The primary aim of the study is to evaluate the 5 yr locoregional recurrence rate (LRR) in cT1-2cN0-1(cytology/histology and/or positive SN, excluding patients with > 3 pathologic axillary nodes on imaging) breast cancer patients, treated with neoadjuvant chemotherapy, breast surgery, and radiotherapy that is protocolized based on the pathology findings after chemotherapy and definitive surgery (ypTNM stage).

Primary systemic treatment for breast cancer patients used to be given only to patients with locally advanced disease. Although until now no studies have been reported that primary systemic treatment leads to a superior survival compared to adjuvant chemotherapy [Mauri et al, 2005; Mieog et al, 2007], the last years have been showing an increase in the use of primary systemic treatment , also for patients with earlier stages of breast cancer. The suggested advantages of this policy are 1) that primary systemic treatment allows for monitoring of the response on the treatment, such that the type of chemotherapy can be changed in case of no response, and 2) that primary systemic treatment may shrink the tumour volume, allowing for a higher percentage of breast conserving therapy [Mieog et al, 2007]; and 3) the overall 40% chance of converting positive axillary nodes pre-PST to negative, questioning the need for an axillary dissection [Fontein et al, 2013; Kuehn et al, 2013]. A major disadvantage of primary systemic treatment is however, that the indications for post-operative radiotherapy are based upon studies where loco-regional recurrences were correlated to the pathological T and N stage in patients who had not been treated with chemotherapy before surgery. Since primary systemic treatment is affecting the pathological T and N stage, the indications for post-operative radiotherapy in these patients have become uncertain.

Objective: The primary aim of the study is to evaluate the 5 yr locoregional recurrence rate (LRR) in cT1-2cN0-1(cytology/histology and/or positive SN, excluding patients with > 3 pathologic axillary nodes on imaging) breast cancer patients, treated with neoadjuvant chemotherapy, breast surgery, and radiotherapy that is protocolized based on the pathology findings after chemotherapy and definitive surgery (ypTNM stage). The secondary aim is to develop a risk model based on risk factors, that can be used to predict which of the patients with a cT1-2cN0-1 breast carcinoma, treated with neoadjuvant chemotherapy and surgery, have a 5 yr LRR > 8 % if radiotherapy is withheld.

Study design: This study is a multicentre prospective cohort study. Study population: In total 710 patients with cT1-2pN0-1, excluding ≥cN2 and patients with > 3 pathologic axillary nodes on imaging, breast cancer, treated with at least three cycles of chemotherapy followed by breast and axillary surgery are eligible for the study.

During 5 years (2011-2015) patients diagnosed for primary breast cancer and eligible according to the criteria will be registered by the National Cancer Registry in this project.

Currently, three surgical strategies are being followed in cT1-2N0-1 patients, treated with primary systemic treatment :

1. A full axillary lymph node dissection is performed after the primary systemic treatment , OR
2. A sentinel node procedure is carried out prior to neoadjuvant treatment, and no further axillary surgery is performed after chemotherapy, if the patient is clinically node negative (ycN0)), OR
3. A sentinel node procedure is carried out only after primary systemic treatment , in case patient is still/has become clinically node negative (ycN0).

For all three above mentioned strategies, patients are divided into three risk groups, mainly based on the post chemotherapy pathological nodal status (strategy 1 and 3), and on the pre-chemotherapy pathological nodal status and ycN0 status (strategy 2). In addition, for all three strategies the cT and the ycT status are taken into account to choose the recommended guideline.

The radiation treatment guidelines for the subsequent three risk groups consist of:

1. Group I - low risk (N = 237):

   1. after MRM: no radiotherapy
   2. after BCT: radiation treatment of the breast with boost (optional)

2. Group II - intermediate risk (N = 237):

   1. after MRM: radiation treatment of the thoracic wall
   2. after BCT: radiation treatment of the breast with boost (optional)
   3. if no full ALND is performed: add radiation treatment to level 1 and 2

3. Group III - high risk group(N = 237):

   1. after MRM: radiation treatment of the thoracic wall and supraclavicular nodes
   2. after BCT: radiation treatment of the breast with boost (optional), and supraclavicular nodes
   3. if no full ALND is performed (not recommended): add radiation treatment to the axilla level 1 and 2 RT of the axillary (after ALND) and internal mammary chain nodes is optional for group III, based on the local protocol. In case of a positive sentinel node in the internal mammary chain prior to chemotherapy, internal mammary chain irradiation is strongly recommended Main study parameters/endpoints: The primary endpoint is the 5 yr locoregional recurrence rate (LRR). Secondary endpoints are 10 year LRR, 5, 10, and 15 yr relapse free survival rates (all events except lost to follow-up, invasive contralateral cancer, and secondary primary (non-breast) invasive cancer) and overall survival rates. In addition, analyses will be performed to investigate whether pre-radiotherapy factors (e.g. like age < 40 yr, response to chemotherapy, tumour size) can be identified that correlate with a high LRR.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Currently no clear data are present in literature showing the indications for radiotherapy in this patient group. Based on literature that is available for patients treated with chemotherapy after surgery we have chosen what we think might be the optimal treatment from a benefit/risk perspective. The study focuses on adequate registration of all risk factors, treatment, and outcome.

Date amendment: 1 July 2013

The main reason for writing an amendment is that current guidelines on axillary treatment are changing, both with respect to surgery and with respect to radiation treatment. Not sufficient data are yet present in literature to define a sound evidence based guideline. However, recent new data strongly suggest that the guidelines should be adapted. Therefore, we adapted the guidelines within the framework of this protocol, with as aim to carefully follow and record the outcome of patients treated with these new guidelines. Whilst writing this amendment, we also used this opportunity to better define "suspicious nodes" on imaging, and to add another very relevant endpoint: relapse free survival.

Inclusion criteria:

• cT1-2 invasive breast cancer, without or with one or more pathologically proven tumour positive axillary lymph nodes (either by sentinel node biopsy, ultrasound/palpation guided biopsy or fine needle aspiration)
• At least 3 cycles of primary systemic treatment have been given (irrespective of the regimen)
• No standard axillary lymph node dissection is performed prior to chemotherapy

Exclusion criteria:

• cT3-T4 invasive breast cancer prior to any treatment
• Patients with > 3 suspicious axillary nodes on imaging
• cN2-3 prior to any treatment
• More than focally irradical surgery and breast conserving therapy

To investigate whether a patient is eligible for the RAPCHEM study, a meticulous examination of the axilla is necessary. Therefore each patient should undergo an ultrasound of the axilla and if possible an ultrasound guided needle biopsy UNB (FNA or core). The US/UNB can be performed instantly or as second look in case of enlarged nodes on MRI. The criteria for performing an UNB are:

• Cortex >2.3 mm not measured at the poles of the node; or
• Disappearance of the fatty hilum; or
• Asymmetric bulging of the cortex of a lymph node;

If a PET-CT is performed the worst outcome of the two studies is accepted as the real clinical stage of the axilla (i.e. 1 PA proven positive lymph node on ultrasound and 3 on PET-CT; means 3 positive lymph nodes)

The N status of the axilla prior to chemotherapy is based upon:

• Positive PET-CT of more than one but less than 4 axillary nodes; since the specificity of PET positive nodes in a proven breast cancer patient is very high, pathology confirmation is not absolutely required
• Positive US of axillary nodes; at least one should be pathology proven tumour positive
• The worst outcome of 1 and 2 represents the most reliable clinical axillary staging.

patients with cT1-2cN0-1(cytology/histology and/or positive SN, excluding patients with > 3 pathologic axillary nodes on imaging) breast cancer, treated with at least three cycles of chemotherapy followed by breast surgery are eligible for the study.