Disclosures Introduction This is an exciting and potentially pivotal time in the management of invasive breast cancer as we begin to test the new paradigm that not all patients will need surgery for the management of their malignancy. We have known for a long time that neoadjuvant therapy can eliminate both invasive and in situ carcinoma in up to 50% of patients, particularly when their subtypes are triple-negative disease or HER2-positive cancers. That is, if the patient will need systemic therapy to increase their survival from breast cancer, neoadjuvant systemic therapy, given as the primary therapy before consideration of surgery and radiotherapy, can also have a dramatic affect locally. One potential advantage of this is not only allowing for breast conserving surgery but potential elimination of surgery altogether prior to receiving radiotherapy. The difficulty in the past was differentiating patients with residual disease after the systemic therapy from those patients without any residual cancer because the systemic therapy had eradicated all disease. In general, breast imaging after systemic therapy lacks sufficient sensitivity and specificity to safely determine which patients might be safe to move on to radiotherapy without the surgery. Recently, our group demonstrated that utilizing percutaneous biopsy after the neoadjuvant therapy can accurately identify patients without residual disease . Combined biopsy demonstrated an accuracy of 98%, false-negative rate of 5%, and negative predictive value of 95% in predicting residual breast cancer . Critical information for physicians and patients First off, patients should not be offered elimination of surgery after neoadjuvant systemic therapy unless they are on a prospective clinical trial, as the safety of this approach has not been proven yet. The key here is the optimal, accurate and safe selection of patients who have had a pathologic complete response (pCR), which is no residual invasive or in situ carcinoma after neoadjuvant systemic therapy. If there is no detectable residual disease among patients who will be receiving radiotherapy, the benefit of surgery would appear to be very low and potentially unnecessary (Figure 1). This new field requires meticulous and precise image-guided biopsy of the tumor bed, which was performed in the MD Anderson feasibility trial . Using the MD Anderson approach to optimize selection with extensive image-guided biopsy, about 48% of patients were found to have no evidence of disease in the breast after neoadjuvant systemic therapy and the rest of the cases demonstrated either residual carcinoma, atypia, the clip, and/or therapy changes consistent with representative sampling of the tumor bed. In fact, false-negative cases utilizing vacuum-assisted core biopsy in our study clearly demonstrated therapy related changes in the biopsy specimens, but these cases were unique in that they only had four or six core biopsies taken, while the median for the rest of the study was 12. This led to our conclusion that to safely test the elimination of surgery in our ongoing trial we need to insist upon a minimum of 12 cores of the residual region of prior carcinoma in and around the area of the marker clip, and we are limiting the trial to patients who present with less than 5 cm of disease by initial breast imaging prior to neoadjuvant systemic therapy . The decision to not include HER2-negative/estrogen receptor (ER)-positive cases in our initial and subsequent studies was made after retrospective review of all HER2-negative/ER–positive cases from our database, even when only including cases with extremely high Ki-67 and lower ER expression, revealed that approximately 5% of these tumors had a pCR for invasive and in situ disease. Thus, only one in 20 cases might become eligible for no surgery. Additional information related to parameters associated with these tumor subtypes will be derived from the recently opened US multi-center cooperative group NRG BR005 biopsy feasibility study, as well as other key international studies . Mammogram before and after neoadjuvant systemic therapy demonstrating a near complete radiologic response as well as core biopsy proved pCR. × Managing the axilla among exceptional responders to neoadjuvant systemic therapy There is also controversy as to how the axilla will be managed when no breast surgery will take place. In the MD Anderson feasibility study, the pathologic response in the breast was concordant with the pathologic status in the axilla and approximately 98% of cases. The most straightforward management approach to the axilla among patients who will not have breast surgery after neoadjuvant systemic therapy, is to enroll cases without any evidence of nodal disease by ultrasound. For patients with initial biopsy proved limited axillary nodal disease and where a clip has been placed, one alternative is to perform targeted axillary dissection (removal of the documented lymph node that had metastases with the clip along with any other sentinel nodes) and if no axillary residual disease is identified, no axillary lymph node dissection would be indicated . Conclusions The current accruing MD Anderson-initiated multicenter trial, “Eliminating breast cancer surgery in exceptional responders with neoadjuvant systemic therapy”, is a phase 2 prospective clinical trial and not randomized. Future other well-designed studies will establish greater confidence and scientific merit when additional phase 2 and randomized trials are performed in this groundbreaking new arena for breast cancer patients. A paradigm shift from breast cancer surgery in all patients to selective elimination of breast cancer surgery in some patients with a biopsy proven pCR after neoadjuvant systemic therapy will likely require a randomized trial if feasible. In the interim, a good place to start to test and advance the field towards safe, minimally invasive procedures for breast cancer, is with well-designed phase 2 prospective clinical trials, utilizing evidence-based data from preliminary feasibility studies where there is meticulous collaboration among key multidisciplinary specialties including radiologists, pathologists, and surgical, medical and radiation oncologists.