Ann Surg Oncol DOI 10.1245/s10434-015-5052-8
ORIGINAL ARTICLE – BREAST ONCOLOGY
Axillary Staging After Neoadjuvant Chemotherapy for Breast Cancer: A Pilot Study Combining Sentinel Lymph Node Biopsy with Radioactive Seed Localization of Pre-treatment Positive Axillary Lymph Nodes Emilia J. Diego, MD1, Priscilla F. McAuliffe, MD, PhD1, Atilla Soran, MD, MPH1, Kandace P. McGuire, MD2, Ronald R. Johnson, MD1, Marguerite Bonaventura, MD1, and Gretchen M. Ahrendt, MD1 1
Division of Surgical Oncology, Department of Surgery, University of Pittsburgh College of Medicine, Magee Womens Hospital of UPMC, Pittsburgh, PA; 2Division of Surgical Oncology, Department of Surgery, University of North Carolina, Chapel Hill, NC
ABSTRACT Background. Neoadjuvant chemotherapy (NAC) downstages axillary disease in 55 % of node-positive (N1) breast cancer. The feasibility and accuracy of sentinel lymph node biopsy (SLNB) after NAC for percutaneous biopsy-proven N1 patients who are clinically node negative (cN0) by physical examination after NAC is under investigation. ACOSOG Z1071 reported a false-negative rate of\10 % if C3 nodes are removed with dual tracer, including excision of the biopsy-proven positive lymph node (BxLN). We report our experience using radioactive seed localization (RSL) to retrieve the BxLN with SLNB (RSL/SLNB) for cN0 patients after NAC. Methods. We performed a retrospective review of a single-institution, prospectively maintained registry for the years 2013 to 2014. Patients with BxLN who received NAC and had RSL/SLNB were identified. All BxLNs were marked with a radiopaque clip before NAC to facilitate RSL. Results. Thirty patients with BxLN before NAC were cN0 after NAC and underwent RSL/SLNB. Median age was 55 years. Disease stage was IIA–IIIB. Twenty-nine of 30 had ductal cancer (12 triple negative and 16 HER-2 positive). One to 11 nodes were retrieved. Twenty-nine of 30 BxLN were successfully localized with RSL. Note was made of the BxLN-containing isotope and/or dye in 22 of
Ó Society of Surgical Oncology 2015 First Received: 15 May 2015 E. J. Diego, MD e-mail: [email protected]
30. Nineteen patients had no residual axillary disease; 11 had persistent disease. All who remained node positive had disease in the BxLN. Conclusions. RSL/SLNB is a promising approach for axillary staging after NAC in patients whose disease becomes cN0. The status of the BxLN after NAC predicted nodal status, suggesting that localization of the BxLN may be more accurate than SLNB alone for staging the axilla in the cN0 patient after NAC.
Axillary lymph node status remains one of the most important prognostic indicators in breast cancer. In patients with a clinically negative axilla (cN0), a sentinel lymph node biopsy (SLNB) is an acceptable approach to axillary staging.1–3 The results from the ACOSOG Z0011, IBCSG 23-01, and EORTC 10981-22023 AMAROS trials support the omission of a completion axillary lymph node dissection (ALND) in women with small tumors and a small burden of axillary disease who receive appropriate adjuvant systemic chemotherapy, endocrine therapy, and radiotherapy, thus making axillary staging a largely diagnostic tool in breast cancer care.4–7 Neoadjuvant chemotherapy (NAC) is increasingly used for the benefits of tumor downstaging to facilitate breastconservation therapy, to assess in vivo response to therapy, and to potentially downstage axillary lymph nodes.8–10 Improved understanding of breast tumor biology and phenotype and use of targeted therapies have resulted in higher pathologic complete response (pCR) rates.11–13 Minimizing the extent of breast surgery in patients whose disease has a partial or complete response to NAC is routinely
E. J. Diego et al.
performed.10 A SLNB after completion of chemotherapy can also be performed in patients with a clinically negative axilla.9,14 However, the concept of less extensive axillary surgery is not as readily embraced when biopsy-proven axillary metastasis has been established before the start of NAC.15,16 In the ACOSOG Z1071 trial, the accuracy of a SLNB after NAC was investigated in women who had biopsy-proven axillary disease that demonstrated a clinical response in the axilla by physical examination. A falsenegative rate (FNR) of 12.6 % was deemed unacceptably high to allow routine recommendation of a SLNB in women who had a percutaneous biopsy-proven positive node. Several factors found to decrease the FNR to \10 % included the use of dual tracer for lymphatic mapping and removal of at least 3 sentinel lymph nodes. In addition, in patients where a radiopaque clip had been placed in the positive node at the time of biopsy, when this node was identified and removed as part of the sentinel node procedure, the FNR was \7 %.4,17 Incorporating these mapping strategies are now part of the National Comprehensive Cancer Network guidelines for axillary management after NAC.18 Our institution has implemented a protocol to routinely mark the positive axillary lymph node with a radiopaque clip at the time of biopsy. At the time of definitive surgery after NAC, the clipped node is localized with a 125I-labeled radioactive seed using image guidance to facilitate retrieval of this percutaneous biopsy-proven positive node. We report our experience of surgically addressing the axilla in patients who have pathologic evidence of nodal metastasis, who have received NAC, and whose disease is clinically node negative (cN0) by physical examination at the end of treatment. METHODS After receipt of approval from the institutional review board, a retrospective review of a prospectively maintained cancer registry and 125I-radioactive seed database were searched for all patients diagnosed with percutaneous biopsy-proven, node-positive (N1) breast cancer who received NAC before definitive surgery from May 2013 to June 2014. Patients with cN0 disease by physical examination at the end of NAC and who underwent radioactive seed localization (RSL) of the biopsy-proven positive lymph node combined with SLNB (RSL/SLNB) were identified. At the time of percutaneous biopsy, the lymph node was marked with a radiopaque clip to facilitate future localization. The time period was selected as the results from the ACOSOG 1071 trial had been recently reported, and the practice of performing a SLNB in this circumstance was considered to have a FNR of \10 % if dual tracer was
used, at least 3 lymph nodes were retrieved, and the previously assessed positive lymph node was included. None of the patients had undergone axillary staging surgery before receiving NAC. Preoperative localization via ultrasound or mammogram of the previously assessed axillary lymph node containing the radiopaque biopsy clip was done using a 4.5 9 0.8 mm titanium seed containing 0.1 to 0.25mCi 125I labeled through a preloaded 18-gauge needle. All surgeries were performed on the main campus or at affiliated satellite ambulatory surgery centers by 6 dedicated breast surgeons. Intraoperative subcutaneous injection of 0.3 miC 99mTc and a subareolar injection of dilute methylene blue dye were performed in the same fashion as the surgeon’s standard SLNB practice. Upon entering the axilla, retrieval of the targeted lymph node was first performed with a handheld gamma probe set to detect the 125I seed. Intraoperative specimen radiograph was obtained to document the excision of the targeted node, including the radiopaque clip and the 125I seed. The SLNB was then performed in the usual fashion. The axillary staging surgery was done as a standalone operation or in conjunction with definitive breast surgery. All pathology specimens were processed and examined at the main campus’s department of pathology. All 125 I-seed localized and sentinel lymph nodes were evaluated via serial hematoxylin and eosin examination. Immunohistochemistry was not routinely used to detect sentinel lymph node metastasis. Patients who had persistent disease in any of the sentinel lymph nodes were recommended to have a completion ALND. All patients in the study had cN0 disease by physical examination at the end of NAC and had 125I seed localization of the previously assessed positive lymph node. Electronic medical records were reviewed to obtain patient demographics, breast cancer stage and type, tumor receptor status, NAC regimen, and pathology results from the percutaneous, preoperative breast and axillary biopsy samples, as well as definitive surgical specimens. The sampled and localized lymph node was considered successfully retrieved if the surgical pathology report confirmed presence of biopsy site changes with a radiopaque clip in the lymph node with the 125I seed. Note was also made of 99mTc radiotracer activity or blue dye uptake in the targeted lymph node. RESULTS Review of the prospectively maintained cancer registry and radioactive seed database identified 80 patients with nonmetastatic N1 breast cancer who received NAC between May 2013 and June 2014. Patients who did not
Axillary Staging After Neoadjuvant Chemotherapy
have RSL and SLNB combination axillary procedure or those who had an immediate ALND were excluded. Thirty patients with planned RSL/SLNB combination surgery remained for analysis. The median patient age was 55 years (range 30– 71 years). A total of 84 % of patients had stage II and 16 % stage III disease at presentation; 97 % had invasive ductal carcinoma. Fifty-seven percent were HER-2 positive, 36 % were triple negative, and 7 % were luminal breast cancers (Table 1). Because it is an institutional practice to perform ultrasound interrogation of the axilla in patients with known invasive carcinoma who will receive NAC, all patients underwent percutaneous biopsy of the most suspiciousappearing axillary lymph node with placement of a radiopaque clip before the start of NAC to establish nodepositive disease. All patients completed the NAC regimens as planned before surgery. Patients with HER-2-positive breast cancers received anti-HER-2-containing regimens. Patients with cN0 disease by physical examination at the end of NAC were offered RSL/SLNB combination surgery. RSL was performed via ultrasound guidance in 28 patients and mammogram guidance in 1 patient. One patient did not have RSL placed as a result of the inability of the radiologist to visualize the lymph node with a biopsy clip via ultrasound or mammogram at the time of scheduled localization. Twenty-five patients had definitive breast surgery in conjunction with the axillary surgery. Five had the RSL/ SLNB combination surgery alone to stage the axilla and assess the need for postmastectomy radiation and timing of breast reconstruction. Intradermal 99mTc and retroareolar blue dye injections were performed in the operating room by the surgeon after TABLE 1 Patient demographics n = 30 Median age
55 (range 30–71)
Stage (AJCC, 7th edition) IIA IIB
8 (27 %) 16 (57 %)
IIIA
5 (13 %)
IIIB
1 (3 %)
Tumor morphology Invasive ductal cancer
29 (97 %)
Invasive lobular CANCER
1 (3 %)
Phenotype Luminal
2 (7 %)
HER2 positive
16 (57 %)
Triple negative
12 (36 %)
AJCC American Joint Committee on Cancer
induction of general anesthesia. Standard axillary incisions were used to access axillary lymph nodes except in cases where a mastectomy was also performed. Using the handheld gamma probe set to detect 125I, the axillary lymph node containing the 125I seed was excised first. In 22 of 30 cases, intraoperative note of blue dye or 99mTc activity in the 125I-localized lymph node was also made. In 91 % (20/22), the targeted lymph node also had blue dye, 99m Tc activity, or both. However, in 9 % (2/22), the targeted lymph node did not have any blue dye or 99mTc activity. In 27 % (8/30) of cases, there was no intraoperative or pathologic note regarding presence of blue dye or 99m Tc activity in the 125I-localized lymph node. Specimen radiographs were performed to confirm retrieval of the 125I seed and lymph node containing the biopsy clip. All 125I seeds were successfully retrieved. Two patients had specimen radiographs with confirmation of 125 I seed in a lymph node; however, the biopsy clip was not seen. Subsequent pathologic examination confirmed biopsy site changes in these 2 cases. In the 1 patient where RSL was aborted as a result of nonvisualization of the clip, standard SLNB was performed, and specimen radiographs confirmed retrieval of a lymph node containing a clip. Excision in this circumstance was facilitated by concomitant 99mTc and blue dye uptake of the lymph node. After excision of the 125I-seed localized node, SLNB was subsequently performed in standard fashion with excision of all lymph nodes with uptake of blue dye, or [10 % of highest ex vivo 99mTc count and removal of any palpably suspicious nodes. The median number of lymph nodes retrieved with the RSL/SLNB combination surgery was 4 (range 1–11). Pathologic evaluation revealed biopsy site changes in 100 % of the targeted lymph nodes. Thirty-seven percent (11/30) of patients had a pCR, defined as no residual invasive carcinoma in the breast or axilla. In 63 % (19/30) of patients, there was a complete pathologic response in the axilla (ypN0). In all cases that were ypN0, there were identifiable chemotherapy related changes in the node. pCR and the axillary downstaging rate are stratified by tumor phenotype in Table 2. In the 11 patients with residual disease in the RSL lymph node, 7 underwent a completion ALND. Of this subset, 57 % (4/7) were found to have additional disease in the axillary specimen. In the 4 patients who did not go on to have a completion ALND, 2 patients had small-volume disease (isolated tumor cells and micrometastasis, \2 mm) with multidisciplinary agreement to omit ALND, 1 patient had 11 lymph nodes in the specimen, and 1 patient opted not to undergo completion ALND. There were no patients who had other pathologically positive lymph nodes when the 125I-localized lymph node was negative (Table 2).
E. J. Diego et al. TABLE 2 Lymph node status Lymph nodes Median number of RSL/SLNB nodes excised
4 (range 1–11)
Target node excised with RSL
29/30 (97 %)
Biopsy site changes in target node
30/30 (100 %)
Pathologic response Complete In breast and axilla (i.e. pCR)
11/30 (37 %)
Luminal
0/2 (0 %)
HER2 positive
6/16 (38 %)
Triple negative
5/12 (42 %)
In axilla (i.e. downstage from cN1to ypN0) Luminal
19/30 (63 %) 0/2 (0 %)
HER2 positive
11/16 (69 %)
Triple negative
8/12 (67 %)
Chemotherapy related changes in axilla Residual axillary disease
19/30 (63 %)
RSL node positive
11/30 (37 %)
Additional positive nodes identified on SLNB after RSL?
6/11 (55 %)
Additional positive nodes identified on SLNB after RSL-
0 (0 %)
Completion ALND for persistent disease in RSL/SLNB
7/11 (64 %)
Total number of nodes examined in patients with RSL? (mean)
14 (range 2–25)
Additional disease on completion ALND
4/7 (57 %)
RSL radioactive seed localization, SLNB sentinel lymph node biopsy, pCR pathologic complete response, cN1 clinically node positive, ypN0 pathologically node negative after chemotherapy, ALND axillary lymph node dissection
DISCUSSION A better understanding of breast cancer phenotypes and the use of targeted therapies have resulted in pCR and axillary downstaging of up to 55 % in women with invasive breast cancer who receive NAC.11 For a patient with biopsy-proven axillary metastasis with cN0 disease by physical examination at the end of NAC, axillary status may influence decisions for or against additional therapy such as postmastectomy radiation. Though an ALND can provide this information, this procedure is associated with risks of lymphedema, numbness, and limitations in upperextremity range of motion.19–24 For patients who experience a pCR in the axilla, ALND offers no therapeutic benefit. MD Anderson and the Netherlands Cancer Institute have reported an identical approach to staging the axilla after NAC, with very similar success rates in retrieving the previously biopsy-assessed lymph node.25–27 The MD Anderson experience demonstrates a FNR of 11.6 % for
SLNB alone and only 2.3 % when the assessed lymph node is retrieved in conjunction with SLNB. In their series, 25 % of the time, the previously assessed lymph node was not identified as a sentinel lymph node in that the node did not contain blue dye or 99mTc activity. Use of the 125I seed facilitates retrieval and removal of this node, which may not take up conventional tracers as a result of changes in lymphatic circulation or chemotherapy-related changes in the node.27 Without the 125I seed, the FNR is expected to be higher for SLNB after NAC. Our findings support these above findings; in addition, SLNB in combination with RSL of the previously assessed positive node may be able to accurately stage the cN0 axilla after completion of NAC, sparing a subset of patients the potential morbidity of an ALND. This is one of the larger series to date reporting the experience of localizing the biopsy-proven positive lymph node in addition to SLNB when staging the axilla after NAC in patients with cN0 disease assessed by physical examination at the completion of treatment. Though the previously assessed lymph node may be retrieved in a standard SLNB procedure, it would have been missed in 9 % of patients if not targeted for localization, leading to a possibly higher FNR, as supported by the MD Anderson and Netherlands Cancer Institute data. In all patients, the status of the assessed lymph node represented the status of the remaining lymph nodes retrieved. This finding raises the question of whether excising this RSL lymph node alone at the end of treatment would be sufficient for staging and for adjuvant therapy decision making. Limitations of this series include the single-institution, retrospective nature of the study without any control group for comparison. In addition, not all patients who had residual axillary disease went on to have a completion ALND, at the discretion of the multidisciplinary team as a result of a very small burden of residual nodal disease, the number of lymph nodes retrieved at SLNB, or patient refusal. Therefore, the true FNR cannot be determined. The presence or absence of radiocolloid/blue dye in the excised lymph node was unknown in 27 % (8/30) of the patients in this study. Last, a greater proportion of patients in this series had HER-2-positive or triple-negative disease, leading to a higher pCR and axillary downstaging rate, possibly contributing to the lower FNR findings. In conclusion, for patients with node-positive breast cancer with cN0 disease by physical examination after NAC, staging the axilla with SLNB alone is associated with [10 % FNR.4,16 Axillary status after treatment may be more accurately staged by localization of the previously biopsy-sampled lymph node in conjunction with a SLNB. Localization of this lymph node is facilitated when a radiopaque marker is placed in the node at the time of biopsy. Surgical retrieval with 125I seed localization is
Axillary Staging After Neoadjuvant Chemotherapy
achieved 97 % of the time and represents a meaningful improvement in axillary staging after NAC. Pathologic status of the previously assessed lymph node may be a more accurate representation of the axillary status compared to SLNB alone. Further investigation of this technique is warranted. DISCLOSURE
The authors declare no conflict of interest.
REFERENCES 1. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymphnode dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol. 2007;8:881–8. 2. Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010;11:927–33. 3. Lyman GH, Temin S, Edge SB, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2014;32:1365–83. 4. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer: the ACOSOG Z1071 (Alliance) clinical trial. JAMA. 2013;310:1455–61. 5. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs. no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305:569–75. 6. Galimberti V, Cole BF, Zurrida S, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial. Lancet Oncol. 2013;14:297–305. 7. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15: 1303–10. 8. Kuerer HM, Sahin AA, Hunt KK, et al. Incidence and impact of documented eradication of breast cancer axillary lymph node metastases before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg. 1999;230:72–8. 9. Erdahl LM, Boughey JC. Use of sentinel lymph node biopsy to select patients for local-regional therapy after neoadjuvant chemotherapy. Curr Breast Cancer Rep. 2014;6:10–6. 10. Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008;26:778–85. 11. Hicks M, Macrae ER, Abdel-Rasoul M, et al. Neoadjuvant dual HER2-targeted therapy with lapatinib and trastuzumab improves pathologic complete response in patients with early stage HER2positive breast cancer: a meta-analysis of randomized prospective clinical trials. Oncologist. 2015;20:337–43.
12. Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2–positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33:983–91. 13. Lips EH, Mukhtar RA, Yau C, et al. Lobular histology and response to neoadjuvant chemotherapy in invasive breast cancer. Breast Cancer Res Treat. 2012;136:35–43. 14. Kang SH, Kang JH, Choi EA, Lee ES. Sentinel lymph node biopsy after neoadjuvant chemotherapy. Breast Cancer. 2004;11: 233–41. 15. Canavese G, Dozin B, Vecchio C, et al. Accuracy of sentinel lymph node biopsy after neo-adjuvant chemotherapy in patients with locally advanced breast cancer and clinically positive axillary nodes. Eur J Surg Oncol. 2011;37:688–94. 16. 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;14:609–18. 17. Boughey JC, Suman VJ, Mittendorf EA, et al. Factors affecting sentinel lymph node identification rate after neoadjuvant chemotherapy for breast cancer patients enrolled in ACOSOG Z1071 (Alliance). Ann Surg. 2015;261:547–52. 18. National Comprehensive Cancer Network. Breast cancer, version 2.2015. http://www.nccn.org/professionals/physician_gls/pdf/breast. pdf. Accessed 12 Apr 2015. 19. DiSipio T, Rye S, Newman B, Hayes S. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol. 2013;14:500–15. 20. McLaughlin SA, Wright MJ, Morris KT, et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol. 10 2008;26:5213–9. 21. Norman SA, Localio AR, Kallan MJ, et al. Risk factors for lymphedema after breast cancer treatment. Cancer Epidemiol Biomarkers Prev. 2010;19:2734–46. 22. Sagen A, Kaaresen R, Sandvik L, Thune I, Risberg MA. Upper limb physical function and adverse effects after breast cancer surgery: a prospective 2.5-year follow-up study and preoperative measures. Arch Phys Med Rehabil. 2014;95:875–81. 23. Wernicke AG, Shamis M, Sidhu KK, et al. Complication rates in patients with negative axillary nodes 10 years after local breast radiotherapy after either sentinel lymph node dissection or axillary clearance. Am J Clin Oncol. 2013;36:12–9. 24. Yen TW, Fan X, Sparapani R, Laud PW, Walker AP, Nattinger AB. A contemporary, population-based study of lymphedema risk factors in older women with breast cancer. Ann Surg Oncol. 2009;16:979–88. 25. 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 Surg. 2015;150:137–43. 26. Donker M, Straver ME, Wesseling J, et al. Marking axillary lymph nodes with radioactive iodine seeds for axillary staging after neoadjuvant systemic treatment in breast cancer patients: the MARI procedure. Ann Surg. 2015;261:378–82. 27. Caudle AS, Yang WT, Mittendorf EA, et al. Targeted axillary dissection improves axillary evaluation following neoadjuvant chemotherapy in node positive breast cancer. Paper presented at: 68th SSO Annual Cancer Symposium; March 25–28, 2015; Houston, TX.
ORIGINAL ARTICLE – BREAST ONCOLOGY
Axillary Staging After Neoadjuvant Chemotherapy for Breast Cancer: A Pilot Study Combining Sentinel Lymph Node Biopsy with Radioactive Seed Localization of Pre-treatment Positive Axillary Lymph Nodes Emilia J. Diego, MD1, Priscilla F. McAuliffe, MD, PhD1, Atilla Soran, MD, MPH1, Kandace P. McGuire, MD2, Ronald R. Johnson, MD1, Marguerite Bonaventura, MD1, and Gretchen M. Ahrendt, MD1 1
Division of Surgical Oncology, Department of Surgery, University of Pittsburgh College of Medicine, Magee Womens Hospital of UPMC, Pittsburgh, PA; 2Division of Surgical Oncology, Department of Surgery, University of North Carolina, Chapel Hill, NC
ABSTRACT Background. Neoadjuvant chemotherapy (NAC) downstages axillary disease in 55 % of node-positive (N1) breast cancer. The feasibility and accuracy of sentinel lymph node biopsy (SLNB) after NAC for percutaneous biopsy-proven N1 patients who are clinically node negative (cN0) by physical examination after NAC is under investigation. ACOSOG Z1071 reported a false-negative rate of\10 % if C3 nodes are removed with dual tracer, including excision of the biopsy-proven positive lymph node (BxLN). We report our experience using radioactive seed localization (RSL) to retrieve the BxLN with SLNB (RSL/SLNB) for cN0 patients after NAC. Methods. We performed a retrospective review of a single-institution, prospectively maintained registry for the years 2013 to 2014. Patients with BxLN who received NAC and had RSL/SLNB were identified. All BxLNs were marked with a radiopaque clip before NAC to facilitate RSL. Results. Thirty patients with BxLN before NAC were cN0 after NAC and underwent RSL/SLNB. Median age was 55 years. Disease stage was IIA–IIIB. Twenty-nine of 30 had ductal cancer (12 triple negative and 16 HER-2 positive). One to 11 nodes were retrieved. Twenty-nine of 30 BxLN were successfully localized with RSL. Note was made of the BxLN-containing isotope and/or dye in 22 of
Ó Society of Surgical Oncology 2015 First Received: 15 May 2015 E. J. Diego, MD e-mail: [email protected]
30. Nineteen patients had no residual axillary disease; 11 had persistent disease. All who remained node positive had disease in the BxLN. Conclusions. RSL/SLNB is a promising approach for axillary staging after NAC in patients whose disease becomes cN0. The status of the BxLN after NAC predicted nodal status, suggesting that localization of the BxLN may be more accurate than SLNB alone for staging the axilla in the cN0 patient after NAC.
Axillary lymph node status remains one of the most important prognostic indicators in breast cancer. In patients with a clinically negative axilla (cN0), a sentinel lymph node biopsy (SLNB) is an acceptable approach to axillary staging.1–3 The results from the ACOSOG Z0011, IBCSG 23-01, and EORTC 10981-22023 AMAROS trials support the omission of a completion axillary lymph node dissection (ALND) in women with small tumors and a small burden of axillary disease who receive appropriate adjuvant systemic chemotherapy, endocrine therapy, and radiotherapy, thus making axillary staging a largely diagnostic tool in breast cancer care.4–7 Neoadjuvant chemotherapy (NAC) is increasingly used for the benefits of tumor downstaging to facilitate breastconservation therapy, to assess in vivo response to therapy, and to potentially downstage axillary lymph nodes.8–10 Improved understanding of breast tumor biology and phenotype and use of targeted therapies have resulted in higher pathologic complete response (pCR) rates.11–13 Minimizing the extent of breast surgery in patients whose disease has a partial or complete response to NAC is routinely
E. J. Diego et al.
performed.10 A SLNB after completion of chemotherapy can also be performed in patients with a clinically negative axilla.9,14 However, the concept of less extensive axillary surgery is not as readily embraced when biopsy-proven axillary metastasis has been established before the start of NAC.15,16 In the ACOSOG Z1071 trial, the accuracy of a SLNB after NAC was investigated in women who had biopsy-proven axillary disease that demonstrated a clinical response in the axilla by physical examination. A falsenegative rate (FNR) of 12.6 % was deemed unacceptably high to allow routine recommendation of a SLNB in women who had a percutaneous biopsy-proven positive node. Several factors found to decrease the FNR to \10 % included the use of dual tracer for lymphatic mapping and removal of at least 3 sentinel lymph nodes. In addition, in patients where a radiopaque clip had been placed in the positive node at the time of biopsy, when this node was identified and removed as part of the sentinel node procedure, the FNR was \7 %.4,17 Incorporating these mapping strategies are now part of the National Comprehensive Cancer Network guidelines for axillary management after NAC.18 Our institution has implemented a protocol to routinely mark the positive axillary lymph node with a radiopaque clip at the time of biopsy. At the time of definitive surgery after NAC, the clipped node is localized with a 125I-labeled radioactive seed using image guidance to facilitate retrieval of this percutaneous biopsy-proven positive node. We report our experience of surgically addressing the axilla in patients who have pathologic evidence of nodal metastasis, who have received NAC, and whose disease is clinically node negative (cN0) by physical examination at the end of treatment. METHODS After receipt of approval from the institutional review board, a retrospective review of a prospectively maintained cancer registry and 125I-radioactive seed database were searched for all patients diagnosed with percutaneous biopsy-proven, node-positive (N1) breast cancer who received NAC before definitive surgery from May 2013 to June 2014. Patients with cN0 disease by physical examination at the end of NAC and who underwent radioactive seed localization (RSL) of the biopsy-proven positive lymph node combined with SLNB (RSL/SLNB) were identified. At the time of percutaneous biopsy, the lymph node was marked with a radiopaque clip to facilitate future localization. The time period was selected as the results from the ACOSOG 1071 trial had been recently reported, and the practice of performing a SLNB in this circumstance was considered to have a FNR of \10 % if dual tracer was
used, at least 3 lymph nodes were retrieved, and the previously assessed positive lymph node was included. None of the patients had undergone axillary staging surgery before receiving NAC. Preoperative localization via ultrasound or mammogram of the previously assessed axillary lymph node containing the radiopaque biopsy clip was done using a 4.5 9 0.8 mm titanium seed containing 0.1 to 0.25mCi 125I labeled through a preloaded 18-gauge needle. All surgeries were performed on the main campus or at affiliated satellite ambulatory surgery centers by 6 dedicated breast surgeons. Intraoperative subcutaneous injection of 0.3 miC 99mTc and a subareolar injection of dilute methylene blue dye were performed in the same fashion as the surgeon’s standard SLNB practice. Upon entering the axilla, retrieval of the targeted lymph node was first performed with a handheld gamma probe set to detect the 125I seed. Intraoperative specimen radiograph was obtained to document the excision of the targeted node, including the radiopaque clip and the 125I seed. The SLNB was then performed in the usual fashion. The axillary staging surgery was done as a standalone operation or in conjunction with definitive breast surgery. All pathology specimens were processed and examined at the main campus’s department of pathology. All 125 I-seed localized and sentinel lymph nodes were evaluated via serial hematoxylin and eosin examination. Immunohistochemistry was not routinely used to detect sentinel lymph node metastasis. Patients who had persistent disease in any of the sentinel lymph nodes were recommended to have a completion ALND. All patients in the study had cN0 disease by physical examination at the end of NAC and had 125I seed localization of the previously assessed positive lymph node. Electronic medical records were reviewed to obtain patient demographics, breast cancer stage and type, tumor receptor status, NAC regimen, and pathology results from the percutaneous, preoperative breast and axillary biopsy samples, as well as definitive surgical specimens. The sampled and localized lymph node was considered successfully retrieved if the surgical pathology report confirmed presence of biopsy site changes with a radiopaque clip in the lymph node with the 125I seed. Note was also made of 99mTc radiotracer activity or blue dye uptake in the targeted lymph node. RESULTS Review of the prospectively maintained cancer registry and radioactive seed database identified 80 patients with nonmetastatic N1 breast cancer who received NAC between May 2013 and June 2014. Patients who did not
Axillary Staging After Neoadjuvant Chemotherapy
have RSL and SLNB combination axillary procedure or those who had an immediate ALND were excluded. Thirty patients with planned RSL/SLNB combination surgery remained for analysis. The median patient age was 55 years (range 30– 71 years). A total of 84 % of patients had stage II and 16 % stage III disease at presentation; 97 % had invasive ductal carcinoma. Fifty-seven percent were HER-2 positive, 36 % were triple negative, and 7 % were luminal breast cancers (Table 1). Because it is an institutional practice to perform ultrasound interrogation of the axilla in patients with known invasive carcinoma who will receive NAC, all patients underwent percutaneous biopsy of the most suspiciousappearing axillary lymph node with placement of a radiopaque clip before the start of NAC to establish nodepositive disease. All patients completed the NAC regimens as planned before surgery. Patients with HER-2-positive breast cancers received anti-HER-2-containing regimens. Patients with cN0 disease by physical examination at the end of NAC were offered RSL/SLNB combination surgery. RSL was performed via ultrasound guidance in 28 patients and mammogram guidance in 1 patient. One patient did not have RSL placed as a result of the inability of the radiologist to visualize the lymph node with a biopsy clip via ultrasound or mammogram at the time of scheduled localization. Twenty-five patients had definitive breast surgery in conjunction with the axillary surgery. Five had the RSL/ SLNB combination surgery alone to stage the axilla and assess the need for postmastectomy radiation and timing of breast reconstruction. Intradermal 99mTc and retroareolar blue dye injections were performed in the operating room by the surgeon after TABLE 1 Patient demographics n = 30 Median age
55 (range 30–71)
Stage (AJCC, 7th edition) IIA IIB
8 (27 %) 16 (57 %)
IIIA
5 (13 %)
IIIB
1 (3 %)
Tumor morphology Invasive ductal cancer
29 (97 %)
Invasive lobular CANCER
1 (3 %)
Phenotype Luminal
2 (7 %)
HER2 positive
16 (57 %)
Triple negative
12 (36 %)
AJCC American Joint Committee on Cancer
induction of general anesthesia. Standard axillary incisions were used to access axillary lymph nodes except in cases where a mastectomy was also performed. Using the handheld gamma probe set to detect 125I, the axillary lymph node containing the 125I seed was excised first. In 22 of 30 cases, intraoperative note of blue dye or 99mTc activity in the 125I-localized lymph node was also made. In 91 % (20/22), the targeted lymph node also had blue dye, 99m Tc activity, or both. However, in 9 % (2/22), the targeted lymph node did not have any blue dye or 99mTc activity. In 27 % (8/30) of cases, there was no intraoperative or pathologic note regarding presence of blue dye or 99m Tc activity in the 125I-localized lymph node. Specimen radiographs were performed to confirm retrieval of the 125I seed and lymph node containing the biopsy clip. All 125I seeds were successfully retrieved. Two patients had specimen radiographs with confirmation of 125 I seed in a lymph node; however, the biopsy clip was not seen. Subsequent pathologic examination confirmed biopsy site changes in these 2 cases. In the 1 patient where RSL was aborted as a result of nonvisualization of the clip, standard SLNB was performed, and specimen radiographs confirmed retrieval of a lymph node containing a clip. Excision in this circumstance was facilitated by concomitant 99mTc and blue dye uptake of the lymph node. After excision of the 125I-seed localized node, SLNB was subsequently performed in standard fashion with excision of all lymph nodes with uptake of blue dye, or [10 % of highest ex vivo 99mTc count and removal of any palpably suspicious nodes. The median number of lymph nodes retrieved with the RSL/SLNB combination surgery was 4 (range 1–11). Pathologic evaluation revealed biopsy site changes in 100 % of the targeted lymph nodes. Thirty-seven percent (11/30) of patients had a pCR, defined as no residual invasive carcinoma in the breast or axilla. In 63 % (19/30) of patients, there was a complete pathologic response in the axilla (ypN0). In all cases that were ypN0, there were identifiable chemotherapy related changes in the node. pCR and the axillary downstaging rate are stratified by tumor phenotype in Table 2. In the 11 patients with residual disease in the RSL lymph node, 7 underwent a completion ALND. Of this subset, 57 % (4/7) were found to have additional disease in the axillary specimen. In the 4 patients who did not go on to have a completion ALND, 2 patients had small-volume disease (isolated tumor cells and micrometastasis, \2 mm) with multidisciplinary agreement to omit ALND, 1 patient had 11 lymph nodes in the specimen, and 1 patient opted not to undergo completion ALND. There were no patients who had other pathologically positive lymph nodes when the 125I-localized lymph node was negative (Table 2).
E. J. Diego et al. TABLE 2 Lymph node status Lymph nodes Median number of RSL/SLNB nodes excised
4 (range 1–11)
Target node excised with RSL
29/30 (97 %)
Biopsy site changes in target node
30/30 (100 %)
Pathologic response Complete In breast and axilla (i.e. pCR)
11/30 (37 %)
Luminal
0/2 (0 %)
HER2 positive
6/16 (38 %)
Triple negative
5/12 (42 %)
In axilla (i.e. downstage from cN1to ypN0) Luminal
19/30 (63 %) 0/2 (0 %)
HER2 positive
11/16 (69 %)
Triple negative
8/12 (67 %)
Chemotherapy related changes in axilla Residual axillary disease
19/30 (63 %)
RSL node positive
11/30 (37 %)
Additional positive nodes identified on SLNB after RSL?
6/11 (55 %)
Additional positive nodes identified on SLNB after RSL-
0 (0 %)
Completion ALND for persistent disease in RSL/SLNB
7/11 (64 %)
Total number of nodes examined in patients with RSL? (mean)
14 (range 2–25)
Additional disease on completion ALND
4/7 (57 %)
RSL radioactive seed localization, SLNB sentinel lymph node biopsy, pCR pathologic complete response, cN1 clinically node positive, ypN0 pathologically node negative after chemotherapy, ALND axillary lymph node dissection
DISCUSSION A better understanding of breast cancer phenotypes and the use of targeted therapies have resulted in pCR and axillary downstaging of up to 55 % in women with invasive breast cancer who receive NAC.11 For a patient with biopsy-proven axillary metastasis with cN0 disease by physical examination at the end of NAC, axillary status may influence decisions for or against additional therapy such as postmastectomy radiation. Though an ALND can provide this information, this procedure is associated with risks of lymphedema, numbness, and limitations in upperextremity range of motion.19–24 For patients who experience a pCR in the axilla, ALND offers no therapeutic benefit. MD Anderson and the Netherlands Cancer Institute have reported an identical approach to staging the axilla after NAC, with very similar success rates in retrieving the previously biopsy-assessed lymph node.25–27 The MD Anderson experience demonstrates a FNR of 11.6 % for
SLNB alone and only 2.3 % when the assessed lymph node is retrieved in conjunction with SLNB. In their series, 25 % of the time, the previously assessed lymph node was not identified as a sentinel lymph node in that the node did not contain blue dye or 99mTc activity. Use of the 125I seed facilitates retrieval and removal of this node, which may not take up conventional tracers as a result of changes in lymphatic circulation or chemotherapy-related changes in the node.27 Without the 125I seed, the FNR is expected to be higher for SLNB after NAC. Our findings support these above findings; in addition, SLNB in combination with RSL of the previously assessed positive node may be able to accurately stage the cN0 axilla after completion of NAC, sparing a subset of patients the potential morbidity of an ALND. This is one of the larger series to date reporting the experience of localizing the biopsy-proven positive lymph node in addition to SLNB when staging the axilla after NAC in patients with cN0 disease assessed by physical examination at the completion of treatment. Though the previously assessed lymph node may be retrieved in a standard SLNB procedure, it would have been missed in 9 % of patients if not targeted for localization, leading to a possibly higher FNR, as supported by the MD Anderson and Netherlands Cancer Institute data. In all patients, the status of the assessed lymph node represented the status of the remaining lymph nodes retrieved. This finding raises the question of whether excising this RSL lymph node alone at the end of treatment would be sufficient for staging and for adjuvant therapy decision making. Limitations of this series include the single-institution, retrospective nature of the study without any control group for comparison. In addition, not all patients who had residual axillary disease went on to have a completion ALND, at the discretion of the multidisciplinary team as a result of a very small burden of residual nodal disease, the number of lymph nodes retrieved at SLNB, or patient refusal. Therefore, the true FNR cannot be determined. The presence or absence of radiocolloid/blue dye in the excised lymph node was unknown in 27 % (8/30) of the patients in this study. Last, a greater proportion of patients in this series had HER-2-positive or triple-negative disease, leading to a higher pCR and axillary downstaging rate, possibly contributing to the lower FNR findings. In conclusion, for patients with node-positive breast cancer with cN0 disease by physical examination after NAC, staging the axilla with SLNB alone is associated with [10 % FNR.4,16 Axillary status after treatment may be more accurately staged by localization of the previously biopsy-sampled lymph node in conjunction with a SLNB. Localization of this lymph node is facilitated when a radiopaque marker is placed in the node at the time of biopsy. Surgical retrieval with 125I seed localization is
Axillary Staging After Neoadjuvant Chemotherapy
achieved 97 % of the time and represents a meaningful improvement in axillary staging after NAC. Pathologic status of the previously assessed lymph node may be a more accurate representation of the axillary status compared to SLNB alone. Further investigation of this technique is warranted. DISCLOSURE
The authors declare no conflict of interest.
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