De-escalation of axillary interventions in the management of breast cancer patients following neoadjuvant systemic treatment
Review Article

De-escalation of axillary interventions in the management of breast cancer patients following neoadjuvant systemic treatment

Ashutosh Tondare1, Mangesh A. Thorat2,3,4 ORCID logo

1MGM’s Medical College and MCRI Superspecialty Hospital, Chhatrapati Sambhajinagar, India; 2Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London, UK; 3Breast Services, Homerton University Hospital, London, UK; 4School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK

Contributions: (I) Conception and design: MA Thorat; (II) Administrative support: None; (III) Provision of study materials or patients: Both authors; (IV) Collection and assembly of data: A Tondare; (V) Data analysis and interpretation: Both authors; (VI) Manuscript writing: Both authors; (VII) Final approval of manuscript: Both authors.

Correspondence to: Dr. Mangesh A. Thorat, MBBS, MS, DNB, FEBS, CEBS, PhD. Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; Breast Services, Homerton University Hospital, London, UK; School of Cancer & Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK. Email: thoratmangesh@gmail.com; m.thorat@qmul.ac.uk.

Abstract: The role of axillary surgery in the management of breast cancer continues to evolve as our understanding of breast cancer biology improves, coupled with an increasing availability and efficacy of systemic therapy options. In the current context, the main goal of axillary surgery is staging. In this review, we discuss the role of axillary surgery in patients receiving neoadjuvant systemic therapy and appraise the current state of de-escalation of axillary interventions. We argue that accuracy of limited axillary staging procedure is important, not so much from axillary control point of view but from the systemic undertreatment point of view. We suggest that comparative evaluation of different limited axillary staging procedures from oncological safety perspective should therefore not be based on local axillary control endpoint. We discuss the comparative diagnostic accuracy of sentinel lymph node biopsy (SLNB) vs. targeted axillary dissection (TAD). SLNB does not meet the level of accuracy needed for safe de-escalation in node-positive patients, particularly true de-escalation of axillary intervention, where the omission of completion axillary lymph node dissection (ALND) is not replaced with axillary radiotherapy. We discuss the arguments against the use of intraoperative assessment of lymph nodes in this context. We identify the areas of unmet research need, these include developing tools to predict residual axillary nodal burden in patients with incomplete nodal response, and true de-escalation studies in this patient population, especially those who will receive extended or modified adjuvant treatment. We also underscore the urgent need for research in patients with locally advanced breast cancer (LABC) with an emphasis on tumour biology paradigm.

Keywords: Neoadjuvant chemotherapy (NACT); de-escalation; sentinel lymph node biopsy (SLNB); targeted axillary dissection (TAD); axillary radiotherapy


Received: 18 November 2024; Accepted: 28 February 2025; Published online: 27 April 2025.

doi: 10.21037/tbcr-24-59


Introduction

Axillary surgery has been an essential component of locoregional treatment of breast cancer since Halsted demonstrated that surgery as a treatment of breast cancer improves survival. Our understanding of breast cancer biology has changed substantially since then. Consequently, the role of axillary surgery continues to evolve. In this review, we appraise the role of axillary surgery in patients undergoing neoadjuvant chemotherapy (NACT) and discuss the unmet research needs (Box 1).

Box 1 Summary points

The main goal of axillary surgery is staging
Limited axillary staging procedure needs to be accurate to avoid under-staging and resulting under-treatment
In the context of adequate systemic treatment, axillary nodal burden does not translate into axillary recurrence
A comparative evaluation of different limited axillary staging procedures from oncological safety perspective should therefore use IDFS as the primary endpoint instead of axillary control as an endpoint
Excellent response to NACT in certain subtypes of breast cancer means that de-escalation of axillary surgery is feasible and desired
De-escalation of one treatment modality (for example, surgery) and replacing it with another (for example, radiotherapy) does not represent true de-escalation
True de-escalation in node-positive patients is feasible only if the limited axillary staging procedure is sufficiently accurate
Current evidence suggests that TAD has a superior accuracy as compared with SLNB-alone, the latter may lead to under-staging and under-treatment in a substantial proportion of patients
Leveraging data from multiple ongoing trials in patients who remain node positive after NACT to develop tools to predict overall axillary burden is urgently needed so that de-escalation of axillary intervention can be achieved in these patients
De-escalation of axillary surgery in LABC remains an unmet research need and focused international collaborative efforts are needed to address the issue

IDFS, invasive disease-free survival; LABC, locally advanced breast cancer; NACT, neoadjuvant chemotherapy; SLNB, sentinel lymph node biopsy; TAD, targeted axillary dissection.


The evolving purpose of axillary surgery in breast cancer

The approach to axillary intervention in breast cancer patients has evolved from Halstedian axillary dissection to omitting any surgery for axilla in a select group of patients, through intermediate interventions like sentinel lymph node biopsy (SLNB), targeted axillary dissection (TAD) and axillary radiotherapy which are now the standard of care in a vast majority of patients (1-5). This shift from radical axillary surgery to axillary surgery of smaller magnitude has also been applied to patients undergoing NACT (6-9). In many ways, the axillary conservation has followed the trend of conservative surgery for primary tumour in the form of breast conservation, albeit a decade or two later. A better understanding of disease biology and substantial advancement in systemic treatments has had a significant role to play in such de-escalation.

The primary role of axillary surgery is accurate pathological staging of disease and better long-term regional control to avoid complications due to axillary nodal recurrence (1). The lymphatic drainage patterns of breast mean that a vast majority of breast cancers drain exclusively to axilla (10-13) and therefore axillary lymph node dissection (ALND) provides the most accurate lymph node staging information in a vast majority of patients. The substantial extent of axillary nodal involvement (Table S1) in the trials (2,4,5,14-21) that compared more (often ALND) axillary surgery vs. less axillary surgery with or without axillary radiotherapy demonstrates that most of the axillary nodal burden does not manifest as axillary recurrence in the context of adequate adjuvant systemic treatment. Therefore, in the contemporary context, the primary goal of axillary surgery is staging and not treatment except in locally advanced breast cancer (LABC). In the patients with axillary lymph nodal involvement, axillary surgery following NACT also provides the opportunity to assess response to systemic therapy along with the primary tumour, thus providing additional information regarding tumour biology.

The primary reason for investigating the oncological safety of axillary conservation is to avoid complications of ALND like lymphedema, dysesthesia, axillary web syndrome, etc. However, for the reasons discussed above, the concept of oncological safety in early-stage breast cancer now needs to take into account primarily the impact of under-staging of lymph node burden than local control in the axilla. As the efficacy of systemic treatment improves and more biologically directed therapies become available, systemic undertreatment as a consequence of axillary under-staging in conservative axillary surgery will have a greater impact on oncological outcomes like invasive disease-free survival (IDFS) than impact of undertreatment of axillary nodal burden on outcomes like axillary recurrences. Therefore, studies investigating axillary de-escalation should now move away from traditionally used endpoint of axillary control to overall endpoints like IDFS or overall survival (OS).

The body of evidence available for the favourable complication profile of SLNB as compared with ALND is robust. Incidence of ipsilateral lymphedema ranges from 19.3% to 24.6% in patients who undergo ALND, the risk is much lower at 2.2–8.3% in patients who undergo SLNB (22-24). Shoulder arm restriction and pain have also been found to be significantly lower in patients undergoing SLNB (25,26). Axillary web syndrome or cording is a unique and frequently under reported complication of axillary surgery. Its reported incidence following ALND is 36–72%, while in SLNB it ranges from 11% to 58%, depending on how long patients were followed and how keenly clinicians were looking for it (27).


SLNB

In clinically node negative (cN0) patients, whether the SLNB should be offered before systemic treatment or after NACT along with definitive surgery for primary tumour has been debated. The comparative assessment of contemporary data (7,28-32) shows that upfront SLNB has a higher sentinel node identification rate (SNIR) and a lower false-negative rate (FNR) thus offering a better staging opportunity; the difference is however smaller for cN0 patients. Furthermore, it requires an additional surgical procedure, can delay initiation of NACT and misses the opportunity to de-escalate axillary surgery in those sub-clinical node positive patients who would have become lymph node negative (ypN0) following a complete response to NACT. For example, a retrospective observational study (33) in cN0 patients reported axillary dissection rates of 29.9% in pre-NACT SLNB compared with 7.4% in post-NACT SLNB. Post-NACT SLNB/axillary staging has the advantage of opportunity to de-escalate axillary surgery by assessing the chemosensitivity of nodal metastasis in sub-clinical node positive patients as well as in cN+ patients if the involved node is marked before NACT (28). Therefore, the small advantage of a higher SNIR and lower FNR of pre-NACT SLNB is substantially outweighed by its disadvantages and pre-NACT SLNB has no role in contemporary context.

With the third-generation chemotherapy that includes anthracycline and taxane-based chemotherapy the incidence of complete clinical nodal response is as high as 43% (34). Depending on agents used, the rates of pathological complete response (pCR) (combined primary and nodal) range from 50% to 65% for triple negative breast cancer and these range from 40% to 60% for ERRB2-positive cancers (35,36). The nodal pCR rate in the cN+ patients (all subtypes included) in the NSABP-B27 trial (37) was 10% higher (16.3% vs. 26.2%) with the addition of docetaxel, a regimen similar to current chemotherapy regimens. Indirect estimation suggests that the nodal pCR rate with dual-agent anti-HER2 therapy (current standard of care) and docetaxel in the neoSPHERE trial (35) in ERBB2-positive patients was at least 61% (46 of 75) as compared with 43% (32 of 75) in the single-agent anti-HER2 therapy and docetaxel arm. In the triple-negative subtype, the nodal pCR rates with and without immunotherapy were 65% and 44% respectively in the KEYNOTE-522 trial (38). Such high complete response rates underscore the opportunity and the need for axillary de-escalation to reduce morbidity. Axillary de-escalation approach in cN+ patients would involve SLNB alone, TAD alone or the combination of TAD and SLNB as the first stage surgery, the latter two procedures need marking of the involved node prior to systemic therapy.

Two factors need to be taken into account when considering the impact of SLNB following systemic therapy. The first is a structural factor, with implications for the SNIR (Table 1) and the second is the biological factor with implications with respect to FNR. Systemic treatment may cause scarring from tumour regression in lymph node and lymphatics and thus alter the lymphatic pathways and adversely affect SNIR. The identification rate of sentinel node following systemic treatment is therefore dependent on nodal involvement at presentation (structural aspects) and the use of single vs. combination of tracers (technical aspects). Results from the prospective studies ACOSOG Z1071 (8,41,42), SENTINA (9), the French prospective multicentre study (43) have shown that identification rates were higher in patients with clinically node negative disease at presentation as compared to patients with involved nodes. Univariate and multivariate analysis of ACOSOG Z1071 trial showed that the combination of blue dye and radiotracer was better than any of the single agents while only methylene blue dye had the worst identification rate. While the structural aspects are beyond the control of surgeons, the technical aspects certainly are and use of dual-tracers should be the standard of care if SLNB is performed following systemic therapy.

Table 1

SNIR, FNR, and overall accuracy of nodal staging by SLNB following neo-adjuvant chemotherapy [reprinted with permission from Thorat et al. (28)]

Studies, n Rate (95% CI) (%) Overall accuracy (95% CI) (%)
Summary 76.9 (73.8–79.8)
   SNIR 71 89.6 (87.8–91.2)
   FNR 65 14.2 (12.5–16.0)
After bias-correction 72.7 (69.2–76.4)
   SNIR 91 86.6 (84.7–88.9)
   FNR 84 16.1 (14.1–18.3)
cN0 73.4 (57.2–82.2)
   SNIR 7 96.0 (86.0–97.6)
   FNR 5 23.5 (15.8–33.5)
cN1 75.9 (69.3–81.2)
   SNIR 16 89.5 (85.0–92.7)
   FNR 15 15.2 (12.4–18.5)

, overall accurate nodal staging achieved by SLNB alone. , after correction of publication bias by trim-and-fill method (39). A summary from the systematic review by Mocellin and colleagues (40). CI, confidence interval; cN0, clinically node negative; cN1, clinically node positive; FNR, false-negative rate; SLNB, sentinel lymph node biopsy; SNIR, sentinel node identification rate.

The second factor that merits consideration is the biological factor. Phenotypic discordance between the primary and synchronous axillary nodal metastasis. Approximately 3–30% of discordance in oestrogen receptor (ER), 0–14% discordance in ERRB2 overexpression, and 11–46% discordance in Ki-67 has been reported (44). Therefore, a differential response between primary and nodal metastatic disease as well as internodal differential response remain a possibility. While there is no evidence to suggest that such response discrepancy would adversely affect SNIR or FNR, it does increase the possibility of undertreatment at the same level of FNR with the said technique. As discussed above, residual axillary burden may not manifest as axillary recurrence in general (Table S1) when adjuvant systemic treatment is given. However, the same may not be true for treatment-resistant residual axillary burden following NACT, especially in the absence of further adjuvant systemic therapy, even though limited available evidence does not show excess axillary recurrence risk (45,46). More important consideration however is that the primary role of systemic treatment is to eradicate/control distant spread if it has occurred. In these situations of discrepancy in response between primary tumour and axillary metastasis, the same may apply to any distant spread, which may be resistant to systemic treatment given. Missing the lack of response in axillary node due to a false-negative SLNB would therefore mean missing an opportunity to intervene with a different systemic treatment, thus resulting in undertreatment. Therefore, FNR becomes even more important in post-NACT SLNB than upfront SLNB and the 10% threshold of acceptable FNR may be too high in the post-NACT settings. Extrapolation of the interim results from the Alliance A011202 trial (47) suggests that an FNR of 10% could translate in at least 3.3% patients being understaged and possibly undertreated systemically with a residual chemo-resistant disease in axilla. This consideration coupled with the evidence available so far (45,46) indicates that the oncological safety of such threshold in the post-NACT settings can therefore only be determined with endpoints like IDFS as discussed above (48). The current literature (Table 1) indicates the FNR of SLNB-alone to be well above the 10% threshold unless dual-tracers are used and at least three sentinel nodes are found (8,41,42). It is worth noting that, it is not possible to pre-operatively predict whether at least three sentinel nodes will be found and therefore relying on this variable to justify SLNB-alone procedure is not prudent.


TAD

Identification of the true sentinel node and assessing in vivo response in the metastatic lymph node/s, both can be achieved by TAD. Multiple studies (41,49-54) of TAD combined with SLNB have shown a much lower FNR (up to 4%) and a much higher lymph node identification rate than SLNB-alone in post-NACT setting. It is worth noting that with a range of different localisers (Figure 1) and variations in the timing of localiser placement represents the potential for between-study heterogeneity. Multicentre studies are also prone to within-study heterogeneity due to differing institutional practices as well as patient populations. However, the evidence for improved precision of this approach over SLNB-alone is consistent.

Figure 1 Methods for the identification of biopsy-proven metastatic node during targeted axillary dissection. IOR, intra-operative reading; NACT, neoadjuvant chemotherapy.

A node clipped at the beginning of neoadjuvant treatment needs to be retrieved accurately and reliably after systemic treatment is completed (Figure 1). Studies suggest that the two-stage marking (e.g., clip before NACT and tattoo/wire after NACT), and image-guided retrieval becomes more difficult as the interval between the first marker and second marker (localiser) placement lengthens, especially with significant response to systemic treatment (55,56). Current evidence favours single-stage marking-localisation procedures using localisers such as radioactive seed (53,57) or radiofrequency (radar reflector) marker (58) that can be directly identified during the procedure. Hartmann et al. (59) recently have shown identification rate of 96% using a magnetic marker in one-stage procedure in a multicentre cohort of 151 patients, although response assessment with MRI was compromised in 10% of patients. The ongoing MAGELLAN trial (NCT03796559) (60) is recruiting patients in a prospective study evaluating a magnetic marker-localiser in a one-stage procedure.


The goal of true de-escalation of axillary treatment

De-escalation of treatment, i.e., reducing magnitude, duration or intensity of treatment is widely understood. However, sometimes de-escalation of one treatment modality is followed by escalation of another treatment modality. For example, reduction in the magnitude of axillary surgery (SLNB-only instead of ALND after one or two positive sentinel nodes) is followed by administration of axillary radiotherapy which would not have been otherwise administered. Even though such approach may mean lower overall treatment morbidity, it does not represent true de-escalation. True treatment de-escalation is defined as de-escalation of a treatment without escalating another treatment.

Node positive patients with complete pathological nodal response (cN+ to ypN0)

Montagna and colleagues (61) recently published a study evaluating the role of SLNB and TAD in axillary de-escalation in cN+ patients and reported that omission of ALND in ypN0 patients as assessed by SLNB or TAD has acceptable low axillary recurrence at median follow-up of 3.5 years. The authors also suggest that TAD and SLNB are equivalent to each other as a staging procedure. We (48) have however questioned this claim since this study is underpowered for such a comparison. Furthermore, even though the study demonstrated de-escalation of axillary surgery, it does not represent true de-escalation of therapy as 80% of patients received axillary radiotherapy. While it is true that axillary radiotherapy has a much lower morbidity like lymphoedema and restriction in shoulder mobility than ALND, it is not free of morbidity. A true de-escalation of axillary intervention in cN+ patients converting to ypN0 would mean omitting axillary radiotherapy after the de-escalated staging procedure. The clinical community would need to have confidence that the staging procedure is accurate with a high lymph node identification rate and low FNR. In our opinion, SLNB-alone does not meet this requirement but TAD/SLNB does. The early results of the NSABP B-51 trial (62) of omission of regional nodal irradiation (RNI) in cN+ patients converting to ypN0 do not show any oncological safety concerns with the omission of RNI. However, 45% of patients in the trial underwent ALND and therefore the trial will not be informative regarding true de-escalation. The MARI (marking axillary lymph nodes with radioactive iodine seeds) protocol (57) which relies on single-stage marking and post-NACT retrieval of involved node has demonstrated the concept of true de-escalation in this subset of patients, although the study (63) cohort is rather small and follow-up is also short. The regulatory issues around access to radioactive seed mean that MARI as a procedure may not be widely available. The eligibility criteria of the ATNEC trial (64) are designed to ensure low FNR and high SNIR, and therefore the trial will be able to address the oncological safety of true de-escalation in this patient population (Table 2).

Table 2

Ongoing clinical studies investigating de-escalation of axillary treatment following systemic treatment

Name Type of study Projected sample size Included patients Intervention arm Control arm Nodal irradiation Primary endpoint Secondary endpoints
MINIMAX, NCT04486495 (65,66) Retrospective analysis for oncological safety; prospective analysis for QoL Retrospective: 4,000; prospective: 549 Node positive non metastatic unilateral breast cancer undergoing NACT f/b surgery (SLNB/TAD/ALND) Not applicable Not applicable Axillary RT: no; SCF + IMLN RT: if ALND omitted Retrospective and prospective study: oncological safety (DFS, BCSS, OS, ARR); prospective study: QoL Not mentioned
ALLIANCE A011202, NCT01901094 (67) Phase III randomized controlled trial 1,576 cN+M0 becoming ycN0 post-NACT but are ypN+ on SLNB Axillary RT ALND alone Axillary RT: intervention arm; SCF + IMLN RT: both arms Invasive breast cancer recurrence-free interval OS; ILR-REC
NSABP B-51, NCT01872975 (62,68) Phase III randomized controlled trial 1,636 cN1 becoming ypN0 or ypN0(i+) or ypN0(mol+) post-NACT (cT4 and cN2/3 excluded) RNI No RNI Axillary RT: in intervention arm; SCF + IMLN RT: in intervention arm Invasive breast cancer recurrence-free interval OS; LRRFI
ATNEC trial, NCT04109079 (64,69) Phase III randomized controlled trial 1,900 cN+ becoming ypN0 on SLNB randomized No further axillary treatment ALND or axillary RT Axillary RT: only in control arm if no ALND; SCF: only control arm; IMLN RT: unclear DFS; patient reported lymphedema Arm mobility assessment; HR QoL; ARFI
EUBREAST-03 AXSANA study (59,70) Prospective international multicentre cohort study 3,000 cT1–4cN+M0 becoming ycN0 undergoing SLNB/TLNB/TAD or ALND Not applicable Not applicable According to institutional or national standards 5-year IDFS; 3-year ARR; QoL Feasibility of different forms of axillary staging techniques
ADARNAT, NCT04889924 (71,72) Randomized, open-label, multicentre, phase 3, non-inferiority trial 1,660 cN0/1 → ycN0/1; SLNB finding 1 or 2 metastatic SLNs SLNB-only followed by axillary RT SLNB followed by ALND Axillary RT: intervention arm; SCF + IMLN RT: both arms 5-year axillary recurrence Lymphedema or arm dysfunction; QoL; DFS; OS
(Neo)TAXIS (73) Multicentre, phase-III, non-inferiority, randomized trial 1,500 (upfront, post-NACT and IBTR with past SLNB >3 years ago) All cN+ve, except N2b and N3c undergoing NACT followed by targeted axillary surgery randomized TAS followed by axillary RT TAS followed by ALND Axillary RT: intervention arm; SCF + IMLN RT: both arms DFS OS; BCSS; physician reported morbidity outcomes

ALND, axillary lymph node dissection; ARFI, axillary recurrence-free interval; ARR, axillary recurrence rate; BCSS, breast cancer-specific survival; DFS, disease-free survival; f/b, followed by; HR QoL, health-related quality of life; IBTR, ipsilateral breast tumour recurrence; IDFS, invasive disease-free survival; ILR-REC, ipsilateral/local/regional invasive breast cancer recurrence; IMLN, internal mammary lymph node; LRRFI, loco-regional recurrence-free interval; NACT, neoadjuvant chemotherapy; OS, overall survival; QoL, quality of life; RNI, regional nodal irradiation; RT, radiotherapy; SCF, supraclavicular fossa; SLN, sentinel lymph node; SLNB, sentinel lymph node biopsy; TAD, targeted axillary dissection; TAS, targeted axillary surgery.

Node positive patients with incomplete pathological nodal response (cN+ to ypN+)

Even with the significant improvements in systemic therapies, not all patients with nodal involvement experience complete pathological response of metastases. While the current standard-of-care in such patient remains ALND, this is an active area of research. The most obvious approach to de-escalation in these patients is replacing ALND with axillary radiotherapy. One of the key questions in that regard is whether the chemoresistant clone of presumed residual metastatic burden in the remainder of axilla (non-sentinel nodes) be sensitive to radiotherapy for oncologically safe de-escalation. Such burden is not insignificant. An interim analysis of additional lymph node metastasis in ALND group of patients in Alliance A011202 trial (47) observed 46% patients who were ypN+ on SLNB had additional nodes involved. A combined analysis (74) of retrospective and prospective NEOSENTITURK studies (75) suggests low axillary recurrence risk with replacement of completion ALND by axillary radiotherapy irrespective of whether the residual nodal disease on SLNB or TAD was isolated tumour cells (ITCs) or micro/macrometastases. The results of the OPBC-05/ICARO study (46) show that in patients with incomplete response as indicated by the presence of ITCs, omission of ALND did not significantly increase the risk of axillary recurrence. A quarter of patients in this study were cN0 at presentation. At least three quarters of patients however received nodal radiotherapy. One of the key findings from the study was that intraoperative assessment of nodes led to a higher likelihood of completion ALND. It is increasingly clear that assessment of response at the primary tumour site plays an important role in treatment decisions including axillary intervention and this information is not available at the time of surgery. Therefore, even though it may avoid the need for a second anaesthesia and surgery, intraoperative assessment of nodes should be strongly discouraged, unless significant residual nodal burden that was not apparent on preoperative imaging is suspected intraoperatively. Another important finding from the study indicates that those undergoing SLNB had a higher likelihood of completion ALND as compared to those undergoing TAD/MARI. This underscores the argument discussed above regarding the accuracy as well as the perceived differences in the accuracy of these procedures. SLNB-alone does not provide sufficiently accurate staging information in a substantial proportion of patients for treating clinicians and patients themselves to feel confident regarding de-escalation of axillary surgery.

Multiple trials (Table 2) like the ALLIANCE A011202 (NCT01901094) (67), ADARNAT (NCT04889924) (71,72) and neoadjuvant component of TAXIS (73) are addressing this question. Apart from the establishing or refuting oncological safety of this approach, these trials provide an opportunity to identify predictors of residual axillary burden in the contemporary context. Our ability to accurately identify the probability of residual axillary burden in patients undergoing upfront surgery has been rather limited and therefore tools like nomograms (76) are not widely used. One of the reasons for limited accuracy of these tools is that they are primarily based on baseline tumour and sentinel nodal metastasis characteristics. The neoadjuvant therapy setting however offers the opportunity to investigate and incorporate many additional variables including different imaging techniques and response to treatment in the primary as well as node (77,78). Therefore, it is not inconceivable that diligent prospective collection of data on imaging variables in addition to pathology and treatment variables in these trials will allow development of highly accurate tools to predict residual axillary burden after the primary staging procedure. Indeed, the model developed using histopathological, biomarker and imaging response features based on the early data from the GANEA-3 study (54) has shown good accuracy (82% of patients correctly classified) in predicting overall pCR. Similarly, the interim results from the Alliance A011202 trial (47) show that micrometastasis in sentinel lymph node (SLN) (vs. macrometastasis) had a non-significantly (P=0.064) lower (38.4% vs. 47.8%) incidence of additional nodal burden on ALND. The incidence of additional nodal burden on ALND was non-significantly (P=0.053) higher in HR+/HER2-negative (49.1%) tumours as compared with HER2-positive (40.3%) and triple negative (39.8%) tumours. Poor response in primary as well as a greater number of sentinel nodes harbouring metastasis were predictors of additional nodal disease; 33.2% of patients with one involved SLN harboured additional disease as compared with 83.9% of those with 4 or more involved SLNs (P<0.0001). Such granular data will allow rapid development of accurate tools, especially since the endpoint for these tools is completion ALND without having to wait for primary endpoint data to become available. This will allow us to ask the question that is currently not addressed—can we completely de-escalate axillary intervention if the probability of residual axillary burden is low? With the availability of a wide range of targeted agents (39,79-81) and biological therapies (82,83), a substantial proportion of patients now receive extended or modified adjuvant systemic treatment in view of lack of complete response. The time may be ripe to address this complete de-escalation question in patients who will receive such therapy. For example, in the OPBC-05/ICARO cohort, additional positive lymph nodes were found at ALND in 30% of patients but contained macrometastases in only 5% (46). Those who did not achieve complete response at the primary tumour site and would therefore go on to receive additional/modified systemic treatment could be de-escalated for axillary intervention (new study/trial). On the other hand, those with complete response at the primary tumour site risk being undertreated or overtreated due to understaging if their residual axillary burden cannot be assessed without ALND or estimated (using desired new tools) accurately.


LABC

The proportion of patients presenting as LABC varies from region to region. In regions with healthcare access issues and lack of population-based screening, it is largely a manifestation of disease chronology. On the other hand, in developed regions, majority of these are a manifestation of disease biology, especially the interval cancers. However, our surgical approach to treating these is still largely based on chronology paradigm (stage at presentation) than biology paradigm (response to treatment). The MARI protocol (57,63) includes N2–3 patients and incorporates response to treatment as the guide to axillary intervention. TAXIS (73) and AXSANA (59,70) studies include T4 and N3 patients. However, barring these exceptions, majority of the trials (47,59,62,64-73) still exclude these patients (Table 2). The studies investigating the role of limited axillary staging are few (84) and far between. There is an urgent need to investigate axillary de-escalation in LABC starting with those patients who convert to ypN0 since up to a third of these patients achieve complete pathological response as determined by ALND (85). Since practically all LABC patients are treated with RNI, a trial investigating omission of ALND in ypN0 on TAD, a locally advanced version of the ATNEC trial is needed. Extensive international collaboration will be necessary to conduct an adequately powered trial. It is however also worth noting that a higher event rate in such patients means that the sample size with IDFS as an endpoint will not be prohibitively large. Recent research collaborations (59,61) suggest that mounting such an effort will be feasible.

There is no robust evidence to suggest that response to NACT would be substantially different between different nodes in the same patient. However, in patients with large baseline axillary burden, axillary surgery may also be considered to have a role as a therapeutic procedure in addition to being a staging procedure. With this consideration, many surgeons may feel uncomfortable in de-escalating surgery since managing recurrence at higher axillary levels can be surgically more challenging. Therefore, one of the questions worth exploring in patients with large baseline axillary burden is “Do we need to also mark the anatomically highest involved node?”. The trial could address this question by means of a second randomisation to mark vs. not mark the highest node. Concerns regarding a much greater probability of residual axillary burden prevent clinicians and researchers from contemplating de-escalation in these patients and therefore the tools (above) to accurately predict the probability of residual axillary burden are urgently needed. Once such tools accurately predicting residual nodal burden in the remainder of axilla in ypN+ patients become available, the locally advanced version of Alliance A011202 trial can also be contemplated.

Does ALND lead to detrimental survival?

Two recent studies (86,87) suggest such possibility at the face value. A retrospective cohort study by Tinterri et al. (86), compared direct axillary dissection (before 2018 cohort) vs. SLNB-based axillary surgery (SLN-only if ypN0 or ALND in ypN+ in sentinel node) in post-NACT patients who presented with cN+ disease and converted to cN0 status after NACT. This small study has several limitations including comparison between two treatment periods and multiple confounders, nodal response being one of the major confounders. Therefore, authors are correct in pointing out that better survival observed in SLNB patients suggests that the benefits are biological rather than that of surgical approach. The study however contributes to existing body of evidence supporting de-escalation of axillary surgery in cN+ patients. The study by Limberg and colleagues (87) using data from the US National Cancer Database observed a higher OS with ALND omission, but the association was not maintained after the adjustment. A lower pathological burden was associated with the omission of ALND in this study and this highlights the importance for appropriate confounder handling when analysing observational studies. Patients with poor response are more likely to undergo ALND and these are the same patients who are likely to have poorer outcome due to their biologically non-responsive disease, thus resulting in a false impression of ALND being associated with poor survival. A rigorous scrutiny of current evidence does not suggest that ALND leads to poorer survival.


Conclusions

A substantial progress has been made in reducing morbidity of axillary intervention through de-escalation of axillary surgery following neoadjuvant systemic therapy. However, a significant component of this progress does not represent true de-escalation as completion ALND is replaced with axillary radiotherapy. Increasing availability of even more efficacious systemic therapy options mean that true de-escalation of axillary intervention should be an achievable goal, at least in ypN0 patients. This however hinges on the accuracy of the staging procedure and the available evidence still clearly suggests that SLNB-only procedure does not reach the required level of accuracy, whereas TAD/MARI does. The available evidence also suggests that intraoperative assessment of nodes should be discouraged. A large number of trials are underway to evaluate de-escalation approaches, but these largely exclude LABC patients and this represents an unmet research need. True de-escalation of axillary intervention in patients with incomplete nodal response, at least in patients who will receive extended or modified adjuvant treatment, is a research question that merits our urgent attention. Willingness of patients and clinicians in participating in such research will depend on how accurately we can predict the probability of residual axillary nodal burden after the limited staging procedure. Therefore, research to develop such tools is urgently needed.


Acknowledgments

None.


Footnote

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-59/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-24-59/coif). The authors have no conflicts of interest to declare.

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doi: 10.21037/tbcr-24-59
Cite this article as: Tondare A, Thorat MA. De-escalation of axillary interventions in the management of breast cancer patients following neoadjuvant systemic treatment. Transl Breast Cancer Res 2025;6:14.

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