De-escalation of axillary surgery in breast cancer patients treated in the neoadjuvant setting: a Dutch population-based study

In breast cancer, systemic therapy is increasingly administered in the neoadjuvant setting [i.e., neoadjuvant systemic therapy (NST)] [1, 2]. One of the advantages of NST is the possibility of downsizing or even downstaging disease, which can occur in breast and/or axilla. In the best-case scenario, patients achieve a pathologic complete response (pCR), meaning that there is no histologic evidence of residual tumor. Downstaging is not only associated with a favorable prognosis but it also enables surgeons to opt for less extensive surgery after NST.

In clinically node-negative (cN0) patients, sentinel lymph node biopsy (SLNB) is widely accepted as primary regional staging procedure. In the case of a positive SLNB with limited tumor burden, it is safe to omit completion axillary lymph node dissection (ALND) in patients treated with lumpectomy in terms of disease-free and overall survival [3‐7]. In the AMAROS trial, cT1-2N0 patients with a positive SLNB and treated with lumpectomy or mastectomy were randomly assigned to completion ALND or axillary radiotherapy [8]. The 5-year axillary recurrence rate was comparable in both groups, but measurable lymphedema occurred significantly less frequently in the axillary radiotherapy arm. The results of these trials resulted in decreasing use of ALND, as was proven by several cohort studies over the past years [9‐12]. In these studies, patients treated with NST were not included and it is yet unknown if this decrease in axillary surgery also affects cN0 patients who were treated with NST.

In clinically node-positive (cN+) patients, axillary staging is an area of controversy. Traditionally, ALND was performed in all patients. However, at least 1 out of 3 cN+ patients treated with NST converts to a pathological node-negative axilla [13]. Since cN+ patients with an axillary pCR are not expected to benefit from ALND, different less invasive methods have been proposed to replace ALND, such as SLNB, MARI (marking the axillary positive lymph node with an iodine seed), and Targeted Axillary Dissection (i.e., a combination of the SLNB and a MARI-like procedure). However, since sufficient data are lacking on the outcome of cN+ patients in whom ALND is omitted after NST, broad implementation of less invasive staging procedures in clinical practice may be hampered.

With the increased use of NST in both cN0 and cN+ patients, and the de-escalation of axillary surgery in patients treated in the adjuvant setting, it is hypothesized that a trend of de-escalation will also be noticed in patients treated with NST. Therefore, the aim of this study was to evaluate the trends in de-escalation of axillary surgery in cT1-4N0-3 breast cancer patients treated with NST in the Netherlands.

Data were collected from the Netherlands Cancer Registry (NCR) [14]. The NCR is hosted by the Netherlands Comprehensive Cancer Organisation (IKNL). Specially trained registration clerks gather data directly form the patient files in all hospitals in the Netherlands. Patients with cT1-4N0-3 breast cancer treated with NST, between 2006 and 2016, were included. Patients with occult breast cancer were also included. For each patient, the following variables were documented: hospital type (academic, teaching, community), age, morphological subtype, receptor status, TNM status prior to and after NST, NST regimens, type of breast, and axillary surgery, axillary pCR, and adjuvant treatment plans. Axillary pCR was defined as the absence of residual axillary disease in all examined lymph nodes independent of the type of axillary surgery. Isolated tumor cells were included in the definition of axillary pCR. Patients were excluded if no lymph nodes were identified during surgery or if the number of positive lymph nodes was unknown. Patients with unknown cN status, distant metastasis, or patients in whom surgery of the breast was not performed were also excluded.

A total of 15,725 breast tumors treated with NST (10% of all breast tumors) were identified between January 2006 and December 2016 and registered in the NCR. Cases were excluded for the following reasons: distant metastasis (n = 683), treated with neoadjuvant radiotherapy (n = 21), unknown cN status (n = 165), unknown cT status (n = 136), unknown hospital type (n = 1), no breast surgery (n = 838), unknown type of axillary surgery (n = 674), unknown outcome of axillary surgery (n = 193), and unknown timing of SLNB (n = 553). Altogether, 12.461 breast tumors were included for the final analysis. See Table 1 for clinicopathologic characteristics. In 7106 of 12,461 (57%) cases, ALND was performed. From 2006 to 2016, an overall decrease in the rate of ALND was observed from 96 to 29% (p < 0.001).

This large Dutch population-based cohort study showed that axillary surgery has changed considerably in daily practice over the past decade in cT1-4N0-3 breast cancer patients treated with NST. In cN0 patients, a substantial decrease in ALND and increase in SLNB only was observed, with SLNB being increasingly performed after NST. Additionally, this study revealed that ALND has increasingly been omitted after NST in cN+ patients.

In patients who undergo adjuvant systemic therapy, indications for omitting ALND in cN0 patients have extended over the years from patients with negative SLNS(s) to patients with positive SLN(s) [15]. Even 10-year survival outcomes from the ACOSOG Z0011 and IBCSG 23-01 trials corroborated non-inferiority of SLNB alone compared to ALND for patients with limited positive SLN(s) [4, 16]. Abandoning completion ALND in cN0 patients with positive SLN(s) treated with adjuvant systemic therapy is already ongoing for years, even prior to the publication of the abovementioned trials [17‐20]. Ever since the publication of these trial results, implementation of SLNB only in this population is expanding [11, 21]. The current study shows that abandoning completion ALND in cN0 patients with positive SLN(s) is also taking place in patients treated with NST, even though results of the previous trials only apply to patients treated with adjuvant systemic therapy. Over the past decade, SLNB was increasingly performed after NST rather than prior to NST. Several previous studies demonstrated that performing SLNB after NST is associated with lower rates of a positive SLNB [22‐24]. Thus, ALND can be omitted more often when SLNB is performed after NST. Hence, the change in timing of SLNB found in this study contributed to the decreasing use of ALND.

Regarding cN+ patients treated with NST, several less invasive procedures have been proposed over the past years in an attempt to prevent unnecessary ALND in patients who achieve axillary pCR: SLNB, excision of a pre-treatment marked positive lymph node (like MARI) or a combination of these two procedures (like Targeted Axillary Dissection and RISAS) [13, 25‐27]. Despite limited evidence for the safety of replacing ALND by these procedures, implementation of such strategies is occurring worldwide [28]. The results of the current study confirm this trend: from 2013 (prior to publications on accuracy of MARI and TAD), rates of SLNB and/or MARI for axillary staging after NST started increasing up to 58% in 2016. The increase in rates of SLNB and/or MARI in cN+ patients was present in all three types of hospitals. Although SLNB and/or MARI is offered more and more to cN+ patients in order to omit ALND in case of axillary pCR, 42% of patients with an axillary pCR still underwent (completion) ALND in 2016. This indicates that selecting the right patient for the appropriate procedure is challenging. At the same time, completion ALND may have been performed as part of validating studies. In some institutions, ALND is performed in all cN+ patients, irrespective of response to NST, which may also in part explain this finding. Again, it is unknown to what extent ALND has been replaced by regional radiotherapy.

Notably, the decrease in ALND rates in cN+ patients treated with NST is also present in patients who do not achieve an axillary pCR. In 2016, 44% of the cN+ patients with post-NST residual axillary disease did not undergo completion ALND. Multiple studies reported improved survival for patients with a complete response (ypT0/ypN0) to NST compared to patients without a complete response [29, 30]. These results indicate the necessity of treatment escalation rather than de-escalation in patients without axillary pCR to improve prognosis, especially in certain subtypes (such as triple negative breast cancer) [31]. Whether current practices of omitting ALND in cN+ patients without axillary pCR will negatively impact prognosis is yet unknown. In the Alliance 11,202 trial, prognosis of cN + patients with positive SLN(s) after NST is compared between those treated with completion ALND and those treated with axillary radiotherapy [32].

Although the current study describes a large cohort of patients, several limitations have to be taken into account. Regarding adjuvant treatment plans, sufficient data on radiotherapy fields were not available for the whole cohort. It is expected that simultaneously with the decreasing rates of ALND, rates of regional radiotherapy increase. This study did suggest such a trend in cN+ patients, but further research is needed for a thorough assessment of (regional) radiotherapy administration in patients treated with NST. Furthermore, the impact of omitting ALND on prognosis in terms of overall and disease-free survival could not be assessed since data on recurrences are not (yet) available for this cohort.

To conclude, axillary surgical staging changed significantly with a major decrease in ALND rates in breast cancer patients treated with NST over the past decade. However, selecting the right patients for whom omitting ALND is oncologic safe appears challenging, especially in pre-treatment cN+ patients and patients with residual axillary disease. Studies assessing long-term prognosis of such patients in whom ALND is omitted are urgently needed.