Article

Testing the Power of Neoadjuvant Systemic Therapy in Breast Cancer

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.

Henry Kuerer, MD, PhD

Henry Kuerer, MD, PhD

Henry Kuerer, MD, PhD

The concept of de-escalating surgical therapy for breast cancer continues to find acceptance. This is an exhilarating and potentially pivotal time in the management of invasive breast cancer, as we begin to test the new paradigm that not all patients need surgery for the management of their malignancy after neoadjuvant systemic therapy.

We have known for a very 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. If systemic therapy will increase a patient’s survival from breast cancer, neoadjuvant systemic therapy, given as the primary therapy before consideration of surgery and radiotherapy, can have a dramatic effect locally.

Proceeding With Caution

This allows for not only breast-conserving surgery but also potential elimination of surgery altogether prior to radiotherapy. In the past, following systemic therapy, the difficulty has been to distinguish patients with residual disease from patients without any residual cancer. 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 percutaneous biopsy after neoadjuvant therapy can accurately identify patients without residual disease.1 Combined biopsy demonstrated an accuracy of 98%, a false-negative rate of 5%, and a negative predictive value of 95% in predicting residual breast cancer.1Patients 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 proved 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.

This burgeoning new paradigm requires meticulous and precise image-guided biopsy of the tumor bed, which was performed in The University of Texas MD Anderson Cancer Center feasibility trial.1 Using the MD Anderson approach to optimize selection with extensive image-guided biopsy, the trial found that about 48% of patients had no evidence of disease in the breast after neoadjuvant systemic therapy, and the rest of the cases demonstrated either residual carcinoma, atypia (with the correct area sampled, by clip), and/or therapy changes consistent with representative sampling of the tumor bed. In fact, false-negative cases using vacuum-assisted core biopsy in our study clearly demonstrated therapy-related changes in the biopsy specimens, but these cases were unique in that they had only 4 or 6 core biopsies taken, while the median for the rest of the study was 12. This led us to conclude that to safely test the elimination of surgery in our ongoing trial, there should be a minimum of 12 cores of the residual region of prior carcinoma in and around the area of the marker clip; we have limited the trial to patients who present with less than 5 cm of disease by initial breast imaging prior to neoadjuvant systemic therapy.2

Nonsurgical Axilla Management

Importance of Phase II Studies

The decision to not include HER2-negative/ estrogen receptor (ER)—positive cases in our initial and subsequent studies was made after a retrospective review of all HER2-negative/ ER-positive cases from our database revealed that—even when including only cases with extremely high Ki-67 and lower ER expression— approximately 5% of these tumors had a pCR for invasive and in situ disease. Thus, only 1 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 multicenter cooperative group NRG-BR005 biopsy feasibility study as well as other key international studies.3There 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 in 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 [in whom] initial biopsy showed limited axillary nodal disease and where a clip has been placed, 1 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.4The currently accruing MD Anderson—initiated multicenter trial, Eliminating Breast Cancer Surgery in Exceptional Responders With Neoadjuvant Systemic Therapy, is a phase II prospective clinical trial that is not randomized. Future phase II and randomized trials that are well designed will establish greater confidence and scientific merit when they are performed in this groundbreaking new arena for patients with breast cancer. It will likely take a randomized trial to spark 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. A phase II singlearm national trial showing very low local recurrence rates among patients not treated with surgery would likely be sufficient to convince patients that this is a potentially safe alternative; however, clinical trialists might require a higher level of evidence.

In the interim, a good place to start to test and advance the field toward safe, minimally invasive procedures for breast cancer is with well-designed phase II prospective clinical trials using evidencebased data from preliminary feasibility studies where there is meticulous collaboration among key multidisciplinary specialties including radiologists, pathologists, and surgical, medical, and radiation oncologists.

References

  1. Kuerer HM, Rauch GM, Krishnamurthy S, et al. A clinical feasibility trial for identification of exceptional responders in whom breast cancer surgery can be eliminated following neoadjuvant systemic therapy [published online May 25, 2017]. Ann Surg. doi: 10.1097/ SLA.0000000000002313.
  2. Eliminating Breast Cancer Surgery in Exceptional Responders With Neoadjuvant Systemic Therapy. clinicaltrials.gov/ct2/show/ NCT02945579. Updated December 29, 2017. Accessed January 29, 2018.
  3. Kuerer HM, Vrancken Peeters M, Rea DW, Basik M, De Los Santos J, Heil J. Nonoperative management for invasive breast cancer after neoadjuvant systemic therapy: conceptual basis and fundamental international feasibility clinical trials. Ann Surg Oncol. 2017;24(10):2855- 2862. annsurgoncol.org/journals/abstract.html?v=24&j=10434&i=10 &a=5926_10.1245_s10434-017-5926-z&doi=.
  4. Tadros AB, Yang WT, Krishnamurthy S, et al. Identification of patients with documented pathologic complete response in the breast after neoadjuvant chemotherapy for omission of axillary surgery. JAMA Surg. 2017;152(7):665-670. doi: 10.1001/jamasurg.2017.0562.
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