Abstract
Axillary surgery in breast cancer has evolved from radical dissections to selective de-escalations. Identifying patients who may safely omit sentinel lymph node biopsy (SLNB) can further reduce the surgical burden, post operative complications and financial toxicity associated with breast cancer surgical care. The MD Anderson “Nomogram To Predict Positive Sentinel Lymph Nodes After Neoadjuvant Chemotherapy” is widely available and free of charge to assess SLNB positivity post neoadjuvant chemotherapy (NACT). This study externally validates its accuracy in a sample of Pakistani women and assesses its implications for cost effective breast cancer care in a resource limited setting. Retrospective chart review of 150 women who underwent axillary sentinel lymph node biopsy post NACT at Shaukat Khanum Memorial Cancer Hospital from January 2023 to August 2024. Predicted node probability and observed positivity on histopathology were recorded. Calibration (Hosmer-Lemeshow test) and discrimination (C-index) were calculated. 98% were ductal carcinomas; tumor sub-types showed luminal A (42.7%), luminal B (4.7%), her2neu (H2N) enriched (14%) and triple negative (TNBC; 38.7%). 18% (n = 27) nodes were positive on final pathology closely aligning with the nomogram’s predicted probability of 17.1 ± 10.3%. Calibration showed good model fit (P = .89) while C-index (0.64) indicated moderate discrimination. 12.6% of women would avoid costs of SLNB if omitted in the 0% to 5% bracket and 31.3% of women in the 0% to 10% bracket. TNBC demonstrated lowest positivity of 6.89% (P = .01). The MD Anderson Clinical Calculator for predicting positive sentinel lymph nodes post NACT may have a role in tailoring decisions for axillary de-escalation especially in patients with a low probability score between 0% and 10% with decrease in costs of breast cancer care in LMICs. Future studies incorporating safety of axillary surgery omission using the calculator and its economic impact are warranted.
Keywords: breast cancer, neoadjuvant, sentinel lymph node, financial toxicity, cost-effectiveness, LMIC, Pakistan
Introduction
Since the advent of breast cancer surgery a radical axillary dissection with removal of all axillary fat including level 3 axillary lymph nodes was used to address frequent axillary metastasis. However, since the 1990s there has been an increasing trend of axillary de-escalation as imaging and sentinel lymph node biopsies show fair sensitivity and specificity of predicting a clinically negative axilla. 1 The Z011 trial was one of the first few trials that showed axillary surgery could be safely replaced with a sentinel lymph node biopsy alone. 2 This was followed by targeted axillary dissection which has shown that post NACT a cN1 axilla that is down-staged to cN0 may avoid radical axillary dissection. 3 Similarly, the SOUND trial has further de-escalated axillary surgery in stage 1 breast cancer to omission of SLNB in a select group of women for upfront surgery as the disease free survival was similar with or without a SLNB. This study however excluded patients who have received neoadjuvant chemotherapy who may similarly benefit from axillary surgery omission. 4 In patients who have clinically negative nodes the chances that a sentinel lymph node will remain negative reach upto 90% or more and in patients with initially clinically positive nodes the chances of conversion to a negative axilla decrease to less than 20% with luminal A subtypes. However, odds of conversion to a negative axilla increase to upto 70% with triple negative or her2neu enriched subtypes which have robust pathological complete responses to chemotherapy.5-7 Keeping in mind that tumor biology may dictate the chances of a negative axilla post chemotherapy raises the question as to whether we can predict the chances of a sentinel lymph node being negative and thus safely omit sentinel lymph node biopsy further de-escalating axillary surgery. There are multiple cost related implications of sentinel lymph node biopsy omission especially for women in resource limited settings. Technetium based sentinel lymph node injections can cost upto 800 U.S dollars. Further, SLNB surgery involves increased cost of extra anesthesia time, extra suture material, cost of a second procedure, additional pathology including frozen section all of which can range upto 10 000 U.S dollars per patient. Omission of axillary surgery safely may reduce these costs and the burden borne by the healthcare system especially in resource limited settings like Pakistan.8-10
The MD Anderson “Nomogram To Predict Positive Sentinel Lymph Nodes After Neoadjuvant Chemotherapy” Clinical Calculator is easily available on their website and is a simple tool that uses age, histology, grade, tumor size, percent decrease in tumor size post neoadjuvant chemotherapy, multifocal or multicentric tumor presence, lymphovascular invasion status, and triple negative biology to calculate the chance of the sentinel lymph node biopsy being positive. All evidence thus far has evaluated the safe omission of sentinel lymph node biopsy in patients receiving upfront surgery, however; there is no evidence post chemotherapy. This study aimed to bridge that gap and provide evidence that this may be feasible by comparing the incidence of sentinel lymph node positivity post neoadjuvant to the chances of positivity given by the MD Anderson calculator for external validation. Further, it is imperative to validate the calculator in women of different ethnicities as chemotherapy responses may vary and the MD Anderson calculator was formulated based on women presenting to their center. This study validates the findings of the calculator on a small sample of Pakistani women to evaluate whether the calculator is applicable on all women despite ethnicity. This also serves the purpose of including women from resource limited settings who may be overlooked in literature emerging from the West.
Materials and Methods
Study Design and Participants
We did a retrospective chart review of 150 patients who underwent axillary sentinel lymph node biopsy from 1st January 2023 to 30th August 2024 post NACT at Shaukat Khanum Memorial Cancer Hospital. IRB approval was obtained numbered EX-09-01-24-08. We recorded all the parameters needed for the MD Anderson calculator along with tumor biology, probability of positive nodes calculated by the calculator, the number of sentinel lymph nodes removed, number of nodes involved on frozen section and on final pathology. The probability of a positive node as identified by the calculator was divided into brackets with 5% increments that is, 0% to 5%, 6% to 10%, 11% to 15%, 16% to 20%, 21% to 25%, 26% to 30%, 31% to 35%, 36% to 40%, 41% to 45% and greater than 45%. Patients included had cT1-3 and cN0 disease who underwent either breast conservation or mastectomy post NACT. All patient data was kept anonymous. Ethical board review approval was obtained prior to commencement of the study.
Statistical Analysis
All data was entered and analyzed using SPSS V 25.0. Quantitative data was presented as mean with standard deviation and was assessed using the student T-test while qualitative data was presented using frequencies and percentages using the chi-square analysis with a P-value of less than .05 as significant. Hosmer-Lemeshow logistic regression analysis was done for calibration analysis of the clinical calculator with calibration plot while C-index calculation was done for discrimination for purpose of external validation of the test.
Results
Of 150 patients reviewed all were women. The mean age was 39.7 ± 8.09 years. 147 (98%) were invasive ductal carcinomas while 3 (2%) were invasive lobular carcinomas. The mean grade of tumor was 2.53 ± 0.50. Tumor biology showed that 64 (42.7%) were Luminal A, 7 (4.7%) were luminal B, 21 (14%) were her2neu enriched and 58 (38.7%) were triple negative. The mean size of tumors was 3.51 ± 1.44 cm. The mean percentage decrease in size was 59.5 ± 32.9%. 40 (26.7%) were multi-centric or multifocal tumors. No tumors identified had lymphovascular invasion. Mean number of sentinel lymph nodes removed were 2.50 ± 0.73 nodes while mean number of positive nodes was 0.30 ± 0.62 nodes on frozen section. 18% (n = 27) nodes were positive on final pathology. The mean percentage probability of nodes being positive was 17.1 ± 10.3%. This shows that calibration-in-large or calibration of the calculator is accurate. For calibration purpose we did a Hosmer-Lemeshow logistic regression analysis of the positive nodes on final pathology and positive nodes probability calculated; P-value of .89 was found showing that it is a good model or calculator with acceptable calibration upto 30% predicted values as determined by the calibration plot (Figure 1).
Figure 1.
Calibration curve for observed and predicted values depicting concordance. The blue line depicts predicted values using the calculator while the black line depicts observed values from the data.
C-index for discrimination was calculated to be 0.64 showing 64.4% concordance of predicted and observed outcomes. The incidence of positive sentinel nodes on frozen section and on final pathology for each probability bracket were calculated that showed final pathology was discordant to initial frozen section in some cases (Table 1). The predicted positivity of sentinel nodes and the observed positivity of sentinel nodes for each bracket were calculated showing discordance increases at higher probability brackets (Table 2).
Table 1.
Sentinel Lymph Node Pathological Positivity Stratified by Clinical Tool Calculated Probability.
| Probability bracket (%) | Rate of positive nodes on frozen section | Rate of positive nodes on final pathology |
|---|---|---|
| 0-5 | 10.5% (2/19) | 5.2% (1/19) |
| 6-10 | 11.1% (3/27) | 11.1% (3/27) |
| 11-15 | 17.9% (5/28) | 17.9% (5/28) |
| 16-20 | 17.2% (5/29) | 6.9% (2/29) |
| 21-25 | 42.8% (6/14) | 35.7% (5/14) |
| 26-30 | 37.5% (6/16) | 31.2% (5/16) |
| 31-35 | 44.4% (4/9) | 44.4% (4/9) |
| 36-40 | 50% (1/2) | 50% (1/2) |
| 41-45 | 20% (1/5) | 20% (1/5) |
| >45 | 0% (0/1) | 0% (0/1) |
Table 2.
Comparison of Predicted Sentinel Node Positivity by MD Anderson Calculator With Observed Sentinel Node Positivity in the Study for Each Bracket.
| Probability bracket (%) | Predicted positivity of sentinel nodes by calculator (%) | Observed sentinel node positivity in study on final pathology |
|---|---|---|
| 0-5 | 4.10 | 5.2% (1/19) |
| 6-10 | 7.55 | 11.1% (3/27) |
| 11-15 | 13.2 | 18.5% (5/28) |
| 16-20 | 17.9 | 6.9% (2/29) |
| 21-25 | 22.4 | 35.7% (5/14) |
| 26-30 | 27.8 | 31.2% (5/16) |
| 31-35 | 33.6 | 44.4% (4/9) |
| 36-40 | 37 | 50% (1/2) |
| 41-45 | 42.4 | 20% (1/5) |
| >45 | 46 | 0% (0/1) |
In the 0% to 5% group the single positive lymph node on frozen was a grade 3 ductal carcincoma (IDCa) TNBC which was initially T1; 1.2 cm in size with a complete pathological response. In the 6% to 10% group the 3 positive nodes on frozen section included a triple negative breast cancer grade 2 IDCa cT2 with initial size of 2.1 cm and a 10% decrease in size post NACT with 3 out of 3 SLN positive for metastasis; a triple negative breast cancer grade 2 IDCa cT2 initially 2.9 cm with a 55% decrease in size and 1 out of 2 SLN positive for metastasis and a triple negative breast cancer grade 2 IDCa cT2 initially 4.5 cm with a 44% decrease in size and 1 out of 1 SLN positive for metastasis.
A further analysis was done to see if the sentinel lymph node negative rate was related to the response seen in the tumor post chemotherapy showed a trend that robust response in tumor had fewer positive nodes however it was not significant statistically (Table 3).
Table 3.
Sentinel Lymph Node Positivity Rate in Relation to Tumor Pathological Response to Neoadjuvant Chemotherapy.
| Probability bracket (%) | Average percentage decrease in size of tumor (%) | Rate of positive nodes on final pathology | P-value |
|---|---|---|---|
| 0-5 | 100 | 5.2% (1/19) | .99 |
| 6-10 | 51.3 (10-100) | 11.1% (3/27) | .61 |
| 11-15 | 56.4 (30-100) | 17.8% (5/28) | .82 |
| 16-20 | 33 (16-50) | 6.9% (2/29) | .26 |
| 21-25 | 41.4 (5-100) | 35.7% (5/14) | .37 |
| 26-30 | 45 (30-56) | 31.2% (5/16) | .14 |
| 31-35 | 40 (15-60) | 44.4% (4/9) | .34 |
| 36-40 | 20 | 50% (1/2) | .15 |
| 41-45 | 5 | 20% (1/5) | .28 |
| >45 | NA | 0% (0/1) | NA |
If sentinel lymph node biopsy was omitted for the 0% to 5% bracket then 12.6% of women would avoid costs of sentinel lymph node biopsy. If it were omitted for the 0% to 10% bracket then 31.3% of women would avoid financial burden of sentinel lymph node biopsy. Analysis using student T-test of mean percentage decrease in size overall for positive versus negative sentinel lymph nodes showed mean 45.1 ± 29.9% and 62.6 ± 32.9% respectively with a significant P-value of .01. Sentinel lymph node positivity was assessed for different tumor biology to assess the impact of biology on positivity triple negative subtypes had the lowest positive sentinel node rate as compared to the other subtypes (Table 4).
Table 4.
Assessment of Sentinel Lymph Node Positivity for Tumor Biology.
| Tumor biology | Luminal A | Luminal B | Her2neu enriched | Triple negative | P-value |
|---|---|---|---|---|---|
| Positive | 26.5% (17/64) | 42.8% (3/7) | 14.2% (3/21) | 6.89% (4/58) | .01 |
23.9% (17/71) grade 2 tumor sentinels were positive while 12.6% (10/79) grade 3 tumors were positive with P-value of .07.
Multicentric or multifocal tumors showed no difference in positivity as compared to unicentric tumors, P = .17. Ductal versus lobular histology showed no difference in positivity, P = .48. Initial mean size of tumor was analyzed between positive versus negative sentinel lymph node and no difference was found, P = .713. Pearson correlation co-efficient showed a weak positive correlation, r = +.185, (P = .02) for probability of sentinel lymph node positivity and number of positive nodes per bracket.
Discussion
As the tides turn toward de-escalation of the axilla it is important to find simpler solutions for assessing which patients may benefit from de-escalation including no axillary surgery at all especially in the neoadjuvant setting. The MD Anderson Calculator is freely available online predictive model unlike other predictive tests that bear significant costs- such tools may improve the equity of cancer care delivery especially in resource limited settings where women may benefit from surgical de-escalation resulting in decreased financial burdens. Further, validated nomograms may improve access to personalized cancer care decisions in resource limited countries improving patient and cancer care and decreasing unnecessary procedures. 11 The MD Anderson nomogram is a relatively new tool made available and has yet not been externally validated- this is mentioned on their webpage which can be accessed from https://www3.mdanderson.org/app/medcalc/bc_nomogram4/index.cfm?pagename=sln- and to the best of our knowledge there is no published data on internal validation either. However, the tool utilizes simple and readily available results in both affluent and lower income countries, which are routinely part of breast cancer baseline investigations. In our study 46 out of the 150 women that is, 30.6% of women who had surgery may have avoided axillary surgery which would result in nearly a decrease in costs of care estimated around 460 000 U.S dollars. The results of our study show that perhaps tailored clinical decisions are the best approach. We found that triple negative and HER2Neu enriched biology along with higher grade of tumor had better chances at complete pathological response; further it was found that the better the response of the initial tumor to neoadjuvant chemotherapy the higher the chances that sentinel lymph nodes would also be negative. We further noted the trend that as the MD Anderson clinical calculator’s positive prediction increased so did the number of the positive nodes noted. Further, for the 0% to 5% and 6% to 10% bracket the positive lymph node incidence was similar to what was predicted and thus these 2 subgroups may benefit from exclusion from axillary surgery decided on an individual case to case basis. This de-escalation would result in tailored care, however; the results of our study are from a small retrospective study following the standard of care. Large sample prospective studies of patients with and without post-neoadjuvant sentinel lymph node biopsy using the clinical calculator with results directed toward comparing patients with and without omission of sentinel biopsies in terms of disease free survival, recurrence and mortality may change practice in the future and lead to de-escalation of axillary surgery using this simple tool. Sentinel lymph node biopsy has shown over the years to be reliable with identification rates of 92.9% and a false negative rate of 14%. 12 Data has shed light to the fact that even in clinically node positive disease 48% pCR is seen in triple negative disease, 35% for luminal B and 13% for Luminal A which is concordant with our study where we saw greater percentage of negative sentinel lymph nodes in similar tumor biology. 6 Studies have also found that pCR in the axilla is associated with pCR in primary breast tumor which is similar to what we observed. 13 Recent studies have also urged that simple online clinical tools may be used for personalized decision making for breast cancer patients thus increasing chances that patients get tailored treatment and not a one size fits all criteria is applied. 14 To the best of our knowledge no other study has externally validated the MD Anderson clinical calculator which from our retrospective study shows great promise in tailoring decisions for management of the axilla post neoadjuvant chemotherapy in a select group of patients who may benefit greatly from axillary de-escalation. Our study was limited by the sample size and a larger sample size may be beneficial for future validation studies.
Conclusion
The MD Anderson Clinical Calculator for predicting positive sentinel lymph nodes post neoadjuvant chemotherapy may have a role in tailoring decisions for axillary de-escalation especially in patients with a low probability score between 0% and 10%. This opens avenues for axillary de-escalation in patients who have received neoadjuvant chemotherapy for which currently no evidence exists as all large trials for axillary de-escalation have been centered on patients receiving upfront surgery first. Applications of such validated nomograms may reduce treatment costs in LMICs associated with surgery and future studies focusing on safety of axillary surgery omission in the neoadjuvant setting along with economic impact of this reduction in LMICs may be well received.
Footnotes
ORCID iD: Vishal Farid Raza 
https://orcid.org/0000-0002-1133-6170
Ethical Considerations: Declaration of Helsinski followed; ethical approval obtained from IRB.
Consent to Participate: Informed consent from each patient were waived by IRB as it was a retrospective study with anonymized data.
Author Contributions: VFR, AE, AIK all three authors contributed to manuscript conceptual design, data collection, and writing and take responsibility of the final work.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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