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Journal of Clinical Oncology, Vol 23, No 8 (March 10), 2005: pp. 1603-1606 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.015
Continuing Evolution in Breast Cancer Surgical ManagementNortheastern Ohio Universities College of Medicine, Rootstown; and Aultman Cancer Center, Canton, OH The surgical management of primary breast cancer underwent significant evolution in the last quarter of the 20th century as a result of changes in the biologic understanding and clinical presentation of the disease. The proposal of an alternative hypothesis for the mechanism of tumor dissemination challenged the previously accepted Halstedian principles that had governed surgical management for the better part of that century.1,2 Randomized clinical trials were supportive of this alternative hypothesis3-6 and eventually established breast-conserving surgery plus radiotherapy as the preferred option for treating appropriate candidates with primary breast cancer.7 The alternative hypothesis was also supported by results from clinical trials indicating that the administration of adjuvant systemic therapy significantly improved disease-free and overall survival of patients with early-stage breast cancer.8-10 Adjuvant systemic therapy played an important role in the successful adoption of breast-conserving surgery plus radiotherapy by decreasing the rates of locoregional failure and by expanding the pool of candidates (by its use as preoperative or neoadjuvant therapy). EXPANDING THE USE OF BREAST-CONSERVING SURGERY In the article by Drs Newman and Kuerer,11 recent trends in utilization of breast-conserving surgery and the evolution of criteria for optimal candidate selection are reviewed. A significant proportion of candidates for breast-conserving surgery are still treated with mastectomy for reasons that primarily relate to surgeons' bias and lack of adherence to established guidelines. It is hoped that as the multidisciplinary management of breast cancer patients continues to expand, mastectomy rates will continue to decrease. The authors provide evidence-based rationale to dispel some of the myths or excuses given by some as reasons to perform a mastectomy. No increased rates of in-breast recurrence have been seen in patients with family history of breast cancer, in those with lobular invasive histology, or in those whose tumors have coexisting lobular carcinoma-in-situ. Although in-breast recurrences are more frequent in younger patients, this should not be a deterrent for using breast-conserving surgery in this group. Finally, the lingering issue of extensive intraductal component as a risk factor for in-breast recurrence has essentially been put to rest, as recent studies demonstrate no such association as long as the lumpectomy margins are free of disease. Recent medical advances have created significant opportunities but also significant challenges in the selection of optimal candidates for breast-conserving surgery. Progress in breast imaging, advances in molecular testing for genetic susceptibility, and increase in the use of neoadjuvant chemotherapy have provided reasons for excitement, but have also created considerable debate. Newer, sensitive breast imaging techniques such as breast magnetic resonance imaging (MRI) can provide a more accurate assessment of the extent of the primary breast tumor and can optimize the performance of breast-conserving surgery or facilitate the decision to perform a mastectomy in case of multicentric disease. On the other hand, the high sensitivity but generally lower specificity of MRI has raised concerns regarding the potential for decreasing the pool of candidates for breast-conserving surgery by identifying additional lesions which are either benign, or if malignant, could be eliminated by the use of postlumpectomy breast irradiation. The proper role of MRI in the surgical management of primary breast tumors can only be evaluated in prospective randomized clinical trials. Genetic testing for hereditary breast cancer can now identify groups of patients with significant risk for developing the disease. As a result, surgeons are sometimes faced with newly diagnosed breast cancer patients who also have known or suspected hereditary susceptibility. The surgical management of these patients is complicated by the need to address their significantly increased risk for developing new ipsilateral or contralateral breast tumors. Although breast-conserving surgery can be offered safely to these patients, there is no current consensus on the magnitude of risk for subsequent malignancies, the modifying effect of adjuvant therapy (tamoxifen, oophorectomy), or the need and timing of prophylactic mastectomy. Lastly, there are unique issues in the surgical management of patients treated with neoadjuvant (preoperative) chemotherapy. New developments in breast imaging, diagnostic interventions, and surgical planning have contributed to the success of this approach. Breast MRI is emerging as a very useful tool for defining the extent and pattern of tumor growth and for assessing the degree and pattern of tumor response (concentric versus honeycomb). Different patterns of tumor growth by MRI have been associated with varying response rates to neoadjuvant chemotherapy and are predictive of the ability to perform breast-conserving surgery in this setting.13,14 Use of core needle biopsy for diagnosis ensures the presence of invasive carcinoma and usually secures enough tissue for assessment of routine biomarkers (estrogen receptor/progesterone receptor, HER-2/neu) in case of pathologic complete response. Marking the exact tumor location within the breast by inserting radiopaque markers under mammographic or sonographic guidance is critical for localizing and resecting any residual tumor (in cases of clinical and/or radiologic complete response) and for accurately identifying the tumor bed area (in cases of pathologic complete response). SENTINEL NODE BIOPSY: NEW DEVELOPMENTS AND CURRENT CONTROVERSIES During the past decade, most of the emphasis in surgical research focused on attempts to reduce the extent of axillary surgery with the emergence and clinical evaluation of lymphatic mapping and sentinel node biopsy (SNB). Although the sentinel node concept is not new to oncology, its applicability in breast cancer was first demonstrated in 1993 in the seminal publication by Krag et al.15 Since that time, thousands of patients have undergone the procedure (with or without completion axillary node dissection), mostly through nonrandomized series and randomized clinical trials. Surgeons experienced with this procedure currently offer SNB without completion axillary dissection, and clinical guidelines set by authoritative groups have included SNB alone as an acceptable method for staging the axilla in appropriate clinical situations.16 We should be reminded, however, that this procedure has not yet passed the true litmus test relative to its comparison to axillary-node dissection in large randomized clinical trials. Although several small and large randomized trials comparing SNB with axillary dissection have been completed, outcome results are only available from a smaller trial and with relatively short follow-up.17 Establishing at least equivalence in long-term outcome between SNB and axillary-node dissection in large randomized trials is crucial for the long-term establishment of SNB as the undisputed standard of care for axillary staging. The widespread evaluation of lymphatic mapping and SNB in randomized and nonrandomized clinical studies has already generated an enormous amount of data on the clinical performance of the procedure and the most appropriate candidates for it. Although there are many key areas of agreement, there are also several remaining areas of controversy. The second review by Kuerer and Newman12 in this Special Series issue addresses some of these new developments and persisting areas of controversy with SNB. They discuss the potential role for this technique in patients with palpable axillary nodes, in those with multicentric disease and ductal carcinoma-in-situ, and in pregnant patients and those who have received neoadjuvant chemotherapy. They also examine the utility of SNB as a bridge to potentially eliminate axillary node dissection even in patients with positive sentinel node(s). The original concept for breast lymphatic mapping and SNB dictated that different parts of the breast may drain to different sentinel nodes. As a result, lymphatic mapping was initially performed by peritumoral injection of the mapping agent. More recent clinical data, however, support the concept that the same sentinel node receives lymphatic drainage from the entire breast. This is based on the high concordance in sentinel node identification when different lymphatic mapping agents are injected in different parts of the breast (different quadrants, subareolar v peritumoral, intradermal v peritumoral). However, superficial injection of the lymphatic mapping agents (subareolar or intradermal) will not identify extra-axillary sentinel nodes (ie, internal mammary nodes),18 since drainage to these nodes appears to originate only from the deep retromammary lymphatic pathway, in contrary to the superficial pathway which uniformly drains to the axilla.19 Thus, addition of peritumoral radiocolloid injection is essential for extra-axillary sentinel node identification, although the clinical utility of removing such sentinel nodes is still the subject of debate.20-25 Resolution of this issue is important because superficial injections offer several potential advantages such as higher identification rates, possibly lower false-negative rates, ease of administration, and avoidance of axillary "shine through" over the radioactive sentinel lymph node when the lesion is located in the upper outer quadrant. After significant initial debate, most researchers and clinicians currently agree on the superiority of combining blue dye with radioactive colloid or albumin for lymphatic mapping. Rates of sentinel node identification and number of identified sentinel nodes are significantly higher with the combination versus single agent, although the difference is generally larger when the combination is compared with blue dye alone rather than to radiocolloid alone.26-28 Debate continues on the optimal particle size and the need for filtration of colloid particles. Most agree that preoperative lymphoscintigraphy provides little, if any, additional value to the intraoperative detection of axillary and extra-axillary sentinel nodes by the gamma probe.29,30 One of the potential advantages of SNB is the ability to perform more extensive pathologic evaluation of the sentinel nodes with multiple serial sections, immunohistochemical (IHC) staining, or more sensitive molecular techniques for identification of micrometastases. Multiple serial sectioning and IHC staining yield additional metastases in a proportion of patients who have negative sentinel nodes on routine hematoxylin and eosin staining. Debate continues on the optimal interval of serial sectioning and on the most appropriate technique beyond hematoxylin and eosin staining. More importantly, the clinical significance of identifying sentinel-node micrometastases by the more sensitive techniques is still unknown. Several of the recently completed and currently ongoing randomized clinical trials evaluating SNB with or without axillary dissection are designed to prospectively evaluate the prognostic significance of micrometastases detected by IHC staining or other sensitive molecular techniques, and will hopefully provide a definitive answer to this question.31,32 Accurate intraoperative evaluation of sentinel nodes is of clinical importance, since identifying involved sentinel nodes means that completion axillary dissection can be carried out in the same setting, avoiding an additional surgical procedure. Touch imprint cytology or frozen section are most commonly used, but both methods have shown low sensitivity, particularly when the involvement of sentinel nodes is limited to micrometastases. There is no clear superiority of one method over the other, although imprint cytology has the advantage of preserving the entire lymph node for permanent evaluation. The value of additional methods for increasing sensitivity, such as intraoperative use of IHC staining, combination of imprint cytology with frozen section, and intraoperative use of sensitive molecular techniques (reverse transcriptase polymerase chain reaction), remains unproven. Several nonrandomized prospective or retrospective comparisons of SNB with axillary node dissection with short median follow-up have consistently shown reduced morbidity with SNB compared to axillary dissection (with or without prior SNB). Significant improvements in favor of SNB have been observed in pain, numbness, paresthesias, arm strength, range of motion, arm/forearm swelling, normal activity resumption, and percentage of patients undergoing out-patient surgery. Results from the large randomized trials are starting to confirm, refine, and further quantify these observations.17,33 A unique, albeit rare (< 1% severe) complication of SNB is the manifestation of allergic reactions to the blue dye used for lymphatic mapping. As Kuerer and Newman12 point out, SNB has the potential for eliminating axillary dissection in the majority of patients with breast cancer whether they are initially node positive or node negative. Currently, most of the completed randomized trials have compared SNB with axillary dissection in patients with negative sentinel node. In this group of patients, this technique will hopefully become the undisputed gold standard if the results from the randomized trials are supportive. For patients with positive sentinel nodes, ongoing randomized trials are comparing SNB to axillary dissection or to axillary radiotherapy.34,35 Until results from these trials dictate otherwise, axillary node dissection remains the gold standard for patients with positive sentinel nodes. Another approach for potentially avoiding axillary dissection in node-positive patients is through the use of neoadjuvant chemotherapy. The use of modern neoadjuvant chemotherapy regimens has resulted in downstaging of involved axillary nodes in 30% to 40% of the patients.36,37 Thus, if SNB is accurate following neoadjuvant chemotherapy, patients who present with involved axillary nodes at diagnosis may potentially be spared the axillary dissection if, following neoadjuvant chemotherapy, the sentinel node is found to be negative. There is much less experience with SNB after neoadjuvant chemotherapy compared with SNB at breast cancer diagnosis. However, when the two collective experiences are compared in similar settings, SNB after neoadjuvant chemotherapy appears to have similar performance characteristics, as does SNB before systemic therapy. Thus, neoadjuvant chemotherapy and SNB can be used as a potential tool for avoiding axillary dissection in some patients with involved axillary nodes at presentation. Naturally, axillary recurrence rates will need to be carefully monitored in these patients to assure that this remains a reasonable approach. THE FUTURE Breast cancer surgical therapy continues to evolve at a rapid pace. Advances in many of the disciplines involved in breast cancer management will continue to have a significant impact in the surgical management of the disease in the years to come. Developments such as new sensitive imaging techniques, gene expression profiling, percutaneous radiofrequency ablation/cryoablation, and partial breast radiation hold significant promise to further individualize and optimize the extent of surgical therapy in the breast and axilla. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. Acknowledgment I thank Christina Morello, MSJ, for editorial assistance with this manuscript. REFERENCES
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31. Giuliano AE, Haigh PI, Brennan MB, et al: Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 18:2553-2559, 2000 32. Clarke D, Mansel RE, on behalf of ALMANAC trialists group: The learning curve in sentinel node biopsy (SNB) in breast cancer: Results from the ALMANAC trial. Breast Cancer Res Treat 69:212, 2001 (abstr 15) 33. Mansel RE, Goyal A, Necombe RG, et al: Objective assessment of lymphedema, shoulder function and sensory deficit after sentinel node biopsy for invasive breast cancer: ALMANAC trial. Breast Cancer Res Treat 88:S12, 2004 (abstr 15) 34. Ross MI: Sentinel node dissection in early-stage breast cancer: Ongoing prospective randomized trials in the USA. Ann Surg Oncol 8:77S-81S, 2001 35. Hurkmans CW, Borger JH, Rutgers EJ, et al: Quality assurance of axillary radiotherapy in the EORTC AMAROS trial 10981/22023: The dummy run. Radiother Oncol 68:233-240, 2003[CrossRef][Medline]
36. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165-4174, 2003 37. Gianni L, Baslega J, Eiermann W, et al: First report of the European Cooperative Trial in operable breast cancer (ECTO): Effect of primary systemic therapy. Proc Am Soc Clin Oncol 21:34a, 2002 (abstr 132) Related Articles
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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