Nomogram Based on Clinicopathologic and US Characteristics: Axillary Nodal Evaluation Following Neoadjuvant Chemotherapy in Patients with Biopsy-Proven Node-Positive Breast Cancer

DOI: https://doi.org/10.21203/rs.3.rs-1699310/v1

Abstract

Objective: To avoid surgical over-treatment of the axilla in patients with lymph node (LN) conversion following neoadjuvant chemotherapy (NAC), high-performing axilla staging procedures are needed. This study is designed to develop a convenient modality to predict the axillary response to NAC in breast cancer patients.

Methods: In this retrospective study, a total of 1046 patients with breast cancer who received NAC followed by axillary lymph node dissection (ALND) between 2015 and 2021 were identified from a maintained database. The training set included 607 breast cancer patients with biopsy proven positive LNs at initial diagnosis, and receiving NAC followed by ALND. Clinicopathologic and ultrasound (US) characteristics were analyzed, and a nomogram was generated to predict the probability of axillary LNs residual metastasis. The predictive performances of models were assessed using multivariate logistic regression and receiver operator characteristic curve (ROC) analyses. The nomogram integrating clinicopathological and US characteristics was validated with an external cohort of 242 patients.

Results: In this study, 49.75% and 32.23% patients achieved axillary pathological complete response (pCR) after NAC in the training and external validation sets, respectively. Multivariate analysis indicated that expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), Ki-67 score, and clinical nodal stage were independently significant factors for predicting the nodal response to NAC. Location and radiological response of primary tumors, cortical thickness and shape of LNs on US were also significantly associated with nodal pCR. The area under the ROC curve (AUC), estimating the ability of clinicopathologic model to determine axillary status after NAC, was 0.72 and that of US model was 0.81 in the training cohort. AUCs of the nomogram based on clinicopathologic and US characteristics for the training and validation sets were 0.86 and 0.82, respectively.

Conclusions: Nomogram incorporating routine clinicopathologic and US characteristics can predict nodal pCR in node-positive breast cancer patients receiving NAC and may be a feasible modality to aid clinicians in treatment decisions.

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Tables

Table 1 . Comparison of clinicopathologic and US characteristics between the training and validation cohorts

Characteristics

SYSUCC

n=607

FMUCH

N=242

p-value

Age

47.16±10.48

49.86±9.52

<0.001

Menopausal status

 

 

0.019

Pre/perimenopausal

377 (62.1%)

171 (70.7%)

 

Postmenopausal

230 (37.9%)

71 (29.3%)

 

Tumor stage

 

 

0.074

1

49 (8.1%)

21 (8.7%)

 

2

314 (51.7%)

141 (58.3%)

 

3

142 (23.4%)

37 (16.3%)

 

4

102 (16.8%)

43 (17.8%)

 

Nodal stage

 

 

<0.001

1

180 (29.7%)

160 (66.1%)

 

2

226 (37.2%)

58 (24.0%)

 

3

201 (33.1%)

24 (9.9%)

 

ER status

 

 

0.708

Negative

205 (33.8%)

85 (35.1%)

 

Positive

402 (66.2%)

157 (64.9%)

 

PR status

 

 

0.572

Negative

248 (40.9%)

104 (43.0%)

 

Positive

359 (59.1%)

138 (57.0%)

 

HER2 status

 

 

0.001

Negative

327 (53.9%)

162 (66.9%)

 

Positive

280 (46.1%)

80 (33.1%)

 

Ki-67

38.73±21.67

42.22±23.53

0.041

Location of breast tumor

 

 

0.142

No residual disease on the lateral part of breast

130 (21.4%)

41 (16.9%)

 

Residual tumor on the lateral part of breast

477 (78.6%)

201 (83.1%)

 

Number of primary tumor

 

 

0.054

Solitary disease

497 (81.9%)

184 (76.0%)

 

Multifocal disease

110 (18.1%)

58 (24.0%)

 

Tumor diameter before NAC（mm）

42.43±19.84

36.94±18.25

<0.001

Tumor diameter after NAC（mm）

23.93±16.26

22.37±14.71

0.339

Radiological response of breast tumor (%)*

41.32±35.95

33.48±50.19

0.006

Long diameter（mm）

14.04±6.97

12.29±4.69

0.002

Short diameter（mm）

6.91±4.11

6.30±2.63

0.078

Ratio of long /short diameter

2.15±0.75

2.03±0.61

0.120

Cortical thickness

 

 

0.373

≤3mm

303 (49.9%)

129 (53.3%)

 

>3mm

304 (50.1%)

113 (46.7%)

 

Shape

 

 

0.006

Oval

513 (84.5%)

188 (77.7%)

 

Round

32 (5.3%)

10 (4.1%)

 

Irregular

62 (10.2%)

44 (18.2%)

 

Margin

 

 

<0.001

Clear

591 (97.4%)

217 (89.7%)

 

Obscure

16 (2.6%)

36 (10.3%)

 

Fatty hilum

 

 

0.002

Absence

169 (27.8%)

43 (17.8%)

 

Presence

438 (72.2%)

199 (82.2%)

 

Microcalcification

 

 

0.546

Absence

578 (95.2%)

228 (94.2%)

 

Prsence

29 (4.8%)

14 (5.8%)

 

Values are expressed as the mean ± standard deviation or number.

US, ultrasound; SYSUCC, Sun Yat-Sen University Cancer Center; FMUCH, fujian medical university cancer hospital; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; NAC, neoadjuvant chemotherapy.

*Relative change in the largest diameter of primary tumor on US according to RECIST 1.1.

Table 2 . pCR and non-pCR rates of breast or axillary node after NAC

 

SYSUCC

FMUCH

 

B-pCR

(n=173)
  1. non pCR

(n=434)

p

B-pCR

(n=54)
  1. non pCR

(n=188)

p

 N-pCR

149

153

<0.001

30

48

<0.001

N-non pCR

24

281

 

24

140

 

NAC, neoadjuvant chemotherapy; pCR, pathological complete response; SYSUCC, Sun Yat-Sen University Cancer Center; FMUCH, fujian medical university cancer hospital.

Table 3 . Univariate logistic regression analysis of characteristics predicting axillary response to NAC in node-positive breast cancer patients (n=607)

Characteristics

OR

95%CI

p-value

Age

1.02

1.01-1.03

0.005

Menopausal status

 

 

 

Pre/perimenopausal

-

-

 

Postmenopausal

1.08

0.81-1.43

0.591

Tumor stage

 

 

 

1

-

-

 

2

0.72

0.40-1.32

0.29

3

1.28

0.67-2.45

0.47

4

1.62

0.81-3.21

0.17

Nodal stage

 

 

 

1

-

-

 

2

4.02

2.62-6.15

<0.001

3

5.11

3.29-7.94

<0.001

ER status

 

 

 

Negative

-

-

 

Positive

2.35

1.76-3.15

<0.001

PR status

 

 

 

Negative

-

-

 

Positive

2.05

1.56-2.71

<0.001

HER2 status

 

 

 

Negative

-

-

 

Positive

0.36

0.27-0.47

<0.001

Ki-67

0.99

0.98-1.00

0.003

Location of breast tumor

 

 

 

No residual disease on the lateral part of breast

-

-

 

Residual tumor on the lateral part of breast

2.13

1.51-2.99

<0.001

Number of primary tumor

 

 

 

Solitary tumor

-

-

 

Multifocal disease

1.45

1.03-2.05

0.035

Tumor diameter before NAC

1

0.99-1.01

0.659

Tumor diameter after NAC

1.03

1.02-1.04

<0.001

Radiological response of breast tumor*

0.26

0.16-0.41

<0.001

Long diameter

1.02

1.00-1.05

0.037

Short diameter

1.22

1.15-1.3

<0.001

Ratio of long /short diameter

0.49

0.40-0.60

<0.001

Cortical thickness

 

 

 

≤3mm

-

-

 

>3mm

8.00

5.86-10.91

<0.001

Shape

 

 

 

Oval

-

-

 

Round

2.33

1.19-4.55

0.014

Irregular

11.25

5.59-22.63

<0.001

Margin

 

 

 

Clear

-

-

 

Obscure

8.05

2.84-22.79

<0.001

Fatty hilum

 

 

 

Presence

-

-

 

Absence

4.58

3.15-6.64

<0.001

Microcalcification

 

 

 

Absence

-

-

 

Prsence

6.61

2.58-16.97

<0.001

OR, odds ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; NAC, neoadjuvant chemotherapy.

*Relative change in the largest diameter of primary tumor on US according to RECIST 1.1.

Table 4 . Multivariate logistic regression analysis of characteristics predicting axillary response to NAC in node-positive breast cancer patients (n=607)

Characteristics

OR

95%CI

p-value

Age

1

0.98-1.03

0.769

Nodal stage

 

 

 

1

-

-

 

2

2.04

1.37-3.03

0.002

3

2.26

1.44-3.54

0.001

ER status

 

 

 

Negative

-

-

 

Positive

2.67

1.81-3.93

<0.001

PR status

 

 

 

Negative

-

-

 

Positive

1

0.57-1.75

0.995

HER2 status

 

 

 

Negative

-

-

 

Positive

0.32

0.22-0.45

<0.001

Ki-67

0.99

0.98-1.00

0.041

Location of breast tumor

 

 

 

No residual disease on the lateral part of breast

-

-

 

Residual tumor on the lateral part of breast

1.99

1.29-3.05

0.013

Number of breast tumor

 

 

 

Solitary tumor

-

-

 

Multifocal disease

1.16

0.64-2.09

0.633

Tumor diameter after NAC

1.00

0.97-1.02

0.716

Radiological response of breast tumor *

0.36

0.22-0.61

0.017

Long diameter

1.04

0.90-1.19

0.614

Short diameter

1.05

0.80-1.38

0.717

Ratio of long /short diameter

0.75

0.31-1.79

0.518

Cortical thickness

 

 

 

≤3mm

-

-

 

>3mm

5.93

4.11-8.57

<0.001

Shape

 

 

 

Oval

-

-

 

Round

3.09

1.15-8.30

0.003

Irregular

4.88

2.15-11.03

<0.001

Margin

 

 

 

Clear

-

-

 

Obscure

6.51

0.74-56.95

0.09

Fatty hilum

 

 

 

Presence

-

-

 

Absence

1.43

0.72-2.80

0.305

Microcalcification

 

 

 

Absence

-

-

 

Prsence

1.41

0.34-5.84

0.637

NAC, ; OR, odds ratio; CI, confidence interval; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; NAC, neoadjuvant chemotherapy.

*Relative change in the largest diameter of primary tumor on US according to RECIST 1.1.

Table 5 . Predictive performance of clinicopathologic model, US model and combined model in the training cohort (n=607)

Models

AUC

Sensitivity

Specificity

Youden index

Clinicopathologic model

0.72

73.13

62.83

0.36

US model

0.81

74.38

78.44

0.53

Combined model

0.86

85.94

76.58

0.63

AUC, area under the receiver operating characteristic curve; US, ultrasound.

Table 6 . Predictive performance of clinicopathologic model, US model and combined model in the external validation cohort (n=242)

Models

AUC

Sensitivity

Specificity

Youden index

Clinicopathologic model

0.68

74.50

53.15

0.28

US model

0.76

68.46

74.77

0.43

Combined model

0.82

81.88

62.16

0.44

AUC, area under the receiver operating characteristic curve; US, ultrasound.