Bibliography on Assisted Reproductive Technology and Gynecological Surgery

This platform serves as a structured resource for clinicians and researchers specializing in assisted reproductive technology (ART) and gynecologic surgery. It has been developed in response to the increasing complexity and rapid evolution of these intersecting fields. The result of collaborative work by gynecologic surgeons highly engaged in both disciplines, each review offers a clear and accessible synthesis of recent studies.

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De-Escalation of Axillary Surgery

Dr Cécile Dupont

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Dr Françoise durand

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Overview

The de-escalation of axillary surgery in breast cancer management is a significant evolution aimed at reducing patient morbidity while maintaining or improving oncological outcomes. Historically, axillary lymphadenectomy (ALND) was the standard, but it has been progressively replaced by less invasive techniques like sentinel lymph node biopsy (SLNB). This shift is driven by a better understanding of breast cancer biology, which emphasizes that systemic spread is a primary driver of recurrence rather than solely locoregional disease, alongside advancements in targeted and neoadjuvant systemic therapies.

The main advantages of de-escalating axillary surgery include:

  • Reduced Morbidity: ALND can lead to significant complications such as lymphedema, nerve damage, reduced shoulder and arm mobility, and chronic pain, which severely impact a patient’s quality of life. SNB, while less invasive, can also have long-lasting complications.
  • Improved Oncological Understanding: Advances in understanding breast cancer subtypes and the advent of targeted therapies have paved the way for reduced axillary interventions, especially for patients with no or minimal nodal disease.
  • Effective Systemic Treatments: Neoadjuvant systemic treatments (NST) have demonstrated high rates of pathological complete response (pCR) in both the breast and axilla, particularly in HER2-positive and triple-negative breast cancers, enabling downstaging and less extensive surgery.
  1. Upfront Surgery (Clinically Node-Negative Axilla):
    • Sentinel Lymph Node Biopsy (SNB): SNB is now the standard of care for women with early-stage breast cancer. It replaced ALND, allowing for axillary staging without removing the entire axillary basin in node-negative patients.
    • Omission of ALND in Low-Volume Disease: For patients with clinically node-negative lymph nodes and up to two positive sentinel nodes (either micrometastases or macrometastases), avoiding ALND is considered a safe option.
      • IBCSG 23-01 Trial: Demonstrated that ALND could be safely omitted in patients with micrometastases in the sentinel lymph nodes without affecting disease-free survival.
      • ACOSOG Z0011 Trial: A pivotal study showing that ALND might not be mandatory for patients with one or two metastatic sentinel lymph nodes undergoing lumpectomy with whole-breast irradiation. It found no significant differences in overall survival or disease-free survival and led to less invasive strategies in breast-conserving surgery. However, its results cannot be directly extrapolated to patients receiving neoadjuvant chemotherapy, partial breast irradiation, or mastectomy.
      • SINODAR-ONE Trial: Explored extending the ACOSOG Z0011 findings to patients undergoing mastectomy with one or two macrometastatic sentinel lymph nodes, demonstrating non-inferior survival and relapse rates without additional axillary treatment.
    • Axillary Radiotherapy (RT) as an Alternative to ALND:
      • AMAROS Trial: Showed that axillary RT was comparable to ALND in preventing axillary recurrence in patients with positive SNB, with a significantly lower occurrence of arm lymphedema in the RT group. This established RT as a viable alternative for selected patients.
      • OTOASOR Trial: Reached similar conclusions, suggesting regional nodal irradiation as an effective alternative for selected patients with positive nodes without increasing axillary relapse risk.
    • Omission of Any Axillary Surgery: This is an appealing practice for carefully selected patients with early-stage breast cancer and clinically negative lymph nodes.
      • SOUND Trial: Indicated that avoiding axillary surgery was non-inferior to SNB in terms of 5-year distant disease-free survival for patients with small tumors (up to 2 cm) and negative preoperative axillary ultrasonography.
      • INSEMA Trial: Showed no significant difference in invasive disease-free survival between patients undergoing less extensive axillary surgery and those receiving standard treatment for cT1–2N0 patients.
      • This approach might be considered for highly selected subgroups with small tumors and lymph nodes negative on clinical and ultrasound evaluation. It is also supported by data for elderly patients (65 or older) with estrogen receptor-positive/HER2-negative breast cancer.
  1. Neoadjuvant Systemic Treatment (NST) Setting (Initially Node-Positive Patients Converting to Node-Negative):
    • NST aims to downstage disease burden in both the breast and axillary lymph nodes, reducing the extent of surgery. There’s growing interest in omitting ALND in “excellent responders” (those who become node-negative after NST).
    • Challenges of SNB after NST: Earlier studies reported unacceptably high false-negative rates (FNRs) for SNB in initially node-positive patients after NST.
      • ACOSOG Z1071 Trial: Found an FNR of 12.6% for SNB after neoadjuvant chemotherapy in initially node-positive patients, exceeding the predefined acceptable threshold. However, FNR decreased with dual mapping agents (10.8%), examination of ≥3 sentinel nodes (9%), and removal of the clipped node (6.8%).
      • SENTINA Trial: Reported an FNR of 14.2% for SNB after NST.
      • SN FNAC Study: Showed a significantly lower FNR of 8.4% with stricter protocol adherence, including mandatory immunohistochemistry and evaluation of nodal response by size.
    • Strategies to Lower FNR (Technical Optimization): The use of dual tracer mapping, retrieval of ≥3 sentinel lymph nodes, and pre-chemotherapy nodal clipping (Targeted Axillary Dissection – TAD) have been advocated to minimize the FNR of SNB after NST. The MARI procedure (marking the cytology-proven axillary lymph node with an I-125 seed before NST) is another alternative.
    • Oncological Outcomes: Despite the historical concerns about FNR, recent findings support the oncological safety of de-escalated axillary surgery post-NST.
      • A meta-analysis indicated an extremely low axillary failure rate for SNB (pooled 2.1%) and MARI/TAD (pooled 1.5%) in patients achieving nodal pCR after NST. The 95% confidence intervals between these two methods highly overlapped, suggesting no statistically significant difference in axillary failure rate.
      • There was no statistically significant benefit of ALND over SNB in patients who achieved nodal pCR after NST.
      • Pooled estimates for 5-year disease-free survival (DFS) were 0.87, 5-year distant disease-free survival (DDFS) were 0.90, and 5-year overall survival (OS) were 0.92 for patients with a negative SNB alone.
      • Studies, such as Tinterri et al. (2024), have shown that SLNB is associated with better long-term outcomes including recurrence-free survival (RFS), DDFS, OS, and breast cancer-specific survival (BCSS) compared to ALND in clinically node-positive patients who convert to ycN0 after NST, with low axillary recurrence rates (0.6–2.1%). This suggests that SLNB is a safe and effective alternative for selected patients.
    • Candidates for Omission of Axillary Surgery in HER2-positive Breast Cancer Post-NAT: Patients who are HER2-positive and show clinically node-negative disease after neoadjuvant therapy (especially with dual anti-HER2 therapy) may be candidates for omitting axillary staging. This is particularly true for those with early tumors (T1), strong HER2+ disease (3+), clinically node-negative status before NAT, and those in whom the primary tumor achieved a complete clinical response. Dual anti-HER2 treatment significantly correlates with axillary pCR.

The field continues to evolve with several ongoing clinical trials:

  • POSNOC Trial: Aims to determine the necessity and effectiveness of additional treatments (ALND or axillary RT) after a positive SNB for one or two sentinel lymph nodes.
  • SENOMAC Trial: Investigates if completion ALND is necessary in cases of limited spread to sentinel lymph nodes, including patients with larger tumors and those who received neoadjuvant chemotherapy.
  • OPBC-03/TAXIS Trial: Evaluates the non-inferiority of axillary RT compared to ALND in terms of disease-free survival for clinically node-positive breast cancer patients (upfront surgery or residual disease post-NAC), including tailored axillary surgery (TAS).
  • Alliance A011202 Trial: Compares ALND to axillary RT in cT1–3N1 breast cancer patients with positive SNB after NAC, assessing invasive breast cancer recurrence-free interval.
  • ADARNAT Trial: Aims to determine if axillary radiation is non-inferior to ALND in terms of 5-year axillary recurrence rates in breast cancer patients with positive SNB following neoadjuvant systemic therapy.
  • NSABP B-51/RTOG 1304 Trial: Designed to determine whether regional nodal irradiation is necessary for breast cancer patients who initially have biopsy-confirmed positive axillary lymph nodes that become pathologically negative after undergoing NAC.
  • SOUND, INSEMA, BOOG 13-08, SOAPET, NAUTILUS Trials: Explore the safety and feasibility of omitting SNB altogether in specific low-risk, node-negative patient populations.
  • AXSANA Study: An ongoing international prospective multicenter cohort study seeking to determine best practices for axillary surgery by comparing various techniques to optimize treatment outcomes and reduce morbidity associated with traditional ALND, particularly in cN+ patients converting to cN0 post-NAC.

Despite significant progress, several challenges remain in de-escalating axillary surgery:

  • Patient Selection: Determining the appropriate axillary treatment remains a complex decision that must be made by multidisciplinary teams with expertise in personalized breast cancer treatment. Patient selection criteria and SNB evaluation methods can vary significantly across centers.
  • Balancing Efficacy and Morbidity: While reducing surgical morbidity is a key goal, it must be balanced with ensuring effective cancer control and appropriate decisions regarding postoperative systemic treatments, which are still based on axillary status.
  • Defining Nodal Status: The definition of clinically negative nodal status after NST is not yet standardized.
  • Patient Preference: Not all patients may desire de-escalation, with some opting for more aggressive surgery for “peace of mind”.
  • Long-Term Data: More long-term oncological data are still needed, especially for newer procedures like MARI/TAD.

Overall, while de-escalation of axillary surgery has greatly improved patient quality of life without compromising oncologic outcomes in many settings, thorough axillary staging remains crucial in specific cases, and ongoing research aims to further refine and validate these less invasive approaches.

FAQ

The historical Halstedian concept viewed breast cancer as a locoregional disease spreading via lymphatics, thus necessitating extensive resection. However, it is now clear that breast cancer biology is the major driver of both systemic and locoregional recurrence, not solely local spread. This advanced understanding, coupled with the advent of targeted therapies, paved the way for further de-escalation of axillary interventions, especially for patients with no or minimal nodal disease. Consequently, SLNB has progressively replaced ALND as the standard method for axillary staging in node-negative patients, providing crucial information without removing the entire axillary basin.

Several pivotal trials support this de-escalation:

  • The IBCSG 23-01 Trial demonstrated that ALND could be safely omitted in patients with micrometastases in the sentinel lymph nodes without affecting disease-free survival.
  • The ACOSOG Z0011 Trial was crucial, showing no significant differences in overall survival or disease-free survival for patients with one or two metastatic sentinel lymph nodes undergoing lumpectomy with whole-breast irradiation, supporting omitting ALND in this setting.
  • The SINODAR-ONE Trial explored extending Z0011 findings to patients undergoing mastectomy with one or two macrometastatic sentinel nodes, demonstrating non-inferior survival and relapse rates without ALND.

Yes, axillary RT can safely replace ALND in selected cases. The AMAROS Trial showed that axillary RT was comparable to ALND in preventing axillary recurrence in patients with positive SNB, with a significantly lower occurrence of arm lymphedema in the RT group. The OTOASOR Trial reached similar conclusions, suggesting regional nodal irradiation as an effective alternative for selected patients with positive nodes without increasing axillary relapse risk. These trials support considering axillary RT as a comparable therapeutic approach to dissection for up to two positive sentinel nodes.

Omission of any axillary surgery has gained interest for carefully selected patients with early-stage breast cancer who present with clinically negative lymph nodes.

  • The SOUND Trial indicated that avoiding axillary surgery was non-inferior to SNB in terms of 5-year distant disease-free survival for patients with small tumors (up to 2 cm) and negative preoperative axillary ultrasonography.
  • The INSEMA Trial showed no significant difference in invasive disease-free survival between patients undergoing less extensive axillary surgery and those receiving standard treatment for cT1–2N0 patients.
  • This approach might be considered for highly selected subgroups with small tumors and lymph nodes negative on clinical and ultrasound evaluation. It is also supported by data for elderly patients (65 or older) with estrogen receptor-positive/HER2-negative breast cancer, showing extremely low axillary recurrence rates.

The main challenge has been the unacceptably high false-negative rates (FNRs) reported for SNB in initially node-positive patients after NST in earlier studies. For example, the ACOSOG Z1071 Trial found an FNR of 12.6% for SNB after neoadjuvant chemotherapy in initially node-positive patients, exceeding the predefined acceptable threshold. Similarly, the SENTINA Trial reported an FNR of 14.2%.

To lower the FNR of SLNB after NST, the following strategies have been advocated:

  • The use of dual tracer mapping.
  • Retrieval of ≥3 sentinel lymph nodes (SLNs).
  • Pre-chemotherapy nodal clipping (Targeted Axillary Dissection – TAD). The MARI procedure, involving the implantation of an I-125 seed into the cytology-proven axillary lymph node before NST, is another alternative.

For patients who achieve nodal pCR after NST, omission of ALND is oncologically safe, with extremely low nodal recurrence rates.

  • A meta-analysis showed an extremely low axillary failure rate for SNB (pooled 2.1%) and MARI/TAD (pooled 1.5%) in patients achieving nodal pCR after NST.
  • There was no statistically significant benefit of ALND over SLNB in patients with nodal pCR after NST.
  • Long-term outcomes for SLNB are reported to be associated with better recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) compared to ALND in cN+ patients converting to ycN0 after NST.

The pooled estimate of axillary recurrence in patients with a post-NST negative SLNB and ALND omission was 2.1% (95% CI 1.4–3.2%). For patients who received nodal marking and excision in the form of MARI or TAD, the pooled axillary recurrence rate was 1.5% (95% CI 0.5–4.1%). The 95% confidence interval between these two methods highly overlapped, suggesting no statistically significant difference in axillary failure rate.

Pre-chemotherapy nodal clipping is significant because the removal of the clipped node, in combination with SLNB, reduced the false-negative rate to as low as 1.4%. This method (TAD) provides a targeted approach to ensure the originally positive lymph node is assessed for response, which is crucial for accurate staging post-NST. However, failure of TAD can occur due to failed sentinel lymph node mapping or failed localization of the clipped node.

Recent systematic reviews and meta-analyses support the oncological safety of de-escalated axillary surgery post-NST:

  • Pooled estimates for 5-year disease-free survival (DFS) were 0.87 (95% CI 0.83–0.90) for patients with a negative SLNB alone.
  • Pooled estimates for 5-year distant disease-free survival (DDFS) were 0.90 (95% CI 0.88–0.92).
  • Pooled estimates for 5-year overall survival (OS) were 0.92 (95% CI 0.88–0.94).
  • These findings suggest excellent survival outcomes in good responders despite the omission of ALND. A recent study found that SLNB was associated with better long-term RFS, DDFS, OS, and BCSS compared to ALND in clinically node-positive patients who convert to ycN0 after NST, with low axillary recurrence rates (0.6–2.1%).

In HER2-positive patients after NAT, several factors were found to be statistically significant predictors of nodal pCR, potentially enabling omission of axillary staging:

  • Degree of HER2 positivity (HER2+ 3 tumors) were more likely to develop nodal pCR.
  • Dual anti-HER2 therapy (e.g., trastuzumab + pertuzumab) was significantly correlated with achieving axillary pCR.
  • Pre-neoadjuvant LN status by imaging: all radiologically negative LNs turned out to be pathologically negative after NAT.
  • Post-neoadjuvant LN status by imaging: all radiologically negative LNs turned out to be pathologically negative.
  • Primary tumor complete clinical response (cCR): all patients who had cCR also had nodal pCR.

T1 primary tumors before NAT: all T1 tumors showed negative LNs after NAT, though this was statistically non-significant in one study.

For patients undergoing a mastectomy in the non-neoadjuvant setting with clinically node-negative T1/T2 tumors and up to two positive nodes by SLNB, for whom postmastectomy RT is intended, ALND may be omitted. If ALND has not been performed, then RT should be delivered to include the undissected axilla at risk. This change reflects data from the AMAROS and OTOASAR trials, which confirmed comparable long-term outcomes with RT to the axilla but less morbidity.

The role of locoregional irradiation in patients who achieved post-NST nodal pCR after NST has not been fully elucidated. While adjuvant full nodal irradiation was used in some centers, some studies found zero axillary recurrence with whole breast irradiation only. Ongoing trials addressing this include:

  • The NRG Oncology/NSABP B-51/RTOG 1304 Trial: Aims to determine whether regional nodal irradiation is necessary for breast cancer patients who initially have biopsy-confirmed positive axillary lymph nodes that become pathologically negative (ypN0) after undergoing NAC. Early results suggest that omitting RNI in these patients may not compromise oncological outcomes and may reduce treatment-related toxicity.
  • The ADARNAT Trial: Aims to determine if axillary radiation is non-inferior to ALND in terms of 5-year axillary recurrence rates in breast cancer patients with positive SNB following neoadjuvant systemic therapy.
  • The Alliance A011202 Trial: Compares ALND to axillary RT in cT1–3N1 breast cancer patients with positive SNB after NAC, assessing invasive breast cancer recurrence-free interval.

Determining the appropriate axillary treatment remains a complex decision that must be made by multidisciplinary teams. Patient selection criteria and SLNB evaluation methods can vary significantly across centers.

  • A major challenge is the lack of standardization for the definition of clinically negative nodal status after NST.
  • Pre-chemotherapy tumor and nodal staging varied among studies.
  • Imaging modalities like AUS, MRI, and PET scans are commonly used for nodal assessment but can have suboptimal positive and negative predictive values in evaluating axillary response after NST.
  • While procedural FNR of SLNB did not appear to be influenced by the presenting nodal staging, its application in locally advanced nodal disease is limited.

Decisions on postoperative systemic treatments are still based on axillary status. For patients with higher-risk hormone receptor-positive/HER2-negative breast cancer and lymph node involvement, adjuvant therapy decisions may include the recommendation for cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. These inhibitors improve outcomes by reducing the risk of recurrence and improving survival rates. However, pivotal adjuvant trials generally did not permit concomitant RT with CDK4/6 inhibitors due to potential hematologic toxicities, leading current recommendations to advise withholding them during RT in early-stage disease.

These trials represent a significant step toward omitting SLNB altogether in specific low-risk, node-negative patient populations, moving beyond just omitting ALND:

  • The SOUND trial demonstrated that avoiding axillary surgery was non-inferior to SLNB in terms of 5-year distant disease-free survival for patients with small tumors (up to 2 cm) and negative preoperative axillary ultrasonography, suggesting these patients can safely skip axillary surgery without impacting their treatment outcomes.
  • The INSEMA trial also showed no significant difference in invasive disease-free survival between patients undergoing less extensive axillary surgery and those receiving standard treatment for cT1–2N0 patients, reinforcing a de-escalation approach in well-selected populations. These findings align with the “Choosing Wisely” campaign, advocating against unnecessary medical interventions.

The AXSANA study (EUBREAST-03) is an ongoing international, prospective, multicenter cohort study. It seeks to determine the best practices for axillary surgery in clinically node-positive breast cancer patients who convert to clinical node negativity through neoadjuvant chemotherapy. The goal is to optimize treatment outcomes and reduce morbidity associated with traditional ALND.

Future research continues to refine de-escalation strategies. Several ongoing trials are exploring these frontiers:

  • Omission of ALND after positive SNB: POSNOC (one or two macrometastatic SN, adjuvant therapy alone vs. ALND or axillary RT), and SENOMAC (up to two macrometastases, completion ALND vs. no further axillary surgery, including NAC patients and larger tumors).
  • RT vs. ALND post-NAC: OPBC-03/TAXIS (axillary RT vs. ALND for cN+ patients, including those with residual disease post-NAC, and tailored axillary surgery), Alliance A011202 (ALND vs. axillary RT in cT1–3N1 patients with positive SNB after NAC), and ADARNAT (axillary RT vs. ALND for positive SNB following NST).
  • Omission of RNI: NSABP B-51/RTOG 1304 (necessity of RNI in initially N1 patients who become ypN0 after NAC).
  • Omission of SNB altogether: BOOG 13-08 (omitting SNB in cT1–2N0 patients undergoing BCT), SOAPET (omitting SNB for patients with negative preoperative axillary assessments including LymphPET), and NAUTILUS (omitting axillary surgery in cT1–2N0 with negative axillary US). The AXSANA study continues to compare various axillary surgery techniques. PHERGain evaluates chemotherapy de-escalation in HER2+ EBC based on PET-based pCR.

Bibliography

Fancellu, A., Giuliani, G., Mulas, S., Contini, A. M., Ariu, M. L., & Sanna, V. (2025).
De-escalation of axillary treatment in early breast cancer—a narrative review of current trials. Translational Breast Cancer Research, 2025, 6:5. doi: 10.21037/tbcr-24-45

Man, V., Duan, J., Luk, W.-P., Fung, L.-H., & Kwong, A. (2025).
Different strategies in de-escalation of axillary surgery in node-positive breast cancer following neoadjuvant treatment: a systematic review and meta-analysis of long-term outcomes. Breast Cancer, 32(638), 638–653. https://doi.org/10.1007/s12282-025-01692-9

Moran, M. S., & Leitch, A. M. (2022).
Locoregional Management of Early-Stage Breast Cancer. J Natl Compr Canc Netw, 20(5.5), e225018. doi: 10.6004/jnccn.2022.5018

Meattini, I., Tecic Vuger, A., Becherini, C., Epstein, E. J., Garcia, J. P., Berger, E. R., & Harbeck, N. (2025).
Multimodal De-Escalation Strategies in Early Breast Cancer. Am Soc Clin Oncol Educ Book, 45, e473462. doi: https://doi.org/10.1200/EDBK-25-473462

Hamdy, O., Atallah, K., Elsergany, A. R., Atwa, S., Abdo, R., Zaher, A., & Abdelhakiem, M. (2025).
Omission of Axillary Surgery After Neoadjuvant Therapy in Her2-Positive Breast Cancer: Who Are the Candidates? Cancers, 17(4), 562. https://doi.org/10.3390/cancers17040562

Tinterri, C., Barbieri, E., Sagona, A., Di Maria Grimaldi, S., & Gentile, D. (2024).
De-Escalation of Axillary Surgery in Clinically Node-Positive Breast Cancer Patients Treated with Neoadjuvant Therapy: Comparative Long-Term Outcomes of Sentinel Lymph Node Biopsy versus Axillary Lymph Node Dissection. Cancers, 16(18), 3168. https://doi.org/10.3390/cancers16183168

Traditionally, axillary lymph node dissection (ALND) was standard, but from the 1990s, it was progressively replaced by sentinel node biopsy (SNB) to assess axillary lymph node status without removing the entire axillary basin in patients without overt metastases. In the last decade, the necessity of performing SNB in all invasive breast cancers and ALND in all patients with SNB involvement has been questioned.

This narrative review comprehensively examines studies on the de-escalation of axillary treatment in various clinical scenarios, including upfront surgery, neoadjuvant systemic treatments (NSTs), and the omission of axillary surgery altogether. The review’s methodology involved an extensive literature search across major databases such as PubMed, Scopus, Web of Sciences, and ClinicalTrials.gov, covering trials published from January 2009 to July 2024. It focused on patients with early breast cancer (stages I, IIA, IIB, and IIIA), excluding studies with more advanced stages.

De-escalation in the Upfront Surgery Setting

The introduction of SNB was a fundamental shift, significantly improving the quality of life for women with breast cancer by sparing most patients from ALND and its associated morbidities, such as lymphedema, nerve damage, reduced shoulder/arm mobility, and chronic pain. Initially, the need for complete ALND in cases of micrometastases (metastases >0.2 mm but ≤2 mm) or isolated tumor cells (ITCs) in the sentinel node was questioned.

Several pivotal trials have shaped the current approach:

  • The IBCSG 23-01 Trial demonstrated that ALND could be safely omitted in breast cancer patients with micrometastases in the sentinel lymph node, showing no difference in disease-free survival between those who underwent ALND and those who did not.
  • The ACOSOG Z0010 trial found that detecting occult metastases in sentinel nodes and bone marrow did not significantly affect survival.
  • The AATRM 048/13/2000 trial also supported omitting ALND for micrometastases, showing no differences in disease-free survival or cancer-related deaths.
  • The MIRROR trial suggested that even a minor load of cancer cells in sentinel nodes could have prognostic significance, though the difference was not substantial enough to alter clinical practice.
  • The ACOSOG Z0011 trial was particularly impactful, showing that ALND might not be mandatory for all patients with one or two metastatic sentinel lymph nodes (T1–2N0M0) undergoing lumpectomy with planned whole-breast irradiation. It found no significant differences in overall or disease-free survival between groups receiving SNB alone or SNB followed by ALND. This trial significantly influenced national guidelines, advising against standard ALND for patients meeting its criteria. However, it did not include patients receiving neoadjuvant chemotherapy (NAC), partial breast irradiation, or those undergoing mastectomy.
  • The SINODAR-ONE trial explored extending ACOSOG Z0011 results to mastectomy patients, finding no inferiority in survival or relapse rates for patients with one or two macrometastatic sentinel lymph nodes who received SNB alone and adjuvant therapy compared to those who underwent ALND.
  • The AMAROS trial was crucial in investigating axillary radiotherapy (RT). It found that axillary RT was comparable to ALND in preventing axillary recurrence in patients with positive SNB (including those undergoing mastectomy), with significantly lower rates of arm lymphedema in the RT group. The OTOASOR trial arrived at similar results, suggesting axillary RT as an effective alternative for selected patients with positive nodes.
  • Ongoing trials like POSNOC and SENOMAC continue to investigate broadening less invasive axillary treatments and the necessity of completion ALND, even for patients undergoing mastectomy or with larger tumors. The TAILOR RT trial (NCT03488693) is also evaluating whether regional RT is needed for nodal basins in all patients with positive sentinel nodes.

De-escalation in the Neoadjuvant Systemic Treatment (NST) Setting

NSTs are increasingly used to downstage disease in the breast and axillary lymph nodes, aiming to reduce surgical extent and personalize treatment. Particular interest lies in patients with initial metastatic lymph nodes who become node-negative after NST.

Challenges with SNB after NST and ongoing research:

  • The ACOSOG Z1071 (Alliance) trial assessed SNB after chemotherapy in initially node-positive (cN1) breast cancer. It found that the false-negative rate (FNR) for SNB (12.6%) was not consistently below the desired 10%, suggesting a need for greater sensitivity if SNB were to replace ALND entirely in this setting. However, the FNR was lower with dual mapping agents, examination of ≥3 sentinel nodes, and retrieval of the clipped node.
  • The SENTINA trial also reported a higher FNR for SNB after systemic treatment compared to before NAC, advising caution.
  • Conversely, the SN FNAC study demonstrated an FNR of <10% for SNB after NAC in biopsy-proven node-positive breast cancer, attributing this to stricter protocol adherence including immunohistochemistry.
  • The GANEA 2 study supported that for patients without initial node involvement (cN0), a negative SNB after NAC safely allows avoidance of ALND.
  • Pooled analysis from a systematic review and meta-analysis confirmed that breast cancer patients who convert to node-negative status after NST have an extremely low nodal recurrence rate, regardless of the axillary surgery choice (SNB or MARI/TAD), and that omission of ALND is oncologically safe in these patients. Axillary recurrence rates were 2.1% for negative SNB and 1.5% for negative MARI/TAD, with no significant difference between them. The 5-year disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) for SNB alone were excellent (0.87, 0.90, and 0.92, respectively).
  • The OPBC-03/TAXIS trial and Alliance A011202 are ongoing Phase III trials evaluating axillary radiotherapy against ALND, including tailored axillary surgery (TAS). The ADARNAT trial is also ongoing, comparing axillary radiation to ALND in patients with positive SNB after NST.
  • The NSABP B-51/RTOG 1304 trial suggests that for patients whose axillary lymph node involvement resolves after NAC, omitting regional nodal irradiation (RNI) may not compromise oncological outcomes and could reduce treatment-related toxicity.

Omission of Any Axillary Surgery

The most significant de-escalation involves omitting any axillary surgery for carefully selected patients with early-stage breast cancer and clinically negative lymph nodes.

  • The INSEMA trial showed that less extensive axillary surgery was non-inferior for 5-year invasive disease-free survival in cT1–2N0 patients undergoing breast-conserving surgery and radiotherapy.
  • The SOUND trial demonstrated the safety of omitting axillary surgery altogether in patients with small tumors (up to 2 cm) and negative preoperative axillary ultrasonography, finding it non-inferior to SNB for 5-year distant disease-free survival. This aligns with the “Choosing Wisely” campaign to avoid unnecessary medical interventions.
  • A recent prospective study supported the omission of SNB in estrogen receptor-positive/HER2-negative breast cancer patients aged 65 or older who received breast-conserving surgery, due to extremely low axillary recurrence rates.
  • For HER2-positive breast cancer patients, the rates of pathological complete response (pCR) in the axilla are high, particularly with dual anti-HER2 treatment. A recent study suggested that axillary staging may be omitted in HER2-positive patients who show clinically node-negative disease after neoadjuvant chemotherapy combined with dual anti-HER2 therapy. This is especially relevant for those with early tumors (e.g., T1–2N0), strong HER2+ disease (HER2+3), clinically negative lymph nodes before NAT, and those whose primary tumor achieved a complete clinical response.
  • Preoperative imaging and careful patient selection are paramount for safely omitting axillary surgery.

Summary and Future Perspectives

The trend towards de-escalation aims to minimize surgical morbidity, such as lymphedema and axillary web syndrome, while ensuring effective cancer management. While ALND might be unnecessary for patients with up to two positive sentinel nodes, especially those undergoing breast-conserving surgery, its omission is not universal due to highly selective inclusion criteria in trials like ACOSOG Z0011.

The omission of ALND in node-positive patients who convert to node-negative after NAC represents a promising opportunity, though current practices remain heterogeneous. The AXSANA study aims to establish best practices in this area. Axillary radiotherapy is also an emerging strategy, with trials like AMAROS demonstrating its comparability to ALND in disease control with reduced side effects.

Despite de-escalation efforts, axillary status continues to be a critical factor in deciding postoperative systemic treatments, such as the recommendation for CDK4/6 inhibitors in higher-risk hormone receptor-positive/HER2-negative breast cancer with lymph node involvement. Multidisciplinary teams are crucial in determining personalized treatment plans.

In conclusion, for patients with clinically node-negative lymph nodes and up to two positive sentinel nodes, avoiding ALND is considered a safe option. For those receiving NST, ALND may be unnecessary if no residual tumor burden remains in the lymph nodes after surgery. Axillary radiotherapy can be as effective as axillary dissection in certain cases. Ultimately, the avoidance of any axillary surgery might be proposed to highly selected subgroups with small tumors and lymph nodes that are negative on both clinical and ultrasound evaluation. The future likely holds a continued progressive de-escalation in axillary treatment, with ALND reserved for fewer patients.

The ongoing evolution extends to patients initially presenting with node-positive (cN+) breast cancer who undergo neoadjuvant systemic treatment (NST) and achieve a pathological complete response (pCR) in the axilla. This synthesis delves into the oncological outcomes of de-escalated axillary surgery in this specific patient population, drawing primarily from a systematic review and meta-analysis published in Breast Cancer (2025), and enriching the discussion with insights from other pertinent sources.

Methodology of the Systematic Review and Meta-Analysis

The systematic review and meta-analysis by Man et al. aimed to evaluate the long-term oncological outcomes of de-escalated axillary surgery—specifically SLNB, the MARI procedure, and targeted axillary dissection (TAD)—in cN+ breast cancer patients who converted to node-negative (ypN0) status after NST. The study systematically searched PubMed, Embase, and the Cochrane Library until May 2023, using terms related to node-positive breast cancer, neoadjuvant chemotherapy, SLNB, and TAD. Eligible studies included those reporting cumulative incidence of axillary recurrence and other oncological outcomes in patients who achieved nodal pCR and avoided ALND after NST, with a minimum of 20 patients. Reviews, commentaries, conference abstracts, and non-English articles were excluded. The quality of included articles was assessed using the Newcastle–Ottawa Scale. Statistical analysis involved inverse variance methods for logit transformed proportions, with heterogeneity assessed by the Chi-square test and I2 statistic.

Key Findings of the Systematic Review and Meta-Analysis

The meta-analysis included 14 studies (11 retrospective, 3 prospective), encompassing 4,268 patients initially diagnosed with node-positive breast cancer. Among these, 1,650 patients achieved nodal pCR and avoided ALND, with 1,382 undergoing SLNB alone and 268 receiving MARI/TAD.

  • Patient Characteristics and Treatment Regimens: Most patients had cT1-3 (95.0%) and cN1 (78.9%) breast cancers. Axillary ultrasonography (AUS) was the most common imaging modality for nodal assessment, often requiring a positive needle biopsy to confirm metastases. After NST, 46.4% of patients achieved clinical nodal complete response. Neoadjuvant chemotherapy regimens typically involved anthracyclines and taxanes, with anti-HER2 treatment added for HER2-positive cancers, often as trastuzumab or trastuzumab/pertuzumab combination.
  • Intraoperative Techniques: For SLNB, five studies used a single tracer, while three used dual tracers, reporting high localization rates (>90%). Most studies reported a median of 3 or more SLNs harvested. The MARI procedure involved marking the largest pathology-proven tumor-positive axillary lymph node with an I-125 seed before NST. TAD involved clipping the biopsy-proven node before NST, followed by wire localization and SLN mapping. The median number of axillary lymph nodes excised for MARI was one, and for TAD, it was three. Unsuccessful TAD attempts occurred in about 10% of cohorts.
  • Adjuvant Treatment: Adjuvant systemic treatment was guided by pathological staging and tumor biology. Adjuvant radiotherapy was common, with nodal field irradiation given to a substantial proportion of patients despite nodal pCR, although some centers spared nodal irradiation in patients with negative SLNs.
  • Oncological Outcomes:
    • Axillary Recurrence (AR): The pooled estimate of AR was 2.1% (95% CI 1.4–3.2%) for patients with negative SLNB alone, and 1.5% (95% CI 0.5–4.1%) for those with negative MARI/TAD. There was no statistically significant difference in axillary failure rate between SLNB and MARI/TAD. When comparing SLNB to ALND in patients with nodal pCR after NST, no significant benefit of ALND was found.
    • Survival Outcomes (for negative SLNB-alone): The pooled estimate of 5-year Disease-Free Survival (DFS) was 0.87 (95% CI 0.83–0.90). The pooled estimate of 5-year Distant Disease-Free Survival (DDFS) was 0.90 (95% CI 0.88–0.92). The pooled estimate of 5-year Overall Survival (OS) was 0.92 (95% CI 0.88–0.94). Sensitivity analyses showed high consistency in these meta-estimations.

Broader Context and Supporting Evidence for De-escalation

The findings from the meta-analysis by Man et al. strongly support the oncological safety of de-escalating axillary surgery in patients achieving nodal pCR after NST. This aligns with a growing consensus in the field to minimize surgical morbidity without compromising cancer control.

  • Evolution of Axillary Management and Rationale for De-escalation: The transition from radical mastectomy to less invasive procedures like SLNB began decades ago, driven by the understanding that breast cancer is a systemic disease and that extensive axillary surgery carries significant morbidity (e.g., lymphedema, nerve damage, chronic pain). Neoadjuvant therapy, especially for triple-negative or HER2-positive breast cancers, has become integral to downstage disease in both the breast and axilla, paving the way for de-escalation. Pathological complete response (pCR) in the axilla is a key indicator for considering omission of ALND.
  • Accuracy and False Negative Rates (FNR) of SLNB after NST: Concerns about the FNR of SLNB after NST have been a practical issue for clinicians. Studies like ACOSOG Z1071 reported an FNR of 12.6%, and SENTINA reported 14.2%, which exceeded the predefined acceptability threshold of 10%. However, stricter adherence to protocols, including dual tracer mapping, retrieving at least three sentinel lymph nodes (SLNs), and excising the clipped node, can lower the FNR to below 10%. Importantly, recent meta-analyses and long-term studies, including the one by Man et al., indicate that despite these procedural FNRs, favorable long-term survival outcomes are achieved, suggesting minimal clinical prognostic significance of FNR in this context.
  • Different De-escalation Strategies (SLNB, MARI, TAD): The systematic review confirms that SLNB and MARI/TAD achieve comparable and extremely low axillary recurrence rates.
    • SLNB: Continues to be a primary method for de-escalation in patients with nodal pCR.
    • MARI (Marked Axillary Lymph Node Excision): Involves implanting an I-125 seed into a cytology-proven axillary lymph node before NST.
    • TAD (Targeted Axillary Dissection): Combines SLNB with excision of the clipped biopsy-proven node, which has been shown to reduce the FNR further. The optimal number of nodes to excise and the best surgical technique remain debated. However, the observed low axillary recurrence rates across these methods suggest their safety. The ongoing international, prospective, multicenter AXSANA study aims to address remaining uncertainties and optimize treatment outcomes by comparing various surgical techniques.
  • Role of Adjuvant Radiotherapy: Despite low axillary recurrence rates with de-escalated surgery, the role of adjuvant locoregional irradiation is complex. Studies like ACOSOG Z0011 and AMAROS have shown low axillary recurrence rates even in patients with some residual nodal disease, suggesting the therapeutic importance of adjuvant radiotherapy and systemic treatment. Some centers routinely administer nodal field irradiation, while others have observed zero axillary recurrence with whole breast irradiation alone. The Phase III randomized clinical trial NSABP B-51/RTOG 1304 (NCT01872975) is expected to provide clearer guidelines on the necessity of adjuvant nodal field irradiation in post-NST patients with nodal pCR. The AMAROS trial notably found that axillary radiotherapy was comparable to ALND in preventing axillary recurrence, with significantly lower rates of lymphedema in the radiotherapy group.
  • Patient Selection and Predictive Factors: Standardizing patient selection for axillary surgical de-escalation is crucial but challenging due to variations in staging and definitions of nodal status after NST. Pre-chemotherapy N2 breast cancers were a small percentage in previous studies. A recent study highlighted several factors that could predict a pathological complete nodal response in HER2-positive breast cancer patients:
    • Strong HER2 positivity (HER2+ 3 vs. HER2+ 2).
    • Dual anti-HER2 therapy (e.g., trastuzumab + pertuzumab).
    • Clinically negative lymph node status both before and after NST as assessed by imaging.
    • Complete clinical response of the primary tumor to NST.
    • Patients with T1 primary tumors before NAT consistently showed negative LNs after NAT. These findings suggest that, for selected HER2+ patients, axillary staging could potentially be omitted, though further multicenter trials are needed to confirm this.

Limitations

The primary meta-analysis acknowledges several limitations, predominantly the retrospective nature of most included studies, which introduces inherent selection bias and heterogeneity in patient populations, pre-NST nodal positivity definitions, post-NST nodal conversion, and adjuvant radiotherapy protocols. The low incidence of axillary recurrence makes it challenging to definitively determine if these heterogeneities significantly impact oncological outcomes. Furthermore, survival data calculated based on odds ratios at specific time points might potentially overestimate treatment effect. MARI and TAD are relatively newer techniques, meaning long-term survival data are still emerging. Single-institution studies also limit the generalizability of findings to diverse clinical settings.

Conclusion

This comprehensive synthesis underscores that for breast cancer patients who achieve a pathological complete response in the axilla after neoadjuvant systemic treatment, de-escalation of axillary surgery to SLNB or MARI/TAD is oncologically safe and associated with extremely low axillary recurrence rates. The observed excellent 5-year DFS, DDFS, and OS rates for patients undergoing de-escalated axillary surgery strongly support this less invasive approach. While the debate continues regarding the optimal technique and the necessity of adjuvant radiotherapy, current evidence points towards reducing surgical morbidity without compromising effective cancer control. Continued long-term oncological data, particularly for newer procedures, and further standardization of pre-chemotherapy and pre-operative workup are crucial to refine optimal axillary treatment strategies and ensure personalized care for breast cancer patients.

Historically, breast cancer treatment, including axillary management, was based on the Halstedian concept that cancer spread locally via the lymphatic system. This led to extensive surgical procedures like radical mastectomy, which involved the removal of the breast, chest wall muscles, and all axillary contents, resulting in significant patient disfigurement and morbidity such as lymphedema, nerve damage, reduced shoulder and arm mobility, and chronic pain.

However, the understanding that breast cancer is a systemic disease, rather than purely locoregional, spurred a movement toward less invasive interventions. Seminal trials demonstrated that de-escalation of extensive axillary surgery was safe and did not compromise oncological outcomes:

  • The NSABP B-04 trial, initiated in 1971, compared radical mastectomy, total mastectomy with regional irradiation, and total mastectomy alone. It found no statistically significant difference in overall or disease-free survival (DFS), even in women with clinically node-positive axillary lymph nodes.
  • The Milan I trial further supported this trend by demonstrating that more conservative treatments (quadrantectomy and axillary dissection with radiation therapy) were comparable to radical mastectomies for clinically node-negative breast cancer.
  • The introduction of sentinel lymph node biopsy (SLNB) marked a fundamental shift, allowing for the assessment of axillary status without removing the entire axillary basin, thereby significantly reducing morbidity. The NSABP B-32 trial confirmed that SLNB alone was comparable to axillary lymph node dissection (ALND) for clinically node-negative patients, with no difference in survival, DFS, or regional control, but significantly lower complication rates for SLNB alone.

Further de-escalation was supported by several pivotal trials focusing on patients with low-volume nodal disease:

  • The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial was crucial, showing that ALND could be safely omitted in patients with clinical T1–2N0M0 breast cancer undergoing lumpectomy and whole-breast irradiation who had one or two metastatic sentinel lymph nodes. This study found no significant differences in overall survival (OS) or DFS between SLNB alone and SLNB with ALND groups, but ALND was associated with higher rates of complications like lymphedema, wound infections, pain, and numbness.
  • The IBCSG 23-01 trial specifically focused on patients with micrometastases in the sentinel nodes and concluded that ALND could be safely omitted without affecting DFS.
  • The AMAROS trial (EORTC 10981-22023) demonstrated that axillary radiotherapy (RT) was comparable to ALND in preventing axillary recurrence for clinically node-negative patients with positive sentinel nodes, with significantly lower rates of arm lymphedema in the radiotherapy group. The OTOASOR trial confirmed similar results.
  • The SINODAR-ONE multicenter randomized clinical trial extended the potential omission of ALND to patients undergoing mastectomy for T1-2 breast cancer with one or two macrometastatic sentinel lymph nodes, finding non-inferior 3-year survival and relapse rates for SLNB alone with adjuvant therapy compared to ALND.

Collectively, these studies provided strong evidence that ALND is not required for clinically node-negative T1/T2 disease with up to two positive nodes (macrometastatic or micrometastatic disease), especially after breast-conserving surgery. For mastectomy patients meeting these criteria, if ALND is omitted, RT to the undissected axilla at risk is recommended.

Current De-Escalation Strategies in Upfront Surgery

For patients with clinically node-negative lymph nodes and up to two positive sentinel nodes, avoiding ALND is considered a safe option. Further de-escalation has led to trials investigating the omission of any axillary surgery in highly selected subgroups of patients with early-stage breast cancer.

  • The SOUND trial demonstrated that patients with small breast cancers (up to 2 cm) and negative preoperative axillary ultrasonography could safely omit SLNB, achieving comparable 5-year distant disease-free survival outcomes to those who underwent SLNB.
  • The INSEMA trial, which included cT1-2N0 patients, showed that a less extensive axillary surgery achieved non-inferior 5-year invasive disease-free survival outcomes compared to standard treatment.
  • Ongoing trials like BOOG 13-08, SOAPET, and NAUTILUS continue to explore the safety of omitting SLNB in clinically node-negative patients.
  • For elderly patients (≥65 years) with ER+/HER2- breast cancer, omission of SLNB has also shown extremely low rates of axillary recurrence in prospective data. This strategy relies heavily on correct preoperative patient selection and accurate use of imaging modalities to assess axillary lymph nodes for disease presence.

Axillary Management in the Neoadjuvant Setting

Neoadjuvant systemic treatment (NST) has become increasingly common, particularly for HER2-positive and triple-negative breast cancers. A main purpose of NST is to downstage the disease burden in both the breast and axillary lymph nodes, which can allow for less extensive surgery. Patients initially presenting with node-positive (cN+) disease who achieve a pathological complete response (pCR) in the axilla after NST are key candidates for de-escalation.

Initial concerns about the accuracy of SLNB after NST stemmed from studies reporting higher false-negative rates (FNRs) than typically acceptable (<10%):

  • The ACOSOG Z1071 trial found an FNR of 12.6% for SLNB after chemotherapy in initially node-positive patients. However, this rate was lower with dual tracer mapping (10.8%), retrieval of ≥3 sentinel lymph nodes (9%), and excision of the clipped node (6.8%).
  • The SENTINA trial similarly reported an FNR of 14.2%.
  • The SN FNAC study achieved a lower FNR of 8.4% through stricter protocol adherence, including mandatory immunohistochemistry.

These findings led to advocating technical optimization for SLNB after NST, such as dual tracer mapping and retrieval of ≥3 sentinel lymph nodes, to lower the FNR to below 10%. The MARI procedure (Marked Axillary Lymph Node Excision), involving the implantation of an I-125 seed into a biopsy-proven positive lymph node before NST, and Targeted Axillary Dissection (TAD), which combines SLNB with excision of the clipped biopsy-proven node, have been introduced to further reduce FNR.

Despite initial FNR concerns, recent meta-analyses and long-term studies, including the systematic review and meta-analysis by Man et al., indicate that de-escalation of axillary surgery is oncologically safe in patients achieving nodal pCR after NST. The Man et al. meta-analysis, encompassing 14 studies and 4,268 patients, reported an extremely low pooled estimate of axillary recurrence (2.1% for SLNB alone and 1.5% for MARI/TAD), with no statistically significant difference between SLNB and MARI/TAD. Pooled 5-year DFS, DDFS, and OS rates for SLNB alone were 0.87, 0.90, and 0.92, respectively, indicating excellent survival outcomes. Comparisons between SLNB and ALND in patients with nodal pCR after NST also showed no significant benefit of ALND.

The role of axillary surgery in HER2-positive breast cancer patients who achieve a good response to NST has been a specific area of interest. A study by Hamdy et al. found that a pathological complete axillary response was achieved in 79.1% of patients after NST with anti-HER2 therapy. This study identified several factors that could independently predict a complete nodal response, potentially allowing for the omission of axillary staging:

  • Clinically negative lymph node status before NST.
  • Clinically and radiologically negative lymph node status after NST.
  • Complete clinical response of the primary tumor to NST.
  • Strong HER2 positivity (HER2+ 3).
  • Dual anti-HER2 therapy (e.g., trastuzumab + pertuzumab).
  • All T1 primary tumors before NAT showed negative LNs after NAT.

Ongoing international trials aim to further define optimal axillary management after NST:

  • Alliance A011202 is a Phase III randomized trial comparing ALND to axillary RT in cT1-3N1 breast cancer patients with positive SLNB after NAC.
  • The NSABP B-51/RTOG 1304 trial assesses whether regional nodal irradiation (RNI) is necessary for patients who become pathologically node-negative (ypN0) after NAC.
  • The AXSANA study seeks to determine best practices by comparing various surgical techniques to optimize outcomes and reduce morbidity.

The Role of Adjuvant Radiotherapy

Adjuvant locoregional irradiation remains a complex aspect of breast cancer management, even with de-escalated surgery.

  • Pivotal trials like MA-20 and EORTC 22922 have shown that RNI can provide modest but statistically significant benefits in reducing locoregional events, improving distant outcomes, and breast cancer mortality in selected high-risk node-negative patients.
  • For patients with positive sentinel nodes not fitting the ACOSOG Z0011 criteria, the AMAROS and OTOASOR trials suggest that axillary RT can be a comparable therapeutic approach to dissection in patients with up to two positive sentinel nodes, with reduced lymphedema.
  • Debates continue regarding the routine inclusion of internal mammary nodes in RNI due to potential cardiac and lung toxicity, though it may be considered for centrally or medially located tumors where the risk of involvement is higher.
  • De-escalation of RT is also being explored. The RAPCHEM study is evaluating the feasibility of reducing or omitting RT after a favorable response to primary systemic therapy (PST).
  • The NSABP B-51/RTOG 1304 trial (NCT01872975) is expected to provide clearer guidelines on the necessity of adjuvant nodal field irradiation in post-NST patients with nodal pCR.
  • The SUPREMO trial (presented at SABCS 2024) indicates that post-mastectomy RT (PMRT) can be safely omitted in some pN1 patients, particularly those with favorable characteristics.
  • The TAILOR RT trial (CCTG MA.39) is a randomized, non-inferiority phase III trial investigating whether regional RT can be omitted in low-risk ER+/HER2- breast cancer patients (Oncotype Dx Recurrence Score ≤25).

Integration of RT with Modern Systemic Therapies

The advent of novel systemic therapies, including immune checkpoint inhibitors (ICIs), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, and antibody-drug conjugates (ADCs), has revolutionized breast cancer treatment. However, their optimal timing, combination, and sequencing with RT present challenges.

  • For triple-negative breast cancer (TNBC), studies like KEYNOTE-522 show improved outcomes with the addition of ICI pembrolizumab to chemotherapy, and it appears safe with concurrent or sequential postoperative RT.
  • For HER2-positive breast cancer, regimens combining trastuzumab and pertuzumab with chemotherapy are highly effective. Adjuvant trastuzumab emtansine (T-DM1) is recommended for residual disease, and combining pertuzumab and trastuzumab with RT is generally safe.
  • In high-risk hormone receptor-positive HER2-negative breast cancer, CDK4/6 inhibitors (e.g., palbociclib, ribociclib, abemaciclib) have significantly transformed systemic therapy. However, current recommendations advise withholding CDK4/6 inhibitors during RT in early-stage disease due to potential hematologic toxicities and preclinical data suggesting enhanced radiosensitivity.

Systemic Treatment De-Escalation through Biomarkers

Beyond locoregional treatment, de-escalation of systemic therapy is also a significant area, particularly for hormone receptor-positive/HER2-negative early breast cancer.

  • Gene Expression Assays (GEAs), such as Oncotype DX and MammaPrint, have been validated to guide chemotherapy decisions in patients with zero to three involved lymph nodes.
    • The TAILORx trial (for N0 patients with Oncotype DX Recurrence Score (RS) 11-25) demonstrated that postmenopausal patients could safely avoid chemotherapy with any RS below 25. For premenopausal patients with RS 16-25, chemotherapy might offer benefit.
    • The MINDACT trial (for N0-1 patients with discordant clinical and genomic risk) showed the possibility of identifying patients who could safely forgo chemotherapy despite high clinical risk features.
    • The RxPonder trial (for N1 patients) indicated that postmenopausal women with Oncotype DX RS below 25 did not significantly benefit from adding chemotherapy to endocrine therapy, whereas premenopausal patients showed a notable benefit.
  • Endocrine Response Assessment, particularly dynamic Ki67 determination after short preoperative induction endocrine therapy, is also used.
    • The POETIC trial showed that a Ki67 decrease after induction endocrine therapy was associated with favorable outcomes in postmenopausal patients.
    • The WSG ADAPT trial demonstrated that combining Oncotype DX RS with endocrine response (Ki67 ≤10%) could spare chemotherapy for more than half of patients with up to three involved lymph nodes, especially premenopausal patients.

Conclusion

The continuous evolution in breast cancer management reflects a strong commitment to reducing treatment burden and morbidity while upholding oncological safety. This synthesis highlights the significant progress in de-escalating axillary surgery, the nuanced role of adjuvant radiotherapy, and the emerging strategies for de-escalating systemic therapy through advanced biomarker utilization.

For patients who achieve a pathological complete response in the axilla after neoadjuvant systemic treatment, de-escalation of axillary surgery to SLNB or Targeted Axillary Dissection (TAD) is oncologically safe and associated with extremely low axillary recurrence rates and excellent survival outcomes. While historical concerns about false-negative rates of SLNB after NST existed, adherence to optimized surgical techniques and supportive long-term data have minimized their clinical significance.

The integration of radiotherapy remains critical, with ongoing research refining its necessity and optimal fields, particularly concerning regional nodal irradiation. The development of new systemic agents necessitates careful consideration of timing and potential toxicities when combined with RT, with guidelines continuously evolving to ensure safety and efficacy.

Ultimately, the appropriate treatment for each breast cancer patient remains a complex decision that must be made by multidisciplinary teams with expertise in personalized breast cancer care, guided by the latest evidence from prospective clinical trials. The future will likely see further de-escalation in all treatment modalities, with traditional aggressive approaches reserved for fewer, highly selected patients.

Surgical De-Escalation: Axillary Management

Historically, breast cancer surgery, particularly axillary surgery, was based on the Halstedian concept of extensive resection, leading to significant patient morbidity. However, modern understanding recognizes breast cancer biology as the primary driver of recurrence, prompting a move towards less invasive surgical techniques.

Sentinel Lymph Node Biopsy (SLNB) as Standard of Care From the radical mastectomy to breast-conserving surgery, the trend has been to reduce invasiveness while maintaining oncologic safety. SLNB has replaced systematic axillary lymphadenectomy (ALND) as the standard of care for women with early-stage breast cancer who have clinically node-negative disease. This change was largely influenced by pivotal trials such as:

  • NSABP B-32 (2010): Compared SLNB + ALND versus SLNB alone in clinically node-negative (cT1-T3N0) patients, finding no difference in overall survival (OS), disease-free survival (DFS), or axillary recurrence, but higher rates of complications (nerve palsies, neuropathies, lymphedema) with ALND.
  • ACOSOG Z0011 (2012): Randomized early-stage breast cancer patients (cT1/T2) undergoing breast-conserving therapy (BCT) with one or two metastatic sentinel lymph nodes to either SLNB alone or SLNB with ALND. It found no statistically significant differences in local recurrence, DFS, or OS, but ALND was associated with higher rates of complications like lymphedema (23% vs. 5%), wound infections, and increased pain/numbness. This trial demonstrated that SLNB alone was sufficient for controlling low-volume disease.
  • AMAROS Trial (2014): Randomized women with early-stage breast cancer and a positive SLNB to receive either ALND or axillary RT. It found no difference in survival outcomes and confirmed that ALND is associated with higher rates of complications.
  • IBCSG 23-01 Trial (2013): Focused on patients with low-volume micrometastatic disease (greater than 0.2 mm but no more than 2 mm) in the sentinel node. It compared patients with and without axillary dissection and found no statistically significant difference in 10-year DFS rate (76.8% in no axillary dissection vs. 74.9% in axillary dissection). These studies have led to significant reductions in ALNDs performed for EBC.

Omission of Axillary Surgery (SLNB) Further de-escalation has questioned the necessity of any axillary surgery in highly selected patient subgroups, especially given the advent of novel systemic therapies and effective radiation therapies.

  • SOUND Trial (2023): Demonstrated that patients with small breast cancers (up to 2 cm) and negative axillary ultrasonography could safely omit SLNB, achieving comparable 5-year distant disease-free survival (DDFS) with those who underwent SLNB. These patients underwent breast-conserving surgery and radiation, randomized to either SLNB or no axillary staging.
  • INSEMA Trial (2025): Included over 5,000 cT1–2N0 patients who were scheduled for breast-conserving surgery followed by radiotherapy. This non-inferiority trial showed no significant difference in invasive disease-free survival (iDFS) between patients who underwent SLNB and those who did not, reinforcing the de-escalation approach in well-selected populations.

These trials underscore the importance of accurate preoperative imaging and stringent patient selection criteria to safely omit axillary surgery without compromising oncologic outcomes, though the majority of patients in these studies had hormone receptor–positive disease.

Axillary Surgery in the Neoadjuvant Setting For patients who are initially clinically node-positive but convert to node-negative after neoadjuvant systemic therapy (NST), axillary management is rapidly evolving. Performing SLNB after neoadjuvant chemotherapy (NAC) can help patients avoid the morbidity of ALND, but maintaining a low false-negative rate (FNR) with SLNB is crucial for appropriate adjuvant therapy decisions.

  • Alliance ACOSOG Z1071 Trial (2013): This trial showed an FNR of 12.6% for SLNB after NAC in initially node-positive patients, exceeding the predefined acceptable threshold. However, the FNR was lowered to below 10% with the use of dual tracer mapping, retrieval of at least three sentinel lymph nodes (SLNs), and removal of the clipped node (the node biopsied and marked before systemic therapy).
  • SENTINA Trial (2013): Similarly reported an FNR of 14.2% for SLNB after NAC.
  • SN FNAC Trial (2015): Demonstrated a lower FNR of 8.4%, attributing this improvement to stricter protocol adherence, including mandatory immunohistochemistry and evaluation of nodal response by size.

These findings support a tailored approach to axillary surgery after NAC, balancing oncologic safety with morbidity reduction. Current long-term data on SLNB after NAC are still limited, but early results suggest no negative impact on OS or DFS. The ongoing Alliance A11202 trial is evaluating the safety of omitting ALND in patients with minimal residual nodal disease after NAC, which could further reduce the extent of axillary surgery if regional nodal irradiation (RNI) alone proves effective in controlling axillary recurrences.

Radiotherapy De-Escalation

The role of RT in conjunction with primary systemic therapy (PST) is a subject of ongoing debate, particularly concerning strategies for de-escalating postoperative RT.

De-escalation of Postoperative RT Studies suggest minimizing RT when systemic therapy has achieved excellent tumor control, aligning with individualized, risk-adapted treatment approaches.

  • RAPCHEM Trial (2022): A Dutch prospective registry study for cT1-2N1 patients, found that 5-year locoregional recurrence (LRR) rates were less than 4% in all risk groups, with even lower rates when guidelines were adhered to. This supports safe RT de-escalation in selected patients with ALND, stratified by pathologically node-negative (ypN) status.
  • NRG Oncology/NSABP B-51/RTOG 1304 Trial (2025): A phase III randomized trial, showed no statistically significant difference in invasive breast cancer recurrence-free interval (IBCRFI) between groups receiving RT versus no RT in patients with biopsy-proven cN1 disease who became ypN0 after PST. This suggests that RT may be safely omitted in ypN0 patients post-PST and requires individualized evaluation.

Challenges and Controversies Despite these findings, the EBCTCG meta-analysis suggests that even lower-risk patients can benefit from postmastectomy RT (PMRT) and RNI. The recently presented SUPREMO trial (2024 SABCS) indicates that PMRT can be safely omitted in some pN1 patients with favorable characteristics, but these findings must be balanced against the broader evidence, as evolving surgical standards might lead to undertreatment if RT is universally omitted. The challenge remains in defining appropriate RT volumes, including PMRT, RNI, or internal mammary node irradiation, especially as biomarker-driven tools in RT are still limited. Future trials should integrate all modalities (surgery, systemic therapy, RT) to avoid overlapping reductions in treatment intensity that could lead to undertreatment.

Integrating RT with Modern Systemic Therapies The integration of RT with novel systemic therapies (e.g., immune checkpoint inhibitors, CDK4/6 inhibitors, antibody-drug conjugates) presents opportunities for enhanced efficacy but also challenges regarding increased toxicity.

  • Immune Checkpoint Inhibitors (ICIs) like Pembrolizumab: The KEYNOTE-522 trial showed that pembrolizumab plus chemotherapy improved pCR rates and event-free survival in triple-negative breast cancer (TNBC). Post-hoc analysis suggested EFS benefit with concurrent or sequential postoperative RT and pembrolizumab, generally well tolerated.
  • Chemotherapy (Capecitabine): While adjuvant capecitabine improves outcomes in residual TNBC, prospective data on its combination with RT are lacking, and existing evidence on toxicity is inconclusive, urging cautious use.
  • PARP Inhibitors (Olaparib): Reduce recurrence in germline BRCA1/2 mutations with residual disease. However, their radiosensitizing properties may increase normal tissue toxicity, and current guidelines recommend their use with RT be confined to clinical trials.
  • HER2-Targeted Therapies (Trastuzumab, Pertuzumab, T-DM1):
    • Combinations like trastuzumab and pertuzumab with chemotherapy are highly efficacious. The APHINITY trial confirmed the safety of combining pertuzumab and trastuzumab in the adjuvant setting, even concurrently with RT, with no increased cardiac toxicity.
    • T-DM1 (trastuzumab emtansine) for residual disease after PST generally has a good safety profile with RT, though slightly higher rates of pneumonitis and skin toxicity have been reported compared to trastuzumab.
  • CDK4/6 Inhibitors (Palbociclib, Ribociclib, Abemaciclib): Enhance radiosensitivity in preclinical data. However, pivotal adjuvant trials did not permit concomitant RT, and retrospective studies highlighted potential hematologic toxicities. As a result, current recommendations advise withholding CDK4/6 inhibitors during RT in early-stage disease.

Careful sequencing and timing are critical to ensuring safety and efficacy when integrating RT with modern systemic therapies. High-quality data collection on RT administration in clinical trials is crucial for reliable interpretation.

Systemic Treatment De-Escalation

Systemic therapy de-escalation often relies on biomarkers, particularly in hormone receptor–positive/HER2– EBC where chemotherapy (CTx) may be unnecessarily overtreatment for many.

Gene Expression Assays (GEAs) GEAs, like Oncotype DX and MammaPrint, assess gene expression to predict recurrence risk and guide CTx decisions, particularly in patients with zero to three involved lymph nodes.

  • TAILORx Trial (2018): For node-negative (N0) patients with intermediate Oncotype DX Recurrence Score (RS) of 11-25, it showed that postmenopausal patients (over 50 years) could safely avoid CTx. For premenopausal patients (50 or younger), CTx may benefit those with RS 16-25. Longer follow-up confirmed non-inferiority of endocrine therapy (ET) alone.
  • MINDACT Trial (2021): For N0-1 patients with discordant risk assessments (traditional vs. genomic), it demonstrated the possibility to identify patients who could safely forgo CTx despite high clinical risk features.
  • RxPonder Trial (2021): For node-positive (N1, one to three involved lymph nodes) patients, it showed that adding CTx to ET did not significantly improve iDFS in postmenopausal women with Oncotype DX RS below 25, whereas premenopausal patients had a notable benefit.
  • ADAPT Trial (2022): Validated Oncotype DX’s utility by correlating RS with dynamic changes in tumor proliferation after short-term presurgical ET. It showed that combining Oncotype DX scores with post-endocrine Ki67 response improved risk stratification and identified additional patients who could safely avoid CTx, especially premenopausal patients.

Second-generation GEAs like PROSIGNA and ENDOPREDICT have also been validated to predict distant recurrence and guide decisions on extended adjuvant treatment.

Endocrine Response Assessment (Ki67) Dynamic Ki67 assessment after short preoperative induction ET is gaining importance.

  • POETIC Trial (2020): Showed that a Ki67 decrease after induction ET is associated with favorable outcomes in postmenopausal hormone receptor–positive EBC patients, even without adjuvant CTx. Patients whose Ki67 did not drop below 10% had a significantly higher risk of recurrence.
  • WSG ADAPT Hormone Receptor–Positive/HER2– Trial (2022): Demonstrated that endocrine response assessment by dynamic Ki67 testing is feasible in clinical routine and, when combined with RS, can spare CTx for more than half of patients with up to three involved lymph nodes. Patients with low RS and a favorable endocrine response (Ki67 ≤10%) could safely avoid CTx, irrespective of age or menopausal status.
  • WSG-ADAPTcycle Trial: Building on ADAPT, this trial evaluates if CDK4/6 inhibitors + ET can replace CTx + ET in intermediate-high clinical risk hormone receptor–positive HER2– EBC selected by tumor burden, Oncotype DX, and endocrine response.

The combination of GEAs and endocrine response assessment provides powerful insights into tumor biology, allowing for more precise and individualized treatment decisions, potentially improving outcomes and reducing overtreatment. This approach also offers an inexpensive alternative to genomic testing in resource-constrained environments.

Clinical Implications and Future Directions

While de-escalation of axillary surgery and other treatments has significantly improved patients’ quality of life without sacrificing oncologic outcomes, gaps remain. The results of ongoing trials, such as Alliance 11202, are highly anticipated to further define axillary management and the role of RNI after PST.

Future directions emphasize integrating clinical, pathological, and molecular factors into a multifactorial framework, guided by prospective trials and multidisciplinary collaboration, to optimize outcomes while balancing efficacy and toxicity. Research into biomarkers for response and toxicity is crucial for more precise, individualized treatments. The ultimate goal of de-escalation—reducing treatment burden without compromising outcomes—must remain evidence-based and validated by prospective clinical trials.

Background and Evolution of Axillary Management

Historically, systematic axillary lymphadenectomy (ALND) was the standard of care for staging and treating breast cancer, based on the understanding that breast cancer spread primarily via the lymphatic system. However, from the 1990s, ALND has been progressively replaced by sentinel lymph node biopsy (SNB). SNB aimed to gain knowledge about the axillary lymph node status without removing the entire axillary basin, particularly in patients without axillary metastases. This shift was driven by the significant morbidity associated with ALND, including lymphedema, nerve damage, reduced shoulder and arm mobility, and chronic pain.

Further de-escalation efforts have challenged the necessity of performing SNB in all invasive breast cancers and the imperative to carry out ALND in all patients with SNB involvement. Recent advancements in understanding breast cancer biology and the advent of targeted therapies have paved the way for further de-escalation of axillary interventions, especially for patients with minimal or no nodal disease.

Neoadjuvant systemic treatments (NST), also known as NAT, have increasingly been utilized, particularly for triple-negative or HER2-positive breast cancer. One of the main purposes of NAT is to downstage the disease in both the breast and axillary lymph nodes, aiming to reduce the extent of subsequent surgery and enable more personalized treatment. A particular area of interest is patients who present with metastatic lymph nodes before NAT but achieve a node-negative status at the time of surgery, known as nodal pathological complete response (pCR). This exceptional response rate, especially in HER2-positive breast cancer with dual HER2 blockade, prompts the question of whether axillary surgery can be entirely omitted in selected subgroups.

Study Methodology

This was a retrospective cohort study conducted at the Oncology Center Mansoura University in Egypt, including patients diagnosed with HER2-positive breast cancer between March 2022 and September 2023. The study included female patients over 18 years old with histological and radiological proof of non-metastatic invasive HER2-positive breast cancer who received neoadjuvant chemotherapy combined with single or dual HER2 blockade. Patients with DCIS, metastatic disease at diagnosis, locally advanced (T4b+) breast cancer, or those unable to receive anti-HER2 therapy were excluded.

Data collected included patient demographics (age, BMI), imaging details (mammogram, MRI, breast density, tumor focality, size, site, BIRADS score, LN status pre-NAT, LN clipping), pathological information (pre-treatment LN biopsy, tumor type, hormonal receptor status, Ki67, HER2 score, luminal type, number of retrieved/positive LNs), NAT specifics (number of cycles, protocols, anti-HER2 type), tumor response (RCB, Miller–Payne, radiological and pathological LN response), surgery type (breast and LN), and adjuvant treatments.

Chemotherapy protocols typically involved combinations of anthracyclines and taxanes, with most patients receiving dual anti-HER2 blockade (trastuzumab + pertuzumab). Post-NAT, patients underwent re-evaluation with breast and axillary imaging before surgery. Surgical decisions for the breast involved breast-conserving surgery or mastectomy, while for the axilla, SNB or ALND was performed based on axillary response and surgeon’s decision. Statistical analyses, including chi-square tests, Fisher’s exact tests, Mann–Whitney U-tests, and binary logistic regression, were used to identify significant predictors and assess diagnostic accuracy.

Key Findings and Results

The study analyzed data from 139 patients. The median age was 50 years, and two-thirds of patients had HR+/HER2+ disease, while one-third had HR−/HER2+ disease. A large majority (92.8%) of patients initially presented with node-positive or suspicious disease, though only 18.7% had biopsy-confirmed nodal involvement.

Following NAT, 112 patients (80.6%) achieved clinically and radiologically negative axillary lymph nodes (cN0). This high rate of nodal response was further confirmed by pathological evaluation: 112 patients (80.6%) ultimately had pathologically node-negative disease (pCR). This implies a complete pathological axillary response in 79.1% of patients within the study cohort. In the study, all patients treated with SNB alone had node-negative disease pathologically, whereas the ALND group showed a mix of node-negative and node-positive cases.

The study identified several statistically significant factors that predicted a complete nodal response (pathologically negative axillary LNs) after NAT:

  • Degree of HER2 Positivity: HER2+ 3 tumors were significantly more likely to achieve nodal pCR compared to HER2+ 2 tumors (p=0.024).
  • Type of Anti-HER2 Therapy: Dual HER2 blockade (Trastuzumab + Pertuzumab) was significantly associated with a higher likelihood of nodal pCR (p=0.023).
  • Pre-NAT LN Status by Imaging: All patients who had radiologically negative LNs before NAT were found to be pathologically negative after NAT.
  • Post-NAT LN Status by Imaging: Critically, all 112 patients who showed clinically and radiologically negative axillary LNs after NAT were confirmed to have pathologically negative LNs. This demonstrated a 100% negative predictive value and accuracy for post-NAT radiological assessment in this cohort.
  • Primary Tumor Radiological Response: All patients whose primary tumor achieved a complete clinical response (cCR) also had nodal pCR (p<0.001).
  • Degree of Pathological Tumor Response: All patients with a residual cancer burden (RCB) of 0 or Miller–Payne Grade 5 in the primary tumor also had nodal pCR.
  • While not statistically significant, all T1 primary tumors before NAT showed negative LNs after NAT.

In multivariate analysis, HER2 score and the type of target therapy (dual vs. single blockade) were significant independent predictors of pathologically negative axillary LNs. Patients with HER2+ 3 tumors and those who received dual anti-HER2 blockade had 5.1 and 14.4 times higher odds, respectively, of exhibiting pathologically negative axillary LNs.

Discussion and Implications for Clinical Practice

The remarkably high rates of pathological complete axillary response (79.1%) observed in this HER2-positive cohort underscore the potential for further de-escalation of axillary surgery. The study’s findings suggest that specific patient subgroups can be identified who might safely avoid axillary surgical staging due to their excellent response to NAT.

The absolute correlation between clinically/radiologically negative axillary LNs post-NAT and pathologically negative LNs is a significant finding of this study, potentially being the first to report such a high predictive value. This suggests that for HER2-positive patients achieving clinical nodal negativity after NAT, imaging alone might be sufficient to confirm axillary pCR, potentially avoiding SNB altogether. The consistent finding that all patients with a complete clinical response in the primary tumor also achieved nodal pCR further reinforces this concept, aligning with previous research indicating that nodal positivity is exceedingly rare in such cases.

The study’s results are consistent with the established literature regarding the effectiveness of dual anti-HER2 blockade in achieving pCR. The observation that HER2+ 3 tumors are more likely to achieve axillary pCR than HER2+ 2 tumors also aligns with prior studies.

While the study’s findings are promising, it acknowledges several limitations inherent to its retrospective design, such as potential selection bias and heterogeneity in chemotherapy protocols, the number of anti-HER2 cycles received, and the variability in axillary staging procedures among surgeons. However, its strengths include the use of prospectively maintained data, a reasonable sample size, and the reflection of real-world clinical practice.

Conclusion

In conclusion, this study strongly suggests that axillary staging may be omitted in HER2-positive breast cancer patients who demonstrate clinically node-negative disease after neoadjuvant chemotherapy combined with dual anti-HER2 therapy. This holds particularly true for patients with:

  • Early tumors (e.g., cT1-2N0).
  • Strong HER2+ disease (HER2+ 3 expression).
  • Clinically negative lymph nodes before NAT.
  • Primary tumors that achieve a complete clinical response.

The study proposes that, at a minimum, patients with cT1-2N0 tumors and breast cCR are strong candidates for the omission of axillary staging. These findings advocate for a highly personalized approach to axillary management, aiming to reduce surgical morbidity while maintaining excellent oncological control. Nevertheless, the authors emphasize the critical need for further multicenter, prospective, randomized controlled trials to validate these findings and evaluate nodal recurrence rates in these carefully selected patient populations when axillary staging is omitted.

Background and the Evolution of Axillary Management

Historically, the management of the axilla in breast cancer patients involved systematic axillary lymph node dissection (ALND), considered the standard for both staging and treatment. This approach, rooted in the Halstedian concept of cancer spread, often resulted in significant morbidity for patients. From the 1990s, sentinel lymph node biopsy (SNB) progressively replaced ALND as the standard of care for patients with clinically node-negative (cN0) early breast cancer. SNB offered equivalent staging information but with significantly reduced arm morbidity, such as lymphedema, nerve damage, and chronic pain.

Further de-escalation efforts questioned the necessity of SNB in all invasive breast cancers and the mandatory performance of ALND in all patients with SNB involvement. Advances in understanding breast cancer biology and the advent of targeted therapies paved the way for further de-escalation, especially for patients with minimal or no nodal disease. Neoadjuvant systemic treatments (NST), or NAT, have gained an expanding role, particularly for triple-negative and HER2-positive breast cancer. One of the primary aims of NAT is to downstage disease burden in both the breast and axillary lymph nodes, thereby reducing the extent of subsequent surgery and enabling more personalized treatment based on tumor characteristics and response. Of particular interest are patients who present with metastatic lymph nodes before NAT but achieve a node-negative status at the time of surgery, known as nodal pathological complete response (pCR). This high rate of nodal response, especially in HER2-positive breast cancer with dual HER2 blockade, prompted the question of whether axillary surgery could be entirely omitted in selected subgroups.

Despite the benefits of NAT in downstaging, the role of SNB and its oncological outcomes in clinically node-positive (cN+) patients before NAT continued to be debated. Earlier studies reported unacceptably high false-negative rates (FNRs) for SNB after NAT in cN+ patients, often exceeding 10%. For example, the ACOSOG Z1071 trial reported an FNR of 12.6%, and the SENTINA trial showed FNRs from 18.5% to 24.3% depending on the number of sentinel nodes removed. Meta-analyses also pooled FNRs around 15.1% to 17%. These concerns led to the introduction of techniques like targeted axillary dissection (TAD) – which involves marking positive nodes before NAT with a clip and removing them along with sentinel nodes – to reduce FNR. However, the correlation between procedural FNR and long-term survival outcomes was not always well established.

Study Objectives

The “De-Escalation of Axillary Surgery in Clinically Node-Positive Breast Cancer Patients Treated with Neoadjuvant Therapy” study aimed to evaluate the characteristics and long-term outcomes of axillary node-positive breast cancer patients treated with NAT. Specifically, it sought to compare the oncological outcomes between two distinct surgical approaches—ALND versus SNB—in patients who converted from cN+ to clinically node-negative (ycN0) post-NAT, and to identify prognostic factors influencing recurrence and survival in this patient population.

Methodology

This was a retrospective analysis of all consecutive cN+ breast cancer patients treated with NAT at the Breast Unit of IRCCS Humanitas Research Hospital in Milan, Italy, from January 2009 to December 2021.

  • Patient Selection and Pre-Operative Assessment: Patients were defined as cN+ based on positive core needle biopsy and/or palpable axillary lymph nodes prior to NAT, and positive findings on axillary ultrasound (US), MRI, or PET scans. After NAT, nodal response was reassessed by physical examination and imaging (US, MRI, or PET if previously used).
  • Surgical Procedures: The study included 322 cN+ patients who achieved ycN0 status after NAT and underwent either breast-conserving surgery or mastectomy. For axillary management, patients were subjected to either ALND or SNB. A transition occurred between late 2017 and early 2018 where single tracer SNB became the standard method for axillary staging in cN+ BC patients who converted to ycN0, replacing the prior predominant direct ALND approach. For SNB, lymphatic mapping used a single tracer radioisotope, and TAD was not employed. At least one sentinel lymph node (SLN) was identified, excised, and subjected to intra-operative frozen section pathological examination. If the SLN was found to contain residual disease during intra-operative assessment, complete axillary dissection was performed. Pathologic complete response (pCR) was defined as no invasive or non-invasive residual tumor in both breast and axillary nodes (ypT0 N0).
  • Exclusion Criteria: Patients undergoing upfront surgery, those with detectable metastases (cM+), cN0 patients receiving NAT, patients remaining ycN+ post-NAT, those with disease progression during NAT, patients with a history of other malignancies, and those with a follow-up period of less than 32 months were excluded.
  • Statistical Analysis: The study utilized chi-square tests for categorical variables and multivariate logistic regression to analyze differences in patient characteristics between groups. Recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were calculated using the Kaplan–Meier method and compared using the log-rank test. Multivariate Cox regression analysis identified independent risk factors. The median follow-up period was 75 months.

Key Findings and Results

The study analyzed data from 322 cN+ BC patients who achieved ycN0 after NAT.

  • Patient Characteristics (SLNB vs. ALND Groups):
    • No significant differences were observed between the direct ALND and SNB groups concerning age, menopausal status, pre-operative tumor size, presence of a single nodule, or clinical stage before NAT.
    • Significant differences were noted in:
      • Type of breast surgery: The ALND group was more likely to undergo mastectomy (69.3% vs. 37.1% in SNB group; p < 0.0001).
      • Tumor subtype: The direct ALND group had a higher proportion of luminal-like tumors (42.3% vs. 27.0% in SNB group; p = 0.014).
      • Post-NAT tumor size: Larger residual tumors were more common in the direct ALND group (p = 0.010).
      • Post-NAT axillary stage: The SNB group had a significantly higher rate of ypN0 status (63.5% vs. 36.8% in direct ALND group; p < 0.0001).
  • Axillary Recurrence Rates: At a median follow-up of 75 months, axillary recurrence was a rare event, documented in only three patients across all treatment groups. This translates to:
    • One patient in the direct ALND group (0.6%).
    • One patient who underwent SNB followed by subsequent ALND (2.1%).
    • One patient who underwent SNB without further axillary clearance (0.9%). These low rates align with previous studies reporting axillary failure rates ranging from 0% to 2.3%.
  • Long-Term Oncological Outcomes (SLNB vs. ALND): The SNB group consistently demonstrated significantly better long-term outcomes compared to the ALND group.
    • Recurrence-Free Survival (RFS) at 10 years: 84.7% for SNB vs. 63.1% for ALND (p = 0.001).
    • Distant Disease-Free Survival (DDFS) at 10 years: 84.7% for SNB vs. 63.1% for ALND (p = 0.001).
    • Overall Survival (OS) at 10 years: 93.3% for SNB vs. 72.3% for ALND (p = 0.001).
    • Breast Cancer-Specific Survival (BCSS) at 10 years: 95.0% for SNB vs. 79.5% for ALND (p = 0.002).
  • Prognostic Factors (ypN0 vs. ypN+): When stratified by post-NAT axillary stage, the ypN0 group showed markedly higher RFS, DDFS, OS, and BCSS rates compared to the ypN+ group. For example, 10-year RFS rates were 79.2% for ypN0 versus 59.5% for ypN+ (p < 0.0001).
  • Multivariate Analysis:
    • Pathologic complete response (pCR) after NAT was a significant favorable prognostic factor for RFS (HR=0.282, p=0.019), DDFS (HR=0.295, p=0.025), and OS (HR=0.041, p=0.004).
    • ypN0 status was a significant favorable prognostic indicator for RFS (HR=1.281, p=0.034), DDFS (HR=1.285, p=0.032), OS (HR=1.493, p=0.003), and BCSS (HR=1.493, p=0.014).
    • SLNB (vs. direct ALND) was a significant favorable prognostic factor for RFS (HR=0.356, p=0.001), DDFS (HR=0.376, p=0.002), OS (HR=0.244, p=0.001), and BCSS (HR=0.228, p=0.004).
    • Vascular invasion was found to be an independent negative prognostic factor for OS (HR=2.497, p=0.005).
    • Adjuvant radiotherapy was a favorable prognostic factor for OS (HR=0.472, p=0.037).
    • T-DM1 (Trastuzumab-emtansine) was a favorable prognostic factor for OS (HR=0.311, p=0.001) and BCSS (HR=0.209, p=0.001).

Discussion and Implications for Clinical Practice

The study’s findings contribute significantly to the ongoing discussion about optimal axillary surgical management in cN+ breast cancer patients who achieve ycN0 status after NAT. The remarkably low axillary recurrence rates observed (0.6%–2.1%), regardless of the specific axillary procedure, suggest that even with historical concerns about SNB false-negative rates, the actual risk of nodal failure appears minimal in this well-selected patient group. This suggests that other factors, such as the therapeutic effects of adjuvant systemic treatments and radiotherapy, may play a crucial role in controlling residual disease.

The observation of significantly better RFS, DDFS, OS, and BCSS in the SNB group compared to the ALND group is notable. However, the authors caution against a universal interpretation of SNB being superior to ALND. They highlight that the SNB group had a higher proportion of patients achieving pCR and smaller residual tumors, indicating a more favorable tumor biology and response to NAT. This selection bias likely influenced the observed outcomes, suggesting that SNB is a suitable option for carefully selected patients who respond well to NAT and convert to ycN0 status.

This study’s results are consistent with other recent research that supports the oncologic safety and favorable prognosis of SNB alone after NAT in selected patients. For instance, studies by Kahler-Ribeiro-Fontana et al. and Barrio et al. reported very low axillary failure rates and high 5-year OS rates (91.3% and 94.2% respectively) among initially cN+ patients who achieved ycN0 after NAT and underwent SNB. Piltin et al. also observed a significant increase in SNB use and low regional recurrence rates (0.9%). A meta-analysis by Keelan et al. similarly found excellent 5-year RFS (86.5%) and OS (93.1%). These findings collectively reinforce the growing evidence that ALND can be safely omitted in these patients without compromising long-term oncological outcomes.

The study also elucidated important prognostic factors, confirming that achieving a pCR and ypN0 status after NAT are strong indicators of better long-term survival outcomes. The fact that ALND itself was identified as a predictor of poorer outcomes (HR=0.244 for OS) underscores the potential morbidity associated with the more aggressive surgical approach, which may not be necessary for patients with an excellent response to NAT. This further emphasizes the importance of de-escalation for quality of life without compromising oncological safety.

Limitations

Despite its significant contributions, the study acknowledges several limitations:

  • Retrospective Design: Inherently subjects the study to selection bias.
  • Incomplete Baseline Nodal Assessment: Not all cN+ patients underwent US-guided axillary biopsy, potentially leading to an incomplete assessment of baseline nodal disease.
  • Single-Institution Study: May limit the generalizability of findings to other clinical settings with different practices and patient populations.
  • Heterogeneity: Observed differences in tumor biology and response to NAT between the SNB and ALND groups, with the ALND group having larger residual tumors post-NAT.

Conclusion

In conclusion, this study strongly suggests that SNB may be a safe and effective alternative to ALND for carefully selected cN+ breast cancer patients who achieve ycN0 status after neoadjuvant therapy. While the findings indicate that SNB could be associated with better long-term oncological outcomes without increasing the risk of axillary recurrence, these results must be applied with caution in clinical practice due to inherent differences in patient groups. The authors emphasize the critical need for further research in more comparable populations to validate these findings and standardize patient selection criteria for axillary de-escalation. The overall trend in breast cancer management continues towards reducing invasiveness and associated morbidity while maintaining excellent oncological control.

Summary sheet

De-escalation of axillary treatment in early breast cancer represents a significant shift in patient management, aiming to reduce surgical morbidity while maintaining or improving oncologic outcomes. Historically, systematic axillary lymphadenectomy (ALND) was the standard, but it has progressively been replaced by sentinel node biopsy (SNB) since the 1990s to avoid complications like lymphedema, nerve damage, and chronic pain associated with complete axillary removal.

Current de-escalation strategies focus on various clinical scenarios:

  • Upfront Surgery: For patients with clinically node-negative (cN0) lymph nodes and up to two positive sentinel nodes (micrometastases or macrometastases), avoiding ALND is a safe option. Key trials supporting this include:
    • IBCSG 23-01 Trial: Demonstrated that ALND could be safely omitted in patients with micrometastases in the sentinel lymph nodes without affecting disease-free survival.
    • ACOSOG Z0011 Trial: Showed no significant difference in overall or disease-free survival when ALND was omitted for patients with one or two metastatic sentinel nodes who underwent lumpectomy and whole-breast irradiation.
    • SINODAR-ONE Trial: Explored the extension of Z0011 findings to mastectomy patients with one or two macrometastatic sentinel nodes, indicating non-inferior outcomes without ALND.
  • Neoadjuvant Systemic Treatments (NST): For patients receiving NST, ALND is unnecessary if no residual tumor burden remained in the lymph nodes after surgery. This is particularly relevant for initially node-positive patients who convert to node-negative (nodal pCR).
    • Early trials like ACOSOG Z1071 and SENTINA initially raised concerns about the false-negative rate (FNR) of SNB after NST.
    • However, refinements like dual tracers, retrieval of ≥3 sentinel lymph nodes, and removal of the clipped abnormal node have been shown to lower the FNR to an acceptable level (<10%).
    • Techniques such as Targeted Axillary Dissection (TAD) and the MARI procedure (marking the initially involved lymph node) are gaining traction, showing extremely low axillary recurrence rates (pooled estimates of 1.5% for MARI/TAD and 2.1% for SNB alone in patients achieving nodal pCR). Pooled analyses confirm the oncological safety of omitting ALND in these excellent responders, with excellent 5-year disease-free survival (DFS) and overall survival (OS).
  • Omission of Any Axillary Surgery: In highly selected subgroups, particularly patients with small tumors and lymph nodes negative on clinical and ultrasound evaluation, the complete omission of axillary surgery is being explored.
    • The SOUND trial found that avoiding axillary surgery was non-inferior to SNB in terms of 5-year distant disease-free survival for patients with small tumors (up to 2 cm) and negative preoperative axillary ultrasonography.

Furthermore, axillary radiotherapy is emerging as an effective alternative to ALND in certain cases, particularly for patients with positive sentinel nodes, offering comparable disease control with reduced side effects like lymphedema. The AMAROS trial was pivotal in establishing axillary radiotherapy as a viable option for selected patients.

Determining the appropriate axillary treatment remains a complex decision that necessitates a multidisciplinary team approach, focusing on personalized breast cancer treatment. A progressive de-escalation of axillary treatment is anticipated, with ALND reserved for fewer patients in the future.

Podcast

Course Plan: De-Escalation of Axillary Surgery in Early Breast Cancer

This course will provide an in-depth review of the evolving landscape of axillary management in early breast cancer. We will trace the historical shift from radical dissection to minimally invasive techniques, analyze the pivotal clinical trials that underpin current de-escalation strategies, and discuss the complex considerations for patient selection, balancing oncological safety with reduced morbidity. Special attention will be given to the impact of neoadjuvant systemic treatments and the role of multidisciplinary decision-making.

Learning Objectives: Upon completion of this course, participants will be able to:

  1. Summarize the historical evolution of axillary surgery in breast cancer and identify the key drivers of de-escalation.
  2. Evaluate the evidence supporting the omission of Axillary Lymph Node Dissection (ALND) in patients with limited axillary disease in both upfront surgery and neoadjuvant settings.
  3. Differentiate the roles of Sentinel Lymph Node Biopsy (SLNB), Targeted Axillary Dissection (TAD), and Axillary Radiotherapy (RT) as de-escalation strategies.
  4. Identify key patient selection criteria for safe omission of axillary surgery, particularly in the context of neoadjuvant therapy and complete pathological response.
  5. Discuss the challenges and ongoing debates related to false-negative rates (FNR) after neoadjuvant chemotherapy and the integration of systemic therapies with axillary management.
  6. Formulate a multidisciplinary approach to tailor axillary treatment decisions for individual patients.

* 0:00 – 0:02: The Halstedian Era and Radical Surgery:

            * Brief overview of radical mastectomy as the historical standard involving complete axillary basin removal, leading to significant morbidity and disfigurement.

            * Introduction of the concept that breast cancer biology is the major driver of recurrence, shifting focus from purely locoregional disease control.

* 0:02 – 0:05: The Advent of Sentinel Lymph Node Biopsy (SLNB): * SNB progressively replaced ALND from the 1990s as the standard of care for patients without axillary metastases, aiming to gain axillary status knowledge without full removal.

                        * Significant morbidity reduction with SNB, including less lymphedema, nerve damage, reduced mobility, and chronic pain compared to ALND.

                        * The overall goal of de-escalation is to reduce treatment burden without compromising patient outcomes.

* 0:05 – 0:10: Management of Micrometastases and Isolated Tumor Cells (ITCs):              

* IBCSG 23-01 Trial: Demonstrated that ALND could be safely omitted in patients with micrometastases in the sentinel lymph nodes, showing no difference in disease-free survival.

                      * AATRM 048/13/2000 Trial: Corroborated these findings, showing no differences in disease-free survival or cancer-related deaths in cN0 patients with SN micrometastasis who omitted ALND.

                      * MIRROR Trial: Indicated that even minor cancer cell loads in sentinel nodes could have prognostic significance, though the difference was not substantial enough to alter clinical practice decisions regarding additional axillary treatment for micrometastases or ITCs.

* 0:10 – 0:15: Management of 1-2 Macrometastatic Sentinel Nodes:

                        * ACOSOG Z0011 Trial: A crucial clinical study that profoundly impacted management. It showed that ALND could be safely omitted in patients with 1 or 2 metastatic sentinel lymph nodes undergoing lumpectomy with planned whole-breast irradiation, with no significant differences in overall or disease-free survival. This trial prompted less invasive strategies for axillary surgery in patients receiving breast-conserving surgery.

                        * SINODAR-ONE Trial: Explored the extension of ACOSOG Z0011 results to mastectomy patients with 1-2 macrometastatic SLNs, demonstrating non-inferior 3-year survival and relapse rates with SNB alone plus adjuvant therapy compared to ALND.

                        * Ongoing trials such as POSNOC and SENOMAC continue to provide evidence to potentially broaden less invasive axillary treatments for patients with limited axillary disease, including those undergoing mastectomy or having larger tumors.

* 0:15 – 0:20: Role of Neoadjuvant Systemic Treatment (NST):

                        * NST has an expanding role in modern breast cancer management, especially for HER2-positive and triple-negative subtypes due to high complete response rates.

                        * Main purpose: to downstage disease burden in both breast and axillary lymph nodes, reducing surgical extent and refining personalized treatment based on tumor characteristics and response.

 * 0:20 – 0:25: Challenges with SLNB and False-Negative Rates (FNR) after NAC:

                        * ACOSOG Z1071 (Alliance) Trial: Found an FNR of 12.6% for SNB after NAC in biopsy-proven cN1 breast cancer, exceeding the predefined acceptable threshold.

                        * SENTINA Trial: Reported an FNR of 14.2% for SNB after NAC, showing a lower detection rate and higher FNR compared to SNB performed before NAC.

                        * SN FNAC Study: Demonstrated a lower FNR of 8.4%, meeting clinical acceptability, which was attributed to stricter protocol adherence including mandatory immunohistochemistry and evaluation of nodal response by size.

                        * Strategies advocated to lower FNR: dual tracers, retrieval of ≥3 sentinel lymph nodes (SLNs), and removal of clipped abnormal nodes (Targeted Axillary Dissection – TAD).

 * 0:25 – 0:30: Targeted Axillary Dissection (TAD) and MARI Procedure:

                        * TAD: Involves marking positive axillary nodes with a clip prior to NST and removing both the clipped node and sentinel lymph nodes during surgery. This approach significantly lowers the FNR (e.g., to 1.4% with combination of SLNB and clipped node excision).

                        * MARI Procedure: Involves implanting an I-125 seed into a cytology-proven axillary lymph node before NST, with these marked nodes excised during definitive surgery.

                        * A recent meta-analysis demonstrated extremely low axillary recurrence rates (2.1% for negative SLNB alone and 1.5% for negative MARI/TAD) in patients who achieved nodal pathological complete response (pCR) after NST.

                        * This meta-analysis found no statistically significant benefit of ALND over SLNB in patients with nodal pCR after NST, supporting the oncological safety of omitting ALND.

                        * Pooled estimates showed excellent 5-year DFS (0.87), DDFS (0.90), and OS (0.92) for patients with negative SLNB alone after NST.

* 0:30 – 0:35: Axillary Radiotherapy (RT) as an Alternative to ALND:

                        * AMAROS Trial: Showed that axillary RT was comparable to ALND in preventing axillary recurrence in patients with positive SNB (cT1–T2, N0), with a significantly lower occurrence of arm lymphedema in the radiotherapy group.

                        * OTOASOR Trial: Arrived at similar results, suggesting that regional nodal irradiation does not increase the risk of axillary relapse compared to ALND.

                        * NCCN Guidelines now reflect these findings, supporting axillary RT as a comparable therapeutic approach to dissection in patients with up to 2 positive sentinel nodes. For mastectomy patients, the undissected axilla at risk should be treated with RNI if ALND is omitted.

* 0:35 – 0:40: Regional Nodal Irradiation (RNI) Considerations:

                        * For node-negative disease, RNI should be considered for high-risk patients (e.g., centrally/medially located tumors, T3N0, T2N0 with <10 nodes and adverse features like grade 3, extensive lymphovascular invasion, or ER-negative status).

                        * The NSABP B-51/RTOG 1304 trial suggests that for cN1 patients whose axillary lymph node involvement resolves after NAC (ypN0), omitting regional nodal irradiation may not compromise oncological outcomes and could reduce treatment-related toxicity.

* 0:40 – 0:45: Omission of Any Axillary Surgery:

                        * This represents the most attractive setting for de-escalation, significantly reducing surgical morbidity and improving patient quality of life.

                        * SOUND Trial: Demonstrated the safety of omitting axillary surgery (SNB) in patients with small tumors (<2 cm) and negative preoperative axillary ultrasonography undergoing breast-conserving surgery, showing non-inferior 5-year distant disease-free survival.

                        * INSEMA Trial: Showed no significant difference in invasive disease-free survival for cT1–2N0 patients undergoing breast-conserving surgery with or without SLNB.

                        * Patient selection and accurate imaging are paramount when no axillary surgery is planned. This approach has been supported by prospective data for specific populations, such as elderly ER-positive/HER2-negative breast cancer patients.

* 0:45 – 0:50: Ongoing Trials and Evolving Practice:

                        * Continuous de-escalation of axillary treatment is expected, with ALND reserved for fewer patients. * Ongoing international trials like Alliance A011202, ADARNAT, OPBC-03/TAXIS, and AXSANA are crucial to further refine guidelines and standardize practices, especially for patients with residual nodal disease after NAC.

                        * Integration of novel systemic therapies requires adaptation of RT timing, with current guidelines advising withholding CDK4/6 inhibitors during RT due to potential hematologic toxicities.

                        * Biomarker-driven de-escalation: Gene Expression Assays (GEAs) like Oncotype DX and MammaPrint, along with endocrine response assessment (Ki67), are increasingly used to safely omit chemotherapy in specific HR+/HER2- cohorts, further influencing the overall treatment burden.

* 0:50 – 1:00: Importance of the Multidisciplinary Team (MDT) and Patient Preferences:

                        * Determining the appropriate axillary treatment remains a complex decision that must be made by multidisciplinary teams with expertise in personalized breast cancer treatment.

                        * It is crucial to remember that de-escalation is not always what patients want; some may elect more aggressive surgery for “peace of mind”. Surgeons should be prepared to adapt techniques to patient preferences, including “going flat” after mastectomy.

                        * All de-escalation concepts must be evidence-based and validated by prospective clinical trials to ensure safety and maintain oncological outcomes.

Slides for a Powerpoint Presentation

Slide 1: Introduction: The Evolving Landscape of Breast Cancer Treatment

  • Axillary status remains a powerful predictor of survival in breast cancer, playing a fundamental role in multidisciplinary patient strategy at all disease stages.
  • The field of surgical oncology is currently in an era of de-escalation, aiming for less invasive techniques to reduce morbidity while maintaining or enhancing oncologic outcomes.
  • For breast cancer, the management of axillary nodes has significantly evolved over the last decade, questioning the necessity of extensive interventions like systematic axillary lymphadenectomy (ALND) in all cases.
  • Advances in understanding breast cancer biology and the advent of targeted therapies have paved the way for further de-escalation of axillary interventions, particularly for patients with minimal or no nodal disease.
  • This review aims to report findings from recent clinical trials evaluating the clinical outcomes of reduced axillary treatment in patients with early-stage breast cancer.

Slide 2: Axillary Status: A Crucial Predictor & Its Implications

  • Knowledge of axillary lymph node involvement is crucial for multidisciplinary management of breast cancer.
  • Despite efforts to reduce surgical interventions, thorough axillary staging remains necessary in specific cases to ensure accurate diagnosis and guide treatment decisions.
  • Decisions on postoperative systemic treatments are still significantly influenced by axillary status.
  • For patients with higher-risk hormone receptor-positive/HER2-negative breast cancer and lymph node involvement, adjuvant therapy may include cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, highlighting the prognostic importance of nodal status.
  • However, improper evaluation of axillary status can negatively influence prognosis and lead to severe local symptoms from unrecognized or untreated lymph node metastases.

Slide 3: From Radical Mastectomy to Sentinel Node Biopsy (SNB)

  • For over 100 years, axillary surgery was based on the Halstedian concept that breast cancer was a locoregional disease spread via the lymphatic system, thus requiring radical mastectomy (removal of breast, chest wall muscles, and axillary contents).
  • By the mid-1960s, new information about cancer biology and significant dissatisfaction with radical mastectomy results led to trials questioning its necessity.
  • The NSABP B-04 trial (1971) and the Milan I trial demonstrated that de-escalation of radical breast and axillary surgeries did not compromise oncologic outcomes, influencing a movement towards less invasive approaches.
  • From the 1990s, systematic axillary lymphadenectomy (ALND) has been progressively replaced by sentinel node biopsy (SNB).
  • The aim of SNB was to gain knowledge about the state of axillary lymph nodes without removing the entire axillary basin in patients with no axillary metastases.

Slide 4: The Advent of SNB: Improving Quality of Life

  • The introduction of SNB marked a fundamental change towards improving the quality of life for women affected by breast cancer.
  • For years, early breast cancer treatment involved ALND for histologically-proven positive SNB, or omitting axillary lymph node resection when SNB showed no cancer.
  • This practice allowed for sparing ALND for the majority of patients, thus avoiding or minimizing the morbidity associated with complete axillary removal.
  • Key morbidities avoided or minimized by SNB include lymphedema, nerve damage, reduced mobility in the shoulder and arm, and chronic pain.
  • Despite SNB being a minimally invasive approach compared to ALND, it can still be challenging to perform and may have long-lasting complications.

Slide 5: Questioning ALND in Low-Volume Disease: Micrometastases/ITCs

  • Shortly after SNB’s introduction, the actual requirement to perform complete ALND in the presence of micrometastases (metastases >0.2 mm but ≤2 mm) or isolated tumor cells (ITCs) in the sentinel node was questioned.
  • The focus shifted to understanding if such minimal nodal disease truly necessitated further aggressive intervention.
  • Several studies began to explore the prognostic significance of micrometastases and ITCs in sentinel nodes.
  • The goal was to determine if omitting ALND in these cases was oncologically safe, potentially reducing treatment morbidity.
  • This questioning reflects the broader de-escalation trend in breast cancer management, seeking to tailor treatment to the actual disease burden.

Slide 6: Key Trial: IBCSG 23-01 – Safety of Omission in Micrometastases

  • The IBCSG 23-01 Trial was designed to determine if ALND could be safely omitted in breast cancer patients with micrometastases in the sentinel lymph node.
  • Participants were randomly allocated to either ALND or no additional axillary treatment beyond SNB.
  • The primary endpoint was disease-free survival (DFS), with secondary endpoints including overall survival and lymphedema.
  • Results showed no difference in DFS between patients undergoing ALND and those without further axillary treatment.
  • The findings greatly influenced breast cancer surgery towards a more conservative approach for axillary lymph nodes with minimal metastatic disease.

Slide 7: Key Trial: ACOSOG Z0011 – A Landmark Study for Limited Metastasis

  • The ACOSOG Z0011 trial was crucial in impacting axillary lymph node management.
  • It investigated if ALND could be safely omitted in patients with one or two metastatic sentinel lymph nodes.
  • Patients with T1-2N0M0 breast cancer undergoing lumpectomy with planned whole-breast irradiation were randomized to standard ALND or no further axillary treatment.
  • Results revealed no significant differences in overall survival (OS) or disease-free survival (DFS) between the two groups over a 6.3-year median follow-up.
  • This study prompted less invasive strategies for axillary surgery in patients receiving breast-conserving surgery, influencing national guidelines against standard ALND for those meeting Z0011 criteria.

Slide 8: Expanding Z0011: The SINODAR-ONE Trial

  • The SINODAR-ONE multicenter randomized clinical trial explored the potential extension of ACOSOG Z0011 results to patients undergoing mastectomy.
  • The trial examined the role of ALND in patients undergoing breast-conserving surgery or mastectomy for T1-2 breast cancer with one or two macrometastatic sentinel lymph nodes.
  • Patients were randomized to no additional axillary treatment or removal of ≥10 axillary level I/II non-sentinel lymph nodes followed by adjuvant therapy.
  • Results demonstrated that 3-year survival and relapse rates for patients with one or two macrometastatic SLNs receiving only SNB and adjuvant therapy were not inferior to those who underwent ALND.
  • This trial may allow for future broadening of the criteria to include patients who have undergone mastectomy, providing more information for radiation decisions.

Slide 9: The Emergence of Axillary Radiotherapy (RT) as an Alternative

  • Axillary radiotherapy (RT) is an emerging strategy to reduce surgical morbidity while maintaining effective disease control.
  • The AMAROS trial was a pivotal Phase III study investigating the role of RT in axillary nodes.
  • It compared ALND with axillary RT in clinically node-negative breast cancer patients with positive SNB, including those undergoing breast-conserving surgery and mastectomy.
  • Results showed that axillary RT was comparable to ALND in preventing axillary recurrence in patients with positive SNB.
  • Notably, the occurrence of arm lymphedema was significantly lower in the RT group, suggesting it as an effective alternative with reduced side effects. The OTOASOR trial arrived at similar results.

Slide 10: Summary for Upfront Surgery (Low Nodal Burden)

  • For clinically node-negative T1/T2 disease with up to two positive nodes (macrometastatic or micrometastatic disease), ALND is strongly suggested to be not required based on ACOSOG Z0011 and SINODAR-ONE.
  • After breast-conserving surgery, axillary events are rare, regardless of whether the axilla is intentionally targeted with RT.
  • If a patient with clinically node-negative T1/T2 tumors undergoes mastectomy, ALND may also be omitted; however, the undissected axilla at risk should be treated with regional nodal irradiation (RNI), supported by AMAROS and OTOASOR.
  • This shift emphasizes replacing ALND with axillary RT to provide similar therapeutic outcomes while diminishing lymphedema morbidity.
  • Ongoing trials like POSNOC and SENOMAC continue to explore and potentially broaden less invasive axillary treatments for patients with limited axillary disease.

Slide 11: Axillary Management in Neoadjuvant Systemic Treatments (NST)

  • Neoadjuvant systemic treatments (NST) are increasingly used in modern breast cancer management, particularly for triple-negative or HER2-positive breast cancer.
  • One main purpose of NST is to downstage the disease burden in both the breast and axillary lymph nodes.
  • This approach aims to reduce the extent of surgery and allows for refined personalized treatment based on tumor characteristics and response to NST.
  • Particular interest is directed towards patients with metastatic lymph nodes before NST who downstage to node-negative at the time of surgery.
  • This trend raises the question of how much axillary surgery is needed for these “excellent responders” who convert to node-negative status.

Slide 12: SNB after NST: Initial Challenges (ACOSOG Z1071 & SENTINA)

  • The ACOSOG Z1071 (Alliance) trial aimed to determine the false-negative rate (FNR) for SNB after chemotherapy in initially biopsy-proven cN1 breast cancer.
  • The trial found the FNR was not ≤10% in women with cN1 breast cancer with two or more sentinel nodes examined after NAC, suggesting that greater sensitivity was needed to support SNB as an ALND alternative.
  • The SENTINA study investigated the timing of SNB in patients scheduled for NAC.
  • It demonstrated that SNB after systemic treatment had a lower detection rate and higher FNR compared to SNB performed before NAC.
  • These early findings cautioned about the limitations of SNB planned after NAC due to accuracy concerns.

Slide 13: Improving SNB Accuracy after NST (SN FNAC & GANEA 2)

  • To address the limitations of SNB after NST, studies explored methods to improve accuracy.
  • The SN FNAC study found the FNR was <10% when using immunohistochemistry and a potential for avoiding ALND in ~30% of cases.
  • Dual tracer mapping and retrieval of ≥3 sentinel lymph nodes were consistently shown to lower the FNR to below 10%.
  • It was also found that if the clipped node (biopsied node with a clip placed pre-NST) was removed at SNB, the FNR was lowest.
  • The GANEA 2 study showed that in patients with no initial node involvement (cN0), a negative SNB after NAC enables the safe avoidance of an ALND.

Slide 14: Targeted Axillary Dissection (TAD) & MARI Procedure

  • Targeted Axillary Dissection (TAD) involves the removal of sentinel lymph nodes (SLNs) combined with the excision of the clipped node (the node suspected of containing cancer identified and marked before NST).
  • The MARI procedure (Marking Axillary lymph node with Radioactive Iodine seeds) was proposed as an alternative, where an I-125 seed is implanted into the cytology-proven axillary lymph node before NST.
  • Both TAD and MARI aim to reduce the false-negative rate compared to SNB alone after NST in initially node-positive patients.
  • Studies have shown that combining SNB and clipped node excision (TAD) can reduce the FNR significantly to 1.4%.
  • The median number of MARI nodes excised was one (range 1–6), while TAD lymph nodes averaged 3 (range 1–11).

Slide 15: Oncological Safety of De-escalation Post-NST

  • Despite initial concerns about false-negative rates, studies suggest that axillary de-escalation is oncologically safe for patients who achieve nodal pathological complete response (pCR) after NST.
  • A systematic review and meta-analysis found an extremely low axillary failure rate for SNB and marked node extirpation in patients with successful nodal conversion after NST.
  • The pooled estimate of axillary recurrence for patients with a post-NST negative SNB and ALND omission was 2.1% (95%CI 1.4–3.2%).
  • For patients with negative MARI/TAD, the pooled axillary recurrence rate was 1.5% (95%CI 0.5–4.1%), with no statistically significant difference from SNB alone.

There was no statistically significant benefit of ALND over SNB in patients with nodal pCR after NST, supporting omission of ALND.

Slide 16: Ongoing Trials for Axillary Management Post-NST

  • Several trials are ongoing to further refine axillary management post-NST.
  • The OPBC-03/TAXIS trial (Phase III) evaluates non-inferiority of axillary radiotherapy compared to ALND, including patients with residual disease after NAC.
  • The Alliance A011202 (Phase III) compares ALND to axillary radiotherapy in cT1-3N1 patients with positive SNB after NAC, assessing invasive breast cancer recurrence-free interval.
  • The ADARNAT trial (Phase III) evaluates the efficacy and safety of axillary radiation compared to ALND in patients with positive SNB following NST.
  • The NSABP B-51/RTOG 1304 trial (Phase III) determines if regional nodal irradiation is necessary for patients with biopsy-confirmed positive axillary lymph nodes who become pathologically negative (ypN0) after NAC.
  • The AXSANA study aims to determine best practices for axillary surgery post-NST, comparing various techniques to optimize outcomes and reduce morbidity.

Slide 17: Omission of Any Axillary Surgery: Selected Subgroups

  • The omission of any axillary surgery has gained interest for early-stage breast cancer patients presenting with clinically negative lymph nodes.
  • This shift is underpinned by pivotal trials demonstrating the oncologic safety of such an approach in carefully selected patient groups.
  • This approach offers important advantages, including reduced surgical morbidity and improved patient quality of life.
  • A correct preoperative patient selection and accurate use of imaging modalities are of utmost importance when no axillary surgery is planned.
  • The avoidance of any axillary surgery might be proposed for highly selected subgroups with small tumors and lymph nodes negative on clinical and ultrasound evaluation.

Slide 18: Key Trials: SOUND and INSEMA Supporting Complete Omission

  • The Italian SOUND trial examined the safety of omitting axillary surgery in patients with breast cancers up to 2 cm and negative preoperative axillary ultrasonography.
  • Results indicated that avoiding axillary surgery was non-inferior to SNB in terms of 5-year distant disease-free survival.
  • The INSEMA trial included cT1-2N0 patients undergoing breast-conserving surgery and radiotherapy.
  • This non-inferiority trial demonstrated that early-stage breast cancer patients undergoing less extensive axillary surgery achieved 5-year invasive disease-free survival outcomes that were not inferior to standard treatment.
  • These findings align with the “Choosing Wisely” campaign, promoting minimizing surgical procedures that do not affect overall survival, local control, or recurrence rates.

Slide 19: Predicting Axillary pCR in HER2-Positive Breast Cancer Patients

  • The addition of anti-HER2 target therapy to neoadjuvant chemotherapy protocols has led to a marked increase in pathological complete response rates in HER2+ breast cancer.
  • Rates of axillary pCR are often higher than those of primary tumors, especially with dual anti-HER2 treatment.
  • Factors found to be statistically significant in predicting nodal pCR include: degree of HER2 positivity (HER2+ 3 tumors more likely to develop nodal pCR) and type of anti-HER2 therapy (dual blockage more likely).
  • Pre-neoadjuvant LN status by imaging (all radiologically negative LNs turned out to be pathologically negative) and post-neoadjuvant LN status by imaging (all radiologically negative LNs turned out to be pathologically negative).
  • Primary tumor radiological response (all patients with complete clinical response also had nodal pCR) and all T1 primary tumors before NAT showed negative LNs after NAT.

Slide 20: Balancing Benefits and Risks of De-escalation

  • Benefits: De-escalation aims to reduce morbidity, especially significant sequelae like lymphedema and axillary web syndrome, which compromise quality of life and are difficult to treat.
  • Benefits: It improves patient quality of life by reducing the extent of surgery.
  • Risks: An improper evaluation of axillary status can negatively influence decisions on postoperative systemic treatments, with relevant effects on overall prognosis.
  • Risks: Patients with unrecognized or untreated lymph node metastases may experience severe local symptoms.
  • The complexity of axillary treatment decision-making is underscored by the multitude of trials and variability among breast centers in different countries, reflecting differing patient selection and SNB evaluation methods.

Slide 21: Multidisciplinary Team Approach & Personalized Treatment

  • Determining the appropriate axillary treatment remains a complex decision that must be made by multidisciplinary teams with expertise in personalized breast cancer treatment.
  • This collaborative approach ensures that the risks and benefits of de-escalation are carefully weighed for each patient.
  • Multidisciplinary teams need to be well-informed and continuously update clinical guidelines to provide personalized treatment plans for breast cancer patients.
  • High-quality data collection regarding RT integration with modern systemic therapies is crucial, even in trials not primarily designed to test RT effects.
  • Tailored treatment based on disease burden, response to neoadjuvant protocols, and tumor biology is becoming the standard.

Slide 22: Future Directions in Axillary Treatment

  • In the coming years, there will likely be a progressive de-escalation in axillary treatment, with ALND reserved for fewer patients.
  • Ongoing trials (e.g., POSNOC, SENOMAC, OPBC-03/TAXIS, Alliance A011202, ADARNAT, NSABP B-51, AXSANA) will continue to provide evidence to refine de-escalation strategies.
  • Research is also evaluating the safety of omitting radiotherapy in low-risk breast cancer, as assessed by genomic risk scores and Oncotype Dx (e.g., TAILOR RT trial).
  • Future clinical trials should be designed with a comprehensive, integrative perspective, accounting for the interplay between surgery, systemic therapy, and RT.
  • The goal is to optimize outcomes while balancing efficacy and toxicity, ensuring that modern de-escalation strategies remain safe and evidence-based.

Slide 23: Conclusion: The Promise of De-escalation

  • The treatment of the axilla in breast cancer has undergone significant de-escalation, improving patient quality of life without sacrificing oncologic outcomes.
  • For patients with clinically node-negative lymph nodes and up to two positive sentinel nodes, avoiding ALND is a safe option.
  • After neoadjuvant systemic treatment, ALND is unnecessary if no residual tumor burden remains in the lymph nodes after surgery, especially for good responders.
  • Axillary radiotherapy can be as effective as axillary dissection in certain cases, offering reduced side effects like lymphedema.
  • The omission of any axillary surgery might be proposed for highly selected subgroups with small tumors and clinically/ultrasound-negative lymph nodes. Adoption of guidelines based on current trials and a thorough multidisciplinary team approach are crucial for personalized treatment.