Progress but Not Perfection: Ongoing Efforts to Optimize Locoregional Treatments for Breast Cancer

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[3] 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.[4] 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[5] 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%.[8] 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.[9] 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.[10] 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[12] 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.

Surgical Trends

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,[16] 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.[19]

Radiation

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.[22] 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.

Conclusion

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.

References:

References

1. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence. Lancet. 2005;17:2087-2106.

2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomized trials. Lancet. 2005;365:1687-1717.

3. Mieog JS, van der Hage JA, van de Velde CJ. Preoperative chemotherapy for women with operable breast cancer. Cochrane Database Syst Rev 2007;(2):CD005002. Available at: http://www2.cochrane.org/reviews/en/ab005002.html. Accessed July 13, 2011.

4. Boughey JC, Peintinger F, Meric-Bernstam F, et al. Impact of preoperative versus postoperative chemotherapy on the extent and number of surgical procedures in patients treated in randomized clinical trials for breast cancer. Ann Surg. 2006;244:464-70.

5. Tan V, Goh B, Fook-Chong S, et al. The feasibility and accuracy of sentinel lymph node biopsy in clinically node-negative patients after neoadjuvant chemotherapy for breast cancer-a systematic review and meta-analysis. J Surg Oncol. 2011;104:97-103.

6. Fisher B, Brown A, Mamounas E, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18.
J Clin Oncol. 1997;15:2483-93.

7. Bear HD, Anderson S, Smith RE, et al. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006;24:2019-27.

8. Shen J, Gilcrease MZ, Babiera GV, et al. Feasibility and accuracy of sentinel lymph node biopsy after preoperative chemotherapy in breast cancer patients with documented axillary metastases. Cancer. 2007;109:1255-63.

9. Holland R, Veling SH, Mravunac M, Hendriks JH. Histologic multifocality of Tis, T1-2 breast carcinomas: implications for clinical trials of breast conserving surgery. Cancer. 1985;56:979-90.

10. Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial. Lancet. 2010. 375:563-71.

11. Solin LJ, Orel SG, Hwang WT, et al. Relationship of breast magnetic resonance imaging to outcome after breast-conservation treatment with radiation for women with early-stage invasive breast carcinoma or ductal carcinoma in situ. J Clin Oncol. 2008;26:386-91.

12. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305:569-75.

13. McGuire KP, Santillan AA, Kaur P, et al. Are mastectomies on the rise? a 13 year trend analysis of the selection of mastectomy versus breast conservation therapy in 5865 patients. Ann Surg Oncol. 2009;16:2682-90.

14. Katipamula R, Degnim A, Hoskin TL, et al. Trends in mastectomy rates at the Mayo Clinic Rochester: effect of surgical year and preoperative magnetic resonance imaging. J Clin Oncol. 2009;27:4082-8.

15. Adkisson CD, Vallow LA, Kowalchik K, et al. Patient age and preoperative breast MRI in women with breast cancer: biopsy and surgical implications. Ann Surg Oncol. 2011;18:1678-83.

16. Habermann EB, Abbott A, Parsons HM, et al. Are mastectomy rates really increasing in the United States? J Clin Oncol. 2010;28:3437-41.

17. Tuttle TM, Habermann EB, Grund EH, et al. Increasing use of contralateral prophylactic mastectomy for breast cancer patients: a trend toward more aggressive surgical treatment. J Clin Oncol. 2007;25:5203-9.

18. King TA, Sakr R, Patil S, et al. Clinical management factors contribute to the decision for contralateral prophylactic mastectomy. J Clin Oncol. 2011;29:2158-64.

19. Bilimoria KY, Bentrem DJ, Stewart AK, et al. Comparison of sentinel lymph node biopsy alone and completion axillary lymph node dissection for node-positive breast cancer. J Clin Oncol. 2009;27:2946-53.

20. Taghian A, Jeong J, Mamounas E, et al. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project Randomized Clinical Trials. J Clin Oncol. 2004;22:4247-54.

21. Truong P, Olivotto I, Kader H, et al. Selecting breast cancer patients with T1-T2 tumors and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys. 2005;61:1337-47.

22. Whelan TJ. NCIC-CTG MA.20: asn intergroup trial of regional nodal irradiation in breast cancer (abstract 1003). J Clin Oncol. 2011;29(18S):779s.