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Clinical subtypes and prognosis of pregnancy-associated breast cancer: results from the Korean Breast Cancer Society Registry database

  • Soo Youn Bae
  • Sei Joong Kim
  • JungSun Lee
  • Eun Sook Lee
  • Eun-Kyu Kim
  • Ho Young Park
  • Young Jin Suh
  • Hong Kyu Kim
  • Ji-Young You
  • Seung Pil Jung
Clinical trial

Abstract

Purpose

We analyzed the clinicopathologic characteristics and prognosis of pregnancy-associated breast cancer (PABC) according to clinical subtypes to better understand the characteristics of PABC.

Methods

A total of 83,792 female patients between the ages of 20 and 49 were enrolled in the Korean Breast Cancer Society Registry database from January 1, 1996 to December 31, 2015. ‘PABC’ is defined as breast cancer diagnosed during pregnancy or within 1 year after delivery. Other patients were defined as ‘non-PABC’ patients.

Results

In non-PABC patients, luminal A subtype was the most common (50.2%). In PABC patients, TNBC was the most common (40.4%) subtype, while luminal A comprised 21.2% and HER2 subtype comprised 17.3%. There was a significant difference in overall survival (OS). In non-PABC patients, TNBC had the highest HR (HR 2.3, 95% CI 2.1–2.6). In PABC patients, the luminal B subtype (HR+ HER2-high Ki67) had the highest HR at 7.0 (95% CI 1.7–29.1). In multivariate analysis of OS by subtypes, PABC patients had significantly higher HR than non-PABC patients in the HER2 subtype (HR 2.0, 95% CI 1.1–3.7) and luminal B subtype (HR+ HER2-high Ki67) (HR 4.4, 95% CI 1.6–12.3).

Conclusion

PABC showed different biologic features than non-PABC. PABC had a particularly poor prognosis in the luminal B (HR+ HER2-highKi67) and HER2 subtypes. To improve the prognosis of PABC, treatment should be considered according to subtype. Development of drugs that can be used during pregnancy is needed.

Keywords

Pregnancy Breast cancer Subtype Prognosis 

Introduction

Although its definition varies widely, pregnancy-associated breast cancer (PABC) refers to breast cancer diagnosed during pregnancy or after delivery, including breast cancer diagnosed within 1 year after delivery. PABC is rare and comprises 0.2–0.4% of all breast cancers [1, 2]. However, it is the most common cancer in pregnancy, and is diagnosed in about 1 of 3000 pregnancies [3].

Recent literature regarding PABC is inconsistent, but a recent meta-analysis showed that PABC has poor prognosis [4, 5, 6]. Young women are not commonly screened for breast cancer, and diagnosis is difficult due to changes to the breast during pregnancy. Furthermore, treatment is limited due to concerns for fetal safety. These are considered the main causes of poor prognosis in PABC [7, 8].

Recent studies have found high overexpression of human epidermal growth receptor 2 (HER2) and low expression of estrogen receptor (ER) and progesterone receptor (PR) in PABC [5, 6, 9]. Young women with breast cancer have a high frequency of triple-negative breast cancer (TNBC) and HER2 subtype, resistance to tamoxifen, high relapse and mortality rates, and poor prognosis [10]. However, it is not clear whether the poor prognosis is due to the high frequency of these subtypes or due to the characteristic biology of breast cancer in young women.

Pregnancy and childbirth in women of childbearing age are significant events, both socially and personally. Pregnancy, childbirth, and breastfeeding are also major physiologic changes in the breast. It is not clear whether the poor prognosis of patients with PABC is due to the characteristics of breast cancer or the influence of pregnancy. This study was initiated to understand the characteristics of PABC by analyzing its pathological features and prognosis while considering clinical subtypes.

Methods

Korean Breast Cancer Society Registry (KBCSR)

The Korean Breast Cancer Society Registry (KBCSR) was established in 1996. More than 100 hospitals participate in the nationwide breast cancer registry data management program, which contains hospital-based breast cancer registry data. The KBCSR program includes a variety of clinicopathologic factors, treatment data, and research resources. Further information on the KBCSR database is described in a previous study [10].

Patients

Among 158,740 patients enrolled in the KBCSR database from January 1, 1996 to December 31, 2015, 83,792 female patients between the ages of 20 and 49 were enrolled in this study. ‘PABC’ is defined as breast cancer diagnosed during pregnancy or within 1 year after delivery. Patients who did not meet these criteria were defined as ‘non-PABC’ patients.

Clinical subtypes

Patients were classified into five groups according to tumor subtype. (1) Luminal A: hormonal receptor (HR, ER and/or PR) positive and HER2 negative; (2) luminal B (with high Ki67): HR positive and HER2 negative and Ki67 ≥ 14.0%; (3) luminal B (with HER2): HR positive and HER2 postive; (4) triple-negative breast cancer (TNBC): ER negative, PR negative, and HER2 negative; and (5) HER2 subtype: HR negative and HER2 positive.

Statistical methods

Clinicopathologic characteristics were analyzed using the Pearson χ2 test. Overall survival (OS) was based on the date of diagnosis and the date of death; the latter was recorded from data of the Ministry of Health and Welfare, Republic of Korea. A Kaplan–Meier curve was used for univariate analysis, and the Cox proportional hazards model (95% confidence interval, CI) was used for multivariate analysis. Differences were considered significant with P < 0.05. IBM SPSS Statistics, version 20.0 was used for statistical analysis (IBM Inc, Chicago, IL).

This study was approved by the institutional review board of Korea University Anam Hospital.

Results

Clinicopathologic characteristics of patients with PABC

The clinicopathologic characteristics of PABC and non-PABC patients are shown in Table 1. With PABC, patients in their 30s were the most common. With non-PABC, patients in their 40s were the most common. Patients with PABC had a higher percentage of stage III and IV and a higher percentage of high nuclear grade (NG, 63.1% vs. 37.3%) than non-PABC patients. In non-PABC patients, Luminal A subtype was the most common (50.2%) and TNBC comprised 16.4% of cases. In PABC patients, TNBC was the most common subtype (40.4%), while luminal A comprised 21.2% and HER2 subtype comprised 17.3% of cases.

Table 1

Clinicopathologic characteristics of PABC patients and non-PABC patients

 

Non-PABC (n = 83,381)

%

PABC (n = 411)

%

P

Age

     

 20–29

2057

2.5

50

12.2

< 0.001

 30–39

20,628

24.7

313

76.2

 

 40–49

60,696

72.8

48

11.7

 

Family history

     

 Yes

5571

9.4

50

13.4

< 0.001

 No

53,714

90.6

322

86.6

 

 Unknown

24,096

 

39

  

Menarche

     

 ≤ 13 years

15,375

29.4

173

48.3

< 0.001

 > 13 years

36,849

70.6

185

51.7

 

 Unknown

31,157

 

53

  

First delivery

     

 ≥ 30 years

8544

21.2

142

44.8

< 0.001

 < 30 years

31,681

78.8

175

55.2

 

 Unknown

43,156

 

94

  

Operation (breast)

     

 Mastectomy

36,036

43.6

199

48.8

< 0.001

 BCS

45,949

55.6

193

47.3

 

 No op

594

0.7

16

3.9

 

 Unknown

802

 

3

  

Operation (axillary)

     

 ALND

37,407

45.5

235

57.2

< 0.001

 SLN biopsy

37,107

45.1

145

35.3

 

 No op

7674

9.3

31

7.5

 

 Unknown

1193

 

0

  

Stage

     

 O

9959

12.3

16

4.0

< 0.001

 I

29,338

36.3

92

22.9

 

 II

30,926

38.2

186

46.3

 

 III

9487

11.7

85

21.1

 

 IV

1148

1.4

23

5.7

 

 Unknown

2523

 

9

  

Nuclear grade

     

 Low/intermediate

34,953

62.7

110

36.9

< 0.001

 High

20,802

37.3

188

63.1

 

 Unknown

27,626

 

113

  

Histology

     

 IDC

61,073

84.3

366

94.8

< 0.001

 ILC

2219

3.1

4

1.0

 

 DCIS

9074

12.5

16

4.1

 

 etc.

59

0.1

0

0.0

 

 Unknown

10,956

 

25

  

ER

     

 Positive

50,452

70.5

143

38.6

< 0.001

 Negative

21,145

29.5

227

61.4

 

 Unknown

11,784

 

41

  

PR

     

 Positive

46,932

66.1

126

34.2

< 0.001

 Negative

24,027

33.9

242

65.8

 

 Unknown

12,422

 

43

  

HER2

     

 Positive

12,649

21.6

91

29.4

< 0.001

 Negative

45,880

78.4

218

70.6

 

 Unknown

24,852

 

102

  

Subtypes

     

 Luminal A

31,642

50.6

65

21.2

< 0.001

 Luminal B (HER2+)

7937

12.7

37

12.1

 

 TNBC

10,230

16.4

124

40.4

 

 HER2

5720

9.1

53

17.3

 

 Luminal B (high Ki67)

7017

11.2

28

9.1

 

 Unknown

20,835

 

104

  

Chemotherapy

     

 Yes

47,431

68.7

345

88.5

< 0.001

 No

21,604

31.3

45

11.5

 

 Unknown

14,346

 

21

  

Chemotherapy

     

 Neoadjuvant

4502

10.1

61

18.2

< 0.001

 Adjuvant

39,422

88.9

265

79.1

 

 Palliative

443

1.0

9

2.7

 

 Unknown

3064

 

10

  

Radiotherapy

     

 Yes

43,391

65.0

230

63.2

0.464

 No

23,342

35.0

134

36.8

 

 Unknown

16,648

 

47

  

BCS breast conserving surgery, ALND axillary lymph node dissection, SLN sentinel lymph node, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, DCIS ductal carcinoma in site, ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2, TNBC triple-negative breast cancer

The differences in clinicopathologic characteristics between PABC and non-PABC were also different according to age group. In non-PABC patients, the proportion of luminal A was the highest in patients in their 20s and 30s (42–43%). In PABC patients, TNBC was the most common subtype (42–48%). In patients in their 40s, luminal A comprised 48.3% of cases and TNBC comprised 17.2% in PABC patients, which was not significantly different from non-PABC patients.

In univariate analysis for OS, PABC patients had a lower survival rate than non-PABC patients. In multivariate analysis adjusted for age, stage, and subtype, PABC had 1.3-fold increased risk compared to non-PABC. After adjusting for age, stage, NG, and subtype in multivariate analysis, there was no difference in risk between PABC and non-PABC patients (Table 2).

Table 2

Multivariate analysis for overall survival of patients by subtype

 

B

Standard error

Wald

P

HR

95.0% CI

Lower

Upper

Total patients

 Age at diagnosis

− 0.031

0.004

77.564

0.000

0.970

0.963

0.976

 Stage

1.099

0.028

1570.088

0.000

3.003

2.844

3.170

 NG, high versus low/intermediate

0.306

0.044

47.890

0.000

1.358

1.245

1.481

 PABC versus non-PABC

0.026

0.166

0.024

0.878

1.026

0.741

1.420

 Luminal A (ref)

    

1

  

 Luminal B (HR+ HER2+)

0.362

0.066

30.186

0.000

1.436

1.262

1.634

 TNBC

0.850

0.055

241.571

0.000

2.339

2.101

2.603

 HER2 subtype

0.785

0.065

146.237

0.000

2.192

1.930

2.490

 Luminal B (HR+ HER2−, high Ki67)

0.074

0.088

0.700

0.403

1.076

0.906

1.279

 CTx, no versus yes

0.084

0.083

1.035

0.309

1.088

0.925

1.279

Luminal A subtype

 Age

− 0.053

0.006

70.510

0.000

0.949

0.937

0.960

 Stage

1.074

0.050

461.098

0.000

2.928

2.655

3.230

 NG, high versus low/intermediate

0.514

0.074

47.828

0.000

1.673

1.446

1.935

 PABC versus non-PABC

− 0.555

0.503

1.214

0.270

0.574

0.214

1.540

 CTx, no versus yes

− 0.234

0.140

2.775

0.096

0.792

0.601

1.042

Luminal B (HR+ HER2+) subtype

 Age

− 0.050

0.009

28.524

0.000

0.951

0.934

0.969

 Stage

0.895

0.075

142.060

0.000

2.447

2.112

2.835

 NG, high versus low/intermediate

0.053

0.110

0.236

0.627

1.055

0.850

1.308

 PABC versus non-PABC

− 0.262

0.585

0.200

0.655

0.770

0.245

2.422

 CTx, no versus yes

− 0.114

0.212

0.287

0.592

0.893

0.589

1.353

TNBC subtype

 Age

− 0.010

0.006

2.856

0.091

0.990

0.978

1.002

 Stage

1.102

0.049

510.836

0.000

3.011

2.736

3.313

 NG, high versus low/intermediate

0.091

0.080

1.302

0.254

1.095

0.937

1.281

 PABC versus non-PABC

− 0.028

0.257

0.012

0.912

0.972

0.587

1.610

 CTx, no versus yes

0.546

0.165

11.001

0.001

1.726

1.250

2.382

HER2 subtype

 Age

− 0.008

0.009

0.808

0.369

0.992

0.974

1.010

 Stage

1.247

0.068

336.071

0.000

3.478

3.044

3.974

 NG, high versus low/intermediate

0.190

0.113

2.815

0.093

1.209

0.969

1.510

 PABC versus non-PABC

0.713

0.314

5.148

0.023

2.041

1.102

3.780

 CTx, no versus yes

0.643

0.212

9.170

0.002

1.901

1.254

2.882

Luminal B (HR+ HER2−, high Ki67) subtype

 Age

− 0.045

0.014

10.172

0.001

0.956

0.931

0.983

 Stage

1.201

0.114

111.768

0.000

3.323

2.660

4.152

 NG, high versus low/intermediate

0.650

0.166

15.375

0.000

1.916

1.384

2.653

 PABC versus non-PABC

1.492

0.521

8.196

0.004

4.445

1.601

12.344

 CTx, no versus yes

0.586

0.262

5.005

0.025

1.797

1.075

3.003

NG nuclear grade, PABC pregnancy-associated breast cancer, CTx chemotherapy, HR hormonal receptor, HER2 human epidermal growth factor 2, TNBC triple-negative breast cancer

Survival analysis according to subtype

In univariate analysis for OS, luminal B (with HER2+) subtype showed no difference in survival rates for PABC and non-PABC. However, PABC patients had worse survival than non-PABC patients in all other subtypes. After adjusting for age, stage, NG, and subtype in multivariate analysis, the risk of PABC was higher in HER2 subtype and luminal B subtype (with high Ki67) than in non-PABC (Table 2; Fig. 1).

Fig. 1

Overall survival of PABC patients and non-PABC patients by subtype: a all patients, b luminal A, c luminal B (HER2+), d luminal B (high Ki67), e triple-negative breast cancer, and f HER2 subtypes

Prognostic factors in PABC and non-PABC patients

The non-PABC and PABC groups showed differences in prognostic factors as a result of multivariate analysis for OS. There was a significant difference in risk between subtypes. For non-PABC patients, TNBC showed the highest risk (Hazard ratio, HR 2.3, 95% CI 2.1–2.6). In PABC patients, luminal B (with high Ki67) had the highest HR of 7.0 (95% CI 1.7–29.1) (Table 3; Fig. 2).

Table 3

Multivariate analysis for overall survival of PABC and non-PABC patients

 

B

Standard error

P

HR

95.0% CI

Lower

Upper

non- PABC

      

 Age

− 0.031

0.004

0.000

0.969

0.963

0.976

 Luminal A (ref)

      

 Luminal B (HER2+)

0.364

0.066

0.000

1.439

1.264

1.638

 TNBC

0.854

0.055

0.000

2.349

2.109

2.616

 HER2 subtype

0.773

0.066

0.000

2.167

1.905

2.464

 Luminal B (high Ki67)

0.054

0.089

0.546

1.055

0.886

1.256

 Stage

1.096

0.028

0.000

2.992

2.833

3.161

 NG, high versus low/intermediate

0.306

0.045

0.000

1.358

1.244

1.482

 Chemotherapy, no versus yes

0.086

0.083

0.298

1.090

0.927

1.282

PABC

      

 Age

− 0.035

0.044

0.422

0.965

0.885

1.052

 Luminal A (ref)

      

 Luminal B (HR+ HER+)

0.030

0.785

0.970

1.030

0.221

4.798

 TNBC

0.757

0.600

0.207

2.132

0.658

6.914

 HER2 subtype

1.469

0.602

0.015

4.346

1.336

14.132

 Luminal B (high Ki67)

1.958

0.722

0.007

7.085

1.721

29.167

 Stage

1.456

0.251

0.000

4.291

2.626

7.011

 NG, high versus low/intermediate

0.619

0.417

0.138

1.857

0.820

4.207

 Chemotherapy, no versus yes

− 11.320

401.778

0.978

0.000

0.000

 

PABC pregnancy-associated breast cancer, NG nuclear grade, CTx chemotherapy, HER2 human epidermal growth factor 2, TNBC triple-negative breast cancer

Fig. 2

Overall survival graph of five subtypes in PABC patients (a) and non-PABC patients (b)

PABC patients versus nulliparous women in non-PABC patients

Clinicopathologic characteristics of PABC patients were compared with nulliparous women in non-PABC patients. In the nulliparous women (non-PABC), luminal A was the most common subtype (47.9%) and HER2 subtype was the least common (7.9%) (P < 0.001, Supplemental Table 1). Univariate analysis and multivariate analysis showed that PABC patients had worse prognosis than nulliparous patients. After adjusting for age, stage, and NG in multivariate analysis, PABC patients had 1.9-fold higher HR (95% CI 1.3–2.7, P < 0.001) than non-PABC patients. After adjusting for age, stage, NG, and subtype in multivariate analysis, PABC patients showed 1.5-fold higher HR (95% CI 1.0–2.3, P = 0.05) than non-PABC patients.

Discussion

Pregnancy is a significant change that affects both individuals and society, and it is also the most significant physiologic change in the breast. Pregnancy is known to lower the risk of breast cancer, but this is the result of studies in postmenopausal women. Recent studies have shown that in premenopausal women, the risk of breast cancer increases 3–5 years after delivery [11, 12, 13]. By univariate analysis for OS, PABC patients had a lower survival rate than non-PABC patients. In multivariate analysis adjusted for age, stage, and subtype, PABC had 1.3-fold increased risk compared with non-PABC. However, the importance of PABC is overlooked because breast cancer is rare in women in their 20s–30s.

PABC often is advanced stage at diagnosis and poor prognosis. Screening for young women is uncommon, and it is difficult to detect tumors early during pregnancy or lactation. In addition, treatment is also limited during pregnancy. In the past, these are considered the main causes for the poor prognosis of PABC. However, recent studies have shown that estrogen receptor expression is low and HER2 overexpression is high in PABC [5, 6, 9]. This suggests that the biology of PABC itself may be aggressive. This phenotype is also characteristic of breast cancer occurring in young women [14].

In this study, we investigated whether the biomarker subtypes of PABC are different from those of breast cancer in young women and whether they are related to prognosis. TNBC and HER2 subtypes were more common than in non-PABC patients. Compared with nulliparous women, patients with PABC had lower expression of hormone receptors and higher expression of HER2, indicating that this breast cancer subtype is associated with pregnancy. In PABC patients, there was no difference between breast cancer in the 20s and 30s and breast cancer in the 40s. There was also no statistically significant difference in the expression of hormone receptors between PABC and non-PABC patients in their 40s.

PABC and non-PABC had different prognostic factors. In non-PABC, TNBC subtype had the worst prognosis and luminal B (with high Ki67) had the best prognosis with no difference from the luminal A subtype. However, in PABC, the HER2 and luminal B (with high Ki67) subtypes had the worst outcomes. The poor prognosis of the HER2 subtype could not be confirmed in this study, but the relevance of treatment with trastuzumab should be considered. Compared with other subtypes, luminal B (with high Ki67) showed the highest frequency of family history (28.6%) and significantly different rates from non-PABC (10.4%). The rate of chemotherapy for luminal B (with high Ki67) was the lowest, with 76.4%. Family history and age at diagnosis of breast cancer are related to the prevalence of BRCA1/BRCA2 mutation [15, 16], and a recent study showed that BRCA1/BRCA2 pathogenic mutations are more prevalent in younger Asian women with breast cancer than in the TCGA cohort [17].

Recent literature has shown that younger women are more resistant to hormone therapy for breast cancer than middle-aged women with breast cancer [18], and luminal subtype has a poor prognosis [19]. In addition, the higher incidence of luminal B breast cancer in young women is itself considered a poor prognostic factor [20, 21]. Recent clinical trial studies have shown that luminal B cancer is less dependent on the estrogen pathway, which is aimed at an alternative pathway EGFR [18] and PI3K/Akt/mTOR in advanced ER+ cancer [22].

This study suggests that PABC has different biologic features than breast cancer in young women. PABC has some characteristics of breast cancer in young women, but it seems to have more aggressive characteristics due to pregnancy. PABC showed a particularly poor prognosis in the luminal B (with high Ki67) and HER2 subtypes. Treatment is limited because fetal health must be considered during pregnancy. Chemotherapy can be performed from the second trimester, but endocrine therapy and target therapy are contraindications during pregnancy. To improve the prognosis of PABC, treatment should be considered according to each subtype. In addition, development of drugs that can be used during pregnancy is needed.

Notes

Acknowledgements

This work was supported by the Korean Breast Cancer Society. This work was supported by the National Research Foundation of Korea (2017R1D1A1B03028103) and Korea University Grant (K1813171).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study informed consent is not required.

Supplementary material

10549_2018_4908_MOESM1_ESM.xlsx (13 kb)
Supplementary material 1 (XLSX 12 KB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Soo Youn Bae
    • 1
  • Sei Joong Kim
    • 2
  • JungSun Lee
    • 3
  • Eun Sook Lee
    • 4
  • Eun-Kyu Kim
    • 5
  • Ho Young Park
    • 6
  • Young Jin Suh
    • 7
  • Hong Kyu Kim
    • 1
  • Ji-Young You
    • 1
  • Seung Pil Jung
    • 1
    • 8
  1. 1.Department of Surgery, Korea University Anam HospitalKorea University College of MedicineSeoulRepublic of Korea
  2. 2.Department of Surgery, Inha University HospitalInha University School of MedicineIncheonRepublic of Korea
  3. 3.Department of Surgery, Haeundae Paik Hospital, College of MedicineInje UniversityBusanRepublic of Korea
  4. 4.Center for Breast CancerNational Cancer CenterGoyang-siRepublic of Korea
  5. 5.Department of Surgery, Seoul National University Bundang HospitalSeoul National University College of MedicineGyeonggiRepublic of Korea
  6. 6.Department of Surgery, Kyungpook National University Medical CenterKyungpook National University School of MedicineDaeguRepublic of Korea
  7. 7.Division of Breast & Thyroid Surgical Oncology, Department of Surgery, College of Medicine, St. Vincent’s HospitalThe Catholic University of KoreaSuwonRepublic of Korea
  8. 8.Division of Breast and Endocrine Surgery, Department of Surgery, Korea University HospitalKorea University College of MedicineSeoulRepublic of Korea

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