Practical consensus recommendations regarding the management of sentinel lymph node issues in early breast cancer.

Axillary lymph node involvement is a very important poor prognostic factor in the clinical staging and management of breast cancer patients. Traditionally, axillary lymph node dissection (ALND) has been used for determining the status of the axillary lymph nodes. More recently the sentinel lymph node biopsy (SLNB) procedure has gained wider acceptance as the standard of care, having the advantage of being less invasivewhile providing good accuracy. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of the two different procedures and other issues in patients with early breast cancer for the benefit of community oncologists.

Introduction

Sentinel lymph node is the hypothetical first lymph node in the axilla that receives the draining lymph from a suspected breast cancer primary – and may contain metastasizing cancerous cells, if any.[1] The sentinel lymph node is the first filter to trap any metastasizing malignant cells and hence its status is well established as an important prognostic factor in patients with breast cancer.[2] The two methods used for determining the status of the axillary lymph nodes are SLNBand ALND. Axillary lymph node dissection is an invasive technique in which almost all the axillary lymph nodes are dissected and has the potential to result in significant lymphedema as an important side effect in almost a quarter of patients. Since SLNB is not as invasive as ALND, it causes less prominent side effects.[34] The high sensitivity rates and the low false negative rates of SLNB gave impetus for widespread acceptance of the technique.[56] Does currently available evidence indicate that SLNB alone is sufficient for accurately staging the axilla or does it require to be combined with ALND for accurate prognosis? This manuscript was prepared to help community oncologists better understand application of these two techniques along with insights on some diagnostic and surgical issues with regards to early breast cancer patients.

Expert oncologists from all over India met to discuss and reach a consensus statement to provide community oncologists with practical guidelines on the use of SLNB and ALND in different scenarios in early breast cancer patients. The discussion was based on published evidence and practical experience in real life management of such patients. The expert group discussions were moderated by Dr. Rajeev Aggarwal and Dr. Vedant Kabra. The core expert group consisted of Dr. Shanti Vardhan, Dr. Mandeep Singh, Dr. Rohan Khandelwal, Dr. Sumeet Jain, Dr. Siddharth Sahai, Dr. Sarah P. Cate, Dr. Narendra Deo and Dr. Rakesh Kaul. The members of the panel were also allowed to share their personal experiences and make comments. This manuscript is the outcome of the expert group discussion and consensus arrived at in 2017.

Defining Clinical Cohort and Practice of Expert Group Panel Members

The primary objective was to provide a consensus statement for community oncologists that could be applicable as ready-to-use practical recommendations. Hence, the applicable setting was outlined by defining the clinical cohort and current practice of the delegates and expert group panel members – on the basis of which this document was prepared. The experts discussed the case of a 62 year old lady who presented with a clinically mobile and painless 2.5 × 2 cm lump in upper outer quadrant of her right breast. Skin overlying the lump was observed to be normal. Clinically there were no palpable axillary lymph nodes. Bilateral mammographic findings were consistent with BIRADS 5 with right breast lump being at 10 o'clock axis, 10 cm from the nipple. There was no significant axillary lymphadenopathy on ultrasonography. Core needle biopsy (CNB) was suggestive of infiltrating ductal carcinoma (IDC), Grade 1, ER 90%, PR 90% and HER2 neu negative. Staging investigations ruled out regional or distant metastases. Based on this scenario, a series of questions were voted upon. Each question had multiple-choice options from which participants were to select the one that was most appropriate for their clinical practice setting. The expert group then discussed the options andarrived at the practical consensus recommendations for the community oncologists.

Role of Magnetic Resonance-Mammography before breast Conserving Surgery

MR-mammography is an imaging modalitythat has recently gained a specific role in selected cases for clinically staging newly diagnosed breast cancer patients.[7] Its wider role in women with moderate risk is still controversial as established data supporting its use in such patients is lacking.[8] A total of 60% of the polled oncologists were of the opinion that MR-Mammogram is an indispensible imaging tool and should be recommendedpre-operatively in all patients before undergoing BCS [Table 1]. The panel did not completely agree with the polled oncologists as MRI has been known to give false positive results which leads to unnecessary tests, biopsies and surgeries.[910111213] This is mainly because of breast MRI's high sensitivity but low specificity.[9101112131415] The panel was of the opinion that breast MRI findings may be the reason behind the increasing recommendations for mastectomy instead of BCS in early breast cancer patients, depriving patients the option of BCS. This is important since it is a less invasive procedure that allows preservation of body image and gives overall survival equal to mastectomy.[1617181920] Another reason not to recommend breast MRI more widely are the results of COMICE and MONET trials. They showed that breast MRI does not result into a reduced re-excision rate in patients with primary breast cancer.[2122] The MONET trial findings paradoxically observed breast MRI to be associated with an increased re-excision rate. The panel consensus was that MR-Mammography is not necessary before BCS in all the patients, however, it can be considered in high risk patients (such as BRCA positive patients and those with dense breasts on mammogram).

Table 1

Question 1 - Is magnetic resonance-mammogram important before breast conserving surgery in all patients?

Can Sentinel Lymph Node Biopsy Replace Axillary Lymph Node Dissection?

SLNB is now an established procedure for predicting axillary lymph node metastasis in early breast cancer. However, it is still not widely available across India.[23] For centers where SLNB is available/practiced, whether SLNB alone is sufficient for accurate staging of the axilla or does it require to be followed by ALND is an important question. The polled oncologists were presented with two different scenarios regarding the number of positive sentinel lymph nodes observed after SLNB and were asked whether they would recommend complete ALND. The polling results for the two scenarios, 1 out of 3 sentinel lymph nodes being positive and 3 out of 4 sentinel lymph nodes being found to have micrometastases are shown in Tables 2 and 3. The ACSOG Z0011 trial discussed the possibility of avoiding ALND in early breast cancer patients with limited sentinel lymph node positivity.[24] The trial randomized 891 early breast cancer patients with 1-2 positive sentinel lymph nodes into two groups: further axillary dissection versus only observation. The 5-year OS and 5-year DFS were similar in both the groups and it was concluded that the use of SLNB alone as compared to ALND in early breast cancer patients with limited sentinel lymph node metastases did not result in an inferior survival. The IBCSG 23-01 study also reported similar findings with regards to the use of SLNB in early breast cancer patients with limited sentinel lymph node metastases.[25262728] With regards to the prognostic impact of micrometastases and isolated tumour cells in lymph nodes, it is comparable as observed in the MIRROR study.[29]

Table 2

Question 2 - Will you proceed with axillary lymph node dissection if 1 out of 3 sentinel lymph nodes is positive?

Table 3

Question 3 - Will you proceed with axillary lymph node dissection if 3 out of 4 sentinel lymph nodes have micro-metastases?

The Indian scenario is varied with frozen section not being available at all centres. For patients in whom a sentinel lymph nodeis found to be positive during frozen section, the consensus of the panel was to recommend axillary nodal dissection as an abundant precaution.[30] If the micrometastasis in sentinel node (s) was identified only on final histopathology, the panel did not recommend repeat completion surgery with ALND. Adequate sampling of lymph node is to be done with standard method to ensure “micrometastasis” label is appropriate.

Acceptable Surgical Margins for Breast Conserving Surgery

BCS followed by radiation therapy is the accepted standard of care for most early breast cancer patients.[1617181920] A negative margin (free of any tumour cells) reduces the local recurrence rate. But the definition of negative margin may be different for different cancer surgeons.[3132] There is some debate over what are the minimum acceptable surgical margins required for BCS to be successful. Majority of the polled oncologists were of the opinion that getting no ink on the invasive tumour should be the minimum acceptable surgical margin in patients with early stage invasive breast cancer undergoing BCS followed by radiation and systemic adjuvant therapy [Table 4].

Table 4

Question 4 - What is the minimum acceptable surgical margin in an invasive early breast cancer patient undergoing breast conserving surgery followed by radiation and systemic therapy?

A meta-analysis by Houssami et al.[33] was carried out to study the impact of surgical margins on the local recurrence in women with early stage invasive breast cancer. The analysis took into account 21 studies which included 14,571 patients. The local recurrence odds ratio for positive margins versus negative margins was observed to be 2.42; however, no significant difference was observed in local recurrence associated with different margin widths (e.g., more than 1 mm, more than 2 mm, or more than 5 mm). The Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) carried out two different meta-analyses for providing a consensus on surgical margins for BCS with whole breast radiation therapy in patients with invasive carcinoma and ductal carcinoma in-situ.[3536] The meta-analysis for invasive carcinoma included 33 studies with 28,162 patients while that for ductal carcinoma in-situ included 20 studies with 7,883 patients. The guidelines formed after the meta-analyses were that no ink on tumour in case of invasive carcinoma while 2 mm in case of ductal carcinoma in-situ should be used as the standard for adequate margins as they are associated with reduction in recurrence and re-excision rates. In view of these established reviews, the expert panel concluded that no ink on tumour should be used as the minimum acceptable safety margin in patients who have invasive breast cancer and 2 mm margin should be used as the minimum safety margin in patients with ductal carcinoma in-situ. The expert group also considered Frozen section unreliable for negative margin status due to its high variance in diagnostic sensitivity.[34]

Breast Conserving Surgery in Multi-Focal or Multi-Centric Cancers

Multi-focal (MF) breast cancers are defined as having at-least 2 invasive tumours in the same quadrant while multi-centric (MC) breast cancers are defined as having at-least 2 invasive tumours in 2 different quadrants.[37] The frequency of these tumours ranges from 5% to 44% in published series.[3839404142] The use of BCS in patients with such tumours is controversial and no specific consensus exists. When asked the question as to whether they would recommend BCS in patients with MF/MC tumours if clear margins are achievable and WBRT is planned, 60% of the polled oncologist gave an affirmative answer [Table 5]. MF and MC tumours are many times considered as relative contraindications for BCS due to the concern over increase in local recurrence.[43444546] Some studies have reported increased risk of local recurrence after BCS in patients with MF and MC breast cancers as compared to that in patients with unifocal tumours.[4547] However, these are all old studies and many recent studies have reported BCS in MF/MC cancers not to be associated with increased risk of local recurrence.[394849] The panel recommended that a very careful selection of patients with MF/MC breast cancers needs to be done prior to providing them BCS as the results are generally acceptable only in a subset of these patients.[39] A good radiological workup is essential in MC disease. In MF disease, the panel recommended BCS only if it is possible to remove all the tumours in a single incision. The panel consensus was that BCS should be provided to only a subset of patients with MF/MC breast cancers, particularly to women aged between 50 and 69, having small tumours and without excessive ductal carcinoma in-situ.

Table 5

Question 5 - Can breast conserving surgery be considered in patients with multifocal/multi-centric tumours if clear margins are achievable and WBRT is planned?

Breast Conserving Surgery in Subareolar/Retroareolar Breast Cancers

BCS has been in the past excluded from the treatment options for patients with centrally located tumours in retro-areolar location with or without involvement the nipple-areola complex (NAC).[50] One of the reasons behind this exclusion may be the unsatisfactory cosmetic results. However, BCS has now been widely accepted as a mode of treatment for patients with subareolar breast cancers.[51] When asked to give their opinion on this matter, the polled oncologists unanimously supported recommending BCS in subareolar breast cancer patients [Table 6]. Traditionally BCS has been suggested as a relative contraindication for patients presenting with tumours within 2 cm of the NAC.[50] BCS in these patients requires the removal of some or all of the NAC for proper tumour excision. This is the main reason why BCS is avoided by some surgeons due to the apparent higher incidence of multifocality and multicentricity in central tumours.[5253545556575859] However, there have been studies reporting BCS to be equally efficient in patients with subareolar breast cancers as compared to that in patients with peripheral breast cancers. A prospective study by Tausch et al.[60] included 44 women who had suspected nipple involvement and underwent BCS with the removal of NAC. The study reported no local failure in any of the patients at 51 months and the cosmetic results were satisfactory to excellent. This study deemed BCS as safe in subareolar breast cancers. Some other studies have also reported similar outcomes and thus BCS is now accepted as an efficient alternative to mastectomy in patients with tumours involving the NAC.[505161] The panel agreed with the polled oncologists and the studies and concluded that BCS is a feasible option in subareolar breast cancers in light of its acceptable rates of local recurrence as well as the cosmetic results. BCS should be extended to these patients as an alternative to mastectomy.

Table 6

Question 6 - Can breast conserving surgery be considered in patients with a solitary subareolar tumour?

Repeat Sentinel Node Biopsy after Local Recurrence

Patients with locally recurrent breast cancer undergo axillary staging for obtaining locoregional control and predicting prognosis. Most locally recurrent patients undergo ALND but SLNB can provide regional nodal status and is now the standard for axillary staging in early breast cancer patients as it is accurate as well as sensitive but less invasive than ALND. However, the high sensitivity and the low false negative rate of SLNB may not be the same in case of local recurrence. When asked whether repeat SLNB is feasible in case of an isolated local recurrence 10 years down the line, the polled oncologists unanimously supported recommending it [Table 7]. Recently, some studies have been undertaken for testing the feasibility of SLNB in patients who have had local recurrence. Two Dutch trials were conducted to determine feasibility, aberrant drainage rates and clinical consequences of repeat SLNB.[6263] One included 150 patients while the other included 536 patients with locally recurrent breast cancer, but the results reported were very similar. Lymphoscintigraphy was done in all the patients to determine any aberrant lymph drainage and then SLNB was provided. A sentinel node was identified in 60% of the patients and was successfully harvested in 50% of the patients. Aberrant lymph drainage was observed in about 55% of the patients. This aberrant lymph drainage was seen significantly more in patients who had undergone ALND earlier as compared in patients who had undergone SLNB. Change in adjuvant plans after the repeat SLNB was very different in the 2 studies with 16.5% of the patients with positive SLNB undergoing a change in adjuvant plan in 1 study as opposed to 63% in the other. Overall, both the studies concluded that repeat SLNB is indeed feasible with reliable results in patients with locally recurrent breast cancer. The panel reached a consensus that repeat SLNB is feasible in locally recurrent patients and provides accurate results with high negative predictive value, thus potentially helping in the omission of ALND in patients with negative repeat sentinel lymph node. The panel recommended that repeat SLNB should be preceded by lymphoscintigraphy and repeat SLNB should be provided to all locally recurrent breast cancer patients regardless of whether ALND or SLNB was done initially.

Table 7

Question 7 - Should repeat sentinel lymph node biopsy be done in case of local recurrence after 10 years?

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Conflict of interest

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