RATIONALE: The use of tailored axillary dissection as a tailored procedure will avoid surgical overtreatment by selectively removing the lymph nodes that are affected by the cancer, thereby sparing many women the unnecessary complications of a radical surgery, providing a better quality of life while keeping the same efficacy.

PURPOSE: The phase III trial is evaluating the optimal treatment for breast cancer patients in terms of surgery and radiotherapy.

The removal of all lymph nodes in the armpit through conventional axillary dissection has been standard care for all patients with breast cancer for almost a century. In the nineties, the sentinel lymph node procedure, which involves the selective removal of the first few affected lymph nodes, was introduced in clinical practice. Today, conventional axillary dissection is still performed on many women with breast cancer that has spread to the nodes. It is the cause for relevant morbidity in the form of lymphedema, impairment of shoulder mobility, sensation disorders and chronic pain in as much as one third of all women undergoing the procedure.

The TAXIS trial will evaluate the optimal treatment for breast cancer patients in terms of surgery and radiotherapy. In particular, it will investigate the value of tailored axillary surgery (TAS), a new technique that aims at selectively removing the positive lymph nodes. TAS combines the removal of palpably suspicious nodes with the sentinel procedure. TAS is a promising procedure that may significantly decrease morbidity in breast cancer patients by avoiding surgical overtreatment.

This trial has the potential to establish a new worldwide treatment standard with hopefully less side effects and a better quality of life, while keeping the same efficacy as provided by radical surgery.

The main objective of the trial is to show that TAS and axillary radiotherapy (RT) is non-inferior to ALND in terms of disease-free survival of node positive breast cancer patients at high risk of recurrence in the era of effective systemic therapy and extended regional nodal irradiation.

Inclusion Criteria:

Inclusion criteria at pre-registration:

• Written informed consent according to ICH/GCP regulations prior to any trial specific procedures.
• Breast cancer, node positive detected by palpation or imaging (with or without planned neoadjuvant treatment)
• Female or male aged ≥ 18 years
• Ability to complete the Quality of Life questionnaires

Inclusion criteria at registration:

• Node-positive breast cancer (histologically or cytologically proven both in primary tumor and in lymph node) AJCC/UICC [42] stage II-III (all molecular subtypes allowed):

  • Node-positivity detected by imaging (iN+) and confirmed by pathology
  • Node-positivity detected by palpation (cN1-3) and confirmed by pathology
  • Occult breast cancer is allowed, if biopsy-proven axillary lymphatic metastasis is present

• Eligible for primary ALND or sentinel lymph node (SLN) procedure with frozen section and either:

  • Newly diagnosed
  • Isolated in-breast recurrence or second ipsilateral breast cancer after previous breast conserving surgery and sentinel procedure and at least 3 years disease free and no prior axillary dissection or axillary RT

• Most suspicious axillary lymph node clipped

• Baseline Quality of Life questionnaire has been completed

• WHO performance status 0-2

• Adequate condition for general anesthesia and breast cancer surgery

• Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and thereafter during the time recommended by the guidelines for adjuvant systemic therapies. A negative pregnancy test before inclusion into the trial is required for all women with child-bearing potential.

• Men agree not to father a child during trial treatment and thereafter during 6 months.

Inclusion criteria at randomization (intraoperatively)

• Node-positive breast cancer (histologically or cytologically proven both in primary tumor and in lymph node) AJCC/UICC stage II-III (all molecular subtypes allowed):

  • Node-positivity initially detected by imaging and non-palpable and residual disease confirmed by pathology** (including residual ITCs) in SLN or non SLN in case of prior neoadjuvant treatment

  • Node-positivity initially palpable and residual disease confirmed by pathology** (including residual ITCs) in case of prior neoadjuvant treatment

    • Note: patients with ypN0(i+) can be included (the AJCC stage II-III refers to the stage before neoadjuvant treatment) **Note: If the fine needle aspiration or core biopsy of the clipped node after neoadjuvant treatment unequivocally shows cancer, repeated confirmation of residual disease by intraoperative frozen section is not mandatory

Exclusion Criteria:

Exclusion criteria at pre-registration:

Any potential patient who meets any of the following criteria has to be excluded from entering the trial.

• Stage IV breast cancer
• Clinical N3c breast cancer (clinical N3a and clinical N3b are allowed)
• Clinical N2b breast cancer (clinical N2a is allowed)
• Contralateral breast cancer within 3 years Note: Contralateral Ductal Carcinoma In Situ (DCIS) is allowed if prior treatment does not interfere with or compromise the trial treatment
• Prior axillary surgery (except prior sentinel node procedure in case of in- breast recurrence)
• Prior regional radiotherapy
• History of hematologic or primary solid tumor malignancy, unless in remission for at least 3 years from pre-registration with the exception of adequately treated cervical carcinoma in situ or localized non-melanoma skin cancer.
• Treatment with any experimental drug within 30 days of pre-registration
• Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.

Exclusion criteria at randomization (intraoperatively):

Any potential patient who meets any of the following criteria has to be excluded from the trial.

• Absence of clip in the specimen radiography
• Palpable disease left behind in the axilla after Tailored Axillary Surgery (TAS)
• No SLN identified in the axilla