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• W2216202722 abstract "Breast Cancer ManagementVol. 4, No. 6 EditorialFree AccessSentinel lymph node biopsy after neoadjuvant chemotherapy in patients with breast cancerJohn Michael DixonJohn Michael Dixon* E-mail Address: Mike.dixon@ed.ac.ukEdinburgh Breast Unit, Western General Hospital, NHS Lothian, Edinburgh EH4 2XU, UKSearch for more papers by this authorPublished Online:23 Nov 2015https://doi.org/10.2217/bmt.15.25AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: neoadjuvant chemotherapysentinel lymph node biopsyOriginally used in patients with locally advanced and large unresectable tumors the use of neoadjuvant chemotherapy has been extended to operable breast cancers in order to increase the number of women able to have breast conserving surgery. Neoadjuvant chemotherapy reduces tumor volume in most and also provides an opportunity for newly developed agents to gain accelerated approval [1,2] as there appears to be a direct correlation between pathologic complete response (path CR) both in the breast and the axilla and long-term therapeutic benefit [1,2].During the evolution of the use of neoadjuvant chemotherapy, there has been a revolution in the management of the axilla. Until recently most women with invasive breast cancer had a lymph node dissection, as lymph node status provided major prognostic significance and the number and extent of nodes was used to assess the need for systemic therapy. The use of sentinel lymph node biopsy avoids completion lymph node dissection for all but a few patients with extensive lymph node disease [3]. Using radio isotope and blue dye sentinel lymph nodes can be identified in 96% of patients having surgery as their first treatment with a false-negative rate of 7.3% although large variation across studies is evident, with more than one-third reporting a false-negative rate of over 10% [4]. There is a very clear relationship between the false-negative rate and the number of sentinel nodes retrieved and in National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 [5] the false-negative rate was 17.7% for one node, 10% for two nodes and 4.8% for three or more nodes. Despite this false-negative rate, few patients after a negative sentinel lymph node biopsy in B32 developed axillary recurrence [6]. More recently studies have shown that patients with involvement of one or two sentinel nodes by cancer get no apparent benefit from completion axillary dissection [3,7].The role of sentinel lymph node biopsy in patients receiving neoadjuvant chemotherapy has been the topic of much debate [8]. There are a number of theoretical advantages of performing sentinel lymph node biopsy after neoadjuvant chemotherapy. It allows the overall sensitivity of chemotherapy to be assessed, as it can clear involved axillary nodes in approximately 40% of patients. Based on an initial unplanned retrospective analysis of a subgroup of patients undergoing sentinel lymph node biopsy after neoadjuvant chemotherapy in NSABP B-27 [9] sentinel lymph node biopsy was shown to be feasible and saved some patients a potentially unnecessary axillary lymph node clearance. A number of prospective clinical studies have since addressed the role of sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with clinically or biopsy-proven axillary node involvement at diagnosis.Six-hundred and forty-nine evaluable patients with biopsy-proven axillary node involvement were enrolled onto the American College of Surgeons Oncology Group Z-1071 Alliance trial with biopsy-proven axillary node involvement [10]. All received neoadjuvant chemotherapy and at the end of chemotherapy all underwent sentinel lymph node biopsy together with a completion axillary node dissection. Approximately 41% of women were node negative after chemotherapy and sentinel nodes were detected in 92.9% of patients with cN1 disease at diagnosis. When two or more nodes were removed the false-negative rate of sentinel node biopsy was 12.6% and the false-negative rate for three or more nodes was 9.1%. Importantly, the false-negative rate was less than 10% in patients who had a clip inserted into the involved node, and the clip was removed or if dual isotope and blue dye were used. In the group of patients with more extensive axillary disease (cN2) at diagnosis the pathology CR rate was 48% and the false-negative rate was 0%. This study performed sentinel node biopsy on all patients irrespective of whether the nodes were still thought to be involved after chemotherapy and the false-negative rate of sentinel node was higher (19.2%) for those who still had matted or fixed nodes after chemotherapy versus 11.3% in the remainder. In patients who had a normal axillary ultrasound after chemotherapy the false-negative rate fell to 9.8% with ≥two sentinel nodes removed [10]. A German study – SENTINA [11] – also studied a series of patients with clinically node positive disease who had neoadjuvant chemotherapy and then had a sentinel lymph node biopsy after chemotherapy and reported a sentinel node detection rate of 80% and a false-positive rate of 14.2%. Again, there was a direct relationship between the false-negative rate and the number of nodes removed. If more than two nodes were removed, the false-negative rate was 4.9%. In SENTINA the false-negative rate was a very acceptable 8.6% when isotope and blue dye were combined. A more recent study of 153 women with biopsy-proven node positive breast cancer who had neoadjuvant chemotherapy reported a sentinel lymph node biopsy identification rate of 87.6% and a false-negative rate of 8.4% [12]. In this study immunohistochemistry of sentinel nodes was used, and if immunohistochemistry had not been performed, the false-negative rate would have been 13.3%. The false-negative rate for ≥two nodes was 4.9 versus 18.2% for one node and for dual isotope and blue dye the false-negative rate was 5.2%.Results from the MD Anderson study of 3746 patients showed a rate of sentinel lymph node identification of 98.7% in 3171 patients who had surgery first and 97.4% in 575 patients who had chemotherapy first [13]. The false-negative rates were 4.1% in the group that had surgery first and 5.9% in the neoadjuvant chemotherapy group. This is a lower false-negative rate than reported in multicenter studies where each center performed only a few cases.There are two views of the value of sentinel lymph node biopsy after neoadjuvant chemotherapy. The first is that the sentinel lymph node biopsy identification rate is too low for routine use, and that the false-negative rate is also too high [8]. By contrast, there are those who believe that the advantages to the patient in reducing an unnecessary axillary clearance is such that sentinel lymph node biopsy has a definite role after neoadjuvant chemotherapy [14]. Anyone who has operated on the axilla after neoadjuvant chemotherapy knows that the tissues feel different. Cancer cells are killed by chemotherapy and this produces an inflammatory response and it is therefore not surprising that identification and dissection of sentinel nodes is a more difficult procedure after neoadjuvant chemotherapy. Just as there was an initial learning curve for sentinel lymph node biopsy [15], there is a learning curve in performing sentinel node after neoadjuvant chemotherapy and this explains the much better results from the MD Anderson Cancer Centre (TX, USA) where they perform large numbers of these procedures post-chemotherapy. It is important not to treat all patients, with a wide range of cancer phenotypes, in an identical manner [16]. Up to 40% of patients with triple negative breast cancers, and up to 70% with HER2+ cancers will have their nodes cleared by adjuvant chemotherapy. This compares with a much lower rate of nodal pathology CR of ˜10% in patients with estrogen receptor (ER) positive cancers.The proponents of performing sentinel lymph node biopsy prior to neoadjuvant chemotherapy argue that important staging information is lost if this is not performed at diagnosis and more patients with involved nodes will be identified. Although it is true that after neoadjuvant chemotherapy information on initial tumor size and node status maybe be lost, information on chemosensitivity is gained. Studies show clearly that lymph node stage after chemotherapy carries much greater prognostic significance than axillary node status at the outset [17]. Pathological CR with no invasive disease in the breast or axilla is of such prognostic value that it is now used as a surrogate for long-term outcome in ongoing trials [2]. More importantly large numbers of patients who would have had a positive sentinel lymph node biopsy before neoadjuvant chemotherapy have no lymph node involvement after chemotherapy and so avoid a completely unnecessary operation. Long term follow-up data from B27 show that patients with no nodal disease on sentinel lymph node biopsy have low rates of subsequent regional recurrence [17].Based on the available literature sentinel lymph node biopsy after neoadjuvant chemotherapy appears safe provided the following criteria are met. First, a clip should be placed in one or more involved nodes prior to neoadjuvant chemotherapy. Second, as patients with extensive nodal disease can still have a path CR, a decision on management of the axilla should wait until assessment of the axilla after chemotherapy. At the end of chemotherapy nodes should be imaged by ultrasound. Patients with initial involved nodes with triple negative and HER2-positive cancers with a normal axilla on ultrasound after neoadjuvant therapy should have a sentinel node. In patients with ER-positive disease the role of postchemotherapy sentinel lymph node biopsy is less clear as 10% or less who are node positive at diagnosis will have a pathology in the axilla [16]. Younger women with grade 3 or HER2-positive and ER-positive cancers or those who have low levels of ER are the most likely to be node negative after chemotherapy [18]. Third, when performing sentinel lymph node biopsy dual tracer must be used and the clip or clips in the nodes should be removed and, if possible, localized. An alternative to placing a radiopaque clip is to place an iridium seed into the involved node at diagnosis that can be localized by a gamma probe at surgery [19]. The surgeon needs to retrieve at least two, and preferably more, sentinel lymph nodes during sentinel node biopsy. If adequate numbers of sentinel lymph nodes are not retrieved then consideration should be given to performing an axillary lymph node dissection.There is huge variation between and within countries in the use of sentinel lymph node biopsy before or after neoadjuvant chemotherapy. There are now large amounts of data available on the use of sentinel node after chemotherapy. In the NSABP/RTOG trial 1304 patients who are clinically node negative after sentinel lymph node biopsy following chemotherapy are being randomized to axillary radiotherapy or no other axillary treatment [20]. This shows that sentinel node after chemotherapy is an accepted technique to evaluate the axilla after neoadjuvant chemotherapy. Node positive patients after sentinel node are being randomized in the Alliance A011202 (NCT 01901094) trial of axillary dissection versus no further axillary surgery [9,21]. The time has come to stop pre-chemotherapy sentinel node and to perform it after neoadjuvant chemotherapy in order to reduce unnecessary surgery in patients who have no nodal involvement after neoadjuvant chemotherapy. The era of believing more surgery will cure patients is past and the harms of surgery are clear [22]. The time for tailoring surgery to patients needs is upon us and the way ahead is clear.Financial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Prowell TM, Pazdur R. Pathological complete response and accelerated drug approval in early breast cancer. N. Engl. J. Med. 366, 2438–2441 (2012).Crossref, Medline, CAS, Google Scholar2 Cortazar P, Zhang L, Untch M et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 384, 164–172 (2014).Crossref, Medline, Google Scholar3 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 305, 569–575 (2011).Crossref, Medline, CAS, Google Scholar4 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. 32, 1365–1383 (2014).Crossref, Medline, Google Scholar5 Krag DN, Anderson SJ, Julian TB et al. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised Phase III trial. Lancet Oncol. 8(10), 881–888 (2007).Crossref, Medline, CAS, Google Scholar6 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. 11(10), 927–933 (2010).Crossref, Medline, Google Scholar7 Li CZ, Zhang P, Li RW et al. Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: a meta-analysis. Eur. J. Surg. Oncol. 41(8), 958–966 (2015).Crossref, Medline, CAS, Google Scholar8 Lyman GH. Appropriate role for sentinel node biopsy after neoadjuvant chemotherapy in patients with early-stage breast cancer. J. Clin. Oncol. 33(3), 232–234 (2015).Crossref, Medline, Google Scholar9 Mamounas EP, Brown A, Anderson S et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J. Clin. Oncol. 23, 2694–2702 (2005).Crossref, Medline, Google Scholar10 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). J. Clin. Oncol. 33(30), 3386–3393 (2015).Crossref, Medline, CAS, Google Scholar11 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. 14, 609–618 (2013).Crossref, Medline, Google Scholar12 Boileau J-F, 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. 33, 258–264 (2015).Crossref, Medline, Google Scholar13 Hunt KK, Yi M, Mittendorf EA et al. Sentinel lymph node surgery after neoadjuvant chemotherapy is accurate and reduces the need for axillary dissection in breast cancer patients. Ann. Surg. 250(4), 558–566 (2009).Crossref, Medline, Google Scholar14 Azvolinsky A. Evolving role of lymph node biopsies after neoadjuvant therapy for breast cancer. OncLive. www.onclive.com/web-exclusives/Evolving-Role-of-Lymph-Node-Biopsies-After-Neoadjuvant-Therapy-for-Breast-Cancer#sthash.5TK9FedA.dpuf.Google Scholar15 Clarke D, Newcombe RG, Mansel RE. ALMANAC Trialists Group. The learning curve in sentinel node biopsy: the ALMANAC experience. Ann. Surg. Oncol. 11(Suppl. 3), 211S–215S (2004).Crossref, Medline, Google Scholar16 Dixon JM, Cody HS 3rd. Role of sentinel node biopsy in patients having neoadjuvant chemotherapy. Eur. J. Surg. Oncol. 36(6), 511–513 (2010).Crossref, Medline, CAS, Google Scholar17 Mamounas EP, Anderson SJ, Dignam JJ. Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J. Clin. Oncol. 30(32), 3960–3966 (2012).Crossref, Medline, Google Scholar18 Huober J, von Minckwitz G, Denkert C et al. Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res. Treat. 124(1), 133–140 (2010).Crossref, Medline, CAS, Google Scholar19 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. 150(2), 137–143 (2015).Crossref, Medline, Google Scholar20 Garg Ak, Buchholz TA. Influence of neoadjuvant chemotherapy on radiotherapy for breast cancer. Ann. Surg. Oncol. 22(5), 1434–1440 (2015).Crossref, Medline, Google Scholar21 White J, Mamounas E. Locoregional radiotherapy in patients with breast cancer responding to neoadjuvant chemotherapy: a paradigm for treatment individualization. J. Clin. Oncol. 32, 494–495 (2014).Crossref, Medline, Google Scholar22 Lizarraga IM, Weigel RJ. Axillary lymph node dissection for breast cancer: primum non nocere. Eur. J. Surg. Oncol. 41(8), 955–957 (2015).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByBreast MRI and tumour biology predict axillary lymph node response to neoadjuvant chemotherapy for breast cancer26 December 2019 | Cancer Imaging, Vol. 19, No. 1Response Letter11 July 2017 | Breast Cancer Research and Treatment, Vol. 165, No. 3Neoadjuvant Therapy in Early Breast Cancer: Treatment Considerations and Common Debates in PracticeClinical Oncology, Vol. 29, No. 10Is it time to relook the management of axilla in post-neoadjuvant breast cancer cases in a re-evolving era of current axillary management?Shaukat Mahmood Mirza, Liaqat Ali, Dhaliwal Rajinder, Maria Asad & Jane Aitken22 November 2017 | Breast Cancer Management, Vol. 6, No. 1 Vol. 4, No. 6 STAY CONNECTED Metrics History Published online 23 November 2015 Published in print December 2015 Information© Future Medicine LtdKeywordsneoadjuvant chemotherapysentinel lymph node biopsyFinancial & competing interests disclosureThe author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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