancer, the increasing appreciation of shared decision making between patients and physicians provides the ethical and legal context for considering nonoperative strategies to manage breast cancer for individual women who for personal and health reasons are seeking an alternative to traditional surgery. Furthermore, in the absence of data showing inferior breast cancer–specific and overall survival outcomes with nonoperative management, it is reasonable for surgeons and patients to include nonoperative strategies when discussing the benefits, risks, and alternatives of traditional surgery.

The opportunity for nonoperative management of breast cancer has been facilitated by the widespread use of screening mammography, which has contributed to the more frequent diagnosis of small, node-negative breast cancers, creating an opportunity for less-invasive and noninvasive management options. Furthermore, the trend favoring targeted local therapy reflects several important clinical observations: control of local disease can be achieved by a variety of strategies targeted at the tumor site; tumor biology is more important than tumor anatomy for estimating prognosis and predicting response to systemic therapy; control of systemic disease, not extent of local treatment, is the chief determinant of overall survival; and surgical removal of lymph nodes is of diminishing significance.

Nonsurgical management of breast cancer can be categorized based on its intent (curative vs. palliative) or by the modality by which it is provided (systemic therapy, radiotherapy, or percutaneous ablation). This chapter will review the most common nonoperative alternatives to breast-conserving surgery and the evidence supporting each approach. Apart from its potential role in the management of poor surgical candidates, a more important factor contributing to growing interest in nonsurgical management of breast cancer is the increasing population of elderly breast cancer patients, most of whom are more likely to die from intercurrent disease rather than breast cancer.

Primary Endocrine Therapy

In contrast with neoadjuvant endocrine therapy to facilitate tumor downstaging prior to surgery, primary endocrine therapy has been the focus of numerous studies since this approach was first introduced by Preece et al. in 1983 as an alternative to surgery in frail and elderly women (1). The rationale for primary endocrine therapy is that estrogen receptor–positive disease is the predominant type of breast cancer among elderly patients and that these patients are most likely to die from nonbreast cancer causes. Thus, endocrine therapy could provide a means to preserve quality of life while also limiting symptomatic local and systemic disease progression.

Seven randomized controlled trials have compared tamoxifen alone to primary surgery (mastectomy or wide local excision) with or without tamoxifen therapy in women aged 70 and older. Though unrepresentative of younger women or those with hormone receptor-negative disease, a meta-analysis of the randomized controlled trials revealed a key finding that should guide the informed consent discussion when considering primary endocrine therapy: with up to 28 years of follow-up, there was no difference in the breast cancer–specific or overall survival between women treated with tamoxifen alone and those treated with surgery with or without tamoxifen (2). Furthermore, a single
randomized controlled trial found no quality-of-life differences between the two groups (3). However, despite the lack of a survival advantage to primary surgical resection, all randomized controlled trials demonstrated lower disease-free survival with primary endocrine therapy which led to local disease progression and recommendations for surgical intervention in a majority of patients.

Although randomized controlled trials showed no survival advantage of tamoxifen alone over surgery, interpretation of the meta-analysis is limited by the fact that all trials were initiated in an era before routine testing of tumor receptors. However, based on the distribution of tumor receptor by age, approximately 10% of study subjects would have had hormone receptor–negative disease and would not have benefitted from endocrine therapy (4). The modern use of genomic assays greatly increases the odds of identifying the subset of tumors that is likely to be keenly sensitive to primary endocrine therapy regardless of age, tumor size, or nodal status. Furthermore, none of the trials utilized third-generation aromatase inhibitors, a more effective alternative to tamoxifen and the current standard of care for postmenopausal women with hormone receptor–positive breast cancer.

Optimal breast cancer therapy employs both surgery and endocrine therapy, not one or the other. However, for the patient opposed to surgery due to personal values or health state, the available data support the compliant use of endocrine therapy for hormone-sensitive breast cancer. The decision to proceed with primary endocrine therapy should consider the fact that a large proportion of patients treated with primary endocrine therapy ultimately require surgical intervention for management of disease progression, which could potentially be associated with greater surgical morbidity and greater quality-of-life impairment than would have been encountered had the tumor been resected when less extensive and when the patient was relatively more fit.

In Situ Ablation

In situ ablation performed under image guidance is a minimally invasive nonsurgical approach to cancer therapy. Using different types of thermal energy to destroy tumor cells, the main aim of in situ ablation is the destruction of the primary lesion as well as an adjacent margin of surrounding normal breast tissue, treating essentially the same volume of breast tissue that would be removed with lumpectomy.

There are several potential advantages to in situ ablation as an alternative to surgery. In situ ablation has the potential to eliminate the morbidity of primary surgery (e.g., symptomatic seroma, hematoma, infection). Most in situ ablation procedures can be performed in the office setting under local anesthesia or conscious sedation, eliminating common side effects of general anesthesia (e.g., nausea, vomiting) and avoiding exacerbation of preexisting comorbidities. In situ ablation also greatly reduces the quality-of-life impact of surgery by enhancing surgical recovery and expediting return to usual activities. Depending on the technique, in situ ablation may be performed percutaneously via a scar of a few millimeters length or transcutaneously, avoiding a scar altogether. Since no breast tissue is removed, in situ ablation preserves breast volume and symmetry while eliminating the need for preemptive or corrective surgical procedures to maintain or restore breast volume, contour, and symmetry. As a result, in situ ablation has the ability to minimize or completely eliminate the adverse cosmetic effects of tumor resection.

There are currently no randomized controlled trials comparing the efficacy or safety of in situ ablation to conventional surgery. However, numerous relatively small publications have reported the feasibility of various types of in situ ablation, nearly all involving ablation followed by surgical resection. Though individual trial results vary widely, a systematic review and meta-analysis of 45 studies involving 1,156 patients demonstrated that image-guided in situ ablation achieved a high level of technical success (96% [93% to 98%]), a moderate rate of complete tumor ablation (75% [49% to 90%], and a low rate of major complications (6% [4% to 8%], e.g., skin necrosis and pneumothorax) and minor complications (8% [5% to 13%], e.g., grade 1 and 2) (Table 8-1) (5). These findings were assessed to be independent of tumor size although most studies involved tumors under 3 cm. While the moderate rate of complete tumor ablation falls well below the threshold that would be accepted for a breast cancer therapy, the widely variant outcomes summarized in the meta-analysis capture the historical learning curves of each of the in situ ablation approaches most of which have since undergone significant technical and/or procedural modification to improve technical success, efficacy, safety, and patient selection.

Patient Selection

The ideal patient for in situ ablation has yet to be fully established since little long-term outcome data exist for patients treated with in situ ablation without surgical resection. Based on the results of postablation excision trials, multiple tumor characteristics have been correlated with successful ablation: unifocality, invasive ductal carcinoma histology, size ≤1.5 cm; well-demarcated borders by mammogram, ultrasound, and/or MRI; and a low percentage of ductal carcinoma in situ. On the other hand, larger or multifocal tumors, invasive lobular histology, poorly visualized lesions, or tumors with an extensive intraductal component have been correlated with a high rate of incomplete ablation. At present, there is no indication that the ablation technique should be influenced by these patient selection criteria.

Complications and procedural discomfort can also be minimized by selecting patients with tumors >1 cm from
the nearest skin or chest wall. However, depending on the ablation approach, the risk of thermal skin injury can be reduced with the use of coolant spray and ice packs to lower skin temperature, warm packs to raise skin temperature, or injection of saline or 5% glucose solution adjacent to the skin or chest wall.

TABLE 8-1 Summary of Data From a Systemic Review of 45 Publications

	Ablation Technique
	Radiofrequency Ablation	Laser Ablation	High-Intensity Focused Ultrasound	Cryoablation	Microwave Ablation	Overall
Number of Publications	23	7	6	6	3	45
Number of Patients	576	227	129	146	78	1,156
Age Range (yrs)	22–92	34–85	41–92	34–82	34–78	22–92
Technical Success (Range)%	87–100	100	93–100	91–100	83–100	83–100
Technique Efficacy (Range)%	29–100	13–90	20–100	36–92	90	13–100
Minor Complications (Range) (%)	0–50	4–62	0–21	0–100	0–36	0–100
Major Complications (Range) (%)	0–19	0–8	0–16	0	0–4	0–19
Adapted with permission from Mauri G, Sconfienza LM, Pescatori LC, et al. Technical success, technique efficacy and complications of minimally-invasive imaging-guided percutaneous ablation procedures of breast cancer: a systematic review and meta-analysis. Eur Radiol 2017;27:3199–3210.