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 trialspecific procedures.

• Breast cancer, node positive detected by palpation or imaging (with or withoutplanned 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 primarytumor and in lymph node) AJCC/UICC [42] stage II-III (all molecular subtypesallowed):

• 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 metastasisis present

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

• Newly diagnosed

• Isolated in-breast recurrence or second ipsilateral breast cancer afterprevious breast conserving surgery and sentinel procedure and at least 3 yearsdisease 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 notpregnant or lactating and agree not to become pregnant during trial treatment andthereafter during the time recommended by the guidelines for adjuvant systemictherapies. A negative pregnancy test before inclusion into the trial is required forall women with child-bearing potential.

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

Inclusion criteria at randomization (intraoperatively)

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

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

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

• Note: patients with ypN0(i+) can be included (the AJCC stage II-III refersto the stage before neoadjuvant treatment) **Note: If the fine needleaspiration or core biopsy of the clipped node after neoadjuvant treatmentunequivocally shows cancer, repeated confirmation of residual disease byintraoperative 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 InSitu (DCIS) is allowed if prior treatment does not interfere with or compromise thetrial treatment

• Prior axillary surgery (except prior sentinel node procedure in case of in- breastrecurrence)

• Prior regional radiotherapy

• History of hematologic or primary solid tumor malignancy, unless in remission for atleast 3 years from pre-registration with the exception of adequately treatedcervical 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 orgeographical condition, which in the judgment of the investigator may interfere withthe planned staging, treatment and follow-up, affect patient compliance or place thepatient 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