Utility of nodal basin staging ultrasound in early-stage breast cancer
Highlight box
Key findings
• Our study demonstrated longer time period to surgery and higher rates of neoadjuvant chemotherapy (NAC) but lower rates of axillary dissection and potential downstaging after adoption of nodal staging ultrasound for early-stage invasive breast cancer (BC) patients.
What is known and what is new?
• Nodal basin staging ultrasound can guide treatment decisions for early-stage BC patients but there is a lack of consensus for its utility in this patient population.
• Our study demonstrated a potential association with nodal basin ultrasound use with higher rates of NAC but lower rates of axillary dissection.
What is the implication, and what should change now?
• Routine use of nodal basin ultrasound is an important tool in treatment decisions for early-stage BC.
Introduction
Axillary lymph node status plays an important role in determining whether to proceed with upfront surgery versus neoadjuvant chemotherapy (NAC) for patients with early-stage breast cancer (BC) (1). Historically, axillary lymph node dissection (ALND) was routinely performed for anatomic staging and regional control (2,3). The ACOSOG Z0011 randomized trial demonstrated that completion of ALND did not provide any benefit in 10-year overall survival or locoregional control for patients with T1–T2 N0 BC and 1–2 positive sentinel lymph nodes treated with breast conservation therapies, thereby leading to further de-escalation of axillary surgery (4-6).
Axillary sentinel lymph node biopsy (SLNB) remains standard of care for axillary staging in clinically node negative patients (7). Compared to ALND, SLNB was shown to have significantly lower rates of wound infection, axillary seroma, axillary paresthesia, and lymphedema (8). During this same decade, the University of Texas MD Anderson Cancer Center began using nodal basin ultrasound for regional staging (9,10). This tool was found to be valuable in the detection of axillary, internal mammary, infraclavicular, and supraclavicular lymphadenopathy that was not detected by physical exam or standard imaging. In a study published by their group in 2017, nodal basin ultrasound resulted in an upgrade in clinical node staging in 23% of patients (11). In addition, the prospective pilot study by Cyr et al. showed the negative predictive value of axillary ultrasound to identify clinically significant axillary disease (>2 mm) was 96.9% and demonstrated the axillary ultrasound could be noninvasive alternative to SLNB in patients with T1–2N0 (12). Currently there are three multicenter prospective randomized non-inferiority trials (SOUND, INSEMA, BOOG 2-13-08) to further investigate the role of axillary ultrasound in locoregional staging in patients with clinically negative axilla in early-stage BC (3).
Despite the aforementioned data, there is a lack of consensus regarding the utility of nodal basin staging ultrasound for early-stage BC patients. In fact, recent American Society of Clinical Oncology (ASCO) guidelines do not recommend preoperative axillary ultrasound in this patient population (13). Our program implemented a routine nodal basin staging ultrasound protocol for all newly diagnosed BC patients in 2013. In this study, we aimed to determine the impact of this protocol on pathologic staging, time to surgery (TTS), as well as rates of NAC, axillary radiation, and ALND for early-stage BC patients. We present this article in accordance with the STROBE reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-24-11/rc).
Methods
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Review Board of Cooper University Hospital (IRB# 20-586) and individual consent for this retrospective analysis was waived.
After obtaining approval by our Institutional Review Board, we performed a retrospective comparative review of patients 18 years and older with clinical stages I and II BC from 2009–2012 and 2015–2018. The pre-intervention group included patients in 2009–2012 who did not undergo routine nodal basin ultrasound whereas the post-intervention group included patients in 2015–2018 who did undergo routine nodal basin ultrasound. Nodal basin ultrasound was conducted by our proficient breast radiologists adhering the MD Anderson protocol, progressively scanning from the axilla to other nodal basins as deemed necessary. The Phillips epiq 5 ultrasound machine, equipped with a 12-5 linear probe, was utilized for this purpose. We then compared TTS, rates of NAC, axillary radiation, and ALND and pathologic staging between the two groups. Of note, patients who underwent NAC were excluded from the TTS analysis.
Statistical analysis
A Chi square test was used to compare categorical variables while a Mann Whitney U test was used to compare continuous and discrete variables. P values less than 0.05 were considered significant. The software IBM SPSS Statistics version 27 was used for statistical analyses.
Results
Demographic and tumor characteristics
There were 586 patients in the pre-intervention group and 1,232 patients in the post-intervention group (Table 1). The majority of patients had clinical stage I disease. There was no significant difference in the distribution of clinical stage I–II between the two groups (P=0.17). There were also no significant differences in demographic characteristics.
Table 1
| Variables | Pre-intervention [2009–2012] (n=586) | Post-intervention [2015–2018] (n=1,232) | P value |
|---|---|---|---|
| Age (years), mean ± SD | 58±12 | 60±12 | – |
| Race distribution | |||
| White | 79.4% | 80.7% | 0.52 |
| Black | 18% | 15.1% | 0.12 |
| Asian/others | 2.6% | 4.2% | 0.09 |
SD, standard deviation.
TTS
The post-intervention group also had a longer TTS (54 vs. 48 days, P=0.004).
Systemic therapy
In the pre-intervention group, there were a total of 289 (49.3%) patients who received systemic chemotherapy. Of these patients, 79 (27.3%) received NAC. In the post-intervention group, a total of 519 (42.1%) patients received systemic chemotherapy and 249 (48.0%) of these patients received NAC. We found a statistically significant difference in the rate of systemic chemotherapy in the pre-intervention group as compared to the post-intervention group (49.3% vs. 42.1%, P=0.004). However, we found that a higher percentage of patients received NAC in the post-intervention group as compared to the pre-intervention group (48.0% vs. 27.3%, P<0.001). This finding is significant as our overall rate of NAC from our study period 2009–2018 in general has declined (58.4% in 2009 to 36.9% in 2018, Figure 1).
Axillary surgery and radiation therapy
We found a lower rate of completion ALND in the post-intervention group as compared to pre-intervention group (16.6% vs. 25.6%, P<0.001). We did not find a statistically significant difference in the rates of axillary radiation between pre and post-intervention groups (21.0% vs. 15.6%, P=0.02).
Staging
There were 586 patients in clinical stage I–II in the pre-intervention group from 2009–2012 (Table 2). Of these patients, 381 (65.0%) patients were diagnosed with clinical stage I and 205 (35.0%) patients were diagnosed with clinical stage II. There were 1,232 patients in clinical stage I–II in the post-intervention group from 2015–2018. Of these patients, 840 (68.2%) patients were diagnosed with clinical stage I and 392 (31.8%) patients were diagnosed with clinical stage II. The post-intervention group had a larger proportion of patients diagnosed with pathologic early-stage disease (69.5% vs. 61.3%, P<0.001).
Table 2
| Variables | Pre-intervention [2009–2012] | Post-intervention [2015–2018] | P value |
|---|---|---|---|
| Clinical tumor stage, n/N (%) | 0.78 | ||
| cT0 (occult) | 0/586 (0.0) | 2/1,232 (0.2) | |
| cT1 | 393/586 (67.1) | 836/1,232 (67.9) | |
| cT2 | 173/586 (29.5) | 354/1,232 (28.7) | |
| cT3 | 19/586 (3.2) | 40/1,232 (3.2) | |
| Clinical nodal stage, n/N (%) | 0.78 | ||
| cN0 | 521/586 (88.9) | 1097/1,232 (89.0) | |
| cN1 | 65/586 (11.1) | 134/1,232 (10.9) | |
| cN2 | 0/586 (0.0) | 1/1,232 (0.1) | |
| AJCC clinical stage, n/N (%) | 0.18 | ||
| Stage 1 | 381/586 (65.0) | 840/1,232 (68.2) | |
| Stage 2 | 205/586 (35.0) | 392/1,232 (31.8) | |
| Pathological tumor stage, n/N (%) | 0.005 | ||
| pT0 | 13/585 (2.2) | 40/1,164 (3.4) | |
| pT1 | 409/585 (69.9) | 825/1,164 (70.9) | |
| pT2 | 134/585 (22.9) | 255/1,164 (21.9) | |
| pT3 | 17/585 (2.9) | 14/1,164 (1.2) | |
| pT4 | 6/585 (1.0) | 2/1,164 (0.2) | |
| pTis | 4/585 (0.7) | 10/1,164 (0.9) | |
| Pathologic nodal stage, n/N (%) | 0.008 | ||
| pN0 | 425/586 (72.5) | 895/1,165 (76.8) | |
| pN1 | 103/586 (17.6) | 191/1,165 (16.4) | |
| pN2 | 19/586 (3.2) | 21/1,165 (1.8) | |
| pN3 | 13/586 (2.2) | 7/1,165 (0.6) | |
| Unknown | 26/586 (4.4) | 51/1,165 (4.4) | |
| AJCC pathologic stage, n/N (%) | <0.001 | ||
| Stage 0 | 3/545 (0.6) | 18/1,078 (1.7) | |
| Stage 1 | 334/545 (61.3) | 749/1,078 (69.5) | |
| Stage 2 | 172/545 (31.6) | 281/1,078 (26.1) | |
| Stage 3 | 36/545 (6.6) | 30/1,078 (2.8) | |
| Histology, n/N (%) | |||
| Ductal | 449/586 (76.6) | 833/1,232 (67.6) | <0.001 |
| Lobular | 40/586 (6.8) | 105/1,232 (8.5) | 0.21 |
| Treatments, n/N (%) | |||
| Chemotherapy | 289/586 (49.3) | 519/1,232 (42.1) | 0.004 |
| NAC | 79/289 (27.3) | 249/519 (48.0) | <0.001 |
| Axillary dissection | 149/583 (25.6) | 192/1,156 (16.6) | <0.001 |
| Axillary radiation | 69/329 (21.0) | 175/1,123 (15.6) | 0.02 |
| Time to surgery (days), median | 48 | 54 | 0.004 |
AJCC, American Joint Committee on Cancer; NAC, neoadjuvant chemotherapy.
Discussion
Our study demonstrated that in the post-intervention group, we performed less axillary surgery while offering higher rates of neoadjuvant systemic therapy thereby potentially leading to downstaging of pathologic staging. De-escalation of axillary surgery has been the trend in breast surgery since the demonstration of the safety of SLNB in breast conservation patients in Z0011 study. Our study continues to show the importance of utilizing different tools including nodal basin US that can lead to less axillary surgery in our patients with early-stage BC.
Two large population-based studies have demonstrated the TTS in the non-NAC setting greater than 90 days decreases 5-year overall survival by 3.1–4.6% (14,15). The implementation of routine nodal US adds 6 days to TTS in the post-intervention group with median 54 days, which is still within 90 days of diagnosis for early-stage BC. While nodal basin ultrasound was associated with a longer TTS, it is unlikely the six-day delay is clinically significant.
Although there have been other studies suggesting a higher incidence of finding axillary disease with the nodal basin ultrasound (11,12), our study did not find a statistical difference in the distribution of clinical stages I and II. Our study demonstrated pathologic downstaging of patients with a greater proportion of patients in pathologic staging I in the post-intervention group as compared to in the pre-intervention group. Prior to the implementation of this protocol, nodal basin US was only performed at our institution on patients with clinically palpable nodes on the exam or suspicious nodes on other imaging. Physical exam has only shown an accuracy rate of 61–68% for identifying abnormal lymph nodes as demonstrated in multiple studies (16,17). In contrast, while overall sensitivity, specificity and accuracy of axillary US alone in detecting diseased nodes can still be variable—45.5%, 80.7% and 60.3% respectively, with the addition of US-guided needle biopsy for suspicious nodes, sensitivity and specificity can increase as high as 88% and 100% respectively (17-20). In our study, we had 88.9% and 89% of patients with cN0 diseases, 11.1% and 10.9% patients with cN1 in pre and post-intervention group respectively. While this lack of difference in distribution of clinical stage I and II may be due to the small percent of patients with cN1 disease, our study did not find a higher incidence of clinically relevant axillary upstaging.
The National Surgical Adjuvant Breast and Bowel Project (NSABP)-04 study has demonstrated that breast conserving surgery (BCS) followed by whole breast irradiation (WBI) significantly reduces local recurrence in the ipsilateral breast and the BC death (21). However, the addition of regional nodal irradiation (RNI) to WBI in T1–2N1 BC after BCS with adjuvant systemic therapy is controversial. Multiple randomized controlled trials of RNI in addition to WBI did not show any difference in overall survival and disease-free survival, but reduced the rate of BC recurrence (22,23). In our study, we did not find any statistical difference in the rates of axillary irradiation between pre- and post-intervention groups (12.9% vs. 14.6%, P=0.37).
Advances in systemic treatment options and better understanding of tumor biologic and genetic profiles have offered more patients the option of receiving NAC. We consider NAC for patients with locally advanced disease or tumors with aggressive tumor biology, such as triple negative or human epidermal growth factor receptor positive types or for a potential assessment of drug response (24). Higher rates of NAC (48%) in the post-intervention group in our study may be partially attributable to advancements in systemic therapy. Multiple studies have demonstrated variable rates from 12–65% in the pathologic complete response in the axilla by NAC (25-30). Our findings of pathologic downstaging and lower rates of ALND demonstrate an important finding of de-escalation in the surgical management of axilla in the setting of an early-stage BC.
Limitations
The retrospective nature of this study results in potential confounding and bias by unmeasured variables. Furthermore, this study only demonstrates an association of nodal basin ultrasound with the variables studied in early-stage BC patients. It does not suggest a causative relationship. We acknowledge the potential for bias arising from the substantial duration between the pre-intervention and post-intervention groups, as treatment protocols, encompassing axillary management and systemic therapy options, may have undergone evolution during this period. We acknowledge the possibility that the increased utilization of NAC agents over time may have influenced the downstaging of the axilla. However, our institutional data indicate a decline in the overall rate of neoadjuvant therapy during the study period.
We also recognize the importance of receptor status in predicting the results of pathologic response in light of receiving NAC (31,32). This important point was recognized as a potential secondary analysis during this first study and we will be reporting the subsequent results in a separate manuscript.
Conclusions
Our study demonstrated longer time period to surgery and high rates of NAC, but lower rates of axillary dissection and potential downstaging for those patients after our adoption of nodal staging US for early-stage invasive BC. The routine use of nodal basin US is an important tool in treatment decisions for early-stage BC.
Acknowledgments
Our abstract has been presented at Society of Surgical Oncology SSO 2022—International Conference on Surgical Cancer Care, Dallas, Texas, taking place between the 9th to 12th of March, 2022.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-24-11/rc
Data Sharing Statement: Available at https://abs.amegroups.com/article/view/10.21037/abs-24-11/dss
Peer Review File: Available at https://abs.amegroups.com/article/view/10.21037/abs-24-11/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-24-11/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Review Board of Cooper University Hospital (IRB# 20-586)
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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Cite this article as: Wang QY, Fantazzio MA, Hunter K, Loveland-Jones CE, Nicholson A, De La Cruz LM, Gittens A, Romero M, Abbasi S, Hilt E, Schenker D, Yoon-Flannery K. Utility of nodal basin staging ultrasound in early-stage breast cancer. Ann Breast Surg 2024;8:31.
