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Management of the axilla in T1-2N1 breast cancer

Management of the axilla in T1-2N1 breast cancer www.nature.com/npjbcancer COMMENT OPEN 1✉ 2,3 Mahmoud El-Tamer and Tibor Kovacs In the setting where the ongoing evolution of management of the axilla in breast cancer is being driven by better understanding of different sub-types of the disease, and of how these respond to chemotherapy, here we discuss management of the axilla in breast cancer patients who present with T1 or T2 N1 disease, while making the distinction between triple negative and HER2 positive tumors as one group, and hormone receptor positive/HER2 negative tumors as a second group. npj Breast Cancer (2022) 8:69 ; https://doi.org/10.1038/s41523-022-00432-y The management of the axilla in breast cancer has been gradually comprising 13 studies, in which all patients had pathologic changing over time. This change is driven by better understanding confirmation of a positive axillary node prior to initiation of of breast cancer metastasis and different sub-types of the disease, chemotherapy. A sentinel lymph node biopsy was performed after and their response to chemotherapy. Furthermore, with the chemotherapy, together with a backup axillary lymph node increase in survival from breast cancer, patients report a dissection, in all studies. Most of the studies were prospective significant impact on their quality of life from the long-term side (12 of 13). The meta-analysis included 1921 patients. The false- effects of axillary lymph node dissection. negative rate of the sentinel node was 14%. Dual mapping had an In this commentary, we discuss the management of the axilla in 11% false-negative rate, compared with 19% for single mapping. breast cancer patients who present with T1 or T2 N1 disease. With The number of harvested sentinel nodes was inversely propor- our better understanding of the different subtypes of breast tional with the false-negative rate; in patients with 3 or more cancer, we address triple negative and human epidermal growth sentinel nodes identified, the false-negative rate fell to 4% . factor receptor 2 (HER2) positive tumors separately from hormone At Memorial Sloan Kettering Cancer Center (New York, NY, USA), receptor positive/HER2 negative tumors. sentinel lymph node biopsy was adopted in all patients with positive nodes who were rendered clinically negative after chemotherapy. Dual-agent mapping, and a minimum of 3 nodes MANAGEMENT OF THE AXILLA IN T1-2N1, TRIPLE NEGATIVE, harvested, were prerequisites for a complete sentinel node AND HER2 AMPLIFIED BREAST CANCERS procedure. In 573 patients between 2013 and 2019, 3 or more sentinel nodes were successfully identified with dual mapping in It is customary nowadays to deliver chemotherapy as a first line of 93%. The sentinel nodes were negative in 41% of the patients, and treatment in all patients with triple negative, and HER2 amplified all were spared an axillary lymph node dissection . tumor subtypes who present with positive nodes. Multiple Sentinel lymph node biopsy can reliably predict the pathologic prospective and retrospective studies have shown that a status of the axilla when 3 or more sentinel nodes are identified significant number of these patients will achieve a pathologic with the use of dual-mapping techniques. Even more important complete response (pCR) in the axillary nodes. Table 1 lists the 1–4 than the false-negative rate, however, is the local control of the pCR rates of these 2 subtypes in 4 different studies . axilla. The Memorial Sloan Kettering Cancer Center study reported Chemotherapy for triple-negative tumors has been reported to on regional control of the axilla with dual-mapping following a achieve a pCR rate of around 50%. In HER2 amplified tumors, the negative sentinel lymph node biopsy after neoadjuvant che- pCR rate is even higher, varying between 49% and 65%. motherapy . Among 234 patients with 3 or more negative Furthermore, the axillary pCR rate has been shown to be higher sentinel nodes without an axillary dissection and a median follow- among HER2 positive tumors when the hormone receptors are up of 40 months, 13 patients developed distant metastasis and negative, as compared to those who are hormone receptor positive . only 1 patient developed local recurrence. An axillary and local There is no known value for an axillary lymph node dissection in recurrence was identified in only 1 patient who refused radiation patients who have achieved pCR. Imaging modalities may reflect therapy. These data are supportive of the reliability of a sentinel nodal pathologic response, but are not highly sensitive and are node procedure after neoadjuvant chemotherapy in patients who not predictive enough to preclude surgical staging. The sensitivity became clinically node negative after neoadjuvant chemotherapy of ultrasound, MRI, and PET/CT to identify residual lymph node when proper techniques are used (Box 1). disease has been reported to be 70%, 61%, and 63%, respec- The American College of Surgeons Oncology Group (ACOSOG) 6–8 tively . Z-1071 trial has demonstrated a decrease in the false-negative The role of a sentinel lymph node biopsy in predicting rate when the positive node is clipped and retrieved after pathologic response of the axilla has been extensively evaluated neoadjuvant chemotherapy, confirming pathologic complete in the literature in multiple prospective studies. Sentinel lymph response. We do not recommend clipping the node for the node biopsy after neoadjuvant chemotherapy has a low false- following reasons: (1) the clip is lost in 3% of patients ; (2) the clip negative rate with dual mapping and the harvesting of 3 or more is localized in only 95% of the patients and is retrieved in 92% of sentinel nodes. Tee and colleagues conducted a meta-analysis those localized. Hence, the success rate of identifying the clip is 1 2 3 Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Breast Institute, Jiahui International Hospital, Shanghai, China. Guy’s and St. Thomas’ NHS Foundation Trust, London, UK. email: eltamerm@mskcc.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; M. El-Tamer and T. Kovacs Management of the Axilla Table 1. Nodal pathologic complete response in triple-negative/HER2 T1-2 N1 positive breast cancers, and in hormone receptor-positive and HER2 TNBC negative breast cancers. HER2 positive Study No. of patients HR positive/ TNBC HER2 (stage) HER2 negative positive Neoadjuvant CTx Boughey 2013 756 (pN+) 21% 49% 65% cN0 cN1 Kim 2015 415 (pN+) 29% 54% 49% Montagna 2020 573 (pN+) 20% 44% 63.3% SLNbx Simons 2019 139 (pN+) 7.4% 44% 74% HR hormone receptor, N node, TNBC triple-negative phenotype, HER2 Node negative Node positive ALND XRT only Alliance A011202 XRT human epidermal growth factor receptor 2. Fig. 1 Suggested management of the axilla with T1/T2 N1 disease who are triple negative or HER2 amplified. (Patients who are cN0 after neoadjuvant chemotherapy and have a positive sentinel node Box 1 Criteria for SLNB after NAC in patients with node-positive may be candidates for the Alliance A011202 trial, which randomized disease at presentation patients to a full axillary lymph node dissection versus none; all patients will receive radiation therapy). TNBC triple-negative breast Criteria for sentinel lymph node biopsy after neoadjuvant chemotherapy in cancer, HER2 human epidermal growth factor receptor 2, CTx patients with node-positive disease at presentation: chemotherapy, SLNB sentinel lymph node biopsy, XRT radiation Limited to patients with N1 disease. therapy, ALND axillary lymph node dissection. Rendered clinically node negative after NAC. A well-versed team in sentinel node procedures. To summarize management of the axilla in T1-2N1, triple Use of dual-mapping techniques. Resect all sentinel nodes and harvest 3 or more nodes. negative, and HER2 amplified breast cancers: (1) we recommend Pathologic confirmation of complete response in the lymph node. abandoning the practice of performing a sentinel lymph node Look for treatment effect in the sentinel nodes. biopsy prior to neoadjuvant chemotherapy; (2) the reliability of sentinel node biopsy after neoadjuvant chemotherapy requires the use of dual-agent mapping technique and identifying a minimum of 3 or more sentinel nodes (the false-negative rate can limited to 85% of patients . However, with dual mapping, be as low as 4%); (3) we do not recommend clipping or tagging 3 sentinel nodes are identified in 93% of patients ; (3) The false- the positive node prior to neoadjuvant chemotherapy, as we find negative rate of the clipped node is 7% , whereas it is 4% when 3 that sentinel lymph node biopsy without node clipping is a negative sentinel nodes are identified without relying on the reliable technique in predicting the status of the axilla after clipped node ; (4) More importantly, the Memorial Sloan Kettering neoadjuvant chemotherapy; (4) the success rate of identifying 3 or Cancer Center group reported no axillary recurrence without more sentinel nodes after neoadjuvant chemotherapy is 93%; and clipping . Similarly, the European Institute of Oncology group (5) completion axillary lymph node dissection is the standard of reported a 1.6% axillary recurrence without clipping the positive care for all patients in whom the sentinel node is positive or in node, albeit using less-stringent criteria than the Memorial Sloan whom there is a failure to identify 3 or more sentinel nodes Kettering Cancer Center group . (consider entering patients with residual positive sentinel nodes The practice of performing a sentinel node procedure prior to into the Alliance A011202 trial) (Fig. 1). neoadjuvant chemotherapy should be abandoned. It is associated with a significant loss of a predictor of response in the axilla. A repeat sentinel lymph node biopsy at the completion of MANAGEMENT OF THE AXILLA IN T1-2N1, HORMONE chemotherapy is unreliable, as the detection rate is 60.8% and RECEPTOR-POSITIVE/HER2 NEGATIVE BREAST CANCERS the false-negative rate is 51.6% as demonstrated in the SENTINA The rate of pCR in axillary nodes for hormone receptor-positive/ trial . This practice would commit patients with initially positive HER2 negative tumors varies between 7.4% and 29.0%. Table 1 nodes to a completion axillary node dissection after neoadjuvant 1–4 compares the nodal pCR in different tumor subtypes . chemotherapy. Three important studies have shaped the creation of guidelines The standard of care for positive sentinel lymph node biopsy for the management of the axilla in hormone receptor-positive/ after neoadjuvant chemotherapy is completion axillary lymph HER2 negative tumors after chemotherapy: The Treatment for node dissection. In patients with a negative sentinel node on frozen section and a positive sentinel node on definitive Positive Node, Endocrine Responsive Breast Cancer (RxPONDER) pathology evaluation, we continue to recommend a completion trial, the ACOSOG Z0011 trial, and the After Mapping of the Axilla: axillary lymph node dissection. The rate of residual positive Radiotherapy or Surgery (AMAROS) trial. disease in the axilla when the frozen section was falsely negative The RxPONDER study accrued patients with estrogen receptor has been reported to be 64% . Currently, the Alliance A011202 and/or progesterone receptor positive (>1%), HER2 negative trial is evaluating the role of a completion axillary lymph node breast cancers with 1-3 positive lymph nodes, and an Oncotype dissection in patients with positive sentinel nodes after neoadju- DX (Exact Sciences, Redwood City, CA) score of 0–25. The patients vant chemotherapy. The study randomizes patients with clinical were randomized to receive chemotherapy and endocrine T1-3N1 disease who are found to have a positive sentinel lymph therapy, or endocrine therapy alone. The study showed that node biopsy in 2 arms. The first arm is the standard-of-care arm, adjuvant chemotherapy has no impact on invasive disease-free which includes a completion axillary lymph node dissection survival in postmenopausal women. However, the study did show followed by radiation therapy to the regional nodes, the breast, or a clear benefit for premenopausal patients . the chest wall, depending on the surgical procedure (mastectomy The ACOSOG Z0011 trial randomized breast cancer patients or breast conservation). In the second arm, the axillary lymph who were clinically node negative with T1-2 tumors and found to node dissection is omitted and the patient receives only radiation have 1-2 positive sentinel nodes to an axillary lymph node therapy to the regional nodes, the breast, or the chest wall. dissection or no further axillary procedure. It concluded that a full npj Breast Cancer (2022) 69 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; M. El-Tamer and T. Kovacs Management of the Axilla Management of the Axilla a. b. T1-2 N1 HR positive/HER2 negative T1-2 N1 HR positive/HER2 negative Premenopausal Patients Premenopausal Patients Palpable No Palpable Axillary Node Axillary Node FNA node Procedure Positive Negative Mastectomy Lumpectomy US AXILLA FNA NCT SLNBx SLNBx SUSPICIOUS NODES Positive Negative Positive Negative Positive Negative NCT SLNBx ALND No ALND No ALND Z0011 AMAROS (+) ALND/AMAROS (-) No ALND Management of the Axilla Management of the Axilla c. d. T1-2 N1 HR positive/HER2 negative T1-2 N1 HR positive/HER2 negative Postmenopausal Patients Postmenopausal Patients Palpable No Palpable Axillary Node Axillary Node FNA Node Procedure Mastectomy Positive Negative Lumpectomy RS RS SLNBx SLNBx > 25 0-25 Positive Negative > 25 0-25 Positive Negative NCT NCT SLNBx ALND or No ALND ALND No ALND Z0011 NET AMAROS (+) ALND (-) No ALND Fig. 2 Suggested management of the axilla with T1/T2 N1 disease who are hormone receptor positive/HER2 negative. a Management of the axilla for premenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with palpable axillary nodes. b Management of the axilla for premenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with no palpable axillary nodes. c Management of the axilla for postmenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with palpable axillary nodes. d Management of the axilla for postmenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with no palpable axillary nodes. TNBC triple negative breast cancer, HER2 human epidermal growth factor receptor 2, CTx chemotherapy, SLNB sentinel lymph node biopsy, XRT radiation therapy, ALND axillary lymph node dissection, HR hormone receptor, FNA fine-needle aspiration, NCT neoadjuvant chemotherapy, RS Oncotype DX recurrence score. axillary lymph node dissection could be safely omitted in that AMAROS included patients with breast conservation or group of patients, as there was no difference in locoregional mastectomy. recurrence, disease-free survival, or overall survival . Based on the above, the management of hormone receptor- The AMAROS trial accrued patients with stage cT1-2N0M0 positive/HER2 negative T1/2 N1 patients depends on their primary breast cancer. Those with positive sentinel nodes were menopausal status, clinical exam of the axilla, surgical procedure, randomized to an axillary lymph node dissection or axillary Oncotype DX score, and number of positive nodes. radiation therapy. At a median follow-up of 10 years, both of these Premenopausal patients with clinically palpable axillary nodes arms showed no difference in regional recurrence, distant should have a cytologic or pathologic evaluation of the palpable 18,19 node to confirm metastatic disease. Patients with positive metastasis, or survival . For hormone receptor-positive/HER2 negative T1-2 tumors, the palpable nodes are recommended neoadjuvant chemotherapy. decision on chemotherapy is dependent on the menopausal Those with negative nodes should have a sentinel node procedure status of the patient as well as on the clinical examination of the that will dictate further management of the axilla as seen in axilla. Fig. 2a. It is clear that patients with N1 disease who are premenopausal In clinically node-negative premenopausal patients, the surgical require chemotherapy irrespective of their Oncotype DX score. In procedure (mastectomy or lumpectomy) determines the manage- postmenopausal patients, the RxPONDER trial showed no benefit ment pathway. When a lumpectomy is planned, patients with from chemotherapy in postmenopausal patients with 1-3 positive positive sentinel nodes may be managed based on the ACOSOG nodes. The ACOSOG Z0011 and AMAROS trials apply to patients Z0011 or AMAROS trials. The patients who are undergoing a who are clinically node negative; ACOSOG Z0011 included only mastectomy have not been included in the ACOSOG Z0011 trial, patients who underwent breast-conservation therapy, while and the benefit of chest wall radiation may not be justified in all Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 69 M. El-Tamer and T. Kovacs patients. We recommend a sonographic evaluation of the axilla 6. Kuhl, C. K., Lehman, C. & Bedrosian, I. Imaging in locoregional management of breast cancer. J. Clin. Oncol. 38, 2351–2361 (2020). with fine-needle aspiration (FNA) of suspicious nodes. Patients 7. Rauch, G. M. et al. Multimodality imaging for evaluating response to neoadjuvant with proven nodal metastasis are started on neoadjuvant chemotherapy in breast cancer. AJR Am. J. Roentgenol. 208, 290–299 (2017). chemotherapy, while those with negative FNA are candidates 8. Weber, J. J. et al. MRI and prediction of pathologic complete response in the for upfront surgical intervention. Fig. 2b summarizes the breast and axilla after neoadjuvant chemotherapy for breast cancer. J. Am. Coll. suggested outline of treatment. Surg. 225, 740–746 (2017). In postmenopausal patients with clinically palpable lymph 9. Tee, S. R. et al. Meta-analysis of sentinel lymph node biopsy after neoadjuvant nodes, the result of an FNA of the axillary node will determine the chemotherapy in patients with initial biopsy-proven node-positive breast cancer. clinical pathway. Patients with negative cytology will undergo a Br. J. Surg. 105, 1541–1552 (2018). sentinel lymph node biopsy with complete axillary lymph node 10. Barrio, A. V. et al. Abstract No. PD4-05. Axillary recurrence is a rare event in node- dissection if the sentinel node is positive, as the number of positive patients. treated with sentinel node biopsy alone after neoadjuvant chemotherapy: results of a prospective study. In San Antonio Breast Cancer positive nodes will dictate if they can be managed as per the RX- Symposium Virtual Meeting, San Antonio, TX, December 8–11 (2020). PONDER trial. In patients with positive FNA, those with Oncotype 11. Donker, M. et al. Marking axillary lymph nodes with radioactive iodine seeds for DX recurrence scores >25 will be candidates for neoadjuvant axillary staging after neoadjuvant systemic treatment in breast cancer patients: chemotherapy. Those with Oncotype DX recurrence scores ≤25 the MARI procedure. Ann. Surg. 261, 378–382 (2015). may be candidates for a full axillary lymph node dissection on 12. El-Tamer, M. B. Session: the great debates. In 22nd Annual Meeting of the Amer- neoadjuvant endocrine therapy as per Fig. 2c. ican Society of Breast Surgeons (2021). In postmenopausal patients who do not have palpable axillary 13. Kahler-Ribeiro-Fontana, S. et al. Long-term standard sentinel node biopsy after nodes, the type of surgical procedure will determine the clinical neoadjuvant treatment in breast cancer: a single institution ten-year follow-up. Eur. J. Surg. Oncol. 47, 804–812 (2021). pathway. Those undergoing a lumpectomy are clearly candidates 14. Kuehn, T. et al. Sentinel-lymph-node biopsy in patients with breast cancer before for the ACOSOG Z0011 or AMAROS trials if they fit their criteria; and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre hence, they should undergo a sentinel node procedure and be cohort study. Lancet Oncol. 14, 609–618 (2013). treated accordingly. For those undergoing a mastectomy, the 15. Moo, T. A. et al. Is low-volume disease in the sentinel node after neoadjuvant recurrence score is helpful in determining the need for chemotherapy an indication for axillary dissection? Ann. Surg. Oncol. 25, neoadjuvant chemotherapy; a need that would be limited for 1488–1494 (2018). those with an Oncotype DX score >25. Those with Oncotype DX 16. Kalinsky, K. et al. Abstract No. GS3-00. First results from a phase III randomized scores ≤25 will undergo a sentinel lymph node biopsy and clinical trial of standard adjuvant endocrine therapy (ET) +/− chemotherapy (CT) completion node dissection only if the sentinel node is positive, as in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2−) breast cancer (BC) with recurrence score (RS) < 25: SWOG shown in Fig. 2d. S1007 (RxPonder). In San Antonio Breast Cancer Symposium Virtual Meeting, San To summarize the management of the axilla in hormone Antonio, TX, December 8–11 (2020). receptor-positive/HER2 negative tumors: (1) sentinel lymph node 17. Giuliano, A. E. et al. Effect of axillary dissection vs no axillary dissection on 10-year biopsy is standard for cN0 patients; (2) sentinel lymph node biopsy overall survival among women with invasive breast cancer and sentinel node is standard for patients with cT1-2 tumors and 1-2 positive nodes metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA 318, who are undergoing a lumpectomy and whole breast irradiation; 918–926 (2017). and (3) axillary dissection is recommended when a patient has 18. Donker, M. et al. Radiotherapy or surgery of the axilla after a positive sentinel palpable positive nodes if no neoadjuvant chemotherapy is node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, planned, when a patient has >2 positive sentinel nodes, and open-label, phase 3 non-inferiority trial. Lancet Oncol. 15, 1303–1310 (2014). 19. Rutgers, E. J. et al. Abstract No. GS4-01. Radiotherapy or surgery of the axilla after when residual positive nodes are present after neoadjuvant a positive sentinel node in breast cancer patients: 10 year follow up results of the chemotherapy. EORTC AMAROS trial (EORTC 10981/22023). In Cancer Res (Proceedings of the 2018 San Antonio Breast Cancer Symposium, December 4-8, San Antonio, TX) Vol. 79 Reporting summary (Suppl. 4) (2019). Further information on research design is available in the Nature Research Reporting Summary linked to this article. AUTHOR CONTRIBUTIONS DATA AVAILABILITY T.K. and M.E.T. wrote and revised the manuscript. T.K. and M.E.T. contributed to the interpretation of the text. All authors read and approved the final version of the Available by contacting the corresponding author upon request. manuscript. Received: 4 October 2021; Accepted: 22 April 2022; COMPETING INTERESTS The authors declare no competing interests. REFERENCES 1. Boughey, J. C. et al. Sentinel lymph node surgery after neoadjuvant che- motherapy in patients with node-positive breast cancer: the ACOSOG Z1071 ADDITIONAL INFORMATION (Alliance) clinical trial. JAMA 310, 1455–1461 (2013). Supplementary information The online version contains supplementary material 2. Kim, J. Y. et al. Prognostic nomogram for prediction of axillary pathologic com- available at https://doi.org/10.1038/s41523-022-00432-y. plete response after neoadjuvant chemotherapy in cytologically proven node- positive breast cancer. Medicine 94, e1720 (2015). Correspondence and requests for materials should be addressed to Mahmoud 3. Montagna, G. et al. Selecting node-positive patients for axillary downstaging with El-Tamer. neoadjuvant chemotherapy. Ann. Surg. Oncol. 27, 4515–4522 (2020). 4. Simons, J. M. et al. Excision of both pretreatment marked positive nodes and Reprints and permission information is available at http://www.nature.com/ sentinel nodes improves axillary staging after neoadjuvant systemic therapy in reprints breast cancer. Br. J. Surg. 106, 1632–1639 (2019). 5. Mamtani, A. et al. How often does neoadjuvant chemotherapy avoid axillary Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims dissection in patients with histologically confirmed nodal metastases? Results of in published maps and institutional affiliations. a prospective study. Ann. Surg. Oncol. 23, 3467–3474 (2016). npj Breast Cancer (2022) 69 Published in partnership with the Breast Cancer Research Foundation M. El-Tamer and T. 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To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. © The Author(s) 2022 Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 69 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png npj Breast Cancer Springer Journals

Management of the axilla in T1-2N1 breast cancer

npj Breast Cancer , Volume 8 (1) – May 30, 2022

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www.nature.com/npjbcancer COMMENT OPEN 1✉ 2,3 Mahmoud El-Tamer and Tibor Kovacs In the setting where the ongoing evolution of management of the axilla in breast cancer is being driven by better understanding of different sub-types of the disease, and of how these respond to chemotherapy, here we discuss management of the axilla in breast cancer patients who present with T1 or T2 N1 disease, while making the distinction between triple negative and HER2 positive tumors as one group, and hormone receptor positive/HER2 negative tumors as a second group. npj Breast Cancer (2022) 8:69 ; https://doi.org/10.1038/s41523-022-00432-y The management of the axilla in breast cancer has been gradually comprising 13 studies, in which all patients had pathologic changing over time. This change is driven by better understanding confirmation of a positive axillary node prior to initiation of of breast cancer metastasis and different sub-types of the disease, chemotherapy. A sentinel lymph node biopsy was performed after and their response to chemotherapy. Furthermore, with the chemotherapy, together with a backup axillary lymph node increase in survival from breast cancer, patients report a dissection, in all studies. Most of the studies were prospective significant impact on their quality of life from the long-term side (12 of 13). The meta-analysis included 1921 patients. The false- effects of axillary lymph node dissection. negative rate of the sentinel node was 14%. Dual mapping had an In this commentary, we discuss the management of the axilla in 11% false-negative rate, compared with 19% for single mapping. breast cancer patients who present with T1 or T2 N1 disease. With The number of harvested sentinel nodes was inversely propor- our better understanding of the different subtypes of breast tional with the false-negative rate; in patients with 3 or more cancer, we address triple negative and human epidermal growth sentinel nodes identified, the false-negative rate fell to 4% . factor receptor 2 (HER2) positive tumors separately from hormone At Memorial Sloan Kettering Cancer Center (New York, NY, USA), receptor positive/HER2 negative tumors. sentinel lymph node biopsy was adopted in all patients with positive nodes who were rendered clinically negative after chemotherapy. Dual-agent mapping, and a minimum of 3 nodes MANAGEMENT OF THE AXILLA IN T1-2N1, TRIPLE NEGATIVE, harvested, were prerequisites for a complete sentinel node AND HER2 AMPLIFIED BREAST CANCERS procedure. In 573 patients between 2013 and 2019, 3 or more sentinel nodes were successfully identified with dual mapping in It is customary nowadays to deliver chemotherapy as a first line of 93%. The sentinel nodes were negative in 41% of the patients, and treatment in all patients with triple negative, and HER2 amplified all were spared an axillary lymph node dissection . tumor subtypes who present with positive nodes. Multiple Sentinel lymph node biopsy can reliably predict the pathologic prospective and retrospective studies have shown that a status of the axilla when 3 or more sentinel nodes are identified significant number of these patients will achieve a pathologic with the use of dual-mapping techniques. Even more important complete response (pCR) in the axillary nodes. Table 1 lists the 1–4 than the false-negative rate, however, is the local control of the pCR rates of these 2 subtypes in 4 different studies . axilla. The Memorial Sloan Kettering Cancer Center study reported Chemotherapy for triple-negative tumors has been reported to on regional control of the axilla with dual-mapping following a achieve a pCR rate of around 50%. In HER2 amplified tumors, the negative sentinel lymph node biopsy after neoadjuvant che- pCR rate is even higher, varying between 49% and 65%. motherapy . Among 234 patients with 3 or more negative Furthermore, the axillary pCR rate has been shown to be higher sentinel nodes without an axillary dissection and a median follow- among HER2 positive tumors when the hormone receptors are up of 40 months, 13 patients developed distant metastasis and negative, as compared to those who are hormone receptor positive . only 1 patient developed local recurrence. An axillary and local There is no known value for an axillary lymph node dissection in recurrence was identified in only 1 patient who refused radiation patients who have achieved pCR. Imaging modalities may reflect therapy. These data are supportive of the reliability of a sentinel nodal pathologic response, but are not highly sensitive and are node procedure after neoadjuvant chemotherapy in patients who not predictive enough to preclude surgical staging. The sensitivity became clinically node negative after neoadjuvant chemotherapy of ultrasound, MRI, and PET/CT to identify residual lymph node when proper techniques are used (Box 1). disease has been reported to be 70%, 61%, and 63%, respec- The American College of Surgeons Oncology Group (ACOSOG) 6–8 tively . Z-1071 trial has demonstrated a decrease in the false-negative The role of a sentinel lymph node biopsy in predicting rate when the positive node is clipped and retrieved after pathologic response of the axilla has been extensively evaluated neoadjuvant chemotherapy, confirming pathologic complete in the literature in multiple prospective studies. Sentinel lymph response. We do not recommend clipping the node for the node biopsy after neoadjuvant chemotherapy has a low false- following reasons: (1) the clip is lost in 3% of patients ; (2) the clip negative rate with dual mapping and the harvesting of 3 or more is localized in only 95% of the patients and is retrieved in 92% of sentinel nodes. Tee and colleagues conducted a meta-analysis those localized. Hence, the success rate of identifying the clip is 1 2 3 Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Breast Institute, Jiahui International Hospital, Shanghai, China. Guy’s and St. Thomas’ NHS Foundation Trust, London, UK. email: eltamerm@mskcc.org Published in partnership with the Breast Cancer Research Foundation 1234567890():,; M. El-Tamer and T. Kovacs Management of the Axilla Table 1. Nodal pathologic complete response in triple-negative/HER2 T1-2 N1 positive breast cancers, and in hormone receptor-positive and HER2 TNBC negative breast cancers. HER2 positive Study No. of patients HR positive/ TNBC HER2 (stage) HER2 negative positive Neoadjuvant CTx Boughey 2013 756 (pN+) 21% 49% 65% cN0 cN1 Kim 2015 415 (pN+) 29% 54% 49% Montagna 2020 573 (pN+) 20% 44% 63.3% SLNbx Simons 2019 139 (pN+) 7.4% 44% 74% HR hormone receptor, N node, TNBC triple-negative phenotype, HER2 Node negative Node positive ALND XRT only Alliance A011202 XRT human epidermal growth factor receptor 2. Fig. 1 Suggested management of the axilla with T1/T2 N1 disease who are triple negative or HER2 amplified. (Patients who are cN0 after neoadjuvant chemotherapy and have a positive sentinel node Box 1 Criteria for SLNB after NAC in patients with node-positive may be candidates for the Alliance A011202 trial, which randomized disease at presentation patients to a full axillary lymph node dissection versus none; all patients will receive radiation therapy). TNBC triple-negative breast Criteria for sentinel lymph node biopsy after neoadjuvant chemotherapy in cancer, HER2 human epidermal growth factor receptor 2, CTx patients with node-positive disease at presentation: chemotherapy, SLNB sentinel lymph node biopsy, XRT radiation Limited to patients with N1 disease. therapy, ALND axillary lymph node dissection. Rendered clinically node negative after NAC. A well-versed team in sentinel node procedures. To summarize management of the axilla in T1-2N1, triple Use of dual-mapping techniques. Resect all sentinel nodes and harvest 3 or more nodes. negative, and HER2 amplified breast cancers: (1) we recommend Pathologic confirmation of complete response in the lymph node. abandoning the practice of performing a sentinel lymph node Look for treatment effect in the sentinel nodes. biopsy prior to neoadjuvant chemotherapy; (2) the reliability of sentinel node biopsy after neoadjuvant chemotherapy requires the use of dual-agent mapping technique and identifying a minimum of 3 or more sentinel nodes (the false-negative rate can limited to 85% of patients . However, with dual mapping, be as low as 4%); (3) we do not recommend clipping or tagging 3 sentinel nodes are identified in 93% of patients ; (3) The false- the positive node prior to neoadjuvant chemotherapy, as we find negative rate of the clipped node is 7% , whereas it is 4% when 3 that sentinel lymph node biopsy without node clipping is a negative sentinel nodes are identified without relying on the reliable technique in predicting the status of the axilla after clipped node ; (4) More importantly, the Memorial Sloan Kettering neoadjuvant chemotherapy; (4) the success rate of identifying 3 or Cancer Center group reported no axillary recurrence without more sentinel nodes after neoadjuvant chemotherapy is 93%; and clipping . Similarly, the European Institute of Oncology group (5) completion axillary lymph node dissection is the standard of reported a 1.6% axillary recurrence without clipping the positive care for all patients in whom the sentinel node is positive or in node, albeit using less-stringent criteria than the Memorial Sloan whom there is a failure to identify 3 or more sentinel nodes Kettering Cancer Center group . (consider entering patients with residual positive sentinel nodes The practice of performing a sentinel node procedure prior to into the Alliance A011202 trial) (Fig. 1). neoadjuvant chemotherapy should be abandoned. It is associated with a significant loss of a predictor of response in the axilla. A repeat sentinel lymph node biopsy at the completion of MANAGEMENT OF THE AXILLA IN T1-2N1, HORMONE chemotherapy is unreliable, as the detection rate is 60.8% and RECEPTOR-POSITIVE/HER2 NEGATIVE BREAST CANCERS the false-negative rate is 51.6% as demonstrated in the SENTINA The rate of pCR in axillary nodes for hormone receptor-positive/ trial . This practice would commit patients with initially positive HER2 negative tumors varies between 7.4% and 29.0%. Table 1 nodes to a completion axillary node dissection after neoadjuvant 1–4 compares the nodal pCR in different tumor subtypes . chemotherapy. Three important studies have shaped the creation of guidelines The standard of care for positive sentinel lymph node biopsy for the management of the axilla in hormone receptor-positive/ after neoadjuvant chemotherapy is completion axillary lymph HER2 negative tumors after chemotherapy: The Treatment for node dissection. In patients with a negative sentinel node on frozen section and a positive sentinel node on definitive Positive Node, Endocrine Responsive Breast Cancer (RxPONDER) pathology evaluation, we continue to recommend a completion trial, the ACOSOG Z0011 trial, and the After Mapping of the Axilla: axillary lymph node dissection. The rate of residual positive Radiotherapy or Surgery (AMAROS) trial. disease in the axilla when the frozen section was falsely negative The RxPONDER study accrued patients with estrogen receptor has been reported to be 64% . Currently, the Alliance A011202 and/or progesterone receptor positive (>1%), HER2 negative trial is evaluating the role of a completion axillary lymph node breast cancers with 1-3 positive lymph nodes, and an Oncotype dissection in patients with positive sentinel nodes after neoadju- DX (Exact Sciences, Redwood City, CA) score of 0–25. The patients vant chemotherapy. The study randomizes patients with clinical were randomized to receive chemotherapy and endocrine T1-3N1 disease who are found to have a positive sentinel lymph therapy, or endocrine therapy alone. The study showed that node biopsy in 2 arms. The first arm is the standard-of-care arm, adjuvant chemotherapy has no impact on invasive disease-free which includes a completion axillary lymph node dissection survival in postmenopausal women. However, the study did show followed by radiation therapy to the regional nodes, the breast, or a clear benefit for premenopausal patients . the chest wall, depending on the surgical procedure (mastectomy The ACOSOG Z0011 trial randomized breast cancer patients or breast conservation). In the second arm, the axillary lymph who were clinically node negative with T1-2 tumors and found to node dissection is omitted and the patient receives only radiation have 1-2 positive sentinel nodes to an axillary lymph node therapy to the regional nodes, the breast, or the chest wall. dissection or no further axillary procedure. It concluded that a full npj Breast Cancer (2022) 69 Published in partnership with the Breast Cancer Research Foundation 1234567890():,; M. El-Tamer and T. Kovacs Management of the Axilla Management of the Axilla a. b. T1-2 N1 HR positive/HER2 negative T1-2 N1 HR positive/HER2 negative Premenopausal Patients Premenopausal Patients Palpable No Palpable Axillary Node Axillary Node FNA node Procedure Positive Negative Mastectomy Lumpectomy US AXILLA FNA NCT SLNBx SLNBx SUSPICIOUS NODES Positive Negative Positive Negative Positive Negative NCT SLNBx ALND No ALND No ALND Z0011 AMAROS (+) ALND/AMAROS (-) No ALND Management of the Axilla Management of the Axilla c. d. T1-2 N1 HR positive/HER2 negative T1-2 N1 HR positive/HER2 negative Postmenopausal Patients Postmenopausal Patients Palpable No Palpable Axillary Node Axillary Node FNA Node Procedure Mastectomy Positive Negative Lumpectomy RS RS SLNBx SLNBx > 25 0-25 Positive Negative > 25 0-25 Positive Negative NCT NCT SLNBx ALND or No ALND ALND No ALND Z0011 NET AMAROS (+) ALND (-) No ALND Fig. 2 Suggested management of the axilla with T1/T2 N1 disease who are hormone receptor positive/HER2 negative. a Management of the axilla for premenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with palpable axillary nodes. b Management of the axilla for premenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with no palpable axillary nodes. c Management of the axilla for postmenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with palpable axillary nodes. d Management of the axilla for postmenopausal patients with hormone receptor positive/HER2 negative T1-2 N1 patients with no palpable axillary nodes. TNBC triple negative breast cancer, HER2 human epidermal growth factor receptor 2, CTx chemotherapy, SLNB sentinel lymph node biopsy, XRT radiation therapy, ALND axillary lymph node dissection, HR hormone receptor, FNA fine-needle aspiration, NCT neoadjuvant chemotherapy, RS Oncotype DX recurrence score. axillary lymph node dissection could be safely omitted in that AMAROS included patients with breast conservation or group of patients, as there was no difference in locoregional mastectomy. recurrence, disease-free survival, or overall survival . Based on the above, the management of hormone receptor- The AMAROS trial accrued patients with stage cT1-2N0M0 positive/HER2 negative T1/2 N1 patients depends on their primary breast cancer. Those with positive sentinel nodes were menopausal status, clinical exam of the axilla, surgical procedure, randomized to an axillary lymph node dissection or axillary Oncotype DX score, and number of positive nodes. radiation therapy. At a median follow-up of 10 years, both of these Premenopausal patients with clinically palpable axillary nodes arms showed no difference in regional recurrence, distant should have a cytologic or pathologic evaluation of the palpable 18,19 node to confirm metastatic disease. Patients with positive metastasis, or survival . For hormone receptor-positive/HER2 negative T1-2 tumors, the palpable nodes are recommended neoadjuvant chemotherapy. decision on chemotherapy is dependent on the menopausal Those with negative nodes should have a sentinel node procedure status of the patient as well as on the clinical examination of the that will dictate further management of the axilla as seen in axilla. Fig. 2a. It is clear that patients with N1 disease who are premenopausal In clinically node-negative premenopausal patients, the surgical require chemotherapy irrespective of their Oncotype DX score. In procedure (mastectomy or lumpectomy) determines the manage- postmenopausal patients, the RxPONDER trial showed no benefit ment pathway. When a lumpectomy is planned, patients with from chemotherapy in postmenopausal patients with 1-3 positive positive sentinel nodes may be managed based on the ACOSOG nodes. The ACOSOG Z0011 and AMAROS trials apply to patients Z0011 or AMAROS trials. The patients who are undergoing a who are clinically node negative; ACOSOG Z0011 included only mastectomy have not been included in the ACOSOG Z0011 trial, patients who underwent breast-conservation therapy, while and the benefit of chest wall radiation may not be justified in all Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 69 M. El-Tamer and T. Kovacs patients. We recommend a sonographic evaluation of the axilla 6. Kuhl, C. K., Lehman, C. & Bedrosian, I. Imaging in locoregional management of breast cancer. J. Clin. Oncol. 38, 2351–2361 (2020). with fine-needle aspiration (FNA) of suspicious nodes. Patients 7. Rauch, G. M. et al. Multimodality imaging for evaluating response to neoadjuvant with proven nodal metastasis are started on neoadjuvant chemotherapy in breast cancer. AJR Am. J. Roentgenol. 208, 290–299 (2017). chemotherapy, while those with negative FNA are candidates 8. Weber, J. J. et al. MRI and prediction of pathologic complete response in the for upfront surgical intervention. Fig. 2b summarizes the breast and axilla after neoadjuvant chemotherapy for breast cancer. J. Am. Coll. suggested outline of treatment. Surg. 225, 740–746 (2017). In postmenopausal patients with clinically palpable lymph 9. Tee, S. R. et al. Meta-analysis of sentinel lymph node biopsy after neoadjuvant nodes, the result of an FNA of the axillary node will determine the chemotherapy in patients with initial biopsy-proven node-positive breast cancer. clinical pathway. Patients with negative cytology will undergo a Br. J. Surg. 105, 1541–1552 (2018). sentinel lymph node biopsy with complete axillary lymph node 10. Barrio, A. V. et al. Abstract No. PD4-05. Axillary recurrence is a rare event in node- dissection if the sentinel node is positive, as the number of positive patients. treated with sentinel node biopsy alone after neoadjuvant chemotherapy: results of a prospective study. In San Antonio Breast Cancer positive nodes will dictate if they can be managed as per the RX- Symposium Virtual Meeting, San Antonio, TX, December 8–11 (2020). PONDER trial. In patients with positive FNA, those with Oncotype 11. Donker, M. et al. Marking axillary lymph nodes with radioactive iodine seeds for DX recurrence scores >25 will be candidates for neoadjuvant axillary staging after neoadjuvant systemic treatment in breast cancer patients: chemotherapy. Those with Oncotype DX recurrence scores ≤25 the MARI procedure. Ann. Surg. 261, 378–382 (2015). may be candidates for a full axillary lymph node dissection on 12. El-Tamer, M. B. Session: the great debates. In 22nd Annual Meeting of the Amer- neoadjuvant endocrine therapy as per Fig. 2c. ican Society of Breast Surgeons (2021). In postmenopausal patients who do not have palpable axillary 13. Kahler-Ribeiro-Fontana, S. et al. Long-term standard sentinel node biopsy after nodes, the type of surgical procedure will determine the clinical neoadjuvant treatment in breast cancer: a single institution ten-year follow-up. Eur. J. Surg. Oncol. 47, 804–812 (2021). pathway. Those undergoing a lumpectomy are clearly candidates 14. Kuehn, T. et al. Sentinel-lymph-node biopsy in patients with breast cancer before for the ACOSOG Z0011 or AMAROS trials if they fit their criteria; and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre hence, they should undergo a sentinel node procedure and be cohort study. Lancet Oncol. 14, 609–618 (2013). treated accordingly. For those undergoing a mastectomy, the 15. Moo, T. A. et al. Is low-volume disease in the sentinel node after neoadjuvant recurrence score is helpful in determining the need for chemotherapy an indication for axillary dissection? Ann. Surg. Oncol. 25, neoadjuvant chemotherapy; a need that would be limited for 1488–1494 (2018). those with an Oncotype DX score >25. Those with Oncotype DX 16. Kalinsky, K. et al. Abstract No. GS3-00. First results from a phase III randomized scores ≤25 will undergo a sentinel lymph node biopsy and clinical trial of standard adjuvant endocrine therapy (ET) +/− chemotherapy (CT) completion node dissection only if the sentinel node is positive, as in patients (pts) with 1-3 positive nodes, hormone receptor-positive (HR+) and HER2-negative (HER2−) breast cancer (BC) with recurrence score (RS) < 25: SWOG shown in Fig. 2d. S1007 (RxPonder). In San Antonio Breast Cancer Symposium Virtual Meeting, San To summarize the management of the axilla in hormone Antonio, TX, December 8–11 (2020). receptor-positive/HER2 negative tumors: (1) sentinel lymph node 17. Giuliano, A. E. et al. Effect of axillary dissection vs no axillary dissection on 10-year biopsy is standard for cN0 patients; (2) sentinel lymph node biopsy overall survival among women with invasive breast cancer and sentinel node is standard for patients with cT1-2 tumors and 1-2 positive nodes metastasis: the ACOSOG Z0011 (Alliance) randomized clinical trial. JAMA 318, who are undergoing a lumpectomy and whole breast irradiation; 918–926 (2017). and (3) axillary dissection is recommended when a patient has 18. Donker, M. et al. Radiotherapy or surgery of the axilla after a positive sentinel palpable positive nodes if no neoadjuvant chemotherapy is node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, planned, when a patient has >2 positive sentinel nodes, and open-label, phase 3 non-inferiority trial. Lancet Oncol. 15, 1303–1310 (2014). 19. Rutgers, E. J. et al. Abstract No. GS4-01. Radiotherapy or surgery of the axilla after when residual positive nodes are present after neoadjuvant a positive sentinel node in breast cancer patients: 10 year follow up results of the chemotherapy. EORTC AMAROS trial (EORTC 10981/22023). In Cancer Res (Proceedings of the 2018 San Antonio Breast Cancer Symposium, December 4-8, San Antonio, TX) Vol. 79 Reporting summary (Suppl. 4) (2019). Further information on research design is available in the Nature Research Reporting Summary linked to this article. AUTHOR CONTRIBUTIONS DATA AVAILABILITY T.K. and M.E.T. wrote and revised the manuscript. T.K. and M.E.T. contributed to the interpretation of the text. All authors read and approved the final version of the Available by contacting the corresponding author upon request. manuscript. Received: 4 October 2021; Accepted: 22 April 2022; COMPETING INTERESTS The authors declare no competing interests. REFERENCES 1. Boughey, J. C. et al. Sentinel lymph node surgery after neoadjuvant che- motherapy in patients with node-positive breast cancer: the ACOSOG Z1071 ADDITIONAL INFORMATION (Alliance) clinical trial. JAMA 310, 1455–1461 (2013). Supplementary information The online version contains supplementary material 2. Kim, J. Y. et al. Prognostic nomogram for prediction of axillary pathologic com- available at https://doi.org/10.1038/s41523-022-00432-y. plete response after neoadjuvant chemotherapy in cytologically proven node- positive breast cancer. Medicine 94, e1720 (2015). Correspondence and requests for materials should be addressed to Mahmoud 3. Montagna, G. et al. Selecting node-positive patients for axillary downstaging with El-Tamer. neoadjuvant chemotherapy. Ann. Surg. Oncol. 27, 4515–4522 (2020). 4. Simons, J. M. et al. Excision of both pretreatment marked positive nodes and Reprints and permission information is available at http://www.nature.com/ sentinel nodes improves axillary staging after neoadjuvant systemic therapy in reprints breast cancer. Br. J. Surg. 106, 1632–1639 (2019). 5. Mamtani, A. et al. How often does neoadjuvant chemotherapy avoid axillary Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims dissection in patients with histologically confirmed nodal metastases? Results of in published maps and institutional affiliations. a prospective study. Ann. Surg. Oncol. 23, 3467–3474 (2016). npj Breast Cancer (2022) 69 Published in partnership with the Breast Cancer Research Foundation M. El-Tamer and T. Kovacs Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. © The Author(s) 2022 Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2022) 69

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