New Insights into the Surgical Management of Breast Cancer David M. Euhus, MD William Halstead is considered by many as the father of modern breast surgery. He popularized the notion that breast cancer progresses in an orderly fashion and that appropriately timed radical surgery can interrupt this progression to save lives. This view dominated for nearly 100 years and still persists to one extent or another in the minds of physicians and patients alike. Rapid advances in breast cancer biology have highlighted the heterogeneity of breast cancer and paradigm-shifting clinical trials have successfully challenged prevailing wisdom to effect a seed change in breast cancer surgery. Advances in radiation and systemic therapies permit more limited surgery for most patients. Recurrence rates of all kinds are on the decline; yet, paradoxically, use of bilateral mastectomy is increasing. Semin Radiat Oncol 26:25-36 C 2016 Elsevier Inc. All rights reserved.

Role of the Breast Surgeon

M

odern breast cancer treatment is an evidence-based, multimodal endeavor. Theoretically, a technician could enter a few medical history, imaging, and pathology variables into a computer and then e-mail the newly diagnosed patient an evaluation and treatment calendar based on the relevant practice guidelines. This should be resisted in the future, though it may be unavoidable. The breast surgeon usually provides the initial consultation after a new breast cancer diagnosis. This is an emotional time when myriad unknowns often fuel crippling anxiety. Consultation with a surgeon who possesses global knowledge of breast cancer biology and treatment options coupled with excellent communication skills ensures that the patient leaves this initial visit in a much better state of mind. At a minimum, the breast surgeon must have a working knowledge of the sources of heterogeneity in breast cancer natural history, genetics, breast imaging, breast surgery, systemic therapies, and radiation oncology. This knowledge is required to plot a likely course through the treatment journey and help the patient see the finite timeline leading to restoration of physical and psychological health.

Department of Surgery, Johns Hopkins University, Baltimore, MD. Conflict of interest: none. Address reprint requests to David Euhus, MD, Blalock 688, 600 N Wolfe St, Baltimore, MD 21287. E-mail: [email protected]

http://dx.doi.org/10.1016/j.semradonc.2015.09.007 1053-4296/& 2016 Elsevier Inc. All rights reserved.

After treatment begins, the breast surgeon shares responsibility with all of the other disciplines for optimizing outcomes. The primary role of the breast surgeon in the treatment phase of care is local-regional control. Operations must be tailored to individuals to maximize physical, psychosocial, and sexual functioning. Zeal to avoid local-regional recurrence must be balanced against the need to preserve breast contour and symmetry and to reestablish a sense of well-being.

Breast-Conserving Surgery Multiple randomized clinical trials have demonstrated that survival for early breast cancer is the same whether the breast is removed or not.1,2 Breast conservation is appropriate for most women diagnosed with early-stage breast cancer. Currently more than two-thirds of women with early breast cancer are treated with breast-conserving surgery (BCS),3,4 but this has been decreasing in recent years.3 The goal of partial mastectomy is to completely remove the cancer while preserving an excellent cosmetic outcome. It is never known with certainty whether there is residual cancer or not after surgery. Indeed, breast whole-mount studies have identified tumor foci more than 2-cm distant from the main tumor mass in 42%-47% of patients.5,6 The current standard is to accept a rim of normal breast tissue all of the way around the tumor as evidence of complete excision. The risk of local recurrence is more than doubled if this is not achieved.7 25

D.M. Euhus

26 Excision volume correlates strongly with eventual cosmetic outcome.8 The breast surgeon must carefully balance the competing goals of avoiding local recurrence while preserving contour and symmetry. Historically, 11%-59% of patients are returned to the operating room for re-excision of close or positive margins,8-12 but residual tumor is identified in only 23%-68%13-17 and this is most likely to be in situ cancer. Routine shaving of additional margins,18,19 intraoperative ultrasound guidance,20 radioisotope guidance,21,22 and intraoperative frozen section analysis23 have been investigated as approaches for reducing re-excision rates, but simply redefining a negative margin as “no ink on tumor” is likely to have the greatest effect (discussed later). For women who desire a smaller breast size, lumpectomy can be combined with bilateral reduction mammoplasty (Fig. 1). This so-called oncoplastic partial mastectomy permits

excision of larger volumes of breast tissue, increasing the probability of negative margins with a single procedure even with larger tumors.24 Positive margins in this setting often result in mastectomy rather than re-excision. Certain tumor features may alert the surgeon to impending margin difficulties. These include the presence of microcalcifications, mammographic density, lobular histology, and the presence of a DCIS component on the core biopsy.25-29 Predictors of residual tumor in the re-excision specimens include tumor size 43 cm, age o45 years, high tumor grade,14 and the extent of the involvement of the initial margins.15 Clinical judgement should dictate whether a given patient is returned to the operating room for re-excision or not. Even if there is “no ink on the tumor,” multiple close margins or even a margin that is close for DCIS increases the probability of finding residual disease.13

Figure 1 Breast reconstruction. (1A and B) “Oncoplastic” partial mastectomy combines a wide local excision with reduction mammoplasty, (2A and B) bilateral skin-sparing mastectomy with DIEP flap and nipple reconstruction, (3A and B) right nipple-sparing mastectomy with implant reconstruction and left augmentation for symmetry. (Adapted with permission from Dr Michele Manahan.)

New insights into the surgical management of breast cancer

27

Figure 2 Hazard estimates for ipsilateral breast tumor recurrence after breast-conserving surgery. (Adapted with permission from Jobsen et al.30)

Local Recurrence and Tumor Biology It has been suggested that “…about one breast cancer death (is) avoided by year 15 for every four recurrences avoided by year 10….”2 This conclusion is derived from survival data for women who received radiation therapy compared to those who did not. It is not at all clear that avoiding local recurrence through more extensive surgery would have any effect on survival. In fact, there are no randomized prospective trials demonstrating the survival advantage of one surgical procedure over another. Rates of ipsilateral breast tumor events after BCS exhibit a bimodal distribution with an initial peak at 4 years (likely representing true local recurrences) and then a second peak at approximately 12 years (likely representing second primary cancers, Fig. 2).30 The hazard ratio for death after a localregional recurrence is 2.58-3.04.31,32 Among node-negative patients, early local-regional recurrence and recurrence of estrogen receptor
negative breast cancer are particularly strongly associated with mortality.32 Positive margins,33 omitting a radiation boost,34 early age at diagnosis,35 and positive lymph nodes32,31 are consistent risk factors for local-regional recurrence after BCS. Each is associated with an approximate doubling of local recurrence risk. Although margins and administration of radiation are easily modifiable technical factors, age and node status reflect tumor biology and are not modifiable. Triple-negative and HER2-positive breast cancers have the greatest risk of local-regional recurrence.36-38 However, data from National Surgical Adjuvant Breast and Bowel Project (NSABP) B14 and B20 showed that a 21-gene recurrence score could identify women with estrogen receptor
positive breast cancer who were at increased risk for local-regional recurrence.39 Early age at diagnosis is increasingly recognized as a risk factor for local-regional recurrence after BCS. This is likely

explained by biology. Breast cancer in young women is more likely to have aggressive biological features including higher grade, higher proliferation, and adverse subtypes (eg, luminal B and triple-negative breast cancer).40-43 Adverse biology in younger women is also demonstrated using a 70-gene recurrence score.44 Local-regional recurrence rates are significantly higher after BCS than mastectomy for women of age r40 years. This risk is significantly reduced by adjuvant systemic therapies but remains approximately 1% per year for up to 15 years.45 It is tempting to apply the maxim that “… about one breast cancer death (is) avoided by year 15 for every four recurrences avoided by year 10…,”2 and recommend mastectomy to younger women to improve survival. However, there is currently no clear evidence that mastectomy improves survival in young women. On the contrary, historical experience with radical nodal surgery suggests that more extensive surgery is not the solution to bad biology.46

Local-Regional Recurrence Risk is Decreasing Historically, ipsilateral breast tumor recurrence rates have been estimated at 0.8% per year.7 A recent retrospective study of 5974 patients with stage 1 breast cancer aged 50 years or older undergoing BCS and radiation therapy found that, between 1989 and 2006, local recurrence rates have decreased from approximately 0.6% per year to 0.2% per year (Fig. 3).47 Similarly, a review of 53 randomized clinical trials including 86,598 patients found that local-regional recurrence events have decreased significantly between 1990 and 2011.48 Localregional recurrence accounted for 30% of recurrence events in the early time period but only 15% in the later time period. The use of systemic chemotherapy was associated with the largest differential decline in local-regional recurrence. Indeed, effective systemic treatment directed to the right patients

D.M. Euhus

28

Figure 3 Time trend of local recurrence rates for patients with stage 1 breast cancer treated with breast-conserving therapy. (Drawn from data included in Canavan et al.47)

significantly reduces local recurrence rates for triple-negative breast cancer,49 hormone receptor
positive breast cancer,50 and HER2/neu-amplified breast cancer.51-53 Local-regional recurrence rates are also declining for young women. A retrospective study that included 1143 women r40 years of age with stage 1-2 breast cancer treated with BCS and radiation therapy between 1988 and 2010 found that local recurrence rates have declined from approximately 2% per year to 0.7% per year. This was attributed to the use of adjuvant systemic therapy, which reduced local recurrence risk by 60%.54,55 Effective adjuvant systemic therapies are making isolated local recurrence a rare event.

Lumpectomy Margins Among the prospective trials of breast conservation, NSABP B06 was the only one that required microscopic negative margins56; the others simply stipulated gross removal of the tumor. Nevertheless, approximately one-fourth of women undergo re-excision after lumpectomy and for nearly half of these the intent is to improve on an already microscopic negative margin.57 This behavior is likely driven by a desire to avoid local recurrence. It is reasonable to ask, however, whether wider margins translate into reduced local recurrence in the era of effective adjuvant systemic therapies, which are known to reduce local recurrence.47,48 This is the context for a recent study-level meta-analysis directed at determining the relationship between margin width and local recurrence.33 This meta-analysis included 33 studies reporting margin status and outcome for 28,162 patients treated between 1984 and 1996. The 2

challenges that had to be dealt with were (1) inconsistency in the definition of negative, close, or positive margins and (2) declining local recurrence rates over time. In general, failure to achieve a clearly negative margin approximately doubled local recurrence risk. There is a suggestion in the data that greater margin distances are associated with lower local recurrence rates; however, after adjustment for median follow-up time, only final margin status (defined as negative, close, or positive) remained statistically significant. Importantly, local recurrence rates were not statistically significantly better for 2- or 5-mm margins as compared to 1-mm margins. Additional conclusions from this meta-analysis are shown in Table 1. This metaanalysis informed a joint consensus statement between the Society of Surgical Oncology and the American Society of Radiation Oncology that proposed “no ink on tumor” as the acceptable excision margin.7 There is some concern that this may not be the correct interpretation of the meta-analysis data. Specifically, local recurrence was statistically significantly greater for close margins as compared with negative margins (odds ratio ¼ 1.74, 95% CI: 1.42-2.15). This suggests that there is some margin distance that would be associated with lower local recurrence risk than that of “no ink on tumor,” but vagaries in the definitions of close or negative used by the different studies make it impossible to specify this value precisely.

Breast Conservation for Multicentric Breast Cancer Recent advances in breast imaging and more widespread use of multiple imaging modalities have increased the prevalence of multicentric breast cancer to 13%-75% depending on how it is defined.58-63 More frequent identification of multicentric disease is linked to the increasing use of bilateral mastectomy to treat early breast cancer.64-69 Dr Bernard Fisher has voiced strong concern about this trend in a recent commentary.70 Autopsy series identify occult breast cancer in 5%-25%,71-74 whereas systematic assessment of mastectomy specimens shows that breast cancer is multicentric in 13%-75% of cases with most studies reporting greater than 50%.5,6,75-77 Nevertheless, the NSABP B-06 trial, which randomized women with early breast cancer to mastectomy or breast conservation, failed to show any benefit for mastectomy in local-regional recurrence or survival.56 Clearly all foci of breast cancer are not equal and many remain quiescent for 20 years or more even with no surgical treatment at all. It should be noted that in the NSABP B-06 trial the addition of whole-breast radiation after

Table 1 Key Observations From a Recent Meta-Analysis Assessing Local Recurrence Rates in Relation to Resection Margins

 Local recurrence rates are not statistically significantly better for 2- or 5-mm margins as compared to 1-mm margins.  A radiation boost does not “fix” positive margins (ie, local recurrence risk is still higher than that in margin-negative patients)  Effective adjuvant systemic therapy does not “fix” positive margins  There is no tumor subtype that does not benefit from negative margins  Lobular cancers do not require wider margins than that of any other cancer  Young patients do not require wider margins than do older patients

New insights into the surgical management of breast cancer lumpectomy was associated with a significant reduction in ipsilateral breast tumor recurrence. Dr Fisher summarizes the findings well, “Because there was no statistically significant difference in outcome among the three treatment groups in the B-06 trial after 20 years of follow-up, tumor multicentricity was deemed not to affect outcome.”70 Indeed, modern studies confirm that multicentric breast cancer is not associated with worse overall survival than unifocal breast cancer.58,78 BCS, including multiple lumpectomies, may be an option for patients with multicentric breast cancer. Early retrospective studies suggested an increase in local recurrence for multiple ipsilateral breast cancers treated by breast conservation,79-83 but more recent studies have not confirmed this.79,80,84-88 The reason for this discrepancy is thought to be the higher rate of larger, clinically apparent tumors in the early studies in contrast with the smaller, largely screen-detected tumors in the contemporary studies. More widespread use of effective adjuvant systemic therapy is also likely to play a role. The largest of the recent studies included 476 women with multiple ipsilateral breast tumors and reported a 5-year local recurrence of 5.1%.84 Available retrospective data show that breast conservation in the setting of multicentric breast cancer is not associated with an increased rate of local recurrence or an increase in breast cancer mortality. Dr Bernard Fisher has summarized this well: “I have concluded that the data in the individual and review articles that I examined provide no scientific justification for performing mastectomy in women with breast cancer multicentricity.”70 In clinical practice, however, some surgeons are comfortable with breast conservation for multicentric breast cancer whereas others are not. This is the source of equipoise that has prompted the American College of Surgeons Oncology Group (ACoSOG) to design and activate a prospective single-arm observational trial evaluating breast conservation in the setting of multicentric breast cancer (Z11102). The primary end point is ipsilateral breast tumor recurrence. Secondary end points include adverse events and cosmesis.

Mastectomy Use of unilateral mastectomy to treat early-stage breast cancer is declining.89 Mastectomy is medically indicated when the tumor-to-breast size ratio precludes cosmetic local excision, when adjuvant radiation therapy, if indicated, is not possible because of logistical or medical issues, or when detection of an ipsilateral breast tumor recurrence would be difficult or impossible for whatever reason. Local recurrence after mastectomy ranges from much less than 1% per year to more than 2% per year depending on patient and tumor factors.90 Lymph node status is, by far, the strongest predictor of local recurrence risk after mastectomy.91,92 The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) recently performed a meta-analysis using patient-level data from women enrolled in clinical trials comparing postmastectomy radiation therapy vs no radiation after mastectomy.90 Local-regional recurrence rates were approximately 3% per year for women with 4 or more positive nodes who were not treated with radiation. A Japanese study of

29 women treated in about the same time period, most of whom received adjuvant systemic therapy, estimated local recurrence risk at 1.5% per year for patients with 4 or more positive lymph nodes and no other risk factors.92 Postmastectomy chest wall radiation is increasingly recommended for women with any positive lymph nodes based on EBCTCG data suggesting a reduction in 10-year local-regional recurrence risk from 20% to 4%, which translated into an 8% improvement in 20-year breast cancer mortality.90 Survival benefit for postmastectomy radiation is limited to women with a high risk of local-regional recurrence (eg, something in excess of 1% per year). EBCTCG data, which are from women treated before 2000, estimated local-regional recurrence rates at approximately 2% per year for women with 1-3 positive lymph nodes who were treated with mastectomy and adjuvant systemic therapy, but no radiation. The addition of radiation reduced local-regional recurrence to less than 0.5% per year and improved 20-year breast cancer mortality by 8%. However, local-regional recurrence risk has decreased over time for patients treated with mastectomy just as it has for those treated with BCS. Retrospective data from MD Anderson Cancer Center suggest that local-regional recurrence rates were in excess of 2% per year for patients with 1-3 positive lymph nodes treated with mastectomy but no radiation between 1978 and 1997, but have decreased to approximately 0.6% per year for women treated between 2000 and 2007.93 Other risk factors for local-regional recurrence after mastectomy include high tumor grade,94 positive margins,95,94 larger tumors,96,92 skin or chest wall involvement,92 marked lymphovascular invasion,92 and hormone receptor
negative phenotype.92,95 Early age at diagnosis is an inconsistent risk factor for local-regional recurrence after mastectomy.97,98 A nomogram for estimating local recurrence risk after mastectomy without radiation has been published.99 An iteration of this model was validated in 1545 patients treated between 2002 and 2007. The model included age, lymphovascular invasion, estrogen receptor status, and number of involved lymph nodes. Overall, 5-year local-regional control rates with and without postmastectomy chest wall radiation in low-risk, intermediate-risk, and high-risk groups were 98% vs 97% (P ¼ 0.41), 97% vs 91% (P ¼ 0.0005), and 89% vs 50% (P ¼ 0.0002), respectively.100

Use of Bilateral Mastectomy is Increasing Before 1990, most women with stage 1 or 2 breast cancer were treated with mastectomy.101 In 1991, the National Institutes of Health published a consensus statement advocating breast conservation for early-stage breast cancer.1 This was followed by a steady rise in the use of breast conservation with a complementary decline in mastectomy. By 2005, 65%-75% of patients with early-stage breast cancer were treated by breast conservation.3,4 Tuttle was among the first to notice a slow trend for increasing use of contralateral mastectomy dating back to at least 1998.102 It is now clear that both breast conservation and unilateral mastectomy rates began to decline

D.M. Euhus

30 Table 2 Observational Studies of Contralateral Prophylactic Mastectomy and Outcome Data Source

CPM

Control

F/U Years

Breast Cancer
Specific Survival Outcome. Hazard Ratio and 95% CI Unless Otherwise Stated

Overall Survival Outcome. Hazard Ratio and 95% CI Unless Otherwise Stated

Institutional Cancer Registry109 Cancer Research Network (6 HMOs)110 SEER112 Mayo Clinic111 MD Anderson114 California Cancer Registry106 SEER113 Regional Cancer Registries 115 Multi-institutional Registry116

64

182*

15

55% vs 28%

64% vs 48%

1072

317†

5.7

0.57 (0.45-0.72)

0.60 (0.50-0.72)

8902 385‡ 532 11,692

98,204* 385*,‡ 3357* 73,622*

4 17.3 4.5 7.4

0.63 (0.57-0.69) 0.66, (0.53-0.82) 0.75 (0.59-0.97) 0.85 (0.76-0.94)

– 0.68 (0.54-0.86) 0.74 (0.56-0.99) 0.75 (0.70-0.82)

25,961 105§

423,217† 593*,§

5 8.6-9.7

0.84 (0.79-0.89) 88-95% vs 71%

0.83 (0.80-0.88) 0.37 (0.17-0.80)

181§

209*,§

14.3

0.52 (0.29-0.93)

0.58 (0.34-0.97)

CPM, contralateral prophylactic mastectomy; F/U, follow-up. *Compared to unilateral mastectomy. † Compared to no contralateral mastectomy (includes breast conservation). ‡ High-risk family history. § BRCA gene mutation carriers.

significantly in approximately 2005 as more and more women with early breast cancer opted for bilateral mastectomy.3,89 This trend is sustained and increasing at the present time. Available evidence suggests that recent increases in bilateral mastectomy are largely driven by the patients themselves. Some view this as a laudable example of respecting patient autonomy and promoting shared decision making as advocated by a recent Institute of Medicine roundtable.103 Others are concerned that fear of recurrence and death may cause some women to mistakenly choose more radical surgery. It has been pointed out that the best interests of the individual are not always served by permitting them to independently make complex medical decisions at a vulnerable, emotional time.104,105 A study from the California Cancer Registry found that nonHispanic white women with private insurance who were treated at an NCI designated cancer center were most likely to opt for bilateral mastectomy.106 This study noted increase in the use of bilateral mastectomy across all age groups, but the trend was most pronounced for women younger than 40 years. Patients rather than surgeons appear to be driving this trend with anxiety and fear of recurrence topping the list of reasons for choosing bilateral mastectomy.107 Because of improved surgical technique and excellent reconstruction options, mastectomy is rarely a disfiguring procedure in the modern era and can actually improve breast appearance in some women (Fig. 1). There is evidence that the availability of reconstruction is one of the drivers behind the increasing rates of bilateral mastectomy in women with early breast cancer.89

Bilateral Mastectomy and Outcome There are no randomized prospective clinical trials addressing disease-specific or overall survival for early-stage breast cancer treated by bilateral mastectomy. Based on randomized trials comparing unilateral mastectomy and breast conservation it is usual to counsel women that their survival would be the same whether they have a lumpectomy or a bilateral mastectomy. More than 80% of young women opting for contralateral prophylactic mastectomy understand this, yet 94% list improving survival as extremely or very important in their decision to undergo contralateral prophylactic mastectomy.108 It is currently not certain that bilateral mastectomy does not improve survival for some subgroups of women with earlystage breast cancer. The available data come from 9 observational studies derived from single- or multi-institutional registry databases, including those of the Surveillance, Epidemiology and End Results (SEER) program and the California Tumor Registry. The published results are surprisingly consistent across studies (Table 2). Contralateral prophylactic mastectomy reduces contralateral breast cancer risk by 95%97%,109-111 reduces breast cancer
specific mortality by 1543%,106,110-114 and reduces all-cause mortality by 17%32%.106,110,111,114,113 The major criticism of these studies is that most also demonstrated a statistically significant reduction in mortality from non
breast cancer causes, suggesting that there is significant selection bias with the healthiest women choosing bilateral mastectomy.113 However, it is not certain that selection bias accounts for all of the observed benefits. It should be noted that the California Cancer Registry study

New insights into the surgical management of breast cancer reported improved outcome only for the comparison between bilateral and unilateral mastectomy and not for the comparison between bilateral mastectomy and breast conservation. Overall survival was identical for women treated with BCS and radiation therapy compared to bilateral mastectomy.106 This could be interpreted to mean that if there is a survival advantage for bilateral mastectomy, the same advantage could be obtained with the use of radiation therapy. Similar or greater outcome effects for bilateral mastectomy were posted by 2 additional studies,115,116 which were limited to women with BRCA gene mutations. In addition, data from MD Anderson suggest that the survival benefits of bilateral mastectomy are largely limited to young women with hormone receptor
negative breast cancer.112,114 This is a subgroup of women with an elevated risk for contralateral breast cancer.

Living With the Decision for Bilateral Mastectomy Most women report satisfaction with their bilateral mastectomy decision on close-ended questioning, but many express negative feelings on open-ended questioning.117 Eliciting feelings of regret is difficult because “A combination of acceptance of our choice and denial of the possibility that we chose unwisely makes life easier.”118 Satisfaction after mastectomy is most strongly linked to patient perception of the quality of the information conveyed preoperatively and overall satisfaction with the plastic surgeon.119 This suggests that large investments of time before surgery pay dividends in the long term. It is important to recognize, however, that the appearance of a reconstructed breast can change over time and satisfaction in the early postoperative period does not necessarily translate into long-term satisfaction. It has been observed that satisfaction with implant reconstruction diminishes with time, whereas satisfaction with autologous tissue reconstruction increases.120,121 This is because the appearance of the reconstructed breast changes with time. An implant reconstruction may contract and elevate over time, whereas autologous tissue reconstructions tend to settle and age more like a normal breast. Implant reconstruction after unilateral mastectomy can result in considerable asymmetry over time; consequently, satisfaction is greater for autologous reconstruction than implant reconstruction after unilateral mastectomy.122 Bilateral implant reconstruction can preserve symmetry over time and is, by far, the most common type of reconstruction.123 A study has reported that breast conservation patients have better quality of life and higher satisfaction rates than mastectomy patients.124 Another found that satisfaction is the greatest and most stable over time for women who had mastectomy with autologous tissue reconstruction.121 Interestingly, satisfaction with implant reconstruction or BCS diminished over time, whereas satisfaction with mastectomy and no reconstruction increased over time, but never reached the level of the autologous tissue reconstruction patients.

31

Figure 4 Local recurrence rate vs follow-up time for skin-sparing (unfilled circles) and nipple-sparing (filled circles) mastectomies series with 100 or more cases.

Nipple-Sparing Mastectomy More widespread use of skin- and nipple-sparing mastectomy coupled with excellent reconstruction have made mastectomy a more acceptable option for many women with early breast cancer. Nipple-sparing mastectomy, in particular, has gained in popularity in recent years.125 Modern nipple-sparing mastectomy performed for breast cancer should not be the same procedure as subcutaneous mastectomy for benign breast disease described in the 1960s.126,127 Subcutaneous mastectomy intentionally leaves glandular breast tissue behind the nipple-areolar complex and any existing scars. Modern nipplesparing mastectomy should be an oncologic procedure that endeavors to remove the entire breast while preserving the skin and nipple. Short of removing all of the skin of the chest wall, no mastectomy completely removes every terminal duct-lobular unit of the breast. Microscopic residual gland tissue can be identified under the peripheral skin, in the inframammary fold, and in the nipple. Nevertheless, nipple recurrence is a rare event after nipple-sparing mastectomy128-130 and has little effect on outcome.131-133 Local recurrence rates are similar for nipple-sparing mastectomy as for standard skin-sparing mastectomy (Fig. 4).134 Nipple ischemia occurs in 9% with complete nipple loss in 2%.134 Nipple sensation is not preserved. Various criteria have been proposed in the past for selecting mastectomy patients for the nipple-sparing approach. With increasing experience, nipple preservation can be considered as long as there is no nipple or skin involvement and the tumor can be completely removed with a negative margin. There are approaches for managing extreme nipple ptosis, but standard skin-sparing mastectomy and nipple reconstruction can be accomplished in these women with excellent patient satisfaction.135 Nipple-sparing mastectomy with expander reconstruction is a reasonable option for the irradiated breast,136 for the patient who would require radiation,137 for patients with prior cosmetic breast surgery,138 and for patients with genetic breast cancer predisposition.139

D.M. Euhus

32

Management of the Axilla The importance of axillary nodal metastases in breast cancer has been recognized at least since the time of Wilhelm Fabry (1560-1634), who described axillary nodal excision in conjunction with primary tumor surgery.140 In the late 19th century, Halstead141 popularized the notion that radical nodal surgery could interrupt breast cancer progression and save lives. This view was challenged by Devitt142 based on retrospective data that failed to show a survival advantage for radical nodal surgery; nevertheless, axillary dissection remained the standard of care for nearly all patients with early breast cancer. The randomized prospective NSABP B-04 trial, which was first reported in 1977, confirmed that the addition of axillary dissection to mastectomy does not improve distant disease-free or overall survival,143 but axillary dissection continued largely because of the importance of nodal status for making adjuvant chemotherapy decisions. The afferent lymphatic drainage patterns of the breast were well worked out by 1953144 and by 1977 Cabanas145 had coined the term “sentinel lymph node” to describe the first inguinal lymph nodes to receive metastases from penile cancer. Sentinel lymph node biopsy did not gain clinical acceptance for cancer staging until Morton again validated the concept of lymphatic mapping in a feline model146 and then established the feasibility of the technique in a series of patients with melanoma reported in 1992.147 Giuliano et al148 quickly adapted the technique to breast cancer and reported his first series of cases in 1994. The safety of omitting axillary dissection in clinically nodenegative patients with negative sentinel nodes has been well established in randomized prospective clinical trials149,150 and is currently the standard of care. The place of sentinel node biopsy in patients receiving neoadjuvant chemotherapy is still debated, with some advocating for its use before chemotherapy and others after. Proponents of nodal assessment before chemotherapy cite an increased false-negative rate after chemotherapy that ranges from 8%-11% 151-153 and also feel that the initial nodal status is required to make decisions on radiation. The counterargument is that chemotherapy reduces the pathologic node-positive rate by 37%,154 potentially sparing axillary dissection in some women, and nodal status after neoadjuvant chemotherapy (not before) should dictate subsequent management. Axillary dissection causes chronic arm and shoulder symptoms, including lymphedema, in nearly one-third of patients155 and its use is currently being challenged even for sentinel-node-positive patients.156 The International Breast Cancer Study Group (IBCSG)-23-01 trial reported 5-year axillary recurrence rates less than 1% for clinically nodenegative patients with micrometastases in sentinel nodes who did not undergo axillary dissection and identical disease-free and overall survival compared with axillary dissection.157 The ACoSOG Z11 trial also reported axillary recurrence rates less than 1% for clinically node-negative patients with positive sentinel nodes treated without axillary dissection.158 Diseasefree and overall survivals were the same as that for axillary dissection.159 Women with positive sentinel nodes who forego

axillary dissection should receive adjuvant radiation and systemic therapy. The AMOROS trial suggests that radiation therapy is to be preferred over axillary dissection because of significantly lower lymphedema rates.160 Sentinel node biopsy is being considered also for patients with clinically positive nodes who achieve a clinically complete response with neoadjuvant chemotherapy. Data from the Sentinel lymph node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA) trial, ACoSOG Z1071, and a meta-analysis suggest that the falsenegative rate in this setting is 13%-14%,161-163 but it is reduced to less than 10% with the use of dual tracers (radiocolloid and blue dye), retrieving at least 3 sentinel nodes, and removing the previously positive node identified by clip placement. Who, if anyone, requires both axillary dissection and axillary radiation is currently unclear. The currently accruing Alliance A011202 trial randomizes clinically node-positive patients with persistent pathologic positive nodes after neoadjuvant chemotherapy to axillary dissection plus axillary radiation vs axillary radiation only. The NSABP B-51/RTOG 1304 (NRG9353) trial randomized clinically node-positive patients who are pathologic node negative after neoadjuvant chemotherapy to regional nodal radiation vs no axillary treatment.

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