Editor’s Note: The axillary lymph node burden after neoadjuvant therapy is closely related to prognosis. Unlike the assessment in initial surgery patients, residual tumor cells after neoadjuvant therapy are considered resistant cells. Thus, can limited sentinel lymph node biopsy (SLNB) metastasis after neoadjuvant therapy exempt patients from axillary lymph node dissection (ALND)? At the 2024 South-North Forum, Prof. Pengfei Qiu from Shandong Cancer Hospital presented a report titled “Do Breast Cancer Patients with cN1 Who Downstage to ycN0 after Neoadjuvant Therapy and Have Limited SLNB Metastasis Need ALND?” This article reviews the key points of his lecture.
Key Issues in Breast Cancer SLNB
Prof. Pengfei Qiu explained that with the accumulation of evidence-based medicine for sentinel lymph node biopsy (SLNB), more patients have benefited from less extensive surgical interventions. Regardless of the era of SLNB, two critical issues remain: diagnostic accuracy and oncological safety. For SLN diagnosis after neoadjuvant therapy, higher diagnostic accuracy is required as it significantly impacts the residual tumor burden in the axilla. Although the technique of SLNB after neoadjuvant therapy has matured and evidence on recurrence risk has been gathered, issues such as insufficient follow-up time remain. Therefore, current CBCS guidelines remain cautious about SLNB after neoadjuvant therapy.
Limited SLN Metastasis
Prof. Qiu explained that limited SLN metastasis includes isolated tumor cells (ITC), micrometastasis, and a limited number of macrometastases, with some controversy around the classification of ITC. In defining pCR (pathologic complete response), “ITC only in lymph nodes” does not qualify as pCR. However, in the AJCC 8th edition N staging evaluation, ITC is not counted as positive lymph nodes, classified as ypN0(i+). The I-SPY2 working group suggests avoiding under-treatment by classifying post-neoadjuvant therapy lymph node ITC as ypN1(i+).
De-escalation Surgery for Limited SLN Metastasis after Neoadjuvant Therapy
Prof. Qiu highlighted that discussions on managing patients with limited SLN metastasis have been ongoing since the 2021 St. Gallen International Breast Cancer Conference, reiterated in the 2023 conference. The conditions for avoiding ALND for these patients have gradually relaxed, provided that radiation therapy is used as a substitute. As the number of detected SLNs increases and the metastatic burden decreases, the expert group’s acceptance grows. Patients with residual tumor burden in SLNs after downstaging still face a higher risk of local recurrence. To determine if ALND can be avoided for cN1 patients who downstage to ycN0 and have limited SLNB metastasis, three questions must be addressed:
1. Is Axillary Residual Tumor Allowed after SLNB?
Prof. Qiu affirmed that it is. SLNB does not aim to remove all metastatic lymph nodes. From initial false negatives to exempting ALND for 1-2 positive SLNs, axillary residual tumors have been an objective reality. After neoadjuvant therapy, stricter standards are needed to ensure local control. Existing evidence indicates a 60% risk of non-SLN metastasis in patients with SLN micrometastasis and macrometastasis, and a 37.5% risk in ITC patients. Higher standards for false-negative rates and residual tumor burden are necessary post-neoadjuvant therapy. Clinical risk factors or prediction models may help, but standards should ultimately aim at survival and local control.
For patients with ITC after downstaging, the 2023 SABCS conference presented the OPBC05/EUBREAST-14R/ICARO study, showing no significant difference in 5-year axillary recurrence, local recurrence, or any invasive recurrence (local or distant) between ALND and non-ALND groups. However, due to the low incidence of ITC, designing prospective studies is challenging, making the retrospective study baseline imbalanced with higher risks in the ALND group. Most non-ALND patients were diagnosed with SLN ITC post-surgery. This study suggests a remedial measure rather than routine clinical decision-making for ITC found in routine pathology post-surgery. Evidence for SLN macrometastasis and micrometastasis patients is still awaited.
2. Is Thorough Axillary Evaluation Needed Post-Neoadjuvant Therapy?
With the presentation of clinical trial results like MonarchE, deciding on post-neoadjuvant therapy necessitates higher standards for evaluating residual axillary lymph node tumor burden. Limited SLN metastasis clearly indicates non-pCR, but further comprehensive axillary staging has limited impact on subsequent adjuvant intensification strategies. The incidence of macrometastasis and micrometastasis post-ALND for ITC patients is low (about 5% and 7%, respectively), and for SLN micrometastasis and macrometastasis patients, the incidence of ≥4 ALN metastases post-ALND is 10% and 30%, respectively. Thus, ALND may rarely alter subsequent adjuvant therapy strategies for these patients. However, within the evidence-based framework, de-escalating axillary surgery post-neoadjuvant therapy should not affect adjuvant therapy strategy formulation.
3. How to Balance Different Local Treatment Modalities?
Prof. Qiu noted that both surgeons and radiotherapists are exploring de-escalation treatments. Existing evidence suggests that de-escalation of radiotherapy post-neoadjuvant therapy also appears safe. Balancing different local treatments becomes a new issue. Clinicians aim to achieve dual de-escalation in surgery and radiotherapy as in the NRG Oncology/NSABP B-51/RTOG 1304 study. However, this study did not specify ITC numbers, while the OPBC05/EUBREAST-14R/ICARO study showed most patients with SLN ITC who did not undergo ALND received regional lymph node radiotherapy. Thus, de-escalation of different local treatments should be based on specific clinical study enrollment criteria and results, through multidisciplinary collaboration to formulate individualized treatment strategies.
Prof. Qiu emphasized that treating breast cancer is a balancing act. To maximize patient quality of life while ensuring oncological safety, effective systemic therapy combined with prudent surgical and radiotherapeutic adjustments is essential.
Summary
Prof. Qiu concluded that evidence for exempting ALND in cN1 patients who downstage to ycN0 with limited SLNB metastasis is insufficient, indicating a long journey ahead. While allowing axillary residual tumors, stricter post-neoadjuvant standards and long-term follow-up data are needed. Further ALND to perfect axillary staging has limited impact on adjuvant intensification strategies for patients with existing SLN metastasis. Surgical de-escalation should not compromise subsequent adjuvant therapy strategy formulation. As both surgery and radiotherapy strive for de-escalation, balancing local treatment modalities should be evidence-based and multidisciplinary. The trend towards surgical de-escalation post-neoadjuvant therapy must continue to address regional lymph node recurrence risks with appropriate supplementary or alternative measures, optimizing radiotherapy targets and doses based on effective systemic therapy.
Prof. Pengfei Qiu
– Deputy Director of Breast Surgery, Shandong Cancer Hospital
– Director of Day Treatment Center
– Chief Physician, MD, PhD Supervisor
– Visiting Scholar at Cambridge University and the UK Cancer Research Center
– Taishan Scholar Youth Expert of Shandong Province
– Outstanding Young Medical Talent of Qilu Health and Wellness
– Member of the Breast Cancer Professional Committee, Chinese Anti-Cancer Association
– Member of the International Medical Exchange Branch, Chinese Anti-Cancer Association
– Member of the Youth Group, Breast Cancer Oncology Branch, Chinese Medical Association
– Standing Member of the Youth Council, Shandong Clinical Oncology Society
– Young Editorial Board Member of Cancer Biology & Medicine
– Lead or corresponding author of over 30 papers and principal investigator of two National Natural Science Foundation projects
