Peter D. Beitsch, MD Objective To determine the effects of complete axillary lymph node dissection (ALND)
on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer.
Pat W. Whitworth, MD
Design, Setting, and Patients The American College of Surgeons Oncology Group
Peter W. Blumencranz, MD Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients
A. Marilyn Leitch, MD from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive
breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases iden-
Sukamal Saha, MD tified by frozen section, touch preparation, or hematoxylin-eosin staining on perma-
Linda M. McCall, MS nent section. Targeted enrollment was 1900 women with final analysis after 500 deaths,
Monica Morrow, MD but the trial closed early because mortality rate was lower than expected.
Interventions All patients underwent lumpectomy and tangential whole-breast irra-
A
XILLARY LYMPH NODE DISSEC- diation. Those with SLN metastases identified by SLND were randomized to undergo ALND
tion (ALND) has been part of or no further axillary treatment. Those randomized to ALND underwent dissection of 10
breast cancer surgery since the or more nodes. Systemic therapy was at the discretion of the treating physician.
description of the radical mas- Main Outcome Measures Overall survival was the primary end point, with a non-
tectomy.1 ALND reliably identifies nodal inferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone
metastases and maintains regional con- is noninferior to ALND. Disease-free survival was a secondary end point.
trol,2,3 but the contribution of local Results Clinical and tumor characteristics were similar between 445 patients ran-
therapy to breast cancer survival is con- domized to ALND and 446 randomized to SLND alone. However, the median num-
troversial.4,5 The Early Breast Cancer Tri- ber of nodes removed was 17 with ALND and 2 with SLND alone. At a median fol-
alists’ Collaborative Group synthesized low-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8%
findings from 78 randomized con- (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-
trolled trials, concluding that local con- 95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-
86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The haz-
trol of breast cancer was associated with ard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without
improved disease-specific survival.6 adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
ALND, as a means for achieving lo-
Conclusion Among patients with limited SLN metastatic breast cancer treated with
cal disease control, carries an indisput-
breast conservation and systemic therapy, the use of SLND alone compared with ALND
able and often unacceptable risk of com- did not result in inferior survival.
plications such as seroma, infection, and
Trial Registration clinicaltrials.gov Identifier: NCT00003855
lymphedema.7-9 Sentinel lymph node
JAMA. 2011;305(6):569-575 www.jama.com
dissection (SLND) was therefore devel-
oped to accurately stage tumor- Author Affiliations: John Wayne Cancer Institute at (Dr Leitch); McLaren Regional Medical Center, Michi-
draining axillary nodes with less mor- Saint John’s Health Center, Santa Monica, California gan State University, Flint (Dr Saha); American College
bidity than ALND.10 SLND alone is the (Dr Giuliano); M. D. Anderson Cancer Center, Hous- of Surgeons Oncology Group, Durham, North Caro-
ton, Texas (Dr Hunt); Mayo Clinic Rochester, Roch- lina (Ms McCall); and Memorial Sloan-Kettering
accepted management for patients whose ester, Minnesota (Dr Ballman); Dallas Surgical Group, Cancer Center, New York, New York (Dr Morrow).
Dallas, Texas (Dr Beitsch); Nashville Breast Center, Corresponding Author: Armando E. Giuliano, MD, John
Nashville, Tennessee (Dr Whitworth); Morton Plant Wayne Cancer Institute at Saint John’s Health Cen-
For editorial comment see p 606. Hospital, Clearwater, Florida (Dr Blumencranz); Uni- ter, 2200 Santa Monica Blvd, Santa Monica, CA 90404
versity of Texas Southwestern Medical Center, Dallas (giulianoa@jwci.org).
©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 569
60 60
50 50 alone group, 42; ALND group, 52). The
40 40
30 30
use of SLND alone compared with ALND
20 ALND 20 did not appear to result in statistically
10 SLND alone Log-rank P = .25 10 Log-rank P = .14
inferior survival (FIGURE 2) (P=.008 for
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 noninferiority). The unadjusted HR
Years Years
No. at risk comparing overall survival between the
ALND 420 408 398 391 378 313 223 141
SLND alone 436 421 411 403 387 326 226 142
74
74
420 369 335 310 286 226 152
436 395 363 337 307 231 147
83
81
37
36
SLND-alone group and the ALND group
was 0.79 (90% CI, 0.56-1.10), which
ALND indicates axillary lymph node dissection; SLND, sentinel lymph node dissection. did not cross the specified boundary of
1.3 (FIGURE 3). The 5-year overall sur-
served mortality rate for pooled data number of nodes with histologically vival rates were 92.5% (95% CI, 90.0%-
from the 2 groups. The date of last fol- demonstrated tumor involvement (in- 95.1%) in the SLND-alone group and
low-up for this analysis was March 4, cluding SLNs) in the ALND group and 91.8% (95% CI, 89.1%-94.5%) in the
2010. SLND-alone group was equal (1 [IQR, ALND group. This was substantially
Patients were enrolled from 115 in- 1-2] for both groups). Hematoxylin- greater than the 80% anticipated at pro-
stitutions, which included affiliates of the eosin–stained tumor deposits no larger tocol design. The HR for overall sur-
Cancer Trials Support Unit and the than 2 mm were defined as microme- vival adjusting for adjuvant therapy
North Central Cancer Treatment Group. tastases and were identified in SLNs of (chemotherapy, endocrine therapy,
Of 891 patients, 445 were randomly as- 137 of 365 patients (37.5%) in the and/or radiation therapy) and age for
signed to the ALND group and 446 to ALND group compared with 164 of 366 the SLND-alone group compared with
the SLND-alone group (FIGURE 1). (44.8%) in the SLND-alone group the ALND group was 0.87 (90% CI,
Thirty-five patients were excluded af- (P=.05). In the ALND group, 97 of 355 0.62-1.23). The adjusted HRs compar-
ter withdrawing consent prior to sur- patients (27.3%) had additional metas- ing the SLND-alone group with the
gery. The 103 ineligible patients were tasis in lymph nodes removed by ALND, ALND group in the other multivari-
included in the analyses reported here. including 10% of patients with SLN able models ranged from 0.86 to 0.92
Because this was a noninferiority trial, micrometastasis who had macroscopi- (T ABLE 2), all similar to the unad-
a more conservative analysis was per- cally involved non-SLNs removed. Total justed rate of 0.79. An exploratory
formed on the treatment-received nodal involvement is summarized in analysis revealed that treatment with
sample (n=813 patients); 32 patients Table 1; 21.0% of patients undergoing ALND vs SLND alone produced no sta-
in the ALND group did not have ALND, ALND had 3 or more involved nodes tistically significant difference in out-
and 11 patients in the SLND-alone compared with 3.7% undergoing SLND come among patients grouped by recep-
group had ALND. No qualitative alone. Four or more involved nodes tor status of the primary tumor (ER⫹/
differences were observed between were seen in 13.7% of patients receiv- PR⫹ or ER−/PR−).
treatment-received sample and intent- ing ALND and 1.0% of those receiving
to-treat sample analyses, so only intent- SLND alone. Disease-Free Survival
to-treat results are reported. Disease Adjuvant systemic therapy was de- Disease-free survival (Figure 2) did not
characteristics at baseline were well bal- livered to 403 women (96.0%) in the differ significantly between treatment
anced between the 2 groups (TABLE 1). ALND group and 423 women (97.0%) groups. The 5-year disease-free survival
in the SLND-alone group.31 No differ- was 83.9% (95% CI, 80.2%-87.9%) for
Treatment Results ences in the proportion of women re- the SLND-alone group and 82.2% (95%
There was an expected difference ceiving endocrine therapy, chemo- CI, 78.3%-86.3%) for the ALND group
between ALND and SLND-alone treat- therapy, or both were observed. The (P=.14). The unadjusted HR compar-
ment groups in total number of removed type of chemotherapy administered was ing the SLND-alone group with the
lymph nodes and total number of similar in the 2 groups; anthracycline- ALND group was 0.82 (95% CI, 0.58-
tumor-involved nodes; the median total and taxane-based combination regi- 1.17), and the HR adjusted for adjuvant
number of nodes removed was 17 (in- mens were the most common. The ma- treatment and age was 0.88 (95% CI,
terquartile range [IQR], 13-22) in the jority of the women (n=605) received 0.62-1.25) (TABLE 3). The adjusted HRs
ALND group and 2 (IQR, 1-4) in the whole-breast radiation therapy: 263 comparing the SLND-alone group with
SLND-alone group.31 The median total of 296 (88.9%) in the ALND group the ALND group in the other multivari-
572 JAMA, February 9, 2011—Vol 305, No. 6 (Reprinted) ©2011 American Medical Association. All rights reserved.
able models ranged from 0.84 to 0.89 COMMENT survival. The findings from Z0011 docu-
(Table 3), all similar to the unadjusted In the American College of Surgeons ment the high rate of locoregional con-
rate of 0.82. Locoregional recurrence and Oncology Group Z0011 randomized trol achieved with modern multimo-
its correlates have been previously trial, ALND did not significantly affect dality therapy, even without ALND.
reported.31 The 5-year rates of local recur- overall or disease-free survival of In contrast to B04, in which about 40%
rence were 1.6% (95% CI, 0.7%-3.3%) patients with clinical T1-T2 breast can- of patients in the radical mastectomy
in the SLND-alone group and 3.1% (95% cer and a positive SLN who were treated group were node-positive and the same
CI, 1.7%-5.2%) in the ALND group with lumpectomy, adjuvant systemic number in the total mastectomy group
(P=.11). Locoregional recurrence–free therapy, and tangential-field whole- were assumed to be node-positive and
survival at 5 years was 96.7% (95% CI, breast radiation therapy. These sur- 5-year overall survival was only about
94.7%-98.6%) in the SLND-alone group vival findings are consistent with those 60%, 100% of patients in Z0011 had
and 95.7% (95% CI, 93.6%-97.9%) in the of the National Surgical Adjuvant Breast nodal involvement; yet the 5-year over-
ALND group (P=.28). and Bowel Project B04 trial, in which
women with clinically negative nodes
Surgical Morbidities were randomized to treatment by radi- Figure 3. Hazard Ratios Comparing Overall
Paresthesias, shoulder pain, weakness, cal mastectomy, total mastectomy plus Survival Between the ALND and SLND-Alone
Groups
lymphedema, and axillary web syn- nodal irradiation, or total mastectomy
drome are recognized morbidities of with delayed ALND if nodal recur- Favors Favors
ALND.7-9 As previously reported,10 the rence was observed.4 Initially and at SLND Alone ALND
rate of wound infections, axillary sero- each interim analysis for up to 25 years Unadjusted
mas, and paresthesias among patients in of follow-up, no statistically signifi-
the Z0011 trial was higher for the ALND cant survival differences were observed Adjusted
group than for the SLND-alone group between any of the groups. For patients
(70% vs 25%, P⬍.001). Lymphedema in treated in the modern era, the rel-
0.5 1.0 1.3 2.0
the ALND group was significantly more evance of the B04 study, which included Hazard Ratio (90% CI)
common by subjective report (P⬍.001) patients with larger tumors undergo- for Overall Survival
and also tended to be higher by objec- ing mastectomy without adjuvant sys-
Blue dashed line at hazard ratio=1.3 indicates non-
tive assessment of arm circumference. temic therapy, is uncertain, because an inferiority margin; blue-tinted region to the left of haz-
These findings are in accordance with axillary recurrence after SLND in ard ratio=1.3 indicates values for which SLND alone
would be considered noninferior to SLND plus ALND.
other randomized comparisons of SLND patients with a lower risk of death from ALND indicates axillary lymph node dissection; CI, con-
with vs without ALND.32,33 distant disease might negatively affect fidence interval; SLND, sentinel lymph node dissection.
Table 2. Adjusted Hazard Ratios for Overall Survival Comparing SLND-Alone vs ALND Groups
No.
Adjusted HR Noninferiority
Model Variables Patients Events (90% CI) P Value
Treatment group (SLND alone vs ALND), age (ⱕ50 vs ⬎50 y), 839 92 0.87 (0.62-1.23) .03
adjuvantly treated (yes vs no)
Variables in row 1 ⫹ primary tumor size (per 1 cm, continuous) 818 92 0.89 (0.62-1.25) .03
Variables in row 1 ⫹ estrogen receptor status (negative vs positive) 778 87 0.92 (0.64-1.30) .05
Variables in row 1 ⫹ modified Bloom-Richardson score (1 vs 2 vs 3) 839 92 0.86 (0.61-1.21) .02
Variables in row 1 ⫹ tumor type (ductal vs lobular vs other) 839 92 0.88 (0.63-1.25) .03
Abbreviations: ALND, axillary lymph node dissection; CI, confidence interval; HR, hazard ratio; SLND, sentinel lymph node dissection.
Table 3. Adjusted Hazard Ratios for Disease-Free Survival Comparing SLND-Alone vs ALND Groups
No.
Adjusted HR
Model Variables Patients Events (95% CI) P Value
Treatment group (SLND alone vs ALND), age (ⱕ50 vs ⬎50 y), 839 127 0.88 (0.62-1.25) .47
adjuvantly treated (yes vs no)
Variables in row 1 ⫹ primary tumor size (per 1 cm, continuous) 818 125 0.86 (0.60-1.22) .40
Variables in row 1 ⫹ estrogen receptor status (negative vs positive) 778 117 0.84 (0.58-1.20) .33
Variables in row 1 ⫹ modified Bloom-Richardson score (1 vs 2 vs 3) 839 127 0.87 (0.61-1.23) .43
Variables in row 1 ⫹ tumor type (ductal vs lobular vs other) 839 127 0.89 (0.62-1.27) .52
Abbreviations: ALND, axillary lymph node dissection; CI, confidence interval; HR, hazard ratio; SLND, sentinel lymph node dissection.
©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 573
all survival was more than 90%. Further- more than 5 years after study entry.4 tastases that would indicate a higher risk
more, a 19% rate of axillary first failure Greco et al37 reported that median time for systemic disease and the need for sys-
was observed in B04,4 whereas the axil- to axillary recurrence was 30.6 months temic therapy to reduce that risk. Re-
lary nodal recurrence rate was only 0.9% for 401 patients who underwent breast- sults from Z0011 indicate that women
in the SLND-alone group in Z0011.31 The conserving procedures and radiation with a positive SLN and clinical T1-T2
excellent local and distant outcomes in therapy with no axillary surgery. Re- tumors undergoing lumpectomy with ra-
this study highlight the effects of mul- cent reports of long-term follow-up in diation therapy followed by systemic
tiple changes in breast cancer manage- randomized trials confirm these find- therapy do not benefit from the addi-
ment during the interval between the 2 ings. 38,39 Because the total locore- tion of ALND in terms of local control,
studies. These changes, which include gional recurrence rate in the Z0011 disease-free survival, or overall sur-
improved imaging, more detailed patho- SLND-alone group at 5 years is only vival. The only additional information
logical evaluation, improved planning of 2.5% compared with 3.6% in the ALND gained from ALND is the number of
surgical and radiation approaches, and group, it is unlikely that further fol- nodes containing metastases. This prog-
more effective systemic therapy, empha- low-up would result in enough addi- nostic information is unlikely to change
size the need for ongoing reevaluation tional recurrences to generate a clini- systemic therapy decisions and is ob-
of “standard” local therapy. cally meaningful survival difference tained at the cost of a significant in-
The well-documented morbidity between groups. The absolute differ- crease in morbidity.10 The only ratio-
from ALND has led other investiga- ence in 5-year overall survival be- nale for ALND in these patients would
tors to explore alternative methods of tween the treatment groups in Z0011 be if the finding of additional nodal me-
axillary treatment in patients with clini- is 0.7%, numerically favoring the SLND- tastases would result in changes in sys-
cally negative nodes, including radia- alone group. The HR for overall sur- temic therapy. Because current guide-
tion, systemic therapy, and axillary vival comparing the SLND-alone group lines do not support differences in
observation. These have consistently with the ALND group was 0.79 (90% adjuvant systemic therapy based on the
demonstrated low axillary failure rates, CI, 0.56-1.10). The worst HR (1.10) is number of positive lymph nodes, ex-
with no significant differences in sur- less than 1.3, which was hypothesized cept in some uncommon select sub-
vival.34,35 The International Breast Can- as the inferiority margin threshold. In groups,40 ALND does not appear to be
cer Study Group trial of ALND vs obser- essence, this means that the 5-year over- warranted in this patient population.
vation is noteworthy because more than all survival for the SLND-alone group The Z0011 trial did not include pa-
half of the patients did not receive breast might be as low as 90.3% if the true tients undergoing mastectomy, those
or axillary radiotherapy. In women 60 5-year overall survival for the ALND undergoing lumpectomy without ra-
years and older receiving adjuvant group was 91.8% and the HR as high diotherapy, those treated with partial-
tamoxifen but no axillary treatment, the as 1.10. Most importantly, there is no breast irradiation, those receiving neo-
rate of axillary recurrence was only 3%, suggestion that rates of locoregional re- adjuvant therapy, and those receiving
and overall survival was 73% at a median currence, the mechanism by which whole-breast irradiation in the prone
follow-up of 6.6 years.36 variations in local therapy result in sur- position, in which the low axilla is not
The low rates of locoregional recur- vival differences, differ between groups treated. In those patients, ALND re-
rence at 5 years and the nearly identi- to the extent needed to produce sur- mains standard practice when SLND
cal overall and disease-free survival be- vival differences or are likely to do so identifies a positive SLN. However,
tween treatment groups in Z0011 in the future. Taken together, this sug- ALND may no longer be justified for
would suggest that differences in sur- gests that contemporary women may women who have clinical T1-T2 breast
vival between study groups are un- sustain the morbidity of ALND with- cancer and hematoxylin-eosin–
likely to emerge with longer follow- out any meaningful improvement in detected metastasis in the SLN and who
up, because ALND would only affect survival rates. Limitations of the study, are treated with breast-conserving sur-
survival by virtue of improved locore- such as failure to achieve target ac- gery, whole-breast irradiation, and ad-
gional control. In the Early Breast Can- crual and possible randomization im- juvant systemic therapy. Implementa-
cer Trialists’ Collaborative Group over- balance favoring the SLND-alone group, tion of this practice change would
view, statistically significant survival must be considered. However, even in improve clinical outcomes in thou-
differences between treatments at 15 high-risk women (ER−/PR−) in Z0011, sands of women each year by reduc-
years were seen only when differences preliminary analysis suggests no effect ing the complications associated with
in locoregional recurrence between of elimination of ALND on survival. ALND and improving quality of life
treatments were greater than 10% at 5 Despite limitations of the Z0011 trial, with no diminution in survival.
years.6 Axillary recurrence is usually an its findings could have important impli- Author Contributions: Dr Giuliano had full access to
early event, occurring at a median of cations for clinical practice. Examina- all of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the data
14.8 months in B04; in that trial, only tion of the regional nodes with SLND can analysis.
7 of 68 axillary recurrences occurred identify hematoxylin-eosin–detected me- Study concept and design: Giuliano.
574 JAMA, February 9, 2011—Vol 305, No. 6 (Reprinted) ©2011 American Medical Association. All rights reserved.
Acquisition of data: Giuliano, Beitsch, Whitworth, 9. Ivens D, Hoe AL, Podd TJ, Hamilton CR, Taylor I, illary surgical care for breast cancer in the era of sen-
Blumencranz, Leitch, Saha, Morrow. Royle GT. Assessment of morbidity from complete tinel lymph node biopsy. Ann Surg Oncol. 2009;
Analysis and interpretation of data: Giuliano, Hunt, axillary dissection. Br J Cancer. 1992;66(1):136- 16(3):687-696.
Ballman, Whitworth, Leitch, McCall, Morrow. 138. 26. Fisher B, Redmond C, Poisson R, et al. Eight-
Drafting of the manuscript: Giuliano, Ballman, Beitsch, 10. Lucci A, McCall LM, Beitsch PD, et al; American year results of a randomized clinical trial comparing
Whitworth, Morrow. College of Surgeons Oncology Group. Surgical com- total mastectomy and lumpectomy with or without
Critical revision of the manuscript for important plications associated with sentinel lymph node dissec- irradiation in the treatment of breast cancer. N Engl J
intellectual content: Giuliano, Hunt, Ballman, Beitsch, tion (SLND) plus axillary lymph node dissection com- Med. 1989;320(13):822-828.
Whitworth, Blumencranz, Leitch, Saha, McCall, pared with SLND alone in the American College of 27. Early Breast Cancer Trialists’ Collaborative Group.
Morrow. Surgeons Oncology Group trial Z0011. J Clin Oncol. Systemic treatment of early breast cancer by hor-
Statistical analysis: Ballman, McCall. 2007;25(24):3657-3663. monal, cytotoxic, or immune therapy: 133 ran-
Administrative, technical, or material support: Giuliano, 11. Lyman GH, Giuliano AE, Somerfield MR, et al; domised trials involving 31,000 recurrences and 24,000
Hunt, Whitworth, Leitch, Saha. American Society of Clinical Oncology. American So- deaths among 75,000 women. Lancet. 1992;339
Study supervision: Giuliano, Whitworth. ciety of Clinical Oncology guideline recommenda- (8785):71-85.
Conflict of Interest Disclosures: All authors have com- tions for sentinel lymph node biopsy in early-stage 28. Early Breast Cancer Trialists’ Collaborative Group.
pleted and submitted the ICMJE Form for Disclosure breast cancer. J Clin Oncol. 2005;23(30):7703- Systemic treatment of early breast cancer by hor-
of Potential Conflicts of Interest and none were re- 7720. monal, cytotoxic, or immune therapy: 133 ran-
ported. 12. Fidler IJ. The pathogenesis of cancer metastasis: domised trials involving 31,000 recurrences and 24,000
Funding/Support: This study was supported by Na- the “seed and soil” hypothesis revisited. Nat Rev deaths among 75,000 women. Lancet. 1992;339
tional Cancer Institute grant U10 CA 76001 to the Cancer. 2003;3(6):453-458. (8784):1-15.
American College of Surgeons Oncology Group 13. Abrams JS. Adjuvant therapy for breast cancer— 29. Rubinstein LV, Gail MH, Santner TJ. Planning the
(ACOSOG). results from the USA consensus conference. Breast duration of a comparative clinical trial with loss to fol-
Role of the Sponsor: The National Cancer Institute had Cancer. 2001;8(4):298-304. low-up and a period of continued observation.
no role in the design and conduct of the study; the 14. Goldhirsch A, Glick JH, Gelber RD, Senn HJ. Meet- J Chronic Dis. 1981;34(9-10):469-479.
collection, analysis, and interpretation of the data; or ing highlights: International Consensus Panel on the 30. Kaji AH, Lewis RJ. Are we looking for superior-
the preparation, review, or approval of the manu- Treatment of Primary Breast Cancer. J Natl Cancer Inst. ity, equivalence, or noninferiority? asking the right
script. 1998;90(21):1601-1608. question and answering it correctly. Ann Emerg Med.
Additional Contributions: We thank the ACOSOG 15. Sørlie T, Perou CM, Tibshirani R, et al. Gene ex- 2010;55(5):408-411.
staff, in particular the leadership of Heidi Nelson, MD pression patterns of breast carcinomas distinguish tu- 31. Giuliano AE, McCall L, Beitsch P, et al. Locore-
(Mayo Clinic, Rochester, Minnesota), David Ota, MD mor subclasses with clinical implications. Proc Natl Acad gional recurrence after sentinel lymph node dissec-
(Duke University, Durham, North Carolina), and Samuel Sci U S A. 2001;98(19):10869-10874. tion with or without axillary dissection in patients with
A. Wells Jr, MD (National Cancer Institute, Bethesda, 16. van de Vijver MJ, He YD, van’t Veer LJ, et al. A sentinel lymph node metastases: the American Col-
Maryland). All 3 of these individuals contributed to gene-expression signature as a predictor of survival lege of Surgeons Oncology Group Z0011 random-
study design, manuscript review, or both; none re- in breast cancer. N Engl J Med. 2002;347(25): ized trial. Ann Surg. 2010;252(3):426-433.
ceived compensation for their contributions. We also 1999-2009. 32. Fleissig A, Fallowfield LJ, Langridge CI, et al. Post-
thank all of the investigators and their site research 17. Albain KS, Barlow WE, Shak S, et al; Breast Can- operative arm morbidity and quality of life: results of
teams. Lastly, we wish to thank the brave patients with cer Intergroup of North America. Prognostic and pre- the ALMANAC randomised trial comparing sentinel
breast cancer who participated in this study and their dictive value of the 21-gene recurrence score assay node biopsy with standard axillary treatment in the
caregivers. in postmenopausal women with node-positive, oes- management of patients with early breast cancer.
trogen-receptor-positive breast cancer on chemo- Breast Cancer Res Treat. 2006;95(3):279-293.
REFERENCES therapy: a retrospective analysis of a randomised trial. 33. Veronesi U, Paganelli G, Viale G, et al. A ran-
Lancet Oncol. 2010;11(1):55-65. domized comparison of sentinel-node biopsy with rou-
1. Halsted WS. The results of radical operations for 18. Paik S, Tang G, Shak S, et al. Gene expression and tine axillary dissection in breast cancer. N Engl J Med.
the cure of carcinoma of the breast. Ann Surg. 1907; benefit of chemotherapy in women with node- 2003;349(6):546-553.
46(1):1-19. negative, estrogen receptor-positive breast cancer. 34. Veronesi U, Orecchia R, Zurrida S, et al. Avoid-
2. Fisher B, Wolmark N, Bauer M, Redmond C, J Clin Oncol. 2006;24(23):3726-3734. ing axillary dissection in breast cancer surgery: a ran-
Gebhardt M. The accuracy of clinical nodal staging and 19. Swedish Organised Service Screening Evaluation domized trial to assess the role of axillary radiotherapy.
of limited axillary dissection as a determinant of his- Group. Effect of mammographic service screening on Ann Oncol. 2005;16(3):383-388.
tologic nodal status in carcinoma of the breast. Surg stage at presentation of breast cancers in Sweden. 35. Martelli G, Boracchi P, De Palo M, et al. A ran-
Gynecol Obstet. 1981;152(6):765-772. Cancer. 2007;109(11):2205-2212. domized trial comparing axillary dissection to no ax-
3. Graversen HP, Blichert-Toft M, Andersen JA, Zedeler 20. Fisher B, Montague E, Redmond C, et al. Com- illary dissection in older patients with T1N0 breast can-
K. Breast cancer: risk of axillary recurrence in node- parison of radical mastectomy with alternative cer: results after 5 years of follow-up. Ann Surg. 2005;
negative patients following partial dissection of the treatments for primary breast cancer: a first report 242(1):1-9.
axilla. Eur J Surg Oncol. 1988;14(5):407-412. of results from a prospective randomized clinical 36. Rudenstam CM, Zahrieh D, Forbes JF, et al; In-
4. Fisher B, Jeong JH, Anderson S, Bryant J, Fisher trial. Cancer. 1977;39(6)(suppl):2827-2839. ternational Breast Cancer Study Group. Randomized
ER, Wolmark N. Twenty-five-year follow-up of a ran- 21. Rutgers EJ. Sentinel node biopsy: interpretation trial comparing axillary clearance versus no axillary
domized trial comparing radical mastectomy, total mas- and management of patients with immunohistochem- clearance in older patients with breast cancer: first re-
tectomy, and total mastectomy followed by irradiation. istry-positive sentinel nodes and those with sults of International Breast Cancer Study Group Trial
N Engl J Med. 2002;347(8):567-575. micrometastases. J Clin Oncol. 2008;26(5):698- 10-93. J Clin Oncol. 2006;24(3):337-344.
5. Orr RK. The impact of prophylactic axillary node 702. 37. Greco M, Agresti R, Cascinelli N, et al. Breast can-
dissection on breast cancer survival—a Bayesian 22. van la Parra RF, Ernst MF, Bevilacqua JL, et al. Vali- cer patients treated without axillary surgery: clinical
meta-analysis. Ann Surg Oncol. 1999;6(1):109- dation of a nomogram to predict the risk of nonsen- implications and biologic analysis. Ann Surg. 2000;
116. tinel lymph node metastases in breast cancer pa- 232(1):1-7.
6. Clarke M, Collins R, Darby S, et al; Early Breast Can- tients with a positive sentinel node biopsy: validation 38. Martelli G, Miceli R, Daidone MG, et al. Axillary
cer Trialists’ Collaborative Group (EBCTCG). Effects of of the MSKCC breast nomogram. Ann Surg Oncol. dissection versus no axillary dissection in elderly pa-
radiotherapy and of differences in the extent of sur- 2009;16(5):1128-1135. tients with breast cancer and no palpable axillary nodes:
gery for early breast cancer on local recurrence and 23. Amanti C, Lombardi A, Maggi S, et al. Is com- results after 15 years of follow-up [published online
15-year survival: an overview of the randomised trials. plete axillary dissection necessary for all patients with ahead of print July 23, 2010]. Ann Surg Oncol. 2010.
Lancet. 2005;366(9503):2087-2106. positive findings on sentinel lymph node biopsy? vali- doi:10.1245/s10434-010-1217-7.
7. Yeoh EK, Denham JW, Davies SA, Spittle MF. Pri- dation of a breast cancer nomogram for predicting the 39. Veronesi U, Viale G, Paganelli G, et al. Sentinel
mary breast cancer: complications of axillary likelihood of a non-sentinel lymph node. Tumori. 2009; lymph node biopsy in breast cancer: ten-year results
management. Acta Radiol Oncol. 1986;25(2): 95(2):153-155. of a randomized controlled study. Ann Surg. 2010;
105-108. 24. Coutant C, Olivier C, Lambaudie E, et al. Com- 251(4):595-600.
8. Lotze MT, Duncan MA, Gerber LH, Woltering EA, parison of models to predict nonsentinel lymph node 40. Goldhirsch A, Ingle JN, Gelber RD, Coates AS,
Rosenberg SA. Early versus delayed shoulder status in breast cancer patients with metastatic sen- Thürlimann B, Senn HJ; Panel Members. Thresholds
motion following axillary dissection: a randomized tinel lymph nodes: a prospective multicenter study. for therapies: highlights of the St Gallen International
prospective study. Ann Surg. 1981;193(3):288- J Clin Oncol. 2009;27(17):2800-2808. Expert Consensus on the primary therapy of early breast
295. 25. Rescigno J, Zampell JC, Axelrod D. Patterns of ax- cancer 2009. Ann Oncol. 2009;20(8):1319-1329.
©2011 American Medical Association. All rights reserved. (Reprinted) JAMA, February 9, 2011—Vol 305, No. 6 575