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Role of Ultrasonography of Regional Nodal Basins in Staging Triple-Negative Breast Cancer and Implications For Local-Regional Treatment
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Role of Ultrasonography of Regional Nodal Basins in Staging Triple-Negative Breast Cancer and Implications For Local-Regional Treatment Simona F. Shaitelman, MD, EdM,* Welela Tereffe, MD, MPH,* Basak E. Dogan, MD,y Kenneth R. Hess, PhD,z Abigail S. Caudle, MD, MS,x Vicente Valero, MD,k Michael C. Stauder, MD,* Savitri Krishnamurthy, MD,{ Rosalind P. Candelaria, MD,y Eric A. Strom, MD,* Wendy A. Woodward, MD, PhD,* Kelly K. Hunt, MD,x Thomas A. Buchholz, MD,* and Gary J. Whitman, MDy *Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; yDepartment of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas; zDepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas; xDepartment of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; kDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and {Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas Received Mar 4, 2015, and in revised form May 1, 2015. Accepted for publication May 12, 2015.
Summary Ultrasonographic staging of nodes is now recommended prior to neoadjuvant systemic therapy for breast cancer. How this impacts clinical stage and treatment decisions among women with triple-negative breast cancer is uncertain. In this
Purpose: We sought to determine the rate at which regional nodal ultrasonography would increase the nodal disease stage in patients with triple-negative breast cancer (TNBC) beyond the clinical stage determined by physical examination and mammography alone, and significantly affect the treatments delivered to these patients. Methods and Materials: We retrospectively reviewed the charts of women with stages I to III TNBC who underwent physical examination, mammography, breast and regional nodal ultrasonography with needle biopsy of abnormal nodes, and definitive local-regional treatment at our institution between 2004 and 2011. The stages of these patients’ disease with and without ultrasonography of the regional nodal basins were compared using the Pearson c2 test. Definitive treatments of patients whose nodal
Reprint requests to: Simona F. Shaitelman, MD, EdM, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1202, Houston, TX 77030. Tel: (713) 563-8491; E-mail: [email protected] Part of the findings herein were presented at the 56th Annual Meeting of the American Society of Radiation Oncology, San Francisco, CA, Sep 2014. Int J Radiation Oncol Biol Phys, Vol. 93, No. 1, pp. 102e110, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.05.015
Conflict of interest: S.F.S. has received a grant from Elekta for work unrelated to that described in this article and is a consultant for the MD Anderson Physicians Network. M.C.S. is a consultant for the MD Anderson Physicians Network.
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retrospective chart review, 19.4% of patients had an increase in clinical disease stage with the incorporation of ultrasonography. Ultrasonographic upstaging significantly increased the use of axillary lymph node dissection and radiation to the regional nodal basins.
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disease was upstaged on the basis of ultrasonographic findings were compared to those of patients whose disease stage remained the same. Results: A total of 572 women met the study requirements. In 111 (19.4%) of these patients, regional nodal ultrasonography with needle biopsy resulted in an increase in disease stage from the original stage by physical examination and mammography alone. Significantly higher percentages of patients whose nodal disease was upstaged by ultrasonographic findings compared to that in patients whose disease was not upstaged underwent neoadjuvant systemic therapy (91.9% and 51.2%, respectively; P<.0001), axillary lymph node dissection (99.1% and 34.5%, respectively; P<.0001), and radiation to the regional nodal basins (88.2% and 29.1%, respectively; P<.0001). Conclusions: Regional nodal ultrasonography in TNBC frequently changes the initial clinical stage and plays an important role in treatment planning. Ó 2015 Elsevier Inc. All rights reserved.
Introduction The 2014 National Comprehensive Cancer Network guidelines recommend that patients who have breast cancer and clinically negative axillary lymph nodes on physical examination and who are being considered for neoadjuvant systemic therapy undergo axillary ultrasonography (1). When axillary ultrasonography reveals suspicious lymph nodes, the suspicious nodes should be sampled via fineneedle aspiration biopsy (FNAB) or core biopsy, and an image-detectable marker clip should be placed in the biopsied lymph node to ensure its removal at the time of definitive surgery (1). How definitive local-regional treatment is altered on the basis of initial staging using ultrasonography and lymph node biopsy remains uncertain. Accurate initial staging of the lymph nodes before the start of systemic therapy may allow for appropriate local-regional treatment decisions to be made. For example, patients who are staged with nodenegative disease by physical examination and do not undergo ultrasonography could have involved lymph nodes that resolve with neoadjuvant systemic therapy. These lymph nodes would not be detected by sentinel lymph node biopsy, and such patients might not receive adequate surgery or radiation therapy to ensure the eradication of microscopic residual nodal disease. Because patients with triple-negative breast cancer (TNBC) typically undergo neoadjuvant systemic therapy as the standard of care, ultrasonography during initial staging can help ensure that diseased lymph nodes do not go undetected. TNBC has been found to be more responsive to neoadjuvant systemic therapy than other forms of breast cancer (2); as such, accurate initial clinical staging is important to ensure thoughtful targeting of local-regional treatment, particularly for radiation that targets areas at risk of harboring microscopic residual disease. Conversely, identifying those patients whose TNBC is refractory to systemic therapy, which portends worse outcomes, may allow for intensified systemic and local-regional treatments.
The goal of our study was to characterize the rate of nodal disease upstaging as a result of regional nodal ultrasonography and ultrasonography-guided biopsy in TNBC patients. We also sought to determine how changes in nodal staging affected local-regional treatment.
Methods and Materials Using a prospectively maintained database, we conducted a retrospective review of all patients with TNBC evaluated at our institution between 2004 and 2011. This retrospective study was approved by the institutional review board at our institution. Electronic medical records were also reviewed to obtain detailed information about staging evaluation and local-regional treatment delivered. Patients were excluded from analysis for the following reasons: they had stage 0 or IV breast cancer at presentation, had inflammatory breast cancer at presentation, were male, had a history of breast cancer, had synchronous or metachronous contralateral breast cancer, a lack of definitive local-regional surgery, or had had treatment with breast-conserving surgery without adjuvant radiation therapy. Patients were also excluded if all definitive local-regional treatment (including surgery and radiation therapy, if delivered) was not performed at our institution; if the estrogen receptor, progesterone receptor, and HER2/neu amplification status were not confirmed at our institution; or if the initial staging did not include physical examination, diagnostic mammography, and ultrasonography of the breast and regional nodal basins with needle biopsy as clinically indicated. Physical examination of each patient’s breasts and regional lymph nodes had been conducted by a breast oncologist (medical, surgical, or radiation). Bilateral diagnostic mammography was performed and interpreted by one of our institution’s breast radiation specialists. All patients underwent breast and regional nodal basin ultrasonography, which was performed by 1 of 12 dedicated radiologists in our institution, using Antares ultrasonography units (Siemens
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Healthcare) with 13-7 or 5-7 MHz transducers. Ultrasonography examination of the regional nodal basins included the axillary, infraclavicular, and internal mammary chain lymph nodes. For any patient with abnormal findings on axillary ultrasonography, the supraclavicular lymph nodes were also scanned. Lymph nodes were classified as abnormal (ie warranting biopsy) based on criteria published by Bedi et al (3, 4). The index lymph node in the highest involved nodal chain was targeted for FNAB using a 21-gauge needle under ultrasonographic guidance. The decision whether to perform a biopsy of the internal mammary nodes was based on whether the node could be accessed safely and the biopsy’s potential impact on stage. When a biopsy of an abnormal internal mammary nodes was not possible, these nodes were considered involved, and the clinical disease stage was adjusted accordingly. Disease was staged according to the American Joint Committee on Cancer Cancer Staging Manual, 7th edition (5). The clinical stage of each patient based on mammographic and physical examination findings was compared to the disease stage determined with the addition of findings from ultrasonography of the breast and the regional nodal basins. The definitive treatment given to each patient was also examined. Proportions were compared between groups who were versus those who were not upstaged with ultrasonography by using the Pearson c2 test using Spotfire Sþ version 8.2 software (TIBCO) for Windows (Microsoft, Redmond, WA). The false-negative rate of ultrasonography with FNAB was also calculated for the study cohort. Comparisons between upstaged groups were also made after adjustment for potentially confounding study factors (age, grade, histology, lymphovascular space invasion, and menopausal status) using logistic regression analysis.
Results From a total of 2614 patients with TNBC, 572 (21.9%) fit the study criteria. The demographic, clinicopathologic, and treatment characteristics of these 572 patients are summarized in Table 1. Nodal staging was calculated based on physical examination and mammography with and without ultrasonography with FNAB of suspicious nodes (Table 1). Of the 572 patients, 111 (19.4%) had their nodal disease upstaged on the basis of ultrasonography-guided assessment of the regional nodal basins (Table 2). Specifically, disease was upstaged from lymph node-negative (cN0) to node-positive in 50 patients (8.7%), from cN1 to cN3 in 47 patients (8.2%), from cN2 to cN3 in 12 patients (2.1%), and from cN3a to a higher N3 stage in 2 patients (0.4%). A total of 28 patients with clinically palpable and 1 with uncertain axillary adenopathy were found to have node-negative disease when evaluated with ultrasonography with or without FNAB.
International Journal of Radiation Oncology Biology Physics Table 1 Demographic, clinicopathologic, and treatment characteristics of patients with nonmetastatic triple-negative breast cancer who underwent physical examination, mammography, ultrasonography, and definitive local-regional treatment at our institution Characteristic
No. of patients (NZ572) (%)
Race White, non-Hispanic 335 (58.6) Hispanic, Spanish 84 (14.7) Black 115 (20.1) Asian, Pacific Islander 33 (5.8) Native American 1 (0.2) Other 4 (0.7) Year of diagnosis 2004 52 (9.1) 2005 69 (12.1) 2006 53 (9.3) 2007 75 (13.1) 2008 58 (10.1) 2009 91 (15.9) 2010 86 (15.0) 2011 88 (15.4) Age at diagnosis (y) <40 97 (17.0) 40-49 155 (27.1) 50-59 174 (30.4) 60-69 108 (18.9) 70 38 (6.6) Menopausal status Premenopausal 213 (37.2) Perimenopausal 10 (1.7) Postmenopausal 349 (61.0) Trigger event for diagnosis Abnormal mammogram results 163 (28.5) Abnormal ultrasonography results 10 (1.7) Palpable mass 339 (59.3) Nipple discharge 10 (1.7) Breast pain/discomfort 31 (5.4) Inverted nipple 4 (0.7) Breast swelling 8 (1.4) Unknown/other 7 (1.2) Magnetic resonance imaging as part of staging evaluation Yes 79 (13.8) No 493 (86.2) Histology Invasive ductal carcinoma 541 (94.6) Invasive lobular carcinoma 4 (0.7) Other 27 (4.7) Nuclear grade I 0 (0.0) II 43 (7.5) III 524 (91.6) Not reported 5 (0.9) Lymphovascular space invasion Present 113 (19.8) Absent 459 (80.2) (continued on next page)
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Table 1 (continued ) Characteristic
No. of patients (NZ572) (%)
Definitive breast surgical procedure Lumpectomy 244 (42.7) Mastectomy 324 (56.6) No breast surgery 4 (0.7) Definitive axillary surgical procedure Sentinel lymph node biopsy 311 (54.4) ALND 261 (45.6) Neoadjuvant systemic therapy Yes 338 (59.1) No 234 (40.9) Adjuvant systemic therapy Yes 218 (38.1) No 354 (61.9) Radiation therapy Yes 401 (70.1) No 171 (29.9) Radiation therapy targets Breast/chest wall 169 (42.1) Breast/chest wall plus regional nodes 232 (57.9) Boost to regional nodes among patients receiving RNI Yes 77 (33.2) No 155 (66.8) Clinical T stage based on mammography and physical examination Tx 53 (9.3) T0 1 (0.2) Tis 1 (0.2) T1 121 (21.2) T2 255 (44.6) T3 99 (17.3) T4 42 (7.3) Clinical N stage based on mammography and physical examination Nx 1 (0.2) N0 329 (57.5) N1a 214 (37.4) N2 21 (3.7) N3a 3 (0.5) N3b 0 (0.0) N3c 4 (0.7) Clinical N stage based on mammography, physical examination, and ultrasonography with or without FNAB Nx 0 (0.0) N0 355 (62.1) N1a 135 (23.6) N2 4 (0.7) N3a 30 (5.2) N3b 23 (4.0) N3c 25 (4.4) Rate of positive axillary lymph nodes at definitive axillary surgery among 355 cN0 patients Neoadjuvant systemic therapy 11/146 (7.5) No neoadjuvant systemic therapy 36/209 (17.2) Abbreviations: ALND Z axillary lymph node dissection; FNAB Z fine-needle aspiration biopsy; RNI Z regional nodal irradiation.
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Table 2 Clinical upstaging based on ultrasonography and fine-needle aspiration biopsy among 572 patients Nodal upstaging cN0 upstaged to cNþ Total cN0 / cN1 cN0 / cN2 cN0 / cN3a cN0 / cN3b cN0 / cN3c cN1 upstaged to cN3 Total cN1 / cN3a cN1 / cN3b cN1 / cN3c cN2 upstaged to cN3 Total cN2 / cN3a cN2 / cN3b cN2 / cN3c cN3 upstaged to higher cN3 cN3a upstaged to cN3b cN3a upstaged to cN3c Total
No. of patients (%) 50 36 0 5 4 5
(8.7) (6.3) (0.0) (0.9) (0.7) (0.9)
47 23 12 12
(8.2) (4.0) (2.1) (2.1)
12 1 6 5
(2.1) (0.2) (0.2) (0.9)
1 (0.2) 1 (0.2) 111 (19.4)
Patients whose nodal disease was upstaged on the basis of ultrasonography were more likely than patients whose disease was not upstaged to undergo an ALND (99.1% vs 34.5%, P<.0001), neoadjuvant systemic therapy (91.9% vs 51.2%, P<.0001), and radiation therapy (93.7% vs 64.4%, P<.0001) (Table 3). The radiation targets and doses prescribed also differed significantly between patients whose disease was upstaged and those whose disease was not upstaged: 88.2% and 29.1%, respectively, received regional nodal radiation therapy (P<.0001); and 61.3% and 2.0%, respectively, received a boost dose of radiation to a nodal basin (P<.0001). In total, the false-negative rate for ultrasonography with FNAB of suspicious nodes was 19% (49 of 264; 95% confidence interval, 14%-24%). Of the 338 patients who received neoadjuvant systemic therapy prior to surgery, 192 (56.8%) were initially staged with node-positive disease by ultrasonography with FNAB of suspicious nodes, and 146 patients (43.2%) were initially staged as having nodenegative disease. Of the 234 patients who did not receive neoadjuvant systemic therapy prior to surgery, 173 had cN0 disease that was confirmed to be pN0 at the time of surgery. Among the 36 patients who did not receive neoadjuvant systemic therapy with cN0 disease based on ultrasonography with FNAB of suspicious nodes but were found to have pathological node-positive disease at the time of surgery, the median size of the lymph node metastases was 2.5 mm (range, 0.2-14.0 mm). Multivariate logistic analyses were performed to examine whether ultrasonographic upstaging added to the
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Table 3
Definitive treatment delivered based on ultrasonography-based disease upstaging Treatment received
No. of patients (nZ111) with upstaged disease (%)
Axillary lymph node dissection Neoadjuvant chemotherapy Adjuvant chemotherapy Radiation therapy RNI as a part of radiation therapy Boost dose to nodal basin as a part of RNI
110 102 17 104 98 68
(99.1) (91.9) (15.3) (93.7) (88.3) (61.3)
No. of patients (nZ461) with no disease upstaging (%) 159 236 201 297 134 9
(34.5) (51.2) (43.6) (64.4) (29.1) (2.0)
P <.0001 <.0001 <.0001 <.0001 <.0001 <.0001
Abbreviation: RNI Z regional nodal irradiation.
use of clinical patient and tumor characteristics to predict use of systemic and local-regional treatments (Table 4). Controlling for menopausal status (postmenopausal vs preor perimenopausal), age (>40 years vs 40 years), histology (invasive ductal, lobular or other vs aggressive histologies), grade (I/II vs III), lymphovascular space invasion (present vs absent), and ultrasonographic upstaging predicted for greater use of neoadjuvant chemotherapy, axillary lymph node dissection (ALND), radiation therapy, regional nodal irradiation, and boost doses of radiation to particular lymph node regions (all P<.0001).
Discussion In 19.4% of the TNBC patients in our study, regional nodal ultrasonography with FNAB of suspicious nodes led to an increase in preoperative disease stage from that determined by physical examination and mammography alone. This upstaging led to higher rates of use for neoadjuvant systemic therapy, ALND, and radiation therapy, particularly to the regional lymphatics. Controlling for clinical and pathologic features, nodal upstaging still predicted for patterns of usage of systemic and local-regional treatment.
Initial ultrasonographic staging of regional lymphatics We anticipate broad acceptance of the National Comprehensive Cancer Network’s recommendation that breast cancer patients with clinically node-negative disease undergo ultrasonography of the regional lymph nodes before neoadjuvant systemic therapy (1). Based on our findings, such acceptance would be expected to lead to the diagnosis of locoregionally advanced disease in a significantly higher percentage of patients than is currently seen. The increased percentage of patients diagnosed with locoregionally advanced disease likely would in turn lead to substantive shifts in the use of definitive regional treatment of the lymphatics.
Comparison of imaging modalities for axillary staging Ultrasonography has been well studied as a staging tool for breast cancer. Houssami et al (6) conducted a meta-analysis
of the accuracy of ultrasonography and ultrasonographyguided biopsy for axillary staging in breast cancer patients. This analysis of 21 studies, which included 4313 patients who underwent ultrasonography and excluded patients who underwent neoadjuvant systemic therapy, found a median sensitivity of 61.4% and specificity of 82.0% for ultrasonography. A subset of 1733 of these patients underwent ultrasonography-guided biopsy, for which the median sensitivity was 79.4% and the median specificity was 100%. Dipestraten et al (7) recently performed a systematic review and meta-analysis that estimated the false-negative rate of ultrasonography-guided biopsy of the axilla. The investigators found a pooled false-negative rate of 25% in the 31 studies they examined, similar to the rate of 19% found in our study. Other imaging modalities have not been found to be superior to ultrasonography for axillary staging in breast cancer patients. There are limited data to support the use of magnetic resonance imaging (MRI) for initial staging of the axilla in breast cancer patients (8, 9). Positron emission tomography (PET) with fluorodeoxyglucose labeling has a widely variable accuracy for axillary nodal staging and has not been broadly implemented for this purpose (10, 11). Despite the lack of proven alternatives, the wide adoption of ultrasonography as a primary modality for regional nodal staging in breast cancer patients remains uncertain. At our institution, because of the adoption of ultrasonography as a part of standard staging evaluation for TNBC, MRI and PET are selectively used in a minority of patients.
Implications of ultrasonography-based nodal staging for patients undergoing neoadjuvant systemic therapy There has been debate about the optimal approach to axillary staging in patients who will receive neoadjuvant systemic therapy. Although some institutions favor sentinel lymph node biopsy before systemic therapy, ultrasonography with FNAB of suspicious nodes offers an effective, nonsurgical approach to axillary staging with excellent sensitivity. In 1 study from our institution, 93% of axillary nodal metastases larger than 0.5 mm in diameter and 44% of those smaller than 5.0 mm were identified by ultrasonography (4). Not surprisingly, multiple groups have reported that patients with axillary
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Multivariate logistic regression analyses of factors contributing to local-regional and systemic therapy treatment Variable
Endpoint: axillary lymph node dissection (nZ269) Ultrasound upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: neoadjuvant chemotherapy (nZ338) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: adjuvant chemotherapy (nZ218) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: radiation therapy (nZ401) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 years) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: regional nodal irradiation (nZ232) Ultrasound upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: boost dose to any lymph node basin (nZ77) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal)
OR (95% CI)
P
200 0.55 1.14 1.38 3.07 1.19
(28-1448) (.29-1.01) (.34-3.76) (.65-2.95) (1.84-5.12) (.72-1.97)
<.0001 .06 .83 .40 <.0001 .49
11.2 .52 .53 1.11 .72 .63
(5.5-23) (.29-.95) (.18-1.63) (.58-2.12) (.45-1.17) (.41-.99)
<.0001 .03 .27 .75 .19 .05
.22 1.95 2.16 1.23 1.57 1.19
(.13-.39) (1.09-3.48) (.75-6.22) (.65-2.36) (.99-2.48) (.77-1.84)
<.0001 .03 .16 .52 .06 .45
8.1 .92 1.40 .58 1.59 1.25
(3.6-18) (.51-1.64) (.43-4.59) (.27-1.22) (.94-2.69) (.79-1.98)
<.0001 .77 .58 .15 .08 .34
19 .40 4.12 .90 3.55 .74
(8.0-46) (.18-.87) (1.00-17) (.42-1.96) (1.88-6.69) (.41-1.33)
<.0001 .02 .05 .80 .0001 .32
65 .51 .21 .77 1.00 1.50
(29-147) (.18-1.42) (.02-2.44) (.16-3.82) (.46-2.20) (.62-3.65)
<.0001 .20 .21 .75 1.00 .37
* Aggressive histology was defined as metaplastic/sarcomatoid, squamous carcinoma, or pleomorphic lobular carcinoma.
metastases proven by ultrasonography-guided biopsy have a larger burden of nodal disease, with more positive nodes, larger foci of disease, and a higher proportion of extranodal extension, than do patients who had a positive sentinel lymph node biopsy after a negative ultrasonographic examination (12-14). A dramatic axillary response to neoadjuvant systemic therapy was seen in TNBC patients in the American College of Surgeons Oncology Group (ACOSOG) trial Z1071 (15). The trial found that axillary response rates to neoadjuvant systemic therapy varied by tumor subtype, with eradication of nodal disease seen in 49.4% of patients
with TNBC but in only 21.1% of those with hormone receptor-positive/HER2-negative tumors (P<.0001) (15). Because a response to therapy may cause axillary metastases to go undiagnosed, knowing about significant nodal disease before therapy is important to determine the extent of planned nodal surgery as well as the need for adjuvant radiation therapy. Because some micrometastases in the axillary lymph nodes are not seen on ultrasonography, some physicians support the practice of performing sentinel lymph node biopsy on all patients prior to the start of neoadjuvant systemic therapy. However, it seems that committing these
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patients to multiple operations, including axillary surgery, may not be of benefit. Patients who present with a very small volume of axillary disease not detected by ultrasonography who have a pathologic complete response to neoadjuvant systemic therapy have outcomes similar to those without axillary disease. Hunt et al (16) compared the outcomes of patients with cN0 disease who had sentinel lymph node biopsy performed before neoadjuvant systemic therapy to those of patients whose sentinel lymph node biopsy occurred after systemic therapy. The study found no differences in local-regional recurrence rates; however, patients who underwent sentinel lymph node biopsy after systemic therapy had a lower probability of having a positive sentinel lymph node and were consequently spared ALND. Thus, although ultrasonography is not as sensitive in detecting axillary disease as surgical staging, ultrasonography identifies patients whose burden of axillary disease is significant enough to affect treatment decisions and carries less burden of morbidity than an invasive surgical procedure. Initial staging evaluation with nodal ultrasonography has been incorporated into surgical trials investigating the accuracy of sentinel lymph node biopsy for breast cancer patients treated with neoadjuvant systemic therapy. Both the ACOSOG Z1071 and SENTINA trials found high falsenegative rates for sentinel node biopsy in breast cancer patients who had received neoadjuvant systemic therapy (2, 17). Technical factors were found to be important in minimizing the false-negative rate of sentinel lymph node biopsy. These factors included the use of dual tracer techniques (ie, blue dye in combination with technetium-99m sulfur colloid and a minimum resection of at least 3 sentinel lymph nodes). Because the false-negative rate found in ACOSOG Z1071 was 12.6% among patients with cN1 disease and at least 2 sentinel lymph nodes examined, higher than the prespecified acceptable false-negative rate of 10.0% (2). As a result, sentinel lymph node biopsy alone is not considered appropriate in patients found to have biopsy-proven involved lymph nodes at initial presentation. These data were corroborated by the European SENTINA trial (17), which differed from ACOSOG trial Z1071 in the fact that only 28% (63 of 226) of enrolled patients considered to have clinically node-positive disease underwent a needle biopsy to confirm the presence of metastases. The SENTINA trial reported a false-negative rate for sentinel lymph node biopsy of 14%, which improved when dual tracers were used and more than 2 sentinel lymph nodes were removed, findings similar to those of ACOSOG Z1071. Incorporation of postchemotherapy axillary ultrasonography findings in the selection of ideal candidates for sentinel lymph node biopsy following neoadjuvant chemotherapy also appears to lower the false-negative rate (18). The extent of pathologic evaluation also plays an important role in this setting, as demonstrated by the Sentinel Node Biopsy Following Neoadjuvant Chemotherapy (SN FNAC) study. Those investigators found that the incorporation of immunohistochemistry in pathology
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review resulted in a false-negative rate of only 8.4% when isolated tumor cells were considered positive but 13.3% if they were considered negative (19). Efforts are under way to better define the characteristics of patients for whom a less invasive procedure than an ALND can provide appropriate clearance of involved lymph nodes following neoadjuvant systemic therapy (20, 21). Both the Alliance for Clinical Trials in Oncology and NRG Oncology have open clinical trials (A011202 and NSABP B-51/RTOG 1304, respectively) to examine the appropriate local-regional treatment for breast cancer patients based on the degree of response of the lymph nodes to neoadjuvant systemic therapy (22, 23). For patients with residual nodal disease, it remains uncertain whether ALND is necessary or axillary radiation therapy might replace ALND. Conversely, for patients with a pathologic complete response in the lymph nodes, the need for regional nodal irradiation remains uncertain. Our group has historically delivered differential doses of radiation to the lymph node regions based on pathologic involvement at the time of initial staging, the extent of surgery performed, and the response of lymph nodes to neoadjuvant systemic therapy. Radiation therapy in this setting has typically been used adjuvantly to eradicate any microscopic residual disease in those lymph node basins not fully dissected by the surgical oncologist. For patients in whom gross lymphadenopathy is still visualized by ultrasonography following definitive neoadjuvant systemic therapy and surgical treatment, particularly in regions that are not commonly resected, such as the internal mammary chain and the supraclavicular fossa, we typically deliver a higher boost dose of radiation (16 Gy in 8 fractions) to eradicate disease. We propose that thoughtful radiation treatment planning be done in response to the detailed staging that can be performed with guidance from ultrasonographic findings. Such treatment planning should also take into account the extent of surgical excision to avoid irradiating areas that are sufficiently treated with surgical excision alone (22, 23). Thus far, the local-regional control rates and toxicities with versus without usage of higher boost doses of radiation to these regions is not known.
Study limitations This retrospective study has some limitations. Because our institution is a tertiary care referral center, it is possible that patients with breast cancer who elected to have their definitive local-regional treatment at our institution had a higher stage of clinical disease than those who received only part of their treatment at our institution. As mentioned above, owing to technical limitations, not all morphologically abnormal lymph nodes were biopsied, and clinical interpretations of ultrasonography reports were used to guide final staging. The techniques required for accurate assessment and biopsy of lymph nodes is operator dependent. As such, the findings of this study may not be
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generalizable to other institutions. While the lymph node basins evaluated at our institution typically include the axilla, internal mammary, infraclavicular, and supraclavicular regions, at many institutions ultrasonography of the lymphatics is focused on the axilla alone, which would preclude the ability to accurately diagnose stage cN2b and cN3 disease. This study spanned 8 years, during which some technical aspects of ultrasonography and standard definitive treatments changed. Also, the study was restricted to patients with TNBC because such patients are among those most likely to receive neoadjuvant systemic therapy; additional studies will be needed to confirm our findings, particularly the influence of ultrasonographybased staging on definitive treatment, for patients with other types of breast cancer. Whether or not ultrasonographic staging of the lymphatics results in improved treatment algorithms that result in better local control outcomes that outweigh the toxicities of treatment remains to be examined. There is a possibility of reporting bias in the retrospective review of physical examination findings. Many patients in our institution undergo mammography and ultrasonography prior to their initial clinical encounter; thus, the examining physician knows the axillary imaging results before performing the physical examination. It is possible that the knowledge of these results may have biased physicians’ interpretation of whether a patient had clinical lymphadenopathy; therefore, the true effect of ultrasonography in upstaging the clinical disease stage may be underestimated.
14.
Conclusions
15.
Our results suggest that ultrasonography-based nodal staging is important in patients with TNBC who will undergo neoadjuvant systemic therapy. Our data showed that, for a significant number of patients, ultrasonography of the nodal basin with FNAB of suspicious nodes not only resulted in an increase in clinical disease stage but also caused substantial differences in definitive treatments that were delivered.
5. 6.
7.
8.
9.
10. 11.
12.
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17.
18.
References 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines) Breast Cancer (Version 3.2014). http://www.nccn.org/professionals/physician_gls/f_guidelines. asp#breast. Accessed November 18, 2014. 2. Boughey JC, Suman VJ, Mittendorf EA, et al., Alliance for Clinical Trials in Oncology. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: The ACOSOG z1071 (alliance) clinical trial. JAMA 2013;310:1455-1461. 3. Bedi DG, Krishnamurthy R, Krishnamurthy S, et al. Cortical morphologic features of axillary lymph nodes as a predictor of metastasis in breast cancer: In vitro sonographic study. AJR Am J Roentgenol 2008;191:646-652. 4. Krishnamurthy S, Sneige N, Bedi DG, et al. Role of ultrasound-guided fine-needle aspiration of indeterminate and suspicious axillary lymph
19.
20.
21.
22.
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nodes in the initial staging of breast carcinoma. Cancer 2002;95: 982-988. Edge SB, and American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. Houssami N, Ciatto S, Turner RM, et al. Preoperative ultrasoundguided needle biopsy of axillary nodes in invasive breast cancer: Meta-analysis of its accuracy and utility in staging the axilla. Ann Surg 2011;254:243-251. Diepstraten SC, Sever AR, Buckens CF, et al. Value of preoperative ultrasound-guided axillary lymph node biopsy for preventing completion axillary lymph node dissection in breast cancer: A systematic review and meta-analysis. Ann Surg Oncol 2014;21:51-59. Garcia Fernandez A, Fraile M, Gimenez N, et al. Use of axillary ultrasound, ultrasound-fine needle aspiration biopsy and magnetic resonance imaging in the preoperative triage of breast cancer patients considered for sentinel node biopsy. Ultrasound Med Biol 2011;37: 16-22. Mortellaro VE, Marshall J, Singer L, et al. Magnetic resonance imaging for axillary staging in patients with breast cancer. J Magn Reson Imaging 2009;30:309-312. Robertson IJ, Hand F, Kell MR. FDG-PET/CT in the staging of local/regional metastases in breast cancer. Breast 2011;20:491-494. Cooper KL, Harnan S, Meng Y, et al. Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis. Eur J Surg Oncol 2011;37:187-198. Castellano I, Deambrogio C, Muscara F, et al. Efficiency of a preoperative axillary ultrasound and fine-needle aspiration cytology to detect patients with extensive axillary lymph node involvement. PLoS One 2014;9:e106640. van Wely BJ, de Wilt JH, Schout PJ, et al. Ultrasound-guided fineneedle aspiration of suspicious nodes in breast cancer patients; selecting patients with extensive nodal involvement. Breast Cancer Res Treat 2013;140:113-118. Caudle AS, Kuerer HM, Le-Petross HT, et al. Predicting the extent of nodal disease in early-stage breast cancer. Ann Surg Oncol 2014;21: 3440-3447. Boughey J, McCall L, Ballman K, et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: Findings from the ACOSOG z1071 (alliance) prospective multicenter clinical trial. Ann Surg 2014;260:608-614. Hunt K, Yi M, Mittendorf E, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg 2009;250:558-566. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): A prospective, multicentre cohort study. Lancet Oncol 2013;14:609-618. Boughey JC, Ballman KV, Hunt KK, et al. Axillary ultrasound after neoadjuvant chemotherapy and its impact on sentinel lymph node surgery: Results from the American College of Surgeons Oncology Group z1071 trial (alliance) [published online February 2, 2015]. J Clin Oncol http://dx.doi.org/10.1200/JCO.2014.57.8401. Boileau JF, Poirier B, Basik M, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: The SN FNAC study. J Clin Oncol 2015;33:258-264. Mittendorf EA, Caudle AS, Yang W, et al. Implementation of the American College of Surgeons Oncology Group z1071 trial data in clinical practice: Is there a way forward for sentinel lymph node dissection in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy? Ann Surg Oncol 2014;21:2468-2473. Caudle AS, Yang WT, Mittendorf EA, et al. Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: A prospective feasibility trial. JAMA 2015; 150:137-143. Alliance for Clinical Trials in Oncology. Alliance a011202. A randomized phase III trial evaluating the role of axillary lymph node
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dissection in breast cancer patients (cT1e3N1) who have positive sentinel lymph node disease after neoadjuvant chemotherapy. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US); 2000. Available at: https://clinicaltrials.gov/ct2/show/ NCT01901094. Accessed June 10, 2015. 23. NSABP Foundation. NSABP protocol b-51/RTOG protocol 1304, a randomized phase III clinical trial evaluating post-mastectomy chest
International Journal of Radiation Oncology Biology Physics wall and regional nodal XRT and post-lumpectomy regional nodal XRT in patients with positive axillary nodes before neoadjuvant chemotherapy who convert to pathologically negative axillary nodes after neoadjuvant chemotherapy. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US); 2000. Available at: https://clinicaltrials.gov/ct2/show/NCT01872975. Accessed June 10, 2015.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation
Role of Ultrasonography of Regional Nodal Basins in Staging Triple-Negative Breast Cancer and Implications For Local-Regional Treatment Simona F. Shaitelman, MD, EdM,* Welela Tereffe, MD, MPH,* Basak E. Dogan, MD,y Kenneth R. Hess, PhD,z Abigail S. Caudle, MD, MS,x Vicente Valero, MD,k Michael C. Stauder, MD,* Savitri Krishnamurthy, MD,{ Rosalind P. Candelaria, MD,y Eric A. Strom, MD,* Wendy A. Woodward, MD, PhD,* Kelly K. Hunt, MD,x Thomas A. Buchholz, MD,* and Gary J. Whitman, MDy *Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; yDepartment of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas; zDepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas; xDepartment of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; kDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and {Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas Received Mar 4, 2015, and in revised form May 1, 2015. Accepted for publication May 12, 2015.
Summary Ultrasonographic staging of nodes is now recommended prior to neoadjuvant systemic therapy for breast cancer. How this impacts clinical stage and treatment decisions among women with triple-negative breast cancer is uncertain. In this
Purpose: We sought to determine the rate at which regional nodal ultrasonography would increase the nodal disease stage in patients with triple-negative breast cancer (TNBC) beyond the clinical stage determined by physical examination and mammography alone, and significantly affect the treatments delivered to these patients. Methods and Materials: We retrospectively reviewed the charts of women with stages I to III TNBC who underwent physical examination, mammography, breast and regional nodal ultrasonography with needle biopsy of abnormal nodes, and definitive local-regional treatment at our institution between 2004 and 2011. The stages of these patients’ disease with and without ultrasonography of the regional nodal basins were compared using the Pearson c2 test. Definitive treatments of patients whose nodal
Reprint requests to: Simona F. Shaitelman, MD, EdM, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1202, Houston, TX 77030. Tel: (713) 563-8491; E-mail: [email protected] Part of the findings herein were presented at the 56th Annual Meeting of the American Society of Radiation Oncology, San Francisco, CA, Sep 2014. Int J Radiation Oncol Biol Phys, Vol. 93, No. 1, pp. 102e110, 2015 0360-3016/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.05.015
Conflict of interest: S.F.S. has received a grant from Elekta for work unrelated to that described in this article and is a consultant for the MD Anderson Physicians Network. M.C.S. is a consultant for the MD Anderson Physicians Network.
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retrospective chart review, 19.4% of patients had an increase in clinical disease stage with the incorporation of ultrasonography. Ultrasonographic upstaging significantly increased the use of axillary lymph node dissection and radiation to the regional nodal basins.
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disease was upstaged on the basis of ultrasonographic findings were compared to those of patients whose disease stage remained the same. Results: A total of 572 women met the study requirements. In 111 (19.4%) of these patients, regional nodal ultrasonography with needle biopsy resulted in an increase in disease stage from the original stage by physical examination and mammography alone. Significantly higher percentages of patients whose nodal disease was upstaged by ultrasonographic findings compared to that in patients whose disease was not upstaged underwent neoadjuvant systemic therapy (91.9% and 51.2%, respectively; P<.0001), axillary lymph node dissection (99.1% and 34.5%, respectively; P<.0001), and radiation to the regional nodal basins (88.2% and 29.1%, respectively; P<.0001). Conclusions: Regional nodal ultrasonography in TNBC frequently changes the initial clinical stage and plays an important role in treatment planning. Ó 2015 Elsevier Inc. All rights reserved.
Introduction The 2014 National Comprehensive Cancer Network guidelines recommend that patients who have breast cancer and clinically negative axillary lymph nodes on physical examination and who are being considered for neoadjuvant systemic therapy undergo axillary ultrasonography (1). When axillary ultrasonography reveals suspicious lymph nodes, the suspicious nodes should be sampled via fineneedle aspiration biopsy (FNAB) or core biopsy, and an image-detectable marker clip should be placed in the biopsied lymph node to ensure its removal at the time of definitive surgery (1). How definitive local-regional treatment is altered on the basis of initial staging using ultrasonography and lymph node biopsy remains uncertain. Accurate initial staging of the lymph nodes before the start of systemic therapy may allow for appropriate local-regional treatment decisions to be made. For example, patients who are staged with nodenegative disease by physical examination and do not undergo ultrasonography could have involved lymph nodes that resolve with neoadjuvant systemic therapy. These lymph nodes would not be detected by sentinel lymph node biopsy, and such patients might not receive adequate surgery or radiation therapy to ensure the eradication of microscopic residual nodal disease. Because patients with triple-negative breast cancer (TNBC) typically undergo neoadjuvant systemic therapy as the standard of care, ultrasonography during initial staging can help ensure that diseased lymph nodes do not go undetected. TNBC has been found to be more responsive to neoadjuvant systemic therapy than other forms of breast cancer (2); as such, accurate initial clinical staging is important to ensure thoughtful targeting of local-regional treatment, particularly for radiation that targets areas at risk of harboring microscopic residual disease. Conversely, identifying those patients whose TNBC is refractory to systemic therapy, which portends worse outcomes, may allow for intensified systemic and local-regional treatments.
The goal of our study was to characterize the rate of nodal disease upstaging as a result of regional nodal ultrasonography and ultrasonography-guided biopsy in TNBC patients. We also sought to determine how changes in nodal staging affected local-regional treatment.
Methods and Materials Using a prospectively maintained database, we conducted a retrospective review of all patients with TNBC evaluated at our institution between 2004 and 2011. This retrospective study was approved by the institutional review board at our institution. Electronic medical records were also reviewed to obtain detailed information about staging evaluation and local-regional treatment delivered. Patients were excluded from analysis for the following reasons: they had stage 0 or IV breast cancer at presentation, had inflammatory breast cancer at presentation, were male, had a history of breast cancer, had synchronous or metachronous contralateral breast cancer, a lack of definitive local-regional surgery, or had had treatment with breast-conserving surgery without adjuvant radiation therapy. Patients were also excluded if all definitive local-regional treatment (including surgery and radiation therapy, if delivered) was not performed at our institution; if the estrogen receptor, progesterone receptor, and HER2/neu amplification status were not confirmed at our institution; or if the initial staging did not include physical examination, diagnostic mammography, and ultrasonography of the breast and regional nodal basins with needle biopsy as clinically indicated. Physical examination of each patient’s breasts and regional lymph nodes had been conducted by a breast oncologist (medical, surgical, or radiation). Bilateral diagnostic mammography was performed and interpreted by one of our institution’s breast radiation specialists. All patients underwent breast and regional nodal basin ultrasonography, which was performed by 1 of 12 dedicated radiologists in our institution, using Antares ultrasonography units (Siemens
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Healthcare) with 13-7 or 5-7 MHz transducers. Ultrasonography examination of the regional nodal basins included the axillary, infraclavicular, and internal mammary chain lymph nodes. For any patient with abnormal findings on axillary ultrasonography, the supraclavicular lymph nodes were also scanned. Lymph nodes were classified as abnormal (ie warranting biopsy) based on criteria published by Bedi et al (3, 4). The index lymph node in the highest involved nodal chain was targeted for FNAB using a 21-gauge needle under ultrasonographic guidance. The decision whether to perform a biopsy of the internal mammary nodes was based on whether the node could be accessed safely and the biopsy’s potential impact on stage. When a biopsy of an abnormal internal mammary nodes was not possible, these nodes were considered involved, and the clinical disease stage was adjusted accordingly. Disease was staged according to the American Joint Committee on Cancer Cancer Staging Manual, 7th edition (5). The clinical stage of each patient based on mammographic and physical examination findings was compared to the disease stage determined with the addition of findings from ultrasonography of the breast and the regional nodal basins. The definitive treatment given to each patient was also examined. Proportions were compared between groups who were versus those who were not upstaged with ultrasonography by using the Pearson c2 test using Spotfire Sþ version 8.2 software (TIBCO) for Windows (Microsoft, Redmond, WA). The false-negative rate of ultrasonography with FNAB was also calculated for the study cohort. Comparisons between upstaged groups were also made after adjustment for potentially confounding study factors (age, grade, histology, lymphovascular space invasion, and menopausal status) using logistic regression analysis.
Results From a total of 2614 patients with TNBC, 572 (21.9%) fit the study criteria. The demographic, clinicopathologic, and treatment characteristics of these 572 patients are summarized in Table 1. Nodal staging was calculated based on physical examination and mammography with and without ultrasonography with FNAB of suspicious nodes (Table 1). Of the 572 patients, 111 (19.4%) had their nodal disease upstaged on the basis of ultrasonography-guided assessment of the regional nodal basins (Table 2). Specifically, disease was upstaged from lymph node-negative (cN0) to node-positive in 50 patients (8.7%), from cN1 to cN3 in 47 patients (8.2%), from cN2 to cN3 in 12 patients (2.1%), and from cN3a to a higher N3 stage in 2 patients (0.4%). A total of 28 patients with clinically palpable and 1 with uncertain axillary adenopathy were found to have node-negative disease when evaluated with ultrasonography with or without FNAB.
International Journal of Radiation Oncology Biology Physics Table 1 Demographic, clinicopathologic, and treatment characteristics of patients with nonmetastatic triple-negative breast cancer who underwent physical examination, mammography, ultrasonography, and definitive local-regional treatment at our institution Characteristic
No. of patients (NZ572) (%)
Race White, non-Hispanic 335 (58.6) Hispanic, Spanish 84 (14.7) Black 115 (20.1) Asian, Pacific Islander 33 (5.8) Native American 1 (0.2) Other 4 (0.7) Year of diagnosis 2004 52 (9.1) 2005 69 (12.1) 2006 53 (9.3) 2007 75 (13.1) 2008 58 (10.1) 2009 91 (15.9) 2010 86 (15.0) 2011 88 (15.4) Age at diagnosis (y) <40 97 (17.0) 40-49 155 (27.1) 50-59 174 (30.4) 60-69 108 (18.9) 70 38 (6.6) Menopausal status Premenopausal 213 (37.2) Perimenopausal 10 (1.7) Postmenopausal 349 (61.0) Trigger event for diagnosis Abnormal mammogram results 163 (28.5) Abnormal ultrasonography results 10 (1.7) Palpable mass 339 (59.3) Nipple discharge 10 (1.7) Breast pain/discomfort 31 (5.4) Inverted nipple 4 (0.7) Breast swelling 8 (1.4) Unknown/other 7 (1.2) Magnetic resonance imaging as part of staging evaluation Yes 79 (13.8) No 493 (86.2) Histology Invasive ductal carcinoma 541 (94.6) Invasive lobular carcinoma 4 (0.7) Other 27 (4.7) Nuclear grade I 0 (0.0) II 43 (7.5) III 524 (91.6) Not reported 5 (0.9) Lymphovascular space invasion Present 113 (19.8) Absent 459 (80.2) (continued on next page)
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Table 1 (continued ) Characteristic
No. of patients (NZ572) (%)
Definitive breast surgical procedure Lumpectomy 244 (42.7) Mastectomy 324 (56.6) No breast surgery 4 (0.7) Definitive axillary surgical procedure Sentinel lymph node biopsy 311 (54.4) ALND 261 (45.6) Neoadjuvant systemic therapy Yes 338 (59.1) No 234 (40.9) Adjuvant systemic therapy Yes 218 (38.1) No 354 (61.9) Radiation therapy Yes 401 (70.1) No 171 (29.9) Radiation therapy targets Breast/chest wall 169 (42.1) Breast/chest wall plus regional nodes 232 (57.9) Boost to regional nodes among patients receiving RNI Yes 77 (33.2) No 155 (66.8) Clinical T stage based on mammography and physical examination Tx 53 (9.3) T0 1 (0.2) Tis 1 (0.2) T1 121 (21.2) T2 255 (44.6) T3 99 (17.3) T4 42 (7.3) Clinical N stage based on mammography and physical examination Nx 1 (0.2) N0 329 (57.5) N1a 214 (37.4) N2 21 (3.7) N3a 3 (0.5) N3b 0 (0.0) N3c 4 (0.7) Clinical N stage based on mammography, physical examination, and ultrasonography with or without FNAB Nx 0 (0.0) N0 355 (62.1) N1a 135 (23.6) N2 4 (0.7) N3a 30 (5.2) N3b 23 (4.0) N3c 25 (4.4) Rate of positive axillary lymph nodes at definitive axillary surgery among 355 cN0 patients Neoadjuvant systemic therapy 11/146 (7.5) No neoadjuvant systemic therapy 36/209 (17.2) Abbreviations: ALND Z axillary lymph node dissection; FNAB Z fine-needle aspiration biopsy; RNI Z regional nodal irradiation.
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Table 2 Clinical upstaging based on ultrasonography and fine-needle aspiration biopsy among 572 patients Nodal upstaging cN0 upstaged to cNþ Total cN0 / cN1 cN0 / cN2 cN0 / cN3a cN0 / cN3b cN0 / cN3c cN1 upstaged to cN3 Total cN1 / cN3a cN1 / cN3b cN1 / cN3c cN2 upstaged to cN3 Total cN2 / cN3a cN2 / cN3b cN2 / cN3c cN3 upstaged to higher cN3 cN3a upstaged to cN3b cN3a upstaged to cN3c Total
No. of patients (%) 50 36 0 5 4 5
(8.7) (6.3) (0.0) (0.9) (0.7) (0.9)
47 23 12 12
(8.2) (4.0) (2.1) (2.1)
12 1 6 5
(2.1) (0.2) (0.2) (0.9)
1 (0.2) 1 (0.2) 111 (19.4)
Patients whose nodal disease was upstaged on the basis of ultrasonography were more likely than patients whose disease was not upstaged to undergo an ALND (99.1% vs 34.5%, P<.0001), neoadjuvant systemic therapy (91.9% vs 51.2%, P<.0001), and radiation therapy (93.7% vs 64.4%, P<.0001) (Table 3). The radiation targets and doses prescribed also differed significantly between patients whose disease was upstaged and those whose disease was not upstaged: 88.2% and 29.1%, respectively, received regional nodal radiation therapy (P<.0001); and 61.3% and 2.0%, respectively, received a boost dose of radiation to a nodal basin (P<.0001). In total, the false-negative rate for ultrasonography with FNAB of suspicious nodes was 19% (49 of 264; 95% confidence interval, 14%-24%). Of the 338 patients who received neoadjuvant systemic therapy prior to surgery, 192 (56.8%) were initially staged with node-positive disease by ultrasonography with FNAB of suspicious nodes, and 146 patients (43.2%) were initially staged as having nodenegative disease. Of the 234 patients who did not receive neoadjuvant systemic therapy prior to surgery, 173 had cN0 disease that was confirmed to be pN0 at the time of surgery. Among the 36 patients who did not receive neoadjuvant systemic therapy with cN0 disease based on ultrasonography with FNAB of suspicious nodes but were found to have pathological node-positive disease at the time of surgery, the median size of the lymph node metastases was 2.5 mm (range, 0.2-14.0 mm). Multivariate logistic analyses were performed to examine whether ultrasonographic upstaging added to the
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Table 3
Definitive treatment delivered based on ultrasonography-based disease upstaging Treatment received
No. of patients (nZ111) with upstaged disease (%)
Axillary lymph node dissection Neoadjuvant chemotherapy Adjuvant chemotherapy Radiation therapy RNI as a part of radiation therapy Boost dose to nodal basin as a part of RNI
110 102 17 104 98 68
(99.1) (91.9) (15.3) (93.7) (88.3) (61.3)
No. of patients (nZ461) with no disease upstaging (%) 159 236 201 297 134 9
(34.5) (51.2) (43.6) (64.4) (29.1) (2.0)
P <.0001 <.0001 <.0001 <.0001 <.0001 <.0001
Abbreviation: RNI Z regional nodal irradiation.
use of clinical patient and tumor characteristics to predict use of systemic and local-regional treatments (Table 4). Controlling for menopausal status (postmenopausal vs preor perimenopausal), age (>40 years vs 40 years), histology (invasive ductal, lobular or other vs aggressive histologies), grade (I/II vs III), lymphovascular space invasion (present vs absent), and ultrasonographic upstaging predicted for greater use of neoadjuvant chemotherapy, axillary lymph node dissection (ALND), radiation therapy, regional nodal irradiation, and boost doses of radiation to particular lymph node regions (all P<.0001).
Discussion In 19.4% of the TNBC patients in our study, regional nodal ultrasonography with FNAB of suspicious nodes led to an increase in preoperative disease stage from that determined by physical examination and mammography alone. This upstaging led to higher rates of use for neoadjuvant systemic therapy, ALND, and radiation therapy, particularly to the regional lymphatics. Controlling for clinical and pathologic features, nodal upstaging still predicted for patterns of usage of systemic and local-regional treatment.
Initial ultrasonographic staging of regional lymphatics We anticipate broad acceptance of the National Comprehensive Cancer Network’s recommendation that breast cancer patients with clinically node-negative disease undergo ultrasonography of the regional lymph nodes before neoadjuvant systemic therapy (1). Based on our findings, such acceptance would be expected to lead to the diagnosis of locoregionally advanced disease in a significantly higher percentage of patients than is currently seen. The increased percentage of patients diagnosed with locoregionally advanced disease likely would in turn lead to substantive shifts in the use of definitive regional treatment of the lymphatics.
Comparison of imaging modalities for axillary staging Ultrasonography has been well studied as a staging tool for breast cancer. Houssami et al (6) conducted a meta-analysis
of the accuracy of ultrasonography and ultrasonographyguided biopsy for axillary staging in breast cancer patients. This analysis of 21 studies, which included 4313 patients who underwent ultrasonography and excluded patients who underwent neoadjuvant systemic therapy, found a median sensitivity of 61.4% and specificity of 82.0% for ultrasonography. A subset of 1733 of these patients underwent ultrasonography-guided biopsy, for which the median sensitivity was 79.4% and the median specificity was 100%. Dipestraten et al (7) recently performed a systematic review and meta-analysis that estimated the false-negative rate of ultrasonography-guided biopsy of the axilla. The investigators found a pooled false-negative rate of 25% in the 31 studies they examined, similar to the rate of 19% found in our study. Other imaging modalities have not been found to be superior to ultrasonography for axillary staging in breast cancer patients. There are limited data to support the use of magnetic resonance imaging (MRI) for initial staging of the axilla in breast cancer patients (8, 9). Positron emission tomography (PET) with fluorodeoxyglucose labeling has a widely variable accuracy for axillary nodal staging and has not been broadly implemented for this purpose (10, 11). Despite the lack of proven alternatives, the wide adoption of ultrasonography as a primary modality for regional nodal staging in breast cancer patients remains uncertain. At our institution, because of the adoption of ultrasonography as a part of standard staging evaluation for TNBC, MRI and PET are selectively used in a minority of patients.
Implications of ultrasonography-based nodal staging for patients undergoing neoadjuvant systemic therapy There has been debate about the optimal approach to axillary staging in patients who will receive neoadjuvant systemic therapy. Although some institutions favor sentinel lymph node biopsy before systemic therapy, ultrasonography with FNAB of suspicious nodes offers an effective, nonsurgical approach to axillary staging with excellent sensitivity. In 1 study from our institution, 93% of axillary nodal metastases larger than 0.5 mm in diameter and 44% of those smaller than 5.0 mm were identified by ultrasonography (4). Not surprisingly, multiple groups have reported that patients with axillary
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Multivariate logistic regression analyses of factors contributing to local-regional and systemic therapy treatment Variable
Endpoint: axillary lymph node dissection (nZ269) Ultrasound upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: neoadjuvant chemotherapy (nZ338) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: adjuvant chemotherapy (nZ218) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: radiation therapy (nZ401) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 years) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: regional nodal irradiation (nZ232) Ultrasound upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal) Endpoint: boost dose to any lymph node basin (nZ77) Ultrasonographic upstaging (yes/no) Age at diagnosis (>40 vs 40 y) Histology (aggressive vs other)* Grade (III vs I/II) Lymphovascular space invasion (yes/no) Menopausal status (postmenopausal vs pre-/perimenopausal)
OR (95% CI)
P
200 0.55 1.14 1.38 3.07 1.19
(28-1448) (.29-1.01) (.34-3.76) (.65-2.95) (1.84-5.12) (.72-1.97)
<.0001 .06 .83 .40 <.0001 .49
11.2 .52 .53 1.11 .72 .63
(5.5-23) (.29-.95) (.18-1.63) (.58-2.12) (.45-1.17) (.41-.99)
<.0001 .03 .27 .75 .19 .05
.22 1.95 2.16 1.23 1.57 1.19
(.13-.39) (1.09-3.48) (.75-6.22) (.65-2.36) (.99-2.48) (.77-1.84)
<.0001 .03 .16 .52 .06 .45
8.1 .92 1.40 .58 1.59 1.25
(3.6-18) (.51-1.64) (.43-4.59) (.27-1.22) (.94-2.69) (.79-1.98)
<.0001 .77 .58 .15 .08 .34
19 .40 4.12 .90 3.55 .74
(8.0-46) (.18-.87) (1.00-17) (.42-1.96) (1.88-6.69) (.41-1.33)
<.0001 .02 .05 .80 .0001 .32
65 .51 .21 .77 1.00 1.50
(29-147) (.18-1.42) (.02-2.44) (.16-3.82) (.46-2.20) (.62-3.65)
<.0001 .20 .21 .75 1.00 .37
* Aggressive histology was defined as metaplastic/sarcomatoid, squamous carcinoma, or pleomorphic lobular carcinoma.
metastases proven by ultrasonography-guided biopsy have a larger burden of nodal disease, with more positive nodes, larger foci of disease, and a higher proportion of extranodal extension, than do patients who had a positive sentinel lymph node biopsy after a negative ultrasonographic examination (12-14). A dramatic axillary response to neoadjuvant systemic therapy was seen in TNBC patients in the American College of Surgeons Oncology Group (ACOSOG) trial Z1071 (15). The trial found that axillary response rates to neoadjuvant systemic therapy varied by tumor subtype, with eradication of nodal disease seen in 49.4% of patients
with TNBC but in only 21.1% of those with hormone receptor-positive/HER2-negative tumors (P<.0001) (15). Because a response to therapy may cause axillary metastases to go undiagnosed, knowing about significant nodal disease before therapy is important to determine the extent of planned nodal surgery as well as the need for adjuvant radiation therapy. Because some micrometastases in the axillary lymph nodes are not seen on ultrasonography, some physicians support the practice of performing sentinel lymph node biopsy on all patients prior to the start of neoadjuvant systemic therapy. However, it seems that committing these
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patients to multiple operations, including axillary surgery, may not be of benefit. Patients who present with a very small volume of axillary disease not detected by ultrasonography who have a pathologic complete response to neoadjuvant systemic therapy have outcomes similar to those without axillary disease. Hunt et al (16) compared the outcomes of patients with cN0 disease who had sentinel lymph node biopsy performed before neoadjuvant systemic therapy to those of patients whose sentinel lymph node biopsy occurred after systemic therapy. The study found no differences in local-regional recurrence rates; however, patients who underwent sentinel lymph node biopsy after systemic therapy had a lower probability of having a positive sentinel lymph node and were consequently spared ALND. Thus, although ultrasonography is not as sensitive in detecting axillary disease as surgical staging, ultrasonography identifies patients whose burden of axillary disease is significant enough to affect treatment decisions and carries less burden of morbidity than an invasive surgical procedure. Initial staging evaluation with nodal ultrasonography has been incorporated into surgical trials investigating the accuracy of sentinel lymph node biopsy for breast cancer patients treated with neoadjuvant systemic therapy. Both the ACOSOG Z1071 and SENTINA trials found high falsenegative rates for sentinel node biopsy in breast cancer patients who had received neoadjuvant systemic therapy (2, 17). Technical factors were found to be important in minimizing the false-negative rate of sentinel lymph node biopsy. These factors included the use of dual tracer techniques (ie, blue dye in combination with technetium-99m sulfur colloid and a minimum resection of at least 3 sentinel lymph nodes). Because the false-negative rate found in ACOSOG Z1071 was 12.6% among patients with cN1 disease and at least 2 sentinel lymph nodes examined, higher than the prespecified acceptable false-negative rate of 10.0% (2). As a result, sentinel lymph node biopsy alone is not considered appropriate in patients found to have biopsy-proven involved lymph nodes at initial presentation. These data were corroborated by the European SENTINA trial (17), which differed from ACOSOG trial Z1071 in the fact that only 28% (63 of 226) of enrolled patients considered to have clinically node-positive disease underwent a needle biopsy to confirm the presence of metastases. The SENTINA trial reported a false-negative rate for sentinel lymph node biopsy of 14%, which improved when dual tracers were used and more than 2 sentinel lymph nodes were removed, findings similar to those of ACOSOG Z1071. Incorporation of postchemotherapy axillary ultrasonography findings in the selection of ideal candidates for sentinel lymph node biopsy following neoadjuvant chemotherapy also appears to lower the false-negative rate (18). The extent of pathologic evaluation also plays an important role in this setting, as demonstrated by the Sentinel Node Biopsy Following Neoadjuvant Chemotherapy (SN FNAC) study. Those investigators found that the incorporation of immunohistochemistry in pathology
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review resulted in a false-negative rate of only 8.4% when isolated tumor cells were considered positive but 13.3% if they were considered negative (19). Efforts are under way to better define the characteristics of patients for whom a less invasive procedure than an ALND can provide appropriate clearance of involved lymph nodes following neoadjuvant systemic therapy (20, 21). Both the Alliance for Clinical Trials in Oncology and NRG Oncology have open clinical trials (A011202 and NSABP B-51/RTOG 1304, respectively) to examine the appropriate local-regional treatment for breast cancer patients based on the degree of response of the lymph nodes to neoadjuvant systemic therapy (22, 23). For patients with residual nodal disease, it remains uncertain whether ALND is necessary or axillary radiation therapy might replace ALND. Conversely, for patients with a pathologic complete response in the lymph nodes, the need for regional nodal irradiation remains uncertain. Our group has historically delivered differential doses of radiation to the lymph node regions based on pathologic involvement at the time of initial staging, the extent of surgery performed, and the response of lymph nodes to neoadjuvant systemic therapy. Radiation therapy in this setting has typically been used adjuvantly to eradicate any microscopic residual disease in those lymph node basins not fully dissected by the surgical oncologist. For patients in whom gross lymphadenopathy is still visualized by ultrasonography following definitive neoadjuvant systemic therapy and surgical treatment, particularly in regions that are not commonly resected, such as the internal mammary chain and the supraclavicular fossa, we typically deliver a higher boost dose of radiation (16 Gy in 8 fractions) to eradicate disease. We propose that thoughtful radiation treatment planning be done in response to the detailed staging that can be performed with guidance from ultrasonographic findings. Such treatment planning should also take into account the extent of surgical excision to avoid irradiating areas that are sufficiently treated with surgical excision alone (22, 23). Thus far, the local-regional control rates and toxicities with versus without usage of higher boost doses of radiation to these regions is not known.
Study limitations This retrospective study has some limitations. Because our institution is a tertiary care referral center, it is possible that patients with breast cancer who elected to have their definitive local-regional treatment at our institution had a higher stage of clinical disease than those who received only part of their treatment at our institution. As mentioned above, owing to technical limitations, not all morphologically abnormal lymph nodes were biopsied, and clinical interpretations of ultrasonography reports were used to guide final staging. The techniques required for accurate assessment and biopsy of lymph nodes is operator dependent. As such, the findings of this study may not be
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generalizable to other institutions. While the lymph node basins evaluated at our institution typically include the axilla, internal mammary, infraclavicular, and supraclavicular regions, at many institutions ultrasonography of the lymphatics is focused on the axilla alone, which would preclude the ability to accurately diagnose stage cN2b and cN3 disease. This study spanned 8 years, during which some technical aspects of ultrasonography and standard definitive treatments changed. Also, the study was restricted to patients with TNBC because such patients are among those most likely to receive neoadjuvant systemic therapy; additional studies will be needed to confirm our findings, particularly the influence of ultrasonographybased staging on definitive treatment, for patients with other types of breast cancer. Whether or not ultrasonographic staging of the lymphatics results in improved treatment algorithms that result in better local control outcomes that outweigh the toxicities of treatment remains to be examined. There is a possibility of reporting bias in the retrospective review of physical examination findings. Many patients in our institution undergo mammography and ultrasonography prior to their initial clinical encounter; thus, the examining physician knows the axillary imaging results before performing the physical examination. It is possible that the knowledge of these results may have biased physicians’ interpretation of whether a patient had clinical lymphadenopathy; therefore, the true effect of ultrasonography in upstaging the clinical disease stage may be underestimated.
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Conclusions
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Our results suggest that ultrasonography-based nodal staging is important in patients with TNBC who will undergo neoadjuvant systemic therapy. Our data showed that, for a significant number of patients, ultrasonography of the nodal basin with FNAB of suspicious nodes not only resulted in an increase in clinical disease stage but also caused substantial differences in definitive treatments that were delivered.
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References 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines) Breast Cancer (Version 3.2014). http://www.nccn.org/professionals/physician_gls/f_guidelines. asp#breast. Accessed November 18, 2014. 2. Boughey JC, Suman VJ, Mittendorf EA, et al., Alliance for Clinical Trials in Oncology. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: The ACOSOG z1071 (alliance) clinical trial. JAMA 2013;310:1455-1461. 3. Bedi DG, Krishnamurthy R, Krishnamurthy S, et al. Cortical morphologic features of axillary lymph nodes as a predictor of metastasis in breast cancer: In vitro sonographic study. AJR Am J Roentgenol 2008;191:646-652. 4. Krishnamurthy S, Sneige N, Bedi DG, et al. Role of ultrasound-guided fine-needle aspiration of indeterminate and suspicious axillary lymph
19.
20.
21.
22.
109
nodes in the initial staging of breast carcinoma. Cancer 2002;95: 982-988. Edge SB, and American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. Houssami N, Ciatto S, Turner RM, et al. Preoperative ultrasoundguided needle biopsy of axillary nodes in invasive breast cancer: Meta-analysis of its accuracy and utility in staging the axilla. Ann Surg 2011;254:243-251. Diepstraten SC, Sever AR, Buckens CF, et al. Value of preoperative ultrasound-guided axillary lymph node biopsy for preventing completion axillary lymph node dissection in breast cancer: A systematic review and meta-analysis. Ann Surg Oncol 2014;21:51-59. Garcia Fernandez A, Fraile M, Gimenez N, et al. Use of axillary ultrasound, ultrasound-fine needle aspiration biopsy and magnetic resonance imaging in the preoperative triage of breast cancer patients considered for sentinel node biopsy. Ultrasound Med Biol 2011;37: 16-22. Mortellaro VE, Marshall J, Singer L, et al. Magnetic resonance imaging for axillary staging in patients with breast cancer. J Magn Reson Imaging 2009;30:309-312. Robertson IJ, Hand F, Kell MR. FDG-PET/CT in the staging of local/regional metastases in breast cancer. Breast 2011;20:491-494. Cooper KL, Harnan S, Meng Y, et al. Positron emission tomography (PET) for assessment of axillary lymph node status in early breast cancer: A systematic review and meta-analysis. Eur J Surg Oncol 2011;37:187-198. Castellano I, Deambrogio C, Muscara F, et al. Efficiency of a preoperative axillary ultrasound and fine-needle aspiration cytology to detect patients with extensive axillary lymph node involvement. PLoS One 2014;9:e106640. van Wely BJ, de Wilt JH, Schout PJ, et al. Ultrasound-guided fineneedle aspiration of suspicious nodes in breast cancer patients; selecting patients with extensive nodal involvement. Breast Cancer Res Treat 2013;140:113-118. Caudle AS, Kuerer HM, Le-Petross HT, et al. Predicting the extent of nodal disease in early-stage breast cancer. Ann Surg Oncol 2014;21: 3440-3447. Boughey J, McCall L, Ballman K, et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: Findings from the ACOSOG z1071 (alliance) prospective multicenter clinical trial. Ann Surg 2014;260:608-614. Hunt K, Yi M, Mittendorf E, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann Surg 2009;250:558-566. Kuehn T, Bauerfeind I, Fehm T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): A prospective, multicentre cohort study. Lancet Oncol 2013;14:609-618. Boughey JC, Ballman KV, Hunt KK, et al. Axillary ultrasound after neoadjuvant chemotherapy and its impact on sentinel lymph node surgery: Results from the American College of Surgeons Oncology Group z1071 trial (alliance) [published online February 2, 2015]. J Clin Oncol http://dx.doi.org/10.1200/JCO.2014.57.8401. Boileau JF, Poirier B, Basik M, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: The SN FNAC study. J Clin Oncol 2015;33:258-264. Mittendorf EA, Caudle AS, Yang W, et al. Implementation of the American College of Surgeons Oncology Group z1071 trial data in clinical practice: Is there a way forward for sentinel lymph node dissection in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy? Ann Surg Oncol 2014;21:2468-2473. Caudle AS, Yang WT, Mittendorf EA, et al. Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: A prospective feasibility trial. JAMA 2015; 150:137-143. Alliance for Clinical Trials in Oncology. Alliance a011202. A randomized phase III trial evaluating the role of axillary lymph node
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dissection in breast cancer patients (cT1e3N1) who have positive sentinel lymph node disease after neoadjuvant chemotherapy. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US); 2000. Available at: https://clinicaltrials.gov/ct2/show/ NCT01901094. Accessed June 10, 2015. 23. NSABP Foundation. NSABP protocol b-51/RTOG protocol 1304, a randomized phase III clinical trial evaluating post-mastectomy chest
International Journal of Radiation Oncology Biology Physics wall and regional nodal XRT and post-lumpectomy regional nodal XRT in patients with positive axillary nodes before neoadjuvant chemotherapy who convert to pathologically negative axillary nodes after neoadjuvant chemotherapy. In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US); 2000. Available at: https://clinicaltrials.gov/ct2/show/NCT01872975. Accessed June 10, 2015.