# Lymph node positivity in different early breast carcinoma phenotypes: a predictive model

Gilles Houvenaeghel, Eric Lambaudie, Jean-Marc Classe, Chafika Mazouni, Sylvia Giard, Monique Cohen, Christelle Faure, Pierre Charitansky, Roman Rouzier, Emile Daraï, et al.

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Gilles Houvenaeghel, Eric Lambaudie, Jean-Marc Classe, Chafika Mazouni, Sylvia Giard, et al. Lymph node positivity in different early breast carcinoma phenotypes: a predictive model. BMC Cancer, 2019, 19 (1), pp.45. 10.1186/s12885-018-5227-3. hal-01983749

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# Lymph node positivity in different early breast carcinoma phenotypes: a predictive model

Gilles Houvenaeghel<sup>1,14*</sup>, Eric Lambaudie<sup>1,14</sup>, Jean-Marc Classe<sup>2</sup>, Chafika Mazouni<sup>3</sup>, Sylvia Giard<sup>4</sup>, Monique Cohen<sup>1</sup>, Christelle Faure<sup>5</sup>, Hélène Charitansky<sup>6</sup>, Roman Rouzier<sup>7</sup>, Emile Darai<sup>8</sup>, Delphine Hudry<sup>9</sup>, Pierre Azuar<sup>10</sup>, Richard Villet<sup>11</sup>, Pierre Gimbergues<sup>12</sup>, Christine Tunon de Lara<sup>13</sup>, Marc Martino<sup>1</sup>, Jean Fraisse<sup>9</sup>, François Dravet<sup>2</sup>, Marie Pierre Chauvet<sup>4</sup> and Jean Marie Boher<sup>1</sup>

**Abstract**

**Background:** A strong correlation between breast cancer (BC) molecular subtypes and axillary status has been shown. It would be useful to predict the probability of lymph node (LN) positivity. **Objective:** To develop the performance of multivariable models to predict LN metastases, including nomograms derived from logistic regression with clinical, pathologic variables provided by tumor surgical results or only by biopsy.

**Methods:** A retrospective cohort was randomly divided into two separate patient sets: a training set and a validation set. In the training set, we used multivariable logistic regression techniques to build different predictive nomograms for the risk of developing LN metastases. The discrimination ability and calibration accuracy of the resulting nomograms were evaluated on the training and validation set.

**Results:** Consecutive sample of 12,572 early BC patients with sentinel node biopsies and no neoadjuvant therapy. In our predictive macro metastases LN model, the areas under curve (AUC) values were 0.780 and 0.717 respectively for pathologic and pre-operative model, with a good calibration, and results with validation data set were similar: AUC respectively of 0.796 and 0.725. Among the list of candidate's regression variables, on the training set we identified age, tumor size, LVI, and molecular subtype as statistically significant factors for predicting the risk of LN metastases.

**Conclusions:** Several nomograms were reported to predict risk of SLN involvement and NSN involvement. We propose a new calculation model to assess this risk of positive LN with similar performance which could be useful to choose management strategies, to avoid axillary LN staging or to propose ALND for patients with high level probability of major axillary LN involvement but also to propose immediate breast reconstruction when post mastectomy radiotherapy is not required for patients without LN macro metastasis.

**Keywords:** Breast cancer, Sentinel node, Risk prediction, Nomogram, Molecular subtype

<footnote>* Correspondence: g.houvenaeghel@orange.fr;
houvenaeghelg@ipc.unicancer.fr
¹Institut Paoli Calmettes et CRCM, 232 boulevard de Sainte Marguerite, 13009
Marseille, France
¹⁴Aix-Marseille University, Unité Mixte de Recherche S912, Institut de
Recherche pour le Développement, 13385 Marseille, France
Full list of author information is available at the end of the article</footnote>
## Synopsis

A retrospective cohort of 12,572 early BC patients with SN biopsies was randomly divided into two separate patient sets to develop, validate and compare different predictive nomograms for the risk of developing LN metastases from clinical and pathologic variables provided by tumor surgical results or by biopsy.

## Background

In breast cancer (BC), nodal status is a major prognostic factor that determines therapeutic decisions to a large extent. Sentinel lymph node biopsy (SLNB) provides a reliable assessment of the axilla status in early clinically node-negative BC [1]. Since it also causes less morbidity than axillary lymph node dissection (ALND), it is now considered as a standard of care procedure. The omission of completion ALND in patients with negative sentinel lymph nodes (SLN) has been recognized as a reasonable attitude since the publication of the NSABP B-32 results [2]. Moreover, it is likely that it can be safely expanded to patients with minimal SLN involvement (isolated tumor cells and micro metastases), with regard to survival outcomes [3, 4]. Indeed, 40 to 70% of these patients do not have metastatic non-sentinel lymph nodes (NSLN) [5]. Main predictors of LN metastases are tumor size, grade, lymphovascular invasion (LVI), age at diagnosis, extracapsular extension of the positive SLN, and hormonal and HER2 receptor status [6–10]. In addition, a strong correlation between BC molecular subtypes and/or tumor phenotypes on the one hand (determined by hormonal receptor and HER2 status) and axillary status on the other hand has been shown in numerous studies [11–16].

The determination of the risk of positive axillary LN can significantly contribute to therapeutic decisions. However, this risk cannot be immediately induced from the results of multivariate analyses that provide broad statistical information. Only an appropriate prediction tool, using a nomogram, can indicate the individual risk of a given patient. These nomograms can also be used to compare populations from different studies. A large cohort is necessary to reliably determine the probability of positive SN, particularly for less frequent tumor phenotypes. Reyal et al. published such a nomogram predictive of the risk of developing SN metastases in 2011 [11], built on a training set made of 1543 early-stage BC patients, and validated on two cohorts of 615 and 496 patients respectively. This model was further validated in a cohort of 755 consecutive patients treated at Institut Curie in 2009 [17].

The aim of our study was to develop and compare the performance of multivariable models to predict LN metastases, including nomograms derived from logistic regression with clinical, pathologic variables provided by

tumor surgical results or only provided by biopsy as explanatory variables.

## Methods

### Patients

Our cohort consisted of 12,572 consecutive patients with small (≤ 30 mm based on clinical and radiologic findings), clinically node-negative invasive BC, who did not receive neoadjuvant therapy, and underwent SLNB between 1999 and 2012 at 13 French centers. HER2 status was determined for all patients. During the first years of the study, ALND was systematically performed in some sites; thereafter, ALND was performed only in case of SN involvement, this attitude being homogeneous within all the participating sites.

### Evaluation

The following data were retrieved: characteristics of patients (age at the time of SLNB), and tumors [size, clinical stage, histological type, estrogen (ER), progesterone (PR) and HER2 status, LVI, Scarff-Bloom-Richardson (SBR) grade], description of ALND (number of LN sampled and involved), and results of the pathological examination of surgical resection specimens. Tumor size was determined on the results of pathological examination but could be evaluated pre operatively by mammography, sonography and in selected cases by MRI (clinical T stage). LVI was detected on surgical specimen.

Tumor phenotype was defined by the combination of ER, PR and HER2 status, evaluated by immuno-histochemistry (IHC) and confirmed by FISH in case of IHC-HER2 2+. Positivity for ER and PR was determined according to French guidelines (≥ 10% of cancer cells expressing ER/PR). Five molecular subtypes were defined according to clinico-pathological criteria [18]. Because information on Ki-67 was not available, we used grade to capture cell proliferation, as described by von Minckwitz et al [19] The following definitions were used: triple-negative (basal-like, HER2-/HR-), HER2 positive (non-luminal, HER2+/HR-), and luminal (HR+), divided into luminal A (HR+/HER2-/-grade1 or 2), luminal B-HER2-negative like (HR+/HER2-/-grade 3), and luminal B-HER2-positive like (HR+/HER2+ all grades).

Although the methods used for histological examination were not standardized in the protocol, all sites proceeded similarly: serial sections were performed every 200 µm and stained with standard hematoxylin and eosin. The number of sections was six to ten, or pursued until node exhaustion in case of large SN. Additional IHC analysis was done in case of negative results at standard examination. For additional nodes identified by completion ALND, routine HE analysis was performed.

Five categories of LN status were defined: negative LN (pN0i-), isolated tumor cells (pN0(i+): ≤ 0.2 mm), detected
either by hematoxylin and eosin (HE) staining or by cyto-
keratin IHC, micro metastases (pN1mi: > 0.2 mm and ≤ 2
mm), and macro metastases ( > 2 mm), divided into single
and multiple macro metastases [20].

**Statistical methods**

Our main objective was to create prediction models for
the risk of LN positivity and the risk of LN macroscopic
metastases from clinical and pathologic variables pro-
vided by tumor surgical results or by biopsy, and evalu-
ate their performance with respect to three main
features: discrimination (i.e. whether the relative ranking
of individual predictions is in the correct order), *calibra-
tion* (i.e. agreement between observed outcomes and
predictions) *and clinical utility defined as* proportions of
patients classified into risk categories using predefined
cutoff values (< 10%, between 10 and 20%, between 20
and 30%, between 30 and 40%, and > = 40%). Our main
evaluation criteria were based on the final status of LN
metastases (pN0(i+), pN1mi or pN1ma) as the result of
SLNB alone or the final result of both SLNB and ALND.
LN positivity was defined as the presence of isolated
tumor cells, micro or macro LN metastases. We used lo-
gistic regression models [21] including age (<=40, 41-
75, > 75), tumor size (<=20, 20–30, > = 30 mm) or clinical
T stage (T0-T1, T2, T3-T4), tumor grade, histology type,
LVI, and molecular subtypes as predictor factors to predict
each individual risks. The list of predictor factors was set
beforehand, based on the investigator’s experience and
some reference papers [6–11, 13–15, 17]. No additional
procedure was used in regression analysis to reduce the
list of only 5 or 6 predictor factors identified beforehand.
Prior to analysis, we randomly divided our initial cohort
(N = 12,572) in two separate sub-cohorts: a large training
cohort (N = 8381) to create prediction models and a con-
firmatory cohort (N = 4191) to evaluate their individual’s
prediction performance. A split-sample approach was
adopted in order to estimate unbiasedly the model
performance, as these estimates are known to be biased
upwards when regression parameters are estimated on the
same dataset [22]. First we performed a descriptive
analysis using the following criteria: patient’s age at SN bi-
opsy, clinical and pathological tumor size, tumor grade
and histology type, lymphovascular invasion or not (LVI),
presence of estrogen (ER), progesterone (PR) and hormo-
nal receptors (RH), Her2 positivity, tumor subtype, num-
ber of SN removed and final LN status. The evaluation of
each model was assessed in the training sample and the
confirmatory sample. Differences in patient’s and tumor’s
characteristics were compared using Chi Square or exact
Fisher test, Student or Wilcoxon rank sum tests as appro-
priate. The discrimination ability was evaluated by the
area under the ROC (Receiver Operating Characteristic)
curve (AUC). We used the functions roc and pROC

implemented in R to estimate AUC with 95%CI and test
for difference in AUCs along the Delong's method in the
confirmatory sample [23]. Empirical distributions of AUC
observed after re-fitting a model on bootstrap replicates
(B = 2000) were used to estimate AUC and difference in
AUCs with 95% CI in the training sample. Model calibra-
tion was evaluated using Hosmer goodness-of-fit test [24].
All statistical analyses were conducted in the R Language
and Environment for Statistical Computing version 3.2.5
(The R Foundation, Vienna, Austria).

**Results**

**Patients' characteristics**

Patients' main characteristics are summarized in Table 1.
SBR grade was 1, 2 and 3 in 34, 46 and 20% of cases re-
spectively. Hormone receptor-positive tumors (ER+ and/
or PR+) accounted for 88% of cases (11,013 patients).
Final LN status, taking into account ALND results when
performed, was: pN0(i-) in 8253 patients (66%), pN0(i+)
in 355 (3%), pN1mi in 970 (8%) and macro metastasis in
2994 (24%). The comparison between patients with posi-
tive and negative final LN status, and between patients
with LN macro metastases versus pN0 or pNo(i+) or
pN1mi showed statistically significant differences with
regard to age, pathologic tumor size, SBR grade, LVI,
histological type and distribution of molecular subtypes
(Tables 2 and 3).

We first predicted the individual probabilities of final
LN positivity and of detecting LN macro metastases from
selected clinico-pathologic predictor factors provided by
tumor surgical results. The model AUCs with 95% CIs for
confirmatory and training samples were respectively 0.767
[0.750–0.783] and 0.755 [0.744–0.767]. Calibration plot
and Hosmer-Lemeshow test revealed that the calibration
is adequate (*p* = 0.332 in confirmatory sample, *p* = 0.158
in training sample). With respect to clinical utility in con-
firmatory and training samples, the probability of positive
LN were respectively below 10% for 7 patients (< 1%) and
19 patients (< 1%), between 10 and 20% for 1096 (31%)
and 2255 (32%), and ≥ 20% for 2409 (68.6%) and 4859
(68.1%) patients (Table 4) (Fig. 1A, Additional file 1: Fig-
ure S1A and Additional file 2: Figure S2A). The second
pathological model estimated the probability of detecting
LN macro metastases only. The AUC values for confirma-
tory and training samples were respectively 0.798 (0.780–
0.815) and 0.780 [0.767–0.790]. Clinical utility measures,
estimated the probability of LN macro metastases re-
spectively in confirmatory and training samples below
10% for 1004 patients (29%) and 2029 patients (28%),
between 10 and 20% for 1075 patients (31%) and 2289
patients (32%), and > 20% for 1433 patients (41%) and
2815 patients (39.4%). The Hosmer-Lemeshow test re-
vealed a poor calibration of the model (*p* = 0.024 in
<table><caption>**Table 1** Population: all patients and patients according to initial data set or validation set</caption><thead><tr><th rowspan="2"></th><th colspan="2">All patients</th><th colspan="2">Initial set</th><th colspan="2">Validation set</th></tr><tr><th>Nb</th><th>%</th><th>Nb</th><th>%</th><th>Nb</th><th>%</th></tr></thead><tbody><tr><td>Nb patients</td><td>12,572</td><td></td><td>8381</td><td></td><td>4191</td><td></td></tr><tr><td>Age median (range)</td><td>58 (18–101)</td><td></td><td>58 (18–101)</td><td></td><td>58 (18–100)</td><td></td></tr><tr><td>≤ 60</td><td>7231</td><td>58</td><td>4857</td><td>58</td><td>2374</td><td>57</td></tr><tr><td>61–65</td><td>1810</td><td>14</td><td>1166</td><td>14</td><td>644</td><td>15</td></tr><tr><td>> 65</td><td>3525</td><td>28</td><td>2355</td><td>28</td><td>1170</td><td>28</td></tr><tr><td>Median tumor size</td><td>14</td><td></td><td>14</td><td></td><td>14</td><td></td></tr><tr><td>≤ 10</td><td>4701</td><td>38</td><td>3136</td><td>38</td><td>1565</td><td>38</td></tr><tr><td>11 to 20</td><td>5053</td><td>41</td><td>3368</td><td>41</td><td>1685</td><td>41</td></tr><tr><td>> 20</td><td>2679</td><td>22</td><td>1784</td><td>22</td><td>895</td><td>22</td></tr><tr><td>No SN removed</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>3268</td><td>31</td><td>2203</td><td>31</td><td>1065</td><td>31</td></tr><tr><td>2</td><td>3374</td><td>32</td><td>2231</td><td>31</td><td>1143</td><td>33</td></tr><tr><td>3</td><td>2034</td><td>19</td><td>1382</td><td>20</td><td>652</td><td>19</td></tr><tr><td>≥ 4</td><td>1886</td><td>18</td><td>1271</td><td>18</td><td>615</td><td>18</td></tr><tr><td>Tumor type</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ductal</td><td>9793</td><td>78</td><td>6522</td><td>78</td><td>3271</td><td>78</td></tr><tr><td>Lobular</td><td>1645</td><td>13</td><td>1110</td><td>13</td><td>535</td><td>13</td></tr><tr><td>Mixt</td><td>226</td><td>2</td><td>144</td><td>2</td><td>82</td><td>2</td></tr><tr><td>Others</td><td>899</td><td>7</td><td>599</td><td>7</td><td>300</td><td>7</td></tr><tr><td>Grade</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>4246</td><td>34</td><td>2891</td><td>35</td><td>1355</td><td>33</td></tr><tr><td>2</td><td>5756</td><td>46</td><td>3800</td><td>46</td><td>1956</td><td>47</td></tr><tr><td>3</td><td>2448</td><td>20</td><td>1611</td><td>19</td><td>837</td><td>20</td></tr><tr><td>LVI</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Negative</td><td>8430</td><td>78</td><td>5661</td><td>78</td><td>2769</td><td>77</td></tr><tr><td>Positive</td><td>2400</td><td>22</td><td>1595</td><td>22</td><td>805</td><td>23</td></tr><tr><td>Estrogen receptors</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>1730</td><td>14</td><td>1146</td><td>14</td><td>584</td><td>14</td></tr><tr><td>positive</td><td>10,828</td><td>86</td><td>7227</td><td>86</td><td>3601</td><td>86</td></tr><tr><td>Progesterone receptors</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>3464</td><td>29</td><td>2281</td><td>29</td><td>1183</td><td>30</td></tr><tr><td>positive</td><td>8522</td><td>71</td><td>5701</td><td>71</td><td>2821</td><td>70</td></tr><tr><td>Hormonal receptors</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>1541</td><td>12</td><td>1020</td><td>12</td><td>521</td><td>12</td></tr><tr><td>positive</td><td>11,013</td><td>88</td><td>7349</td><td>88</td><td>3664</td><td>88</td></tr><tr><td>Her2 status</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>11,350</td><td>90</td><td>7570</td><td>90</td><td>3780</td><td>90</td></tr><tr><td>positive</td><td>1222</td><td>10</td><td>811</td><td>10</td><td>411</td><td>10</td></tr><tr><td>Tumor sub types</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Luminal A</td><td>8998</td><td>72</td><td>6026</td><td>72</td><td>2972</td><td>71</td></tr><tr><td>Luminal B Her2-</td><td>1178</td><td>9</td><td>756</td><td>9</td><td>422</td><td>10</td></tr><tr><td>HR+ Her2+</td><td>766</td><td>6</td><td>521</td><td>6</td><td>245</td><td>6</td></tr></tbody></table>

<table><caption>**Table 1** Population: all patients and patients according to initial data set or validation set (Continued)</caption><thead><tr><th rowspan="2"></th><th colspan="2">All patients</th><th colspan="2">Initial set</th><th colspan="2">Validation set</th></tr><tr><th>Nb</th><th>%</th><th>Nb</th><th>%</th><th>Nb</th><th>%</th></tr></thead><tbody><tr><td>HR- Her 2+</td><td>450</td><td>4</td><td>288</td><td>3</td><td>162</td><td>4</td></tr><tr><td>Triple Negative</td><td>1091</td><td>9</td><td>732</td><td>9</td><td>359</td><td>9</td></tr><tr><td>pN final</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>pN0(i-)</td><td>8253</td><td>66</td><td>5507</td><td>66</td><td>2746</td><td>66</td></tr><tr><td>pN0(i+)</td><td>355</td><td>3</td><td>233</td><td>3</td><td>122</td><td>3</td></tr><tr><td>pN1mi</td><td>970</td><td>8</td><td>660</td><td>8</td><td>310</td><td>7</td></tr><tr><td>Macro</td><td>2994</td><td>24</td><td>1981</td><td>24</td><td>1013</td><td>24</td></tr><tr><td>Clinical size</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>T0</td><td>2764</td><td>23</td><td>1831</td><td>23</td><td>933</td><td>23</td></tr><tr><td>T1</td><td>6784</td><td>57</td><td>4544</td><td>57</td><td>2246</td><td>56</td></tr><tr><td>T2</td><td>2115</td><td>18</td><td>1383</td><td>17</td><td>732</td><td>18</td></tr><tr><td>≥ T3</td><td>283</td><td>2</td><td>187</td><td>2</td><td>96</td><td>2</td></tr></tbody></table>

confirmatory sample, *p* = 0.427 in training sample) (Table 4 and Additional file 1: Table S1) (Fig. 1B, Additional file 2: Figure S1B, Additional file 3: Figure S2B).

We evaluated the loss in discrimination ability in pre-operative prediction models omitting the information about LVI and substituting pathological tumor size information by clinical T stage. For the overall probability of LN positivity, the AUC values for confirmatory and training samples were respectively 0.687 [0.669–0.705] and 0.682 (0.669–0.694). For the probability of detecting LN macro metastases, the observed AUC results for confirmatory and training samples were respectively 0.727 [0.707–0.746] and 0.717 (0.703–0.732). The calibration of both pre-operative models was found satisfactory. (Table 4) (Fig. 1 C-D, Additional file 2: Figure S1C-D, Additional file 3: Figure S2C-D).

The change in AUCs between pathological and per-operative model were found statistically significantly decreased (*p* < 0.001). We also evaluated in the confirmatory sample the discrimination ability of the prediction models obtained when treating the variable age and tumor size as continuous. The AUC values for predicting LN positivity and the presence of LN metastases were respectively 0.774 [0.758, 0.79] and 0.805 [0.789–0.823]. The observed increases were significantly (*p* = 0.041 and *p* = 0.026), but the results in terms of calibration were judged inadequate (Hosmer-Lemeshow *p* value < 0.001).

Discussion

The aim of this study was to better understand the relationships between tumor characteristics and the probability of axillary LN positivity. The large cohort used in our study is appropriate for less frequent tumor phenotypes (namely Her2+ and HR-Her2-). We distinguished between various histological tumor types, showing
<table><caption>**Table 2** Initial data set and validation set results according to axillary nodal involvement</caption><thead><tr><th rowspan="2"></th><th colspan="2">Initial set</th><th colspan="3">i+/mi/macro</th><th colspan="2">Validation set</th><th colspan="3">i+/mi/macro</th></tr><tr><th>Nb</th><th>%</th><th>Nb</th><th>%</th><th>p</th><th>Nb</th><th>%</th><th>Nb</th><th>%</th><th>p</th></tr></thead><tbody><tr><td>Nb patients</td><td>5507</td><td></td><td>2874</td><td></td><td></td><td>2746</td><td></td><td>1445</td><td></td><td></td></tr><tr><td>Age median (range)</td><td>59 (18–101)</td><td></td><td>55 (20–98)</td><td></td><td></td><td>59 (18–100)</td><td></td><td>56 (22–90)</td><td></td><td></td></tr><tr><td>≤ 60</td><td>3001</td><td>55</td><td>1856</td><td>65</td><td>&lt; 0.0001</td><td>1464</td><td>53</td><td>910</td><td>63</td><td>&lt; 0.0001</td></tr><tr><td>61–65</td><td>818</td><td>15</td><td>348</td><td>12</td><td></td><td>443</td><td>16</td><td>201</td><td>14</td><td></td></tr><tr><td>&gt; 65</td><td>1686</td><td>31</td><td>669</td><td>23</td><td></td><td>836</td><td>30</td><td>334</td><td>23</td><td></td></tr><tr><td>Tumor size (median)</td><td>12</td><td></td><td>19</td><td></td><td></td><td>12</td><td></td><td>20</td><td></td><td></td></tr><tr><td>≤ 10</td><td>2642</td><td>49</td><td>494</td><td>17</td><td>&lt; 0.0001</td><td>1340</td><td>49</td><td>225</td><td>16</td><td>&lt; 0.0001</td></tr><tr><td>11 to 20</td><td>2185</td><td>40</td><td>1183</td><td>41</td><td></td><td>1081</td><td>40</td><td>604</td><td>42</td><td></td></tr><tr><td>&gt; 20</td><td>608</td><td>11</td><td>1176</td><td>41</td><td></td><td>294</td><td>11</td><td>601</td><td>42</td><td></td></tr><tr><td>Tumor type</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ductal</td><td>4244</td><td>77</td><td>2278</td><td>79</td><td>&lt; 0.0001</td><td>2133</td><td>78</td><td>1138</td><td>79</td><td>&lt; 0.0001</td></tr><tr><td>Lobular</td><td>711</td><td>13</td><td>399</td><td>14</td><td></td><td>332</td><td>12</td><td>203</td><td>14</td><td></td></tr><tr><td>Mixt</td><td>73</td><td>1</td><td>71</td><td>2</td><td></td><td>38</td><td>1</td><td>44</td><td>3</td><td></td></tr><tr><td>Others</td><td>473</td><td>9</td><td>126</td><td>4</td><td></td><td>241</td><td>9</td><td>59</td><td>4</td><td></td></tr><tr><td>Grade</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>2142</td><td>39</td><td>749</td><td>26</td><td>&lt; 0.0001</td><td>1007</td><td>37</td><td>348</td><td>24</td><td>&lt; 0.0001</td></tr><tr><td>2</td><td>2410</td><td>44</td><td>1390</td><td>49</td><td></td><td>1245</td><td>46</td><td>711</td><td>49</td><td></td></tr><tr><td>3</td><td>887</td><td>16</td><td>724</td><td>25</td><td></td><td>459</td><td>17</td><td>378</td><td>26</td><td></td></tr><tr><td>LVI</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Negative</td><td>4077</td><td>89</td><td>1584</td><td>59</td><td>&lt; 0.0001</td><td>2004</td><td>89</td><td>765</td><td>58</td><td>&lt; 0.0001</td></tr><tr><td>Positive</td><td>510</td><td>11</td><td>1085</td><td>41</td><td></td><td>256</td><td>11</td><td>549</td><td>42</td><td></td></tr><tr><td>Estrogen receptors</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>747</td><td>14</td><td>399</td><td>14</td><td>0.6964</td><td>371</td><td>14</td><td>213</td><td>15</td><td>0.296</td></tr><tr><td>positive</td><td>4757</td><td>86</td><td>2470</td><td>86</td><td></td><td>2371</td><td>86</td><td>1230</td><td>85</td><td></td></tr><tr><td>Progesterone receptors</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>1568</td><td>30</td><td>713</td><td>26</td><td>0.0004</td><td>782</td><td>30</td><td>401</td><td>29</td><td>0.6346</td></tr><tr><td>positive</td><td>3678</td><td>70</td><td>2023</td><td>74</td><td></td><td>1841</td><td>70</td><td>980</td><td>71</td><td></td></tr><tr><td>Hormonal receptors</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>660</td><td>12</td><td>360</td><td>13</td><td>0.4835</td><td>337</td><td>12</td><td>184</td><td>13</td><td>0.6948</td></tr><tr><td>positive</td><td>4841</td><td>88</td><td>2508</td><td>87</td><td></td><td>2406</td><td>88</td><td>1258</td><td>87</td><td></td></tr><tr><td>Her2 status</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>5837</td><td>91</td><td>1733</td><td>87</td><td>&lt; 0.0001</td><td>2909</td><td>92</td><td>871</td><td>86</td><td>&lt; 0.0001</td></tr><tr><td>positive</td><td>563</td><td>9</td><td>248</td><td>13</td><td></td><td>269</td><td>8</td><td>142</td><td>14</td><td></td></tr><tr><td>Tumor sub types</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Luminal A</td><td>4100</td><td>75</td><td>1926</td><td>67</td><td>&lt; 0.0001</td><td>2029</td><td>75</td><td>943</td><td>66</td><td>&lt; 0.0001</td></tr><tr><td>Luminal B Her2-</td><td>364</td><td>7</td><td>392</td><td>14</td><td></td><td>217</td><td>8</td><td>205</td><td>14</td><td></td></tr><tr><td>HR+ Her2+</td><td>336</td><td>6</td><td>185</td><td>6</td><td></td><td>140</td><td>5</td><td>105</td><td>7</td><td></td></tr><tr><td>HR- Her 2+</td><td>151</td><td>3</td><td>137</td><td>5</td><td></td><td>93</td><td>3</td><td>69</td><td>5</td><td></td></tr><tr><td>Triple Negative</td><td>509</td><td>9</td><td>223</td><td>8</td><td></td><td>244</td><td>9</td><td>115</td><td>8</td><td></td></tr><tr><td>Clinical size</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>T0</td><td>1458</td><td>28</td><td>373</td><td>14</td><td>&lt; 0.0001</td><td>756</td><td>29</td><td>177</td><td>13</td><td>&lt; 0.0001</td></tr><tr><td>T1</td><td>3166</td><td>61</td><td>1378</td><td>50</td><td></td><td>1565</td><td>60</td><td>675</td><td>48</td><td></td></tr><tr><td>T2</td><td>546</td><td>11</td><td>837</td><td>30</td><td></td><td>272</td><td>10</td><td>460</td><td>33</td><td></td></tr><tr><td>≥ T3</td><td>18</td><td>0</td><td>169</td><td>6</td><td></td><td>16</td><td>1</td><td>80</td><td>5</td><td></td></tr></tbody></table>
<table><caption>**Table 3** Initial data set and validation set results according to axillary nodal macro metastasis involvement</caption><thead><tr><th rowspan="3"></th><th colspan="6">Initial set</th><th colspan="6">Validation set</th></tr><tr><th colspan="2">pN0 pN1mi</th><th colspan="2">macro</th><th rowspan="2">p</th><th colspan="2">pN0pN1mi</th><th colspan="2">macro</th><th rowspan="2">p</th></tr><tr><th>Nb</th><th>%</th><th>Nb</th><th>%</th><th>Nb</th><th>%</th><th>Nb</th><th>%</th></tr></thead><tbody><tr><td>Nb patients</td><td>6400</td><td></td><td>1981</td><td></td><td></td><td>3178</td><td></td><td>1013</td><td></td><td></td></tr><tr><td>Age median (range)</td><td>58.4 (18–101)</td><td></td><td>55 (20–98)</td><td></td><td></td><td>59 (18–100)</td><td></td><td>56 (25–90)</td><td></td><td></td></tr><tr><td>≤ 60</td><td>3573</td><td>56</td><td>128/4</td><td>65</td><td>&lt; 0.0001</td><td>1743</td><td>55</td><td>631</td><td>62</td><td>0.0002</td></tr><tr><td>61–65</td><td>934</td><td>15</td><td>232</td><td>12</td><td></td><td>510</td><td>16</td><td>134</td><td>13</td><td></td></tr><tr><td>&gt; 65</td><td>1891</td><td>30</td><td>464</td><td>23</td><td></td><td>922</td><td>29</td><td>248</td><td>24</td><td></td></tr><tr><td>Tumor size</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>≤ 10</td><td>2872</td><td>45</td><td>264</td><td>13</td><td>&lt; 0.0001</td><td>1453</td><td>46</td><td>112</td><td>11</td><td>&lt; 0.0001</td></tr><tr><td>11 to 20</td><td>2665</td><td>42</td><td>703</td><td>36</td><td></td><td>1310</td><td>42</td><td>375</td><td>37</td><td></td></tr><tr><td>&gt; 20</td><td>786</td><td>12</td><td>998</td><td>51</td><td></td><td>380</td><td>12</td><td>515</td><td>51</td><td></td></tr><tr><td>Tumor type</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Ductal</td><td>4981</td><td>78</td><td>1541</td><td>78</td><td>&lt; 0.0001</td><td>2494</td><td>79</td><td>777</td><td>77</td><td>&lt; 0.0001</td></tr><tr><td>Lobular</td><td>800</td><td>13</td><td>310</td><td>16</td><td></td><td>382</td><td>12</td><td>153</td><td>15</td><td></td></tr><tr><td>Mixt</td><td>82</td><td>1</td><td>62</td><td>3</td><td></td><td>43</td><td>1</td><td>39</td><td>4</td><td></td></tr><tr><td>Others</td><td>531</td><td>8</td><td>68</td><td>3</td><td></td><td>257</td><td>8</td><td>43</td><td>4</td><td></td></tr><tr><td>Grade</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>1</td><td>2442</td><td>39</td><td>449</td><td>23</td><td>&lt; 0.0001</td><td>1147</td><td>37</td><td>208</td><td>21</td><td>&lt; 0.0001</td></tr><tr><td>2</td><td>2841</td><td>45</td><td>959</td><td>49</td><td></td><td>1453</td><td>46</td><td>503</td><td>50</td><td></td></tr><tr><td>3</td><td>1048</td><td>17</td><td>563</td><td>29</td><td></td><td>540</td><td>17</td><td>297</td><td>29</td><td></td></tr><tr><td>LVI</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Negative</td><td>4655</td><td>86</td><td>1006</td><td>55</td><td>&lt; 0.0001</td><td>2287</td><td>86</td><td>482</td><td>53</td><td>&lt; 0.0001</td></tr><tr><td>Positive</td><td>780</td><td>14</td><td>815</td><td>45</td><td></td><td>373</td><td>14</td><td>432</td><td>47</td><td></td></tr><tr><td>Estrogen receptors</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>827</td><td>13</td><td>319</td><td>16</td><td>0.0003</td><td>414</td><td>13</td><td>170</td><td>17</td><td>0.0031</td></tr><tr><td>positive</td><td>5570</td><td>87</td><td>1657</td><td>84</td><td></td><td>2760</td><td>87</td><td>841</td><td>83</td><td></td></tr><tr><td>Progesterone receptors</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>1751</td><td>29</td><td>530</td><td>28</td><td>0.4585</td><td>885</td><td>29</td><td>298</td><td>30</td><td>0.6346</td></tr><tr><td>positive</td><td>4330</td><td>71</td><td>1371</td><td>72</td><td></td><td>2140</td><td>71</td><td>681</td><td>70</td><td></td></tr><tr><td>Hormonal receptors</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>negative</td><td>732</td><td>11</td><td>288</td><td>15</td><td>0.0002</td><td>375</td><td>12</td><td>146</td><td>14</td><td>0.0306</td></tr><tr><td>positive</td><td>5662</td><td>89</td><td>1687</td><td>85</td><td></td><td>2800</td><td>88</td><td>864</td><td>86</td><td></td></tr><tr><td>Tumor sub types</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Luminal A</td><td>4780</td><td>75</td><td>1246</td><td>63</td><td>&lt; 0.0001</td><td>2345</td><td>74</td><td>627</td><td>62</td><td>&lt; 0.0001</td></tr><tr><td>Luminal B Her2-</td><td>458</td><td>7</td><td>298</td><td>15</td><td></td><td>272</td><td>9</td><td>150</td><td>15</td><td></td></tr><tr><td>HR+ Her2+</td><td>383</td><td>6</td><td>138</td><td>7</td><td></td><td>161</td><td>5</td><td>84</td><td>8</td><td></td></tr><tr><td>HR- Her 2+</td><td>178</td><td>3</td><td>110</td><td>6</td><td></td><td>106</td><td>3</td><td>56</td><td>6</td><td></td></tr><tr><td>Triple Negative</td><td>554</td><td>9</td><td>178</td><td>9</td><td></td><td>269</td><td>9</td><td>90</td><td>9</td><td></td></tr><tr><td>Clinical size</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>T0</td><td>1601</td><td>26</td><td>230</td><td>12</td><td>&lt; 0.0001</td><td>828</td><td>27</td><td>105</td><td>11</td><td>&lt; 0.0001</td></tr><tr><td>T1</td><td>3731</td><td>61</td><td>813</td><td>43</td><td></td><td>1835</td><td>61</td><td>405</td><td>42</td><td></td></tr><tr><td>T2</td><td>710</td><td>12</td><td>673</td><td>36</td><td></td><td>348</td><td>11</td><td>384</td><td>40</td><td></td></tr><tr><td>≥ T3</td><td>30</td><td>0</td><td>157</td><td>8</td><td></td><td>20</td><td>1</td><td>76</td><td>8</td><td></td></tr></tbody></table>
<table><caption>**Table 4** Discrimination, calibration and clinical utility measures of pathologic and pre-operative prediction models</caption><thead><tr><th colspan="2"></th><th colspan="2">Pathologic model</th><th colspan="2">Pre-operative model</th></tr></thead><tbody><tr><td colspan="2">Probability of LN positivity</td><td></td><td></td><td></td><td></td></tr><tr><td>Criteria</td><td>Parametre</td><td>Initial set</td><td>Validation set</td><td>Initial set</td><td>Validation set</td></tr><tr><td rowspan="2">AUC</td><td>Est</td><td>0.754</td><td>0.767</td><td>0.681</td><td>0.687</td></tr><tr><td>95%CI</td><td>[0.742-0.765]</td><td>[0.75-0.783]</td><td>[0.668-0.693]</td><td>[0.669-0.705]</td></tr><tr><td rowspan="2">AUC (Bootstrap, B = 2000)</td><td>Est</td><td>0.755</td><td>0.766</td><td>0.682</td><td>0.686</td></tr><tr><td>95%CI</td><td>[0.744-0.767]</td><td>[0.762-0.769]</td><td>[0.669-0.694]</td><td>[0.682-0.69]</td></tr><tr><td rowspan="5">Clinical utility</td><td>&lt; 10%</td><td>19 (0%)</td><td>7 (0%)</td><td>1 (0%)</td><td>0 (0%)</td></tr><tr><td>10-20%</td><td>2255 (32%)</td><td>1096 (31%)</td><td>579 (7%)</td><td>279 (7%)</td></tr><tr><td>20-30%</td><td>1258 (18%)</td><td>586 (17%)</td><td>3137 (40%)</td><td>1487 (38%)</td></tr><tr><td>30-40%</td><td>1108 (16%)</td><td>559 (16%)</td><td>2478 (32%)</td><td>1315 (33%)</td></tr><tr><td>40-50</td><td>391 (5%)</td><td>188 (5%)</td><td>228 (3%)</td><td>125 (3%)</td></tr><tr><td></td><td>&gt; = 50%</td><td>2102 (29%)</td><td>1076 (31%)</td><td>1429 (18%)</td><td>746 (19%)</td></tr><tr><td>Calibration</td><td>p-value</td><td>0.158</td><td>0.332</td><td>0.815</td><td>0.200</td></tr><tr><td colspan="2">Probability of macrometastases</td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="2">AUC (Delong)</td><td>Est</td><td>0.780</td><td>0.798</td><td>0.718</td><td>0.727</td></tr><tr><td>95%CI</td><td>[0.767-0.792]</td><td>[0.78-0.815]</td><td>[0.703-0.732]</td><td>[0.707-0.746]</td></tr><tr><td rowspan="2">AUC (Bootstrap, B = 2000)</td><td>Est</td><td>0.780</td><td>0.796</td><td>0.717</td><td>0.725</td></tr><tr><td>95%CI</td><td>[0.767-0.793]</td><td>[0.793-0.799]</td><td>[0.703-0.732]</td><td>[0.721-0.728]</td></tr><tr><td rowspan="5">Clinical utility</td><td>&lt; 10%</td><td>2029 (28%)</td><td>1004 (29%)</td><td>358 (5%)</td><td>184 (5%)</td></tr><tr><td>10-20%</td><td>2289 (32%)</td><td>1075 (31%)</td><td>5049 (64%)</td><td>2450 (62%)</td></tr><tr><td>20-30%</td><td>512 (7%)</td><td>262 (7%)</td><td>829 (11%)</td><td>465 (12%)</td></tr><tr><td>30-40%</td><td>726 (10%)</td><td>358 (10%)</td><td>307 (4%)</td><td>162 (4%)</td></tr><tr><td>40-50</td><td>644 (9%)</td><td>378 (11%)</td><td>573 (7%)</td><td>306 (8%)</td></tr><tr><td></td><td>&gt; = 50%</td><td>933 (13%)</td><td>435 (12%)</td><td>736 (9%)</td><td>385 (10%)</td></tr><tr><td>Calibration</td><td>p-value</td><td>0.427</td><td>0.024</td><td>0.568</td><td>0.174</td></tr></tbody></table>

a lower LN positivity rate in tumors other than ductal, lobular or mixt, as previously reported for BC with favorable histology (tubular, mucinous, papillary, medullary, adenoid cystic and secretory) that are associated with a very low LN positivity rate [25].

In our model, we used the same independent variables as Reyal et al. [11], namely age, tumor size, molecular subtypes and LVI, and we added grade and histological type. However, age intervals were different, as well as tumor phenotype definitions (ER only in the Reyal model) and tumor size description (continuous variable in the Reyal model). We obtained different odds ratios for the same variables and clinical utility results were different and higher for low probability of positive lymph node, particularly for macro metastases in our population for both models. Clinical utility results for low probability of positive lymph node could be contributive to avoid surgical axillary staging by sentinel lymph node biopsy or axillary lymph node dissection.

The models were less reliable when information about LVI was missing. LVI could be detected on pre-operative

biopsies but the difference in accuracy is obviously large in comparison with surgical specimen analysis.

The HER2 status was unknown in old studies [8] and others studies were based on small number of patients. We found that HER2 negative tumors were associated with LN positivity less frequently than HER2 positive tumors (22.9% vs. 31.9%). Lu et al. published that the lowest probability of node metastasis was for ER- / HER2- tumors [12]. Similarly in our study, triple negative tumors had the lowest probability of node metastasis, while HR- / Her2+ tumors had the highest probability. Reyal et al. hypothesized that the axillary LN metastatic process is predominantly related to intrinsic biological properties in ER-negative and HER2-negative BC, while tumor size, proliferation rate and LVI are the main determinants in the ER positive or HER2 positive breast cancers. However, positive axillary lymph nodes in triple negative BC were pejorative prognostic factors for sentinel node macro-metastases but also for occult sentinel node involvement (pN0(i+) and pN1mi) [26].
**A** Nomogram predictive of LN Involvement– Pathologic model.

<figure><img src="image_3.png" /></figure>

**B** Nomogram predictive of LN macro metastases – Pathologic model.

<figure><img src="image_4.png" /></figure>

**C** Nomogram predictive of LN Involvement– Clinical model.

<figure><img src="image_5.png" /></figure>

**D** Nomogram predictive of LN macro metastases – Clinical model.

<figure><img src="image_6.png" /><figcaption>**Fig. 1** Nomograms. 1a: Nomogram predictive of LN Involvement– Pathologic model. 1b: Nomogram predictive of LN macro metastases – Pathologic model. 1c: Nomogram predictive of LN Involvement– Clinical model. 1d: Nomogram predictive of LN macro metastases – Clinical model.</figcaption></figure>

A reliable predictive model of LN positivity, based on pathologic parameters, can be used to compare populations from different studies, particularly for trials with or without axillary surgical procedure. Above all, it might allow avoiding SN biopsy when the probability of positivity is very low (< 10%). Some authors already suggested that SN biopsy could be omitted in tumors with good-prognosis subtypes [25] or that axillary dissection is useless in older patients [27]. We believe that these criteria lack accuracy and we prefer a decision-making approach, based on molecular subtypes. However, we must be aware of the risk of insufficient treatment in small tumors with favorable prognostic factors, in which LN status is a major determinant of adjuvant chemotherapy and regional radiotherapy. Moreover, the model is less reliable when LVI is not documented, which is usually the case before surgery. Ultra-sonography of the axilla and percutaneous biopsy is a growing practice. These clinical predictive tools may be helpful relative to the use of axillary ultra-sonography with percutaneous LN biopsy for patients with high level risk of axillary LN involvement.

These models can also be contributive in order to determined indications of post mastectomy radiotherapy for patients with axillary lymph nodes macro-metastases [28], particularly when immediate breast reconstruction can be proposed.

## Conclusions

We reported a reliable predictive model of LN positivity according to different early breast carcinoma phenotypes in a large cohort. The determination of the risk of positive axillary LN can significantly contribute to therapeutic decisions. These models, with or without LVI results, can also be used to determine the risk of positive axillary LN or the risk of LN macro-metastasis. Before surgery, clinical models can be used to propose SLNB or not according to LN involvement probability. After surgery, in case of SLNB omission, if LN involvement probability is high, with eventually modifications of adjuvant treatment indications according to LN status, a re-operation can be proposed (SLNB or cALND). Thus clinical and pathologic models should be helpful in surgical planning, in the setting of a clinical trial and in clinical practice to avoid SLNB for very low risk of LN involvement and to avoid re-operation in case of SLNB omission or to propose ALND for patients with high level probability of major axillary LN involvement but also to propose immediate breast reconstruction when PMRT is not required for.
## Additional files

**Additional file 1:** Table S1. Logistic regression results. (DOCX 22 kb)

**Additional file 2:** Figure S1. Calibration plots of our models. 1A: Calibration of predictive LN Involvement for validation set- Pathologic model. 1B: Calibration of predictive LN macro metastases for validation set - Pathologic model. 1C: Calibration of predictive LN Involvement for validation set - Clinical model. 1D: Calibration of predictive LN macro metastases for validation set - Clinical model. (DOCX 45 kb)

**Additional file 3:** Figure S2. ROC curves of our models. 2A: ROC curves of predictive LN Involvement - Pathologic model. 2B: ROC curves of predictive LN macro metastases - Pathologic model. 2C: ROC curves of predictive LN Involvement - Clinical model. 2D: ROC curves of predictive LN macro metastases - Clinical model. (DOCX 44 kb)

### Acknowledgments

Not applicable.

### Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

### Availability of data and materials

The datasets generated and analyzed during the current study are available in the ClinicalTrials.gov (Identifier: NCT02869607) repository, https://clinicaltrials.gov/ct2/show/NCT02869607?cond=Breast+Cancer&cntry=FR&city=Marseille&rank=2

### Authors' contributions

All authors have participated to the data collection: acquisition, analysis and interpretation.

All authors been involved in drafting the manuscript.

GH, EL, JMB and MC have written this document.

All authors have read and approve the final version of paper for submission in BMC CANCER. They assure that the manuscript is not, and will not be, under simultaneous consideration by any other publication. The paper reports previously unpublished work. All authors given final approval of the version to be published.

### Ethics approval and consent to participate

This work was approved by our institutional review board (IPC - Comité d'Orientations Stratégique). All procedures performed in this study involving human participants were done in accordance with the French ethical standards and with the 2008 Helsinki declaration. All included patients provided written informed consent.

### Consent for publication

Not applicable.

### Competing interests

The authors declare that they have no competing interests.

## Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

### Author details

de Recherche S912, Institut de Recherche pour le Développement, 13385 Marseille, France.

Received: 24 January 2018 Accepted: 16 December 2018

Published online: 10 January 2019

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