The Early Breast Cancer Trialists' Collaborative Group overviews published in 2005 confirm that local control in breast cancer matters, and they highlight that achieving local control in the modern era is not improved simply by more extensive surgery but instead by the combination of surgery, systemic and hormonal chemotherapies, and radiation therapy.[1,2] This multimodality treatment approach supports the shift in local surgical management away from radical surgery both in the breast and axilla, and it offers an opportunity to further minimize surgical morbidity without compromising local control. In this issue of ONCOLOGY, Rizzo and Wood review the current state of local and regional treatments for breast cancer.
Surgery in the Breast
The benefits of breast-conserving surgery (BCS) are widely known, and efforts to optimize patient eligibility continue. Neoadjuvant chemotherapy (NAC) facilitates BCS by reducing tumor size in otherwise ineligible patients. The adoption of NAC into surgical practice has not been without controversy, however. Unfortunately, although NAC may reduce disease burden within the breast, allowing for smaller-volume resections and therefore increased rates of BCS, it has not resulted in fewer reexcisions or reduced the number of operations performed. In addition, significant surgical debate has revolved around the timing of sentinel lymph node biopsy (SLNB) before or after NAC, given the potential loss of prognostic and treatment information, and around the feasibility and false-negative rates of SLNB after NAC. Results of studies evaluating this question have been heterogeneous, but a recent meta-analysis by Tan evaluating SLNB in patients with a clinically negative axilla after NAC finds an acceptable identification rate of 94.3% and false-negative rate of 7.4%. The ongoing questions now center on the need for axillary lymph node dissection (ALND) after NAC when the patient presented with a positive axillary node prior to chemotherapy, given that NAC can downstage up to 40% of women from node-positive at presentation to node-negative after NAC.[6,7] False-negative rates of SLNB in this scenario after NAC are reported to be as high as 25%. The current American College of Surgeons Oncology Group (ACOSOG) Z1071 trial, which is nearing targeted accrual, will help us to answer this question.
Renewed interest in local control has resulted in the reexamination of margin status after BCS. Authors Rizzo and Wood succinctly document the controversies surrounding what constitutes a negative margin, the lack of standardization in margin analysis, and the poor correlation between margin distance and risk of local recurrence. Although surgeons strive for negative margins, one must recognize that a negative margin does not translate into the absence of microscopic tumor within the breast, as historical series identify microscopic disease remote from the primary tumor in up to 60% of women. Many hoped that magnetic resonance imaging (MRI) of the breast would help to improve surgical planning and reduce positive margins, but thus far this has not proven to be true. MRI clearly identifies occult disease not seen by mammography, however, the COMICE trial, which is the only available evidence from a randomized trial on the impact of MRI on surgical planning, failed to demonstrate a reduction in the rate of positive margins or the need for reoperation, with 19% of patients in both groups needing reoperation. Furthermore, instead of promoting BCS, it appears that MRI may actually contribute to the performance of more extensive surgery, without reducing local recurrence rates or improving survival.[10,11]
Surgery in the Axilla
In the axilla, the shift away from radical surgery continues. The recently published ACOSOG Z0011 trial demonstrated that SLNB alone was not inferior to SLNB and completion axillary lymph node dissection in women with early breast cancer undergoing BCS and whole breast irradiation (WBI) who had only one or two positive lymph nodes. In this trial, Giuliano and colleagues found similar rates of locoregional recurrence and emphasize the contributions of adjuvant therapies, especially radiation therapy, to local control. While these data support a significant surgical practice–changing shift, many have criticized the trial because it failed to meet its original target accrual necessary to determine a survival advantage, enrolled few women younger than 50 years of age, had a relatively short follow-up of only 6.3 years, and had a preponderance of women with estrogen receptor–positive tumors.
Surgeons have successfully demonstrated that less surgery minimizes morbidity without compromising local control, thanks primarily to advances in adjuvant therapies. The irony, however, lies in the fact that current surgical trends in the breast do not necessarily match the well-documented data supporting less surgery. Despite well-executed prospective clinical trials supporting the routine use of BCS, many single-institution series have reported elevated mastectomy rates following BCS, ranging from 40% to 50%.[13-15] Although, recently published data from the Surveillance Epidemiology and End Results national database do not confirm a rise in the unilateral mastectomy rate, they do document mastectomy rates of 37%. In addition, the significant rise in contralateral prophylactic mastectomy rates[17,18] further verifies a surgical trend towards more aggressive breast surgery, suggesting an influential element of patient choice in the surgical decision–making process. To the contrary, evaluation of surgical trends in the axilla demonstrates that omission of ALND in the setting of a positive SLNB began rising years before the publication of the Z0011 dataset documented its noninferiority, suggesting practice changes away from aggressive surgery prior to robust data.
Similar to the attempt by surgeons to minimize surgery, radiation oncologists have also aimed to minimize radiation treatments. As reviewed by Rizzo and Wood, the ongoing NSABP B-39 trial evaluating partial breast irradiation, and outcomes data from Hughes et al, who omitted radiation treatment for select women over age 70, attest to the effort to minimize radiation therapy. Simultaneously, however, large amounts of radiation data also support the use of more aggressive radiation regimens, especially after mastectomy in patients with one to three positive lymph nodes, and even in the setting of high-risk but node-negative disease.[20,21] In fact, at the American Society of Clinical Oncology 2011 meeting, Whelan presented data from the MA.20 trial demonstrating significantly improved locoregional disease-free survival (DFS), distant DFS, and DFS in women with high-risk node-negative or node-positive breast cancer undergoing BCS and WBI with the addition of axillary, supraclavicular, and internal mammary node radiation, compared with women treated with BCS and WBI alone. Of note, all women with positive lymph nodes in MA.20 had ALND, placing these data in direct conflict with the dataset from the Z0011 trial, which did not require ALND and did not allow directed third-field radiation.
In conclusion, the local management of breast cancer continues to evolve. Emerging surgical data continue to validate less-radical surgery without compromising local control, but several questions remain unanswered. Future research should continue to focus on individualizing multimodality treatment based on tumor biology, to further minimize morbidity from surgery and radiation.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.