Management of axilla in breast cancer : the past , present and the future

The role of surgery in treatment of breast cancer has evolved substantially during the last century where radical surgery has gradually been replaced by more conservative approaches. Similarly, surgical treatment of the axilla has changed rapidly especially over last three decades. This is mostly as a result of improvements in understanding of disease behaviour and advances in systemic therapy. Axillary surgery has the dual uses of removing the disease from the axilla and providing information for prognostication which help guide adjuvant therapy. However, surgery to the axilla is associated with substantial morbidly including lymphedema and shoulder stiffness. Hence, less radical approaches for the treatment of the axilla have been of interest. The traditional gold standard of axillary lymph node dissection was challenged by many clinical trials. As result sentinel lymph node biopsy was introduced as an alternative for patients with clinically negative axillae which later became the standard of care for such patients. Subsequent studies proved the safety of omitting completion axillary dissection or replacing with radiotherapy for selected patients with minimal sentinel lymph node involvement. The application of sentinel lymph node biopsy for axillary staging after neoadjuvant chemotherapy has become an area of clinical interest. However, sentinel lymph node biopsy in node-positive patients who become node negative after neoadjuvant chemotherapy is controversial at present due to the relatively high false-negative rate. This however, is improved by careful patient selection combined with some minor changes to the surgical technique of sentinel lymph node biopsy. Novel techniques for lymphatic mapping have shown promising results which further simplify the procedure while improving the accuracy. Axillary reverse mapping, a technique to preserve lymph nodes draining the arm during axillary surgery for breast cancer has been described recently which has further reduced surgical morbidity. The omission of axillary surgery in selected patients with an acceptably low risk of nodal metastasis has gained increasing research interest in the recent past. Furthermore, advances in treatment and newer prognostication techniques have reduced the dependence on axillary nodal status on adjuvant therapy decision-making. This has led to several ongoing clinical trials which will assess the feasibility of avoiding sentinel lymph node biopsy altogether in selected groups of patients without compromising outcomes.


Introduction
Breast cancer is the most common female cancer worldwide including both developing and developed countries [1].In Sri Lanka, breast cancer has become the commonest cancer and a continuous increase in the incidence is observed [1].Treatment of breast cancer initially was based on management of primary cancer and the adjacent region; the breast and the axilla.This however has changed dramatically with the advent of systemic therapy which not only has led to major improvements in survival but also less radical surgery [2].The role of surgery in the management of the axilla especially in patients with early-stage breast cancer has evolved in the past few decades with the improvement in the understanding of the disease together with advances in systemic therapy.This review focuses on the evolution of the surgical management of axilla in breast cancer and summarises the current evidence on sentinel lymph node biopsy (SLNB) in early breast cancer patients, novel techniques for SLNB, and the ongoing clinical trials on management of axilla in breast cancer.

Evolution of breast cancer surgery
The history of management of breast cancer goes back to early 1800s.Rudolf Virchow (1821Virchow ( -1902)), a German pathologist postulated a hypothesis based on his autopsy studies that there was evidence of axillary lymph node (ALN) involvement in females who died from advanced disease [3].Local invasion of cancer with progressive spread to regional and distant structures were key components of his hypothesis.Based on these findings, William Halsted (1852Halsted ( -1922) ) introduced radical mastectomy which comprised of a radical resection of breast with pectoralis major and minor muscles together with ALNs as en bloc [4].David Patey in 1940s introduced modified radical mastectomy which preserved pectoralis major muscle to reduce surgical morbidity without compromising on overall survival [5].Later, Madden and Auchincloss showed that the pectoralis minor muscle can also be preserved while achieving a ALN clearance with comparable outcomes [6].With better understanding of the pathogenesis of the disease and advances of local and systemic adjuvant treatment, the concept of radical surgery was disputed and breast conservative surgery became the standard of care where feasible.The simple mastectomy was first developed by Kennedy and Miller [7].In 1991, Toth and Lappert described skin sparing mastectomy which allowed breast reconstructions with improved cosmetic outcomes [8].
Management of ALNs has been a cornerstone in patients with breast cancer.It helps with regional disease control and provides valuable information for prognostication and for decisions on adjuvant therapy.Axillary lymph node dissection (ALND) remained as the method of axillary staging and routine ALND was the gold standard of managing the axilla until the 1970s, despite the surgical morbidity related to the procedure.This practice started to change after the which National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-04 disputed the value of ALND in patient without any clinical evidence of axillary metastasis as approximately 40% of patients undergoing ALND had negative nodal involvement [9].This proportion increased further with the introduction of mammographic breast cancer screening in 1980s, which led to a rise in early breast cancers.As a result, many researches were conducted to study the usefulness of ALND in such patients with early stage disease with no clinical involvement of the ALNs.

Axillary staging with sentinel lymph node biopsy in breast cancer
Axillary lymph node staging in patients with breast cancer is initially performed with physical examination of regional nodes.However, this is influenced by body habitus and thus has an approximately 50% false-negative rate (FNR) [10].Therefore, ultrasonography is the preferred modality for nodal assessment.Additional advantages of ultrasonography include the ability to obtain guided needle biopsies to allow pathological assessment of suspicious nodes.However, to date no imaging modality has been accurate enough to accurately stage the axilla especially when the nodal burden is minimal.
The concept of SLN is based on the principle of lymphatic drainage from the breast to regional lymph nodes which follows an orderly pattern initially reaching a node or few nodes known as the sentinel lymph nodes (SLN).Initial understanding of different sentinel node groups depending on the site of the tumour was challenged by the subsequent studies which showed that all lymph drains into the same sentinel nodes through the subareolar lymphatic plexus of Sappey [11].Further studies have shown that periareolar or intradermal injections of mapping agents are equivalent or superior to peritumoural injections [12].Although internal mammary nodes can drain the deep retromammary areas, the risk of involvement without axillary nodal involvement is minimal and hence isolated or initial internal mammary nodal recurrences remains very low [13].
SLNs are harvested using different techniques which commonly include a blue coloured dye (methylene blue or isosulphan blue) or a radioactive technetium 99m-labelled colloid.Detection rate for SLNs are approximately 90% with the blue dye and >95% when combined with a radioactive tracer [14].Novel techniques for detection of SLN include indocyanine green fluorescence, contrast-enhanced ultrasound using micro bubbles and superparamagnetic iron oxide nanoparticles which however are not widely practised yet.A recent systematic review has shown that these newer methods to be comparable to existing techniques in relation to detection rates [14].

Management of clinically negative axilla
Sentinel lymph node biopsy vs. axillary lymph node dissection for axillary staging Due to the associated surgical morbidity, ALND was a major concern in patients with negative axillary nodes.NSABP B-32 trial was conducted with the objectives of determining the value of SLNB in regional control and overall survival compared with ALND in resectable breast cancers with clinically negative axillae [15].This randomized phase three multicentre clinical trial randomly assigned 5611 to SLNB plus ALND or SLNB alone with ALND only if sentinel nodes were positive.Identification of SLN was done with a combination of radiocolloid and isosulfan blue dye.SLN identification rate was 97.2% with a FNR of 9.8%.After a median follow up of nearly 8 years no significant differences were observed in disease-free survival (hazard ratio [HR] 1.05, p=0.54) or overall survival (HR: 1.20, p=0.12) between the two groups.A substantial reduction in surgical morbidity was noted in SLNB alone group in terms of shoulder stiffness, lymphedema and upper limb numbness.Similar results were obtained from ALMANAC and Milan trials [16,17].Based on these studies, SLNB is currently considered as the standard of axillary staging in operable breast cancers with clinically negative axillae.

CASE STUDY
Oncology Group assessed impact of avoiding ALND in patients with positive SNLs on local cancer recurrence and survival [18].This phase three non-inferiority randomized control trial included breast cancer patients with clinically negative axilla with T1-T2 cancers undergoing lumpectomy and whole breast irradiation.Patients with 1-2 sentinel nodes positive for micro or macro metastasis were randomized into ALND or no further axillary surgery.There was no significant difference in 5-year overall survival and disease-free survival between the two groups after a median follow up of over 6 years.This land mark trial findings confirmed the safety of omitting ALND in T1 or T2 breast tumours with less than three positive SLNs.Furthermore, 10-year of follow up has confirmed the absence of a difference in outcomes between the two groups [19].Two other randomized trials have evaluated patients with micro metastasis (>0.2 mm but ≤2 mm), the IBCSG 23-01 trial (primary tumour <5cm) and AATRM trial (primary tumour <3.5cm) [20,21].Both showed no statistical significance in disease free survival [20,21].Thus, the place of ALND in those with locally advanced disease in <3 SNLs was disputed.Findings of these trials were incorporated into National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology [22] and American Society for Clinical Oncology (ASCO) guidelines.
With the establishment of SLNB as the standard of care, fewer nodes were available for pathological analysis and hence, immunohistochemistry gradually gained popularity.However, this resulted in identification of isolated tumour cells, which is defined as clusters of metastatic deposits of 0.2 mm or less in size, single tumour cells or clusters of <200 cells in a single cross-section [23].Several prospective trials have shown no differences in overall survival rates between immunohistochemistry positive and negative patients [24].Thus, most current guidelines do not recommend the routine use of immunohistochemistry of SLNs [22].However isolated tumour cells may be clinically relevant in lobular tumours due to their non-cohesive growth patterns [25].Therefore, nodal metastases may present as widely dispersed isolated tumour cells [25].Thus some still perform immunohistochemistry of SNLs in patients with lobular cancers and consider ALND when isolated tumour cells are identified [23].

Axillary lymph node dissection vs. radiotherapy for positive lymph nodes
In the instances where the decision has been taken to proceed with treatment of axilla due to positive SNLs, ALND is considered as the standard.However, this is associated with substantial long-term morbidity.After Mapping of the Axilla, Radiotherapy or Surgery (AMAROS) trial evaluated the place of axillary radiotherapy instead of ALND [26].This multicentre randomised, phase three non-inferiority clinical trial included patients with T1 and T2 breast cancers with absent clinical lymphadenopathy and were randomized into ALND or axillary radiotherapy.After a median follow up of over 6 years, comparable axillary control with less morbidity was observed in axillary radiotherapy group.

Sentinel node biopsy in women older than 70 years
Elderly patients over 70 years of age with clinical stage I (T1N0M0) and oestrogen receptor positive breast carcinoma have less aggressive course of disease.Studies have shown these patients to have no difference in mortality with no surgery for the axilla compared with ALND [27,28].The impact of avoiding radiotherapy in elderly patients undergoing breast conserving surgery was analysed in Cancer and Leukemia Group B 9343 trial.This trial randomized elderly women into radiotherapy with tamoxifen versus tamoxifen only.This study showed that adjuvant radiotherapy did not alter the local recurrence rates or survival of these patients who had oestrogen receptor positive early breast cancers [27].However, this trial was conducted prior to the era of standard SLNB, and as a result 60% of the patients did not undergo axillary surgery.Therefore, these results could be biased due to the inclusion of patients into node negative group based on clinical evaluation alone.Some current guidelines including the Society of Surgical Oncology recommend the omission of routine SLNB in females over 70 years of age with hormone receptor positive and clinically negative axilla [29].Furthermore, the latest NCCN guidelines recommend SLNB as optional in women older than 70 years with tumours with favourable prognostic characteristics, in whom axillary staging has no effect on the decisions regarding systemic adjuvant treatment [22].

Place of sentinel node biopsy in patients undergoing neoadjuvant chemotherapy
Neoadjuvant chemotherapy may be used in patients with clinically negative axilla at presentation due to unfavourable tumour biology, large primary tumour and patients' wish for breast conservative treatment.Although there is consensus that these patients should undergo SLNB, the timing of SLNB is controversial.Data from M.D. Anderson Cancer Centre have shown that comparable false negative rates (5.9% vs. 4.1% in neoadjuvant and in surgery first group respectively, p =0.39) with no significant differences in overall or disease free survival rates [30].Interestingly, patients undergoing SLNB post-neoadjuvant chemotherapy showed significantly lower rates of positive SLNs in T1 to T3 tumour categories (T1 tumours: 12.7% vs. 19%, p=0.2;T2 tumours: 20.5% vs. 36.5%,p<0.0001; and T3 tumours: 30.4% vs. 51.4%,p=0.04).Dual tracer method with removal of two or more sentinel nodes are recommended to reduce the false negative rates associated with SNB after neoadjuvant therapy [30].

Management of the clinically positive axilla
Avoiding axillary surgery is beneficial to the patient due to its associated side effects, some of which carry a substantial morbidity.However, ALND is still considered as the routine The Sri Lanka Journal of Surgery 2018; 35(4): 25-30 The Sri Lanka Journal of Surgery 2018; 35(4): 25-30 reported when a clip was not used or when the clip could not be retrieved during surgery (13.4% and 14.3%, respectively) [36].Hence, retrieving the clipped node with previously confirmed disease, which may or may not be the SLN, is recommended to be added to surgical staging of axilla after neoadjuvant chemotherapy.Targeted axillary dissection is a newer technique which removes both the sentinel nodes and the clipped node, which would help minimize morbidity of ALND while maintaining an acceptability low FNR.Several current studies are evaluating the usefulness of targeted axillary dissection in comparison to the existing techniques [23].
There is still a controversy surrounding the management of pre-neoadjuvant node-positive patients who become node negative after neoadjuvant chemotherapy.At present, here is insufficient good quality data evaluating the oncological outcomes of excluding ALND in this group of patients.However, some are already practising SLNB instead of primary ALND for these patients [23].

Minimizing morbidity of SNB/ALND -Axillary reverse mapping (ARM)
ARM is the mapping of the arm and the breast lymphatic drainage systems simultaneously so that nodes draining the upper limb can be identified separately from the nodes that drain the breast [37].This is performed with two different types of mapping agents injected simultaneously to the arm and the breast i.e. radioisotope to the breast and blue dye to the arm.With this technique, it is feasible to identify the lymphatics and nodes draining the upper limb and preserve them preserve them.However, the preservation of crossover nodes draining both the arm and the breast may result in suboptimal oncological lymph node clearances.A recently published meta-analysis has confirmed the feasibility of ARM and the significantly low rates of lymphedema associated with ARM compared with standard ALND [38].However, further studies are needed to confirm the oncological safety of this technique before it could be incorporated in to standard practice.

Future perspectives in the management of axilla in breast cancer
Several prospective, multicentre, randomized controlled trials are in progress to address the above concerns in clinically node positive patients who receive neoadjuvant chemotherapy.NSABP B-51/Radiation Therapy Oncology Group 1304 Trial is an ongoing randomized phase three clinical trial including patients with T1 to T3, FNAC proven positive axillary nodes undergoing neoadjuvant chemotherapy [23].Patients with clinically node negative axillae post neoadjuvant therapy are randomized to receive no nodal irradiation versus nodal irradiation.Outcomes of interest in this study include overall and disease-free survival and quality of life in irradiated versus non-irradiated patients [23].standard for patients with clinical, radiologically or pathologically proven positive axillae.Furthermore, ALND is performed when SLNB fails or when it is contraindicated.Standard ALND which removes level I and II axillary lymph nodes preserving the axillary vein, thoracodorsal neurovascular pedicle, and the long thoracic nerve allows comprehensive staging of the axilla.Level III clearance is not performed routinely except in situations where level III nodes are clinically involved due to the excess risk of surgical morbidity.
Patients with axillary disease often receive neoadjuvant chemotherapy and with the advancement of efficacy of the agents, response to treatment has also improved with nodal eradication rates of approximately 40% [31].ACOSOG-Z1071 (Alliance) prospective multicentre clinical trial revealed variable nodal conversion rates depending on the receptor status of the tumour [31].Conversion rates were 21.1% for ER/PR positive, HER-2 negative tumours; 49.4% for triple negative tumours and 64.7% for HER-2 positive tumours.Usage of dual tracer technique and removal of three or more sentinel lymph nodes have shown to reduce FNR in this group of patients [32].
Routine use of ALND in patients with clinically node negative axillae after neoadjuvant therapy has been brought to question as there was an increasingly higher complete pathological response rates in the axilla.Three large prospective registry studies have evaluated the role of SLNB followed by ALND after completion of neoadjuvant chemotherapy in clinically T1-4, N1-2, M0 breast cancers who received neoadjuvant chemotherapy [32][33][34].Of these the ACOSOG-Z0171 trial evaluated the FNR of SLNB and reported a FNR of 12.6% (90% CI=9.85%-16.05%).The use of dual tracers, harvesting three or more SLN and use of immunohistochemistry were shown to reduce the FNR substantially [32].Furthermore, ultrasonography was shown to be highly unreliable in assessing the nodal response of neoadjuvant therapy.Of the 430 patients with negative nodes on ultrasonography after neoadjuvant chemotherapy, 243 (56.5%) had residual positive nodes.Furthermore, 28.2% (51/181) of patients with suspicious nodes on ultrasonography after neoadjuvant chemotherapy were found to be negative pathologically [35].The SENTinel NeoAdjuvant (SENTINA) study which was a multicentre European trial showed similar findings in terms of FNR with an overall FNR of 14.2% [34].However, in that trial only 25% underwent pathological confirmation of nodal disease before neoadjuvant chemotherapy.
The ACOSOG Z1071 studied the usefulness of placing a nodal clip in 170 patients with biopsy-proven nodal disease.In 75.9% patients with more than two SLNs retrieved, the clip was found to be inside the retrieved SLN with a FNR of 6.8% (95% CI=1.9%-16.5%)[36].Much higher FNRs were

IMAGES IN SURGERY
Another ongoing randomized trial, the Alliance A11202 trial is studying the impact of avoiding routine regional nodal irradiation after ALND in patients with residual positive nodal disease after neoadjuvant chemotherapy [23].The outcomes of interest of this study include overall and disease free survival and incidence of lymphedema in the two groups [23].Future research will focus to identify patients who have low risk axillary nodal disease where surgery of the axilla can be avoided altogether.To this end, some preliminary studies have shown potential of gene expression profiling in predicting nodal involvement which may potentially help avoid axillary surgery.

Conclusion
The principles of surgical management of ALNs in breast cancer has undergone a major change from the initial radical surgery to minimally invasive and then to no surgery at all at least in some selected groups of patients.SLNB as the standard of care in patients with early breast cancer is well established, and the indications for ALND is becoming less and less due to associated surgical morbidity.Accurate evaluation of ALNs is important in decision making and clinicians should be aware of the pros and cons of various techniques of axillary staging.The role of SLNB after neoadjuvant therapy in clinically negative axilla is gradually being incorporated in practice.However, SLNB after neoadjuvant treatment in clinically positive axilla is still not well established as a routine due to the high FNR.Further studies will be useful to assess the role of SLNB after neoadjuvant chemotherapy in patients with clinically positive axillae.Current and future research focus on identifying patients with an acceptably low risk ALN metastasis where axillary surgery could be omitted.
Positive Sentinel node biopsy -Sentinel node biopsy alone or axillary lymph node dissection?Z0011 trial conducted by the American College of Surgeons The Sri Lanka Journal of Surgery 2018; 35(4): 25-30