Tailored Axillary Surgery With or Without Axillary Lymph Node Dissection Followed by Radiotherapy in Patients With Clinically Node-positive Breast Cancer (TAXIS)

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