Lymphatic Mapping and Targeted Axillary Dissection Procedure After Neoadjuvant Chemotherapy

Introduction

The surgical management of breast cancer has evolved with the development of effective neoadjuvant chemotherapy (NAC) and targeted systemic therapy. In addition to treating early and locally advanced breast cancer, NAC downstages disease in the breast and axilla, allowing for deescalation of surgical therapy, and providing prognostic information regarding responsiveness to chemotherapy. In the ACOSOG Z1071 trial, 45.4% of HER2+ and 38% of triple-negative breast cancer (TNBC) subtypes attained pathologic complete response (pCR) in the breast and axilla. Whereas response to therapy has prognostic benefits, eradication of axillary disease after NAC has implications for the surgical procedures performed in the axilla. In this chapter, we discuss the evolution of axillary management with the advent of NAC, the trials establishing the role of the sentinel lymph node biopsy (SLNB) technique after NAC, and the development of the targeted axillary dissection (TAD) technique to further refine selective axillary surgery after NAC.

Evolution of Axillary Management

Axillary lymph node dissection (ALND) as promoted by Sir William Halsted was the standard of care in the surgical management of breast cancer for many decades. This procedure achieved regional control in the absence of chemotherapeutic options and provided staging information to guide adjuvant therapy. Despite these benefits, removal of regional lymph nodes results in considerable morbidity including lymphedema, sensory deficits, neuropathic pain, and impaired shoulder mobility. As effective systemic therapy was established, the therapeutic role of axillary surgery was questioned. These observations resulted in a series of trials investigating deescalation of surgical therapy in breast cancer. In the National Surgical Adjuvant Breast and Bowel Project (NSABP)-04 trial, the investigators estimated that of 365 women with clinically negative nodes who underwent mastectomy alone, 40% had positive nodes that were not treated surgically or with radiation therapy. Only 18.6% of this cohort developed axillary recurrence and survival was not impacted by regional therapy with surgery or radiation. This finding suggests that perhaps limited axillary surgery was unlikely to compromise long-term oncologic outcomes and may be appropriate in select individuals.

Axillary surgery provides useful prognostic information that also guides recommendations regarding adjuvant therapy. The development of the SLNB technique created an opportunity for axillary staging while avoiding the morbidity of extensive axillary surgery. NSABP-32 confirmed equivalent oncologic outcomes in patients with negative sentinel lymph nodes (SLNs) who underwent SLNB alone or with ALND. In addition, they showed improved patient-reported outcomes and morbidity with limited axillary surgery. The selective approach to axillary surgery subsequently became the standard of care in patients with node-negative disease who do not require NAC.

The deescalation of axillary surgery in patients who undergo surgery first, as well as the development of effective systemic therapy, has guided the approach to axillary management in patients who require NAC. In this population, NAC offers an opportunity to downstage axillary disease with the potential to limit axillary surgery.

Clinically Node-Negative Patients Receiving Neoadjuvant Chemotherapy

The timing of SLNB has been debated in clinically node-negative patients who receive NAC. Some advocate for SLNB prior to treatment, citing the benefit of complete axillary staging at diagnosis, which may guide adjuvant therapy. Those that support this approach often cite concerns that fibrosis may alter lymphatic drainage, resulting in decreased identification rates or increased false-negative rates (FNRs), and that there is a possibility of heterogeneous response to chemotherapy. The accuracy and feasibility of SLNB after NAC was demonstrated in the NSABP B-27 trial with identification and FNR of 84.8% and 10.7%, respectively. The FNR was deemed comparable to rates observed with SLNB prior to systemic therapy, which ranged from 7% to 14%. In a meta-analysis of 16 studies, Geng and colleagues showed identification rates of 97% using dual tracer and pooled FNR of 11% with hematoxylin and eosin staining. Hunt and colleagues compared 575 patients who underwent SLNB after NAC to 3171 patients who underwent surgery first, finding that identification rates were similar between the groups (97.4% in NAC vs. 98.7% in surgery first, P =0.017). The FNR was also similar between the groups (5.9% in NAC vs. 4.1% in surgery first groups, P =0.39). Importantly, patients with T2–3 tumors had a lower probability of requiring ALND when SLNB was performed after NAC (T2: 20.5% vs. 36.5%, P < 0.0001; T3: 30.4% vs. 51.4%, P =0.04) with equivalent recurrence rates and oncologic outcomes. Similar data have been reported from an analysis of the Netherlands Cancer Registry showing equivalent identification rates with decreased probability of identifying a positive node when SLNB is performed after NAC. The recent Ganglion sentinel après chimiotherapie NEoAdjuvante (GANEA) 2 trial followed 419 clinically node-negative patients who received NAC and found a 3-year event-free survival rate of 97.8% with only one axillary recurrence. Given these trials showing that SLNB can be successfully and accurately performed after NAC, most now favor performing SLNB at the completion of NAC.

The SENTinel Neoadjuvant (SENTINA) cohort study was a multicenter study designed to evaluate the accuracy of SLNB in a variety of settings around NAC. Arms A and B evaluated clinically node-negative patients who underwent SLNB before NAC, assigning patients with a negative result to Arm A and those with a positive result to Arm B. The Arm B cohort then underwent a second SLNB at the completion of NAC. While the identification rate of Arms A and B combined was 99.1%, this dropped to 60.8% when a second SLNB procedure was attempted in Arm B. In addition, the FNR was reported as 51.6% when a second SLNB was attempted.