Short summary

Nodal status is a key prognostic factor for survival in breast cancer. 30% has disease in the axillary lymph nodes at the time of diagnosis. Lymph node metastasis are classified as isolated tumour cells, micro-, and macrometastasis. Descriptive register study with demographic and histopathology data. The aim of the study is to assess the risk of additional axillary disease in breast cancer patients with clinically node negative disease but a positive sentinel node after neoadjuvant therapy.

Rationale

Introduction

In Denmark approximately 4700 women are diagnosed with breast cancer each year. The overall survival rate for breast cancer is increasing. The current 5 year age-standardized relative survival after breast cancer in Denmark is 88 % (7), and nodal status is an important prognostic factor for long-term survival (2). This positive development highlights the need to reduce the risk of adverse effects. The aim of this study is to evaluate the risk of additional axillary disease in breast cancer patients with clinically node negative disease but a positive sentinel node after neoadjuvant chemotherapy. Could a de-escalation of the surgical procedure to the axilla be safe after neoadjuvant treatment?

Background

The most important prognostic factors for long-term survival after breast cancer are nodal status, HER2 status, hormone receptor status, tumour size and malignancy-grade (2). Triple negative breast cancers (TNBC) are oestrogen, progesterone and HER2 receptor negative (8). However, progesterone does not have a role in everyday practice anymore and is often not included in the pathological analysis. Patients with TNBC and positive HER 2 have a poorer prognosis than corresponding patients without this receptor profile (2,9,10).

The Danish Breast Cancer Group (DBCG) describes national recommendations regarding diagnosis and treatment of breast cancer.

At the time of diagnosis approximately 30% has involvement of the axillary lymph nodes (3-6). Lymph node metastasis are classified as isolated tumour cells (ITC) ( 0,2 mm and/or  200 cells), micrometastasis (MIC) ( 0,2 but  2 mm and/or > 200 cells) and macrometastasis (MAC) (> 2 mm). The standard evaluation of the axilla in Denmark is a combination of axillary ultrasound (AUS) and fine needle aspiration (FNA) in case US reveals any suspicious features of the axillary lymph nodes. AUS combined with FNA has an accuracy > 70 % (4-6), the accuracy increases with a higher axillary disease burden (4,11,12). However 25 % of AUS/FNA are false negative (13).

Neoadjuvant therapy (NAT) is offered to in an increasing proportion of patients (14). Referral to NAT depends on the size of the tumour and high-risk biological features and has several objectives:

1. down-size the primary tumour and increase the use of breast-conserving surgery (8,10,15)

2. minimize any possible axillary disease and de-escalate the surgical procedure (8,10,16,17)

3. down-stage inoperable patients (locally advanced) (18,19)

4. evaluate chemo-sensitivity pre-operatively (10,16,20,21)

5. treatment of microscopic disease (15)

Patients with HER2 positive and triple-negative breast cancer have the highest rate of pathological complete response (pCR) after NAT (8-10,17). Eradication of tumour from breast and lymph nodes are associated with better event-free and overall survival, than eradication from the breast only (10). It is debated whether pCR can be used as a surrogate for overall-survival, but the prognostic value is greatest in aggressive tumours (TNBC and HER2 positive) (9,10).

Sentinel lymph node dissection (SLND) is performed to evaluate an eventual spread to the axillary lymph nodes in all clinically node negative assessed by AUS and clinical examination. In October 2016 DBCG changed the recommendations regarding the timing of SLND in patients treated with NAT. SLND is currently performed after NAT to all clinically node-negative patients evaluated by AUS/FNA. The recommendations regarding additional axillary surgery depend on whether the patient has received NAT or not. In patients primarily operated, DBCG only recommends axillary lymph node dissection (ALND) if pathologic examination of sentinel nodes reveal macrometastasis (22). ALND is recommended if sentinel node pathology after NAT demonstrate metastatic axillary lymph nodes regardless of amount of metastatic disease (ITC, MIC, MAC) (14). The differentiated approach is based on two assumptions:

1. the accuracy of SLND is reduced after NAT (23)

2. residual axillary disease after NAT indicate chemoresistance and therefore imply the need for a more aggressive approach (16,24,25)

The reliability of SLND after NAT has been questioned due to a theoretical increased risk of false negative SLND because of reactive changes in the tissue after NAT which may affect the lymphatic drainage (23). In clinically node-negative patients the false negative rate (FNR) of SLND is comparable between SLND before and after NAT (FNR 6%) (26-28). The actual nodal status is unknown before surgery and in these studies not all patients were routinely evaluated by AUS/FNA and therefor more patients might have unknown axillary disease compared to Danish breast cancer patients.

The literature is not unanimous whether the nodal status (involvement of axillary lymph nodes) pre-NAT is an independent risk factor for a false negative SLND after NAT (23,28) but the division is applicable in the clinical management of breast cancer patients. The risk of a false negative SLND and additional axillary disease might depend on the tumour burden in the sentinel nodes (MAC, MIC or ITC). Previous studies on known nodal involvement indicates that all levels of tumour burden should be considered positive (25,29), but it is unclear whether this is also the case in node-negative patients.

Two large randomized controlled trials have evaluated the safety of omitting ALND in early breast cancer patients (no NAT) with micrometastasis and did not find a significant difference in disease-free survival (32,33). A previous Danish study also showed no difference in overall survival or risk of axillary recurrence if ALND were omitted in patients with micrometastasis or ITC receiving adjuvant therapy (34). These studies challenge the prognostic value of additional axillary surgery after a positive SLND in patients treated with adjuvant chemotherapy. In contrast, the prognostic value of ALND is still debated in patients treated with neoadjuvant chemotherapy. Recent studies indicate that the clinical importance of ALND after false-negative SLND in the node-negative NAT population is negligible since few patients experience axillary recurrence when ALND is omitted (24,35,36).

ALND has significant risk of adverse effects compared with SN. ALND has a higher risk of lymphedema (37), pain (38,39), impaired range of movement (37,38,40-42), and sensory disturbance (37-40). SLND is also associated with a higher quality of life compared with ALND due to the lower risk of adverse effects (37,40). Lymphedema is one of the most important adverse effects and can be a life-long problem in the effected patients. Several studies report an increased risk of lymphoedema in ALND compared to SLND (37,38,41-44) and a systematic review demonstrated a four times higher risk in patients undergoing ALND compared to SLND (19,9 % vs. 5,9 %) (45). Pain can be persistent for many years and can evolve over time (39). Development of lymphedema, pain and undergoing ALND is associated with an impaired function of daily activities after breast cancer treatment (38). The improved survival rate after breast cancer makes identification of patients that prosper of additional ALND beyond SN is essential because omission of ALND is associated with a lower risk of adverse effects to the surgical treatment.

This study only includes breast cancer patients with a negative AUS and/or negative FNA. The aim is to estimate the risk of additional axillary disease in breast cancer patients with a negative AUS and/or negative FNA but positive SN after NAT - is it possible to identify an association between risk of additional lymphatic spread and size of SN metastases (ITC, MIC or MAC)?

Description of the cohort

Inclusion criteria

- Women > 18 years diagnosed with node-negative breast cancer assessed by AUS/FNA.

- Diagnosed after October 2016 (new guidelines with SLND after NAT)

- Neoadjuvant therapy - initiated.

- Positive sentinel node assessed by SLND.

Exclusion criteria

- Previously diagnosed with breast cancer

- Distant metastatic disease at the time of diagnosis

- Only endocrine therapy

Data and biological material

Descriptive register study with data from the prospectively maintained DBCG database. Patients will be identified, and data will be extracted from DBCG and DPDG. Data will include information regarding demography (age), histopathology (tumour size, type, receptor status, Ki67 index, focality, number of SN removed, number and extend of positive SN (MIC, MAC, ITC), and the result of ALND (number of removed LN, number of positive LN), treatment response in the lymph nodes and breast, and treatment.

Collaborating researchers and departments

Department of Surgery, Vejle Hospital

• Hans B. Rahr

Department of Plastic and Breast Surgery Aarhus University Hospital

• Marianne Djernes Lautrup

Department of Clinical Oncology, Hospitalsenheden Vest, Herning

• Troels Bechmann

Department of Breast Surgery, Rigshospitalet/ Herlev-Gentofte Hospital, Copenhagen University Hos-pital

• Tove Tvedskov

Department of Pathology, Aarhus University Hospital

• Trine Tramm