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Present standards and future concepts of surgery in breast cancer
Not so long ago, most breast cancer patients were treated with mastectomy (without reconstruction) and routine axillary lymph node dissection (ALND). With the increased emphasis on minimally invasive and less morbid surgical procedures, most patients today undergo breast-conserving surgery (BCS) without ALND. The surgical options for patients who require or desire mastectomy have dramatically expanded with the development of skin- and nipple-sparing mastectomies and better access to reconstructive options. Surprisingly, an increasing proportion of patients with unilateral breast cancer are undergoing bilateral mastectomy with contralateral prophylactic mastectomy. Today, surgeons are more involved in the delivery of partial breast irradiation therapy with the development of balloon-catheter brachytherapy and intraoperative radiation therapy. As a result of new technologies, improved surgical techniques and practice-changing studies, the surgeons’ role in breast cancer treatment has become increasingly more complex. The purpose of this review article is to outline the rapidly changing landscape of breast cancer management and to highlight the surgeons’ role in this multifaceted disease.
The use of image-guided percutaneous biopsy, rather than open surgical biopsy, in the evaluation of palpable breast lumps and suspicious mammographic abnormalities is increasing.1 Percutaneous biopsy is a minimally invasive procedure that offers several potential advantages over open surgical biopsy. Image-guided percutaneous biopsy causes less breast deformation and is faster than open surgical biopsy. Also, a concordant histological diagnosis of benign disease on percutaneous biopsy may obviate the need for open surgical biopsy in most patients. In the case of patients who are ultimately diagnosed with ductal carcinoma in situ (DCIS) or invasive breast cancer, percutaneous biopsy eliminates incisions that might compromise cosmetic outcomes after BCS or mastectomy. Also, percutaneous biopsy is less expensive and is associated with fewer overall surgical procedures.1 Finally, important prognostic and predictive factors – including type of tumour, histological grade, oestrogen receptor (ER) status, HER2 status and even the 21-gene recurrence score – can be determined before treatment based on results obtained from an image-guided core needle biopsy.2
Preoperative breast magnetic resonance imaging (MRI) is increasingly used for breast cancer treatment planning. In 2008, Bassett and colleagues3 reported that MRI was offered to patients diagnosed with breast cancer at 74% of breast imaging practices surveyed. Similarly, Hulvat and colleagues4 reported a 46% increase in the utilization of MRI from 1998 to 2008 at a large university hospital. The potential advantages of preoperative MRI rest primarily in its increased sensitivity in detecting occult disease not identified by mammography.4–8 As a result, breast MRI may provide better assessment of tumour extent in the ipsilateral breast and increased detection of ipsilateral multifocal disease and occult contralateral breast cancer than mammography alone. A meta-analysis of 19 studies (2610 patients) published by Houssami and colleagues9 determined that MRI detected additional lesions in the ipsilateral breast in 16% of women, with 66% of those lesions found to be malignant on histology. Additionally, a systematic review of 22 studies (3253 patients) published by Brennan and colleagues10 found that MRI detected occult cancer in the contralateral breast in 4.1% of patients.
However, the additional information provided by breast MRI has not necessarily resulted in better surgical management or patient outcomes. Preoperative breast MRI has been associated with false-positive results, unnecessary preoperative biopsies and increased mastectomy rates.11–13 In a single-centre study with 5405 patients, Katipamula and colleagues13 reported that 54% of patients receiving MRI had mastectomy, while just 36% of patients without MRI had mastectomy. Miller and colleagues14 similarly reported that MRI use predicted a 1.8-fold increase in the odds of undergoing mastectomy at a single institution. In a randomized controlled trial of patients scheduled for BCS, Turnbull and colleagues15 reported that more mastectomies were performed in the group of patients assigned to MRI than in the group assigned to no additional imaging (7% vs. 1%). This trial also demonstrated that the rates of re-excision after BCS were not significantly different between patients who did or did not undergo preoperative MRI. Importantly, current National Comprehensive Cancer Network (NCCN) guidelines outline that there are no data to indicate that the use of MRI to determine local treatment has any impact on patient outcomes such as local recurrence and survival.16
So, the present role of preoperative breast MRI is not clearly established. Preoperative MRI is probably most useful for patients who are younger, have a strong family history of breast cancer and have mammographically dense breast tissue. Indeterminate or suspicious findings on breast MRI should be confirmed by second-look ultrasonography and image-guided biopsy to prevent unnecessary mastectomy based on false-positive findings.
Several randomized trials17–19 published in the late 1980s and early 1990s concluded that the oncological outcomes of BCS with combined whole-breast external beam radiation therapy (XRT) were equivalent when compared with mastectomy. As a result of these studies, the National Institutes of Health (NIH)20 issued a consensus statement in 1990, supporting BCS combined with radiotherapy – over mastectomy – as the preferred treatment of early-stage unilateral breast cancer. In the years subsequent to that statement, mastectomy rates markedly decreased in the USA as BCS increased dramatically.21–23 Lazovich and colaborators23 examined breast cancer surgery trends in the United States using the Surveillance, Epidemiology, and End-Results (SEER) Database. They found that during the years prior to the NIH statement (1985–1990), 35% of women with stage I breast cancer and 19% of women with stage II breast cancer underwent BCS. Following the consensus statement release in 1990, however, rates of BCS rose considerably each year. By 1995, the rates of BCS had nearly doubled; more than half of women with stage I breast cancer (60%) and many with stage II disease (39%) were opting for such treatment.
More recently, however, the trend towards BCS may be moving in the opposite direction, back towards maximum surgical therapy. Recently, several institutions have reported a marked rise in unilateral mastectomy rates within their individual institutions.13,24,25 In a retrospective review of 5865 patients with breast cancer treated at the Moffitt Cancer Center from 1994 to 2007, McGuire and colleagues25 concluded that mastectomy rates within their institution increased from 35% in 2004 to 60% in 2007. Similarly, Sorbero and colleagues24 at the Magee-Womens Hospital at the University of Pittsburgh reported that mastectomy rates increased from 28% during the years 1998–2000 up to 30% during the years 2003–2008. In a third single-institution study, Katipamula and colleagues13 reported that the mastectomy rate increased from 31% in 2003 to 43% in 2006 among 5405 patients treated at the Mayo Clinic.
To corroborate the findings published by these single-institution studies, Habermann and colleagues26 performed a population-based study exploring mastectomy trends in the USA for the treatment of unilateral breast cancer between the years 2000 and 2006. Using the SEER database, they found that mastectomy rates significantly decreased, while BCS rates increased; with the exception of the youngest patients, mastectomy rates decreased among all women regardless of tumour size, grade, oestrogen receptor (ER) status or nodal status and racial group. The contrast between increasing mastectomy rates seen within single institutions and the decreasing rates reported at the national level may reflect variations in referral patterns, patient selection, regional demographics, and local practice patterns; however, the authors could not exclude the possibility that national trends may trail the findings reported from single institutional studies, and that mastectomy rates in the USA may increase in the future.
Although overall survival rates are equivalent after mastectomy and BCS plus radiotherapy, patients treated with BCS are more likely to experience an ipsilateral breast tumour recurrence. Despite the widespread use of BCS, the optimal negative margin width after BCS for patients with DCIS or invasive cancer remains controversial, and prospective studies with standardized methods of margin processing and analysis are not available. Furthermore, randomized studies comparing re-excision versus no re-excision for ‘close’ margins have not been performed. The potential downsides of re-excising close margins include increased patient anxiety, worse cosmetic outcomes, increased costs, and delayed receipt of adjuvant therapy. Not surprisingly, therefore, survey studies confirm wide variation in acceptable margin width among surgeons.27,28 In a survey study of 318 surgeons, Azu and colleagues27 proposed the following scenario: what is the acceptable margin for a 60-year-old woman with a 1.4-cm area of DCIS treated with BCS plus radiotherapy? The responses were: tumour not touching ink, 10.2%; 1–2 mm, 42.2%; > 5 mm, 32.6%; and > 10 mm, 15.0%.
In a systematic review of 34 studies, Singletary and colleagues29 found that positive margins placed patients at greater risk for ipsilateral recurrence after BCS for early-stage invasive cancer, but did not find that wider negative margins resulted in lower recurrence rates. Similarly, in a recently published review, Morrow30 concluded that a negative margin of ‘tumour not touching ink’ was appropriate for invasive cancer, while 2 mm constituted an adequate margin for DCIS. Houssami and colleagues31 – in a meta-analysis of 21 studies including 14 571 patients – similarly found that recurrence rates were associated with positive margins after BCS for invasive cancer, but did not find that that the rate of ipsilateral recurrence changed based on margin status after adjusting for radiation and endocrine therapy. Finally, to distinguish differences between invasive cancer and DCIS, Dunne and colleagues32 performed a meta-analysis of 4660 patients with DCIS treated with BCS plus radiotherapy. They reported that local recurrence rates were increased with margins < 2 mm, but margins wider than 2 mm were not beneficial.
The results of these studies suggest that in the modern era of advanced breast imaging techniques, increasingly effective adjuvant therapies and more precise margin assessment, more extensive margins beyond ‘negative’ after BCS for early-stage invasive cancer and 2 mm for DCIS are unlikely to significantly impact local recurrence rates.
Surgical advances in breast conservation therapy for invasive breast cancer have combined oncological principles with plastic surgery techniques. The goal of ‘oncoplastic surgery’ is to perform complete surgical excision with negative margins while maximizing cosmetic outcomes.33,34 In contrast to the traditionally performed lumpectomy – in which tissue is excised and the cavity is closed at the skin level – oncoplastic surgery combines wide margin specimen removal with volume replacement reconstruction. The defect that results from a large specimen excision is filled by creating breast flaps and performing flap mastopexy; breast tissue flaps are developed along the chest wall adjacent to the lumpectomy site and reapproximated to fill the cavity.33 In addition to strategic placement of skin incisions and the use of mastopexy advancement flaps, oncoplastic surgery may also include bilateral breast reduction or lift to achieve symmetry. The end result may allow for larger breast excisions with acceptable cosmetic outcome, thus increasing the range of women who are acceptable candidates for breast-conserving therapy. However, 26–54% of women undergo a second operation for delayed reconstruction,35,36 the complication rate of which ranges from 10% to 31%,35,36 and which in one study required a mean period of hospitalization of nearly 2 days.35 In early follow-up, local recurrence rates appear to be similar to standard lumpectomy techniques. Published cosmetic outcomes are largely subjective, rated either by the patients or independently by surgeons; the cosmetic failure rate (subjectively defined as ‘moderate’, ‘poor’ or ‘unsatisfactory’ outcomes) ranges from 9% to 25%.37–39
The benefit of whole-breast radiotherapy following BCS has been established by several randomized trials demonstrating that local recurrence rates are higher in patients treated with surgery alone than in those who undergo surgery plus adjuvant postoperative, whole-breast radiotherapy.17–19,40,41 Alternatively, targeted intraoperative radiotherapy and accelerated partial breast irradiation (APBI) offer alternative methods of radiation delivery.
In a prospective, randomized trial of women with invasive breast cancer undergoing BCS, Vaidya and colleagues42 evaluated the use of intraoperative radiotherapy delivered directly to the tumour resection bed at the time of surgery compared with traditional postoperative whole-breast radiotherapy. Of the 1113 patients assigned to targeted intraoperative radiotherapy, 86% received intraoperative treatment only; the remaining 14% received intraoperative, targeted radiotherapy plus postoperative whole-breast radiotherapy. They found that after 4 years of follow-up, local recurrence rates were similar in the two groups (targeted radiotherapy group, 0.95%; whole-breast radiation group,1.2%; P = 0.41). In that study, the authors reported a similar rate of postoperative complications and major toxicity, but lower radiotherapy toxicity among the targeted radiotherapy patients.
In 2002, the US Food and Drug Administration (FDA) approved the use of an implantable balloon catheter, MammoSite (Hologic, Bedford, MA, USA), for use in APBI therapy. The effectiveness of the MammoSite device has been evaluated in several single- and multi-institution studies. A prospective study conducted by Benitez and colleagues43 reported no local or regional recurrences among the 36 patients with early-stage breast cancer who were followed for a median of 5.5 years. Chao and colleagues44 followed 80 patients for a median of 22.1 months after BCS and treatment with MammoSite and reported that two patients (2.5%) developed ipsilateral recurrences. The ASBS MammoSite Brachytherapy Registry reported ipsilateral recurrence rates of 2.2% at 3 years and 2.7% at 4 years of follow-up in its large cohort.45 Although these reports indicate outcomes similar to those whole-breast radiotherapy, the results of large multicentre randomized clinical trials with long-term follow-up are not yet available; consequently, the indications for APBI are not uniform across oncology practices. Currently, the NSABP/Radiation Therapy Oncology Group (RTOG) is conducting a randomized clinical trial to evaluate the effectiveness of APBI in women treated with BCS.
Despite the lack of long-term randomized outcome data, Abbott and colleagues46 found that the use of APBI has increased dramatically in the USA, whereas the use of whole-breast radiation is decreasing. By 2007, 6.8% of women in the SEER database treated with BCS plus radiation therapy had received APBI. Although APBI may be a favourable alternative to whole-breast radiation given a shorter course of therapy, the follow-up data regarding recurrence rates are still premature; as such, recommendations regarding use outside of a clinical trial cannot be made. Nevertheless, surgeons are playing an increasing role in directing and participating in the delivery of adjuvant radiation therapy.
About one-third of breast cancer patients in the USA undergo mastectomy.26 For breast cancer patients who require or request mastectomy treatment, the surgical options have dramatically increased in recent years. The traditional simple mastectomy remains an effective and commonly used treatment option for women who do not desire immediate breast reconstruction. Alternatively, oncological and plastic surgeons presently perform a variety of skin- and nipple-sparing mastectomies combined with reconstruction. Although the various reconstructive procedures are beyond the scope of this review, a discussion of the various mastectomy techniques is warranted.
Skin-sparing mastectomy (SSM) involves the en bloc removal of the breast tissue including the nipple–areola complex (NAC). In contrast to traditional simple mastectomy, the breast skin envelope is preserved to accommodate immediate reconstruction at the same time as mastectomy. Breast reconstruction is then performed immediately after SSM with autologous tissue and/or prosthetic implants. The choice of incision is dependent upon patients’ breast size, the location of any previous breast incisions, management of axilla and surgeon preference. Multiple studies have reported that the local recurrence rates are low after SSM and are similar to those following traditional mastectomy.47–50 In a recent survey study, Shen and collaborators51 reported that most surgeons believed that the oncological outcomes after SSM are equivalent to those after traditional mastectomy while the cosmetic outcomes are better with SSM. However, the complication rates are increased with SSM and immediate reconstruction as compared with traditional mastectomy. Complications include skin-flap necrosis, haematoma, cellulitis and loss of reconstruction.52
Despite technical improvements in mastectomy and reconstruction, removal of the NAC remains a psychological trauma for breast cancer patients. One of the most common negative patient complaints about SSM is dissatisfaction with nipple reconstruction;53 the advancement of nipple-sparing mastectomy (NSM) as an alternative approach, however, has been tempered by concern about occult malignant involvement in the NAC.54,55
Technically, the most commonly used incisions for NSM are the lateral radial incision and the inframammary fold incision (Figure 1). Mastectomy flaps are raised in a similar fashion to SSM and traditional simple mastectomy. The breast tissue deep to the NAC is excised and sent separately for pathological examination. Some institutions prefer to perform frozen section on this tissue while others wait for final pathological analysis. If malignant disease is identified in this tissue, then the NAC is subsequently excised – either at the time of mastectomy or later if malignant disease is found on final pathological examination. In about 3% of patients occult disease in the NAC requiring excision will be identified.56 In a review of 1826 patients who underwent NSM, the rate of recurrence within the NAC was only 0.16%.57 Locoregional recurrence rates are similar after NSM and SSM.58
FIGURE 1 Nipple-sparing mastectomy. Inframammary incision.
Nipple sensitivity and erectile function following NSM may be preserved in some patients. In a prospective study of 33 patients, Wagner and colleagues59 reported that 100% of evaluable patients had successful nipple erection at 6 and 12 months after surgery. In another study, Yeuh and collaborators60 reported that 75% of patients had some nipple sensitivity after NSM. Boneti and colleagues58 reported that the overall complication rates were similar after NSM and SSM; however, patient-rated cosmetic scores were significantly higher after NSM than after SSM. The primary complication unique to NSM is NAC necrosis, which occurs in about 5–10% of patients.59,61,62
Although specific selection criteria vary among authors, generally accepted indications include small tumour size (< 3 cm), adequate distance from tumour to nipple (> 2 cm), unicentric disease, lack of obesity and non-smoking status. Although NSM can be technically challenging and time-consuming, the cosmetic outcomes are outstanding in carefully selected women, with no apparent compromise in oncological outcomes (Figure 2).
FIGURE 2 Nipple-sparing mastectomy. Completed mastectomy and reconstruction.
While the use of BCS has increased or remained stable during the past decade, the rates of contralateral prophylactic mastectomy (CPM) among patients with unilateral breast cancer have markedly increased. An analysis of the SEER database found that the CPM rate among all surgically treated patients with invasive breast cancer increased by150% from 1998 to 2003 in the USA.63 These trends were observed for all cancer stages and continued to increase at the end of the study period with no plateau. Similar findings were observed among patients with DCIS.64 Other studies using different databases have confirmed these findings. In a study using the New York State Cancer Registry, McLaughlin and colleagues65 reported that CPM use more than doubled from 1995 to 2005. Single-institutional studies have also demonstrated marked increases in CPM rates.24,66 Young patient age, lobular histology, white race, higher education, the presence of a BRCA mutation and family history of breast cancer have been associated with higher CPM rates.24,63–68 Conversely, the rates of unilateral mastectomy have significantly decreased in the USA.64
CPM rates outside the USA have not been well documented. Metcalfe and colleagues,68 in a study of an international registry of women with unilateral breast cancer and BRCA mutation, reported that 49% of women in the USA underwent CPM. In contrast, the CPM rates in Europe and Israel were only about 5% for this same population of patients. Presumably, the CPM rates for patients without BRCA mutation are similarly much lower among patients treated outside the USA.
This trend towards more aggressive surgery is curious and counterintuitive in the modern era of minimally invasive surgery. Many factors probably contribute to increased CPM use. Public awareness of genetic breast cancer and increased BRCA testing may partially explain these observations. Improvements in mastectomy (including skin-sparing and nipple-sparing mastectomy) and reconstruction techniques and access to breast reconstruction probably also contribute to increased CPM rates. Additionally, many breast cancer patients substantially overestimate their risk of contralateral breast cancer.69 As young patient age is consistently associated with higher CPM rates, generational differences in the value of breast-conserving treatment (including radiation) may partially explain these trends. Finally, some investigators have suggested that the use of breast MRI is associated with increased CPM rates.24 However, in the SEER study, the sharp increase in CPM use preceded the widespread utilization of breast MRI in the USA.64
Most patients report being satisfied with their decision to undergo CPM.70–72 In a study of 572 women, Frost and colleagues70 reported that 70% were satisfied with their decision to undergo CPM at a mean follow-up of 14.5 years after surgery. The greatest reported benefit contributing to patient satisfaction is a reduction in breast cancer-related concerns.71,73 Some patients, however, may overestimate the cancer risk-reducing effectiveness of CPM. In a review of open-ended comments from women who underwent CPM, Altschuler and colleagues73 recorded comments such as ‘I do not worry about recurrence’ and I am ‘free of worries about breast cancer.’ Such comments suggest a lack of understanding of the benefits of CPM. To date, no prospective study has examined the factors that influence women to choose CPM; future studies should focus on the decision-making processes that lead to the choice of irreversible risk-reducing surgery.
The sentinel node in breast cancer surgery
Sentinel lymph node (SLN) biopsy has replaced routine ALND for most breast cancer patients with clinically normal lymph nodes. Several single- and multi-institutional reports have documented the accuracy of SLN biopsy.74–78 These studies demonstrated that with proper technique, SLN identification rates should be ≥ 95% with a false-negative rate of ≤ 5%. Highly accurate identification and low false-negative rates are desired for SLN biopsy, since the status of the axillary lymph node basin remains the most powerful predictor of long-term survival in patients with breast cancer, and pathological analysis of the axillary nodes provides essential information needed for determining adjuvant therapies.
In early studies radiocolloid, blue dye, or both, were injected peritumorally.74–76 Using the peritumoral injection site, investigators published that the SLN was identified in about 90–95% of patients; however, a significant learning curve was associated with this injection technique. False-negative rates ranged from 9% to 15% and did not drop to an acceptable rate of ≤ 5% until surgeons had performed 20–30 procedures.79,80 Subsequently, the use of alternative injection sites (skin or subareolar) came into practice and offered several advantages over standard peritumoral injection. The skin and subareolar area of the breast contain a much richer lymphatic network than the breast parenchyma; as such, a higher percentage of the tracer injected into the skin reaches the SLN, making identification much easier and more predictable, thus potentially shortening the learning curve. Several reviews of the available literature have demonstrated that subareolar injection is as accurate as peritumoral injection;81–83 furthermore, subareolar injection is an easy procedure that eliminates the need for image-guided injection of non-palpable tumours, making subareolar and cutaneous locations ideal for SLN injection.
In addition to the site of tracer injection, the SLN technique varies between surgeons in other respects. Some surgeons use a single agent (blue dye alone or radiocolloid alone), while others use dual agents for injections. The use of preoperative lymphoscintigraphy also varies among surgeons, as does the timing of injection of the radiocolloid; ‘day-before’, preoperative and intraoperative injections have all been utilized. High identification rates and low false-negative rates have been reported by experienced surgeons regardless of the specific SLN technique.
Today, SLN biopsy is a routine part of cancer staging for women with invasive breast cancer and a clinically negative axilla; conversely, patients who have biopsy-proven axillary disease or clinically positive axillary lymph nodes should undergo axillary lymph node dissection. Where the use of SLN biopsy remains controversial is in the setting of pregnancy, in patients with multicentric or multifocal disease, for those who have had previous axillary surgery and in patients with DCIS.
Current NCCN guidelines63 recommend that pregnant women with a confirmed breast cancer diagnosis and no evidence of distant metastatic disease should undergo axillary staging similar to what is recommended in non-pregnancy. Although blue dye is contraindicated, radiocolloid appears safe for sentinel node biopsy in pregnancy.
Jin Kim and colleagues84 performed peritumoral injections in women with multicentric disease, injecting one tumour with dye and another tumour with radiocolloid. They found that injecting tumours separately resulted in the identification of at least one SLN that was both blue as well as radioactive, thus demonstrating that all tumours of the breast drain via common lymphatic channels regardless of tumour quadrant. In a subsequent study, Kim and associates85 demonstrated that, in women with multicentric or multifocal disease, SLN biopsy identified a sentinel lymph node in 97.8% of women, with a false-negative rate of 7.9%. These rates were comparable to rates of women with unifocal cancer in the same study. Based on the data, the authors concluded that SLN biopsy can be used for women with multiple unilateral tumours. To assess the accuracy of SLN biopsy in women who have had previous axillary surgery, Port and colleagues86 reviewed 35 such patients within a single institution. They found that the SLN was identified in patients 75% of the time, and concluded that SLN biopsy remains a feasible option for women even in the setting of reoperative axillary surgery.
The role of SLN biopsy for axillary staging in the setting of DCIS remains an area of controversy; outcomes have not been validated in well-controlled trials. The rationale for performing SLN biopsy in this setting is that about 15% of women with DCIS diagnosed on core needle biopsy will have a final pathological diagnosis of invasive breast cancer in the excision or mastectomy specimen.87–90 Patients who are at high risk of having invasive cancer within their DCIS specimen are younger (< 55 years), have large mammographic abnormalities (> 4 cm) or have high-grade features or comedo necrosis on needle biopsy.91,92
A recent systematic review, however, reported that the incidence of American Joint Committee on Cancer (AJCC) pathological N1 SLN metastases was less than 1% among patients with pure DCIS.93 Furthermore, SLN biopsy was not associated with any improvement in oncological outcomes, and is not a risk-free procedure. The incidence of subjective and objective lymphoedema after SLN biopsy alone was 6% in the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial.94
Presently, SLN biopsy is indicated for patients with multicentric disease or previous axillary surgery, and selectively for DCIS. If invasive breast cancer is identified in the lumpectomy specimen of a patient with a preoperative diagnosis of DCIS, then SLN biopsy can be performed in a second operation. Finally, since SLN biopsy is not possible after mastectomy, SLN biopsy is recommended for patients with DCIS who undergo mastectomy treatment.91
Occult metastatic disease is defined by the presence of a tumour deposit within the SLN that is not initially detected with routine pathological evaluation using haematoxylin and eosin (H&E) staining, but is subsequently identified by immunohistochemical (IHC) evaluation. To clarify conflicting data that have arisen from retrospective studies,95,96 two large multicentre prospective trials have evaluated the clinical significance of occult disease within SLNs.97,98 Giuliano and colleagues97 published the results of the ACOSOG Z0010 trial in 2011. This study included 5210 women from 126 sites within a cooperative study; all enrolled women had small (≤ T2) tumours without clinically positive axillary nodes or metastatic disease, all underwent BCS with SLN dissection and all received adjuvant whole-breast radiotherapy. Patients were included if they had a SLN that was negative based on H&E analysis. Negative nodes were analysed using IHC at a central laboratory. Adjuvant systemic therapy was administered based on the preference of the individual treating physician; treating physicians were unaware of the results of the IHC staining, thus precluding the results from being used in the treatment decision-making process. With a median follow-up of 6.3 years, the presence of occult metastatic disease in the SLN did not have a negative impact on overall survival. In the NSABP B-32 trial, Weaver and colleagues98 found a 5-year overall survival rate of 96.4% for patients without occult metastases compared with 95.8% for patients with occult disease, a small but statistically significant difference. Notably, more patients in the ACOSOG Z0010 trial received adjuvant systemic therapy than in the NSABP B-32 trial. The authors of each of these trials have concluded that completion ALND is not indicated for patients with occult SLN metastases and that adjuvant therapy decisions should not be based on the presence of occult SLN metastases.
Since the adoption of SLN biopsy in the late 1990s, the practice has been to perform ALND for patients in whom the SLN is positive on H&E evaluation. A landmark multicentre, prospective, randomized trial, ACOSOG Z0011,99,100 was designed to determine the clinical significance of performing ALND for women with a positive sentinel lymph node. In this study, 891 women with a positive SLN were randomized to completion ALND versus SLN biopsy alone with no further specific axillary treatment. All women had early-stage disease (T1–T2) without palpable adenopathy, all underwent negative-margin BCS and SLN biopsy surgery only (mastectomy patients were excluded), and all had whole-breast radiotherapy postoperatively. Women were excluded from the study if they were pregnant, were treated with neoadjuvant chemotherapy or hormonal therapy or if they had bilateral breast cancer or multicentric disease. Patients with matted nodes, gross extranodal disease or three or more involved SLNs at the time of biopsy were also excluded.
In 2010, Giuliano and associates published the early results of Z0011.99 With a median follow-up of 6.3 years, there were no statistically significant differences in the rates of local or regional recurrence between women with positive SLN biopsy who underwent ALND and those who had no further axillary treatment. Although 27% of patients who underwent completion ALND had additional lymph node metastases, the incidence of axillary recurrence was less than 1% among patients who underwent SLN biopsy alone. Subsequently, the authors found that the 5-year overall survival rates were no different for women who had ALND dissection (91.8%) and those who underwent SLN biopsy alone (92.5%) for axillary staging.99 This is of particular import given that the risk of wound infections, seromas and paraesthesiae was significantly higher among women who had completion ALND.94 The authors therefore concluded that for the specific subset of women with early-stage breast cancer and clinically negative axillary lymph nodes who undergo BCS with subsequent whole-breast radiotherapy, there is no benefit in performing completion ALND.
Critics of this study correctly note that Z0011 did not reach the target accrual of 1900 patients with 500 deaths. Nevertheless, the test for non-inferiority between SLN alone versus ALND was 0.008. Other critics point out that the follow-up time was inadequate to fully analyse axillary recurrences. However, in NSABP B-04, the median time to axillary recurrence among mastectomy patients treated without axillary treatment was 14.8 months; also, 90% of axillary recurrences were clinically evident within 5 years.41 The results of this important trial have led clinicians to conclude that, among patients who meet the Z0011 inclusion criteria, ALND increases complications, does not decrease locoregional recurrences, and does not improve survival rates. Further studies will probably evaluate whether the inclusion criteria of Z0011 can be expanded to include a broader range of women, such as those who undergo mastectomy.
The question of when to perform SLN biopsy in the setting of neoadjuvant chemotherapy remains an area of persistent controversy; should the biopsy be performed before or after treatment? Two potential concerns with the use of SLN after neoadjuvant chemotherapy are (1) a lower identification rate and (2) a higher false-negative rate. One proposed explanation for the higher false-negative rate is that neoadjuvant chemotherapy may selectively eradicate metastases in the SLN, but not in other axillary nodes. As a result, a negative SLN biopsy may not accurately reflect the true status of the axilla.
In the NSABP B-27 trial, the success rate for identification of a SLN after neoadjuvant chemotherapy was 84.8%;101 this is considerably lower than the results from NSABP B-32, where the SLN identification rate was 97.2% among patients who did not receive neoadjuvant chemotherapy.102 Notably, the false-negative rate was similar between the two studies (B-27, 10.7%; B-32, 9.8%).
To overcome the potential limitations of performing SLN biopsy after neoadjuvant chemotherapy, some clinicians perform SLN before chemotherapy. The strategy of performing pretreatment SLN biopsy eliminates the potential for selective eradication of metastases in the SLN; however, the performance of SLN before preoperative chemotherapy requires a separate surgical procedure. Additionally, patients with a positive SLN have previously been committed to undergoing formal axillary lymph node dissection, thus limiting some of the benefit of neoadjuvant therapy downstaging. As practice patterns change as a result of the ACOSOG Z0011 trial99,100 and we perform fewer completion axillary lymph node dissections, patients with a favourable pathological response to chemotherapy may be spared the risks of ALND, thus negating one of the major disadvantages of pre-neoadjuvant therapy SLN biopsy.
The surgical options to treat breast cancer have become increasingly diverse during the past 15 years. Advances in surgical techniques have improved cosmetic outcomes with nipple- and skin-sparing mastectomies combined with immediate breast reconstruction. As a result of technological improvements, surgeons are now participating in the planning and treatment of patients with partial breast irradiation after BCS. Practice-changing clinical trials such as ACOSOG Z0011 will likely result in less radical axillary lymph node procedures. In the future, we anticipate that the surgeon’s role in breast cancer treatment will continue to be more complex. While mastectomies will still be required or requested by patients, image-guided ablative procedures (cryotherapy, radiofrequency ablation) may be used for selected patients. Depending upon the results of on-going randomized trials, radiation therapy options will likely expand. We also anticipate that the role of surgical axillary staging will become less important as more treatment decisions are based on genetic characteristics of the primary tumour.
Conflicts of interest
The authors report no potential conflicts of interest.
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