Breast Cancer

, Volume 21, Issue 6, pp 643–650

Clinicopathological features of young patients (<35 years of age) with breast cancer in a Japanese Breast Cancer Society supported study

Authors

    • Breast Surgery Clinic
  • Eriko Tokunaga
    • Department of Surgery and Science, Graduate School of Medical SciencesKyushu University
  • Norikazu Masuda
    • Department of Surgery, Breast OncologyNational Hospital Organization Osaka National Hospital
  • Tadahiko Shien
    • Department of Breast and Endocrine SurgeryOkayama University Hospital
  • Kimiko Kawabata
    • Department of Nursing School of Health and Social ServicesSaitama Prefectural University
  • Mika Miyashita
    • Division of Nursing Science, Graduate School of Biomedical and Health SciencesHiroshima University
Special Feature Breast cancer in young women: Issues and perspectives regarding patients' and survivors' care

DOI: 10.1007/s12282-013-0466-2

Cite this article as:
Kataoka, A., Tokunaga, E., Masuda, N. et al. Breast Cancer (2014) 21: 643. doi:10.1007/s12282-013-0466-2

Abstract

Background

To clarify the clinicopathological features of breast cancer in young females, surveillance data of the Registration Committee of the Japanese Breast Cancer Society were analyzed.

Methods

The clinicopathological characteristics were compared between young (<35) patients and non-young (≥35) patients among 109,617 records registered between 2004 and 2009.

Results

The numbers of young and non-young patients were 2,982 (2.7 %) and 106,295 (97.0 %), respectively. The young patients had more cases of a familial history of breast cancer, more subjective symptoms, fewer bilateral tumors, lower BMIs, larger tumors, more positive lymph nodes, fewer instances of an ER-positive status, more instances of an HER2-positive status, more triple-negative tumors and more advanced TNM stages. The young patients more frequently received neoadjuvant chemotherapy and breast-conserving therapy (BCT) compared with the non-young patients. Eighty percent of all patients received adjuvant therapy. The young patients were more frequently treated with chemotherapy, molecular targeted therapy and radiation therapy than the non-young patients.

Conclusions

In this study, young patients with breast cancer were diagnosed at more advanced stages and had more endocrine-unresponsive tumors than non-young patients. Further prognostic analyses should be conducted in this cohort.

Keywords

Breast cancer in young femalesSurveillance data

Introduction

The incidence of breast cancer in Japanese females is increasing rapidly. Approximately 61,000 females are diagnosed with breast cancer annually in Japan [1]. Breast cancer rarely occurs in very young females; however, management problems in young patients must be considered, not only health and social aspects, but also familial and reproductive problems. Breast cancer arising in younger females is reported to be more aggressive and associated with unfavorable prognoses [28]. Due to the limited number of patients and the lack of clinical trials using young females with breast cancer, both clinicians and patients face a lack of information regarding decision making to select treatment, including the type of surgery and the choice of adjuvant therapy. Because subsequent life plans may be changed by what kind of treatment is chosen, information on the clinical characteristics of breast cancer in young females and trends in medical treatment is needed in clinical practice. The aim of this study was to clarify the clinicopathological features of breast cancer in young Japanese females and recent trends in treatment choices. With the support of the Registration Committee of the Japanese Breast Cancer Society (JBCS), we analyzed 109,617 cases registered between 2004 and 2009.

Materials and methods

Basic patient data

Comprehensive data on breast cancer patients diagnosed in Japan between 2004 and 2009 were registered with the Registration Committee of the JBCS. The final registry data were reported in 2010, although the patient outcome data have not yet been published. Registrations were made by 490 institutions and included 109,617 female cases. The data collected included age at diagnosis, family history, menstrual status, body mass index and clinicopathological features of the tumor, including tumor size, the presence of lymph node metastases and the receptor status (ER, PgR and HER2), the type of surgery, the use of radiation therapy and the regimens of adjuvant therapy. Since the data belong to the JBCS, permission to use the data was obtained from the JBCS.

Statistical processing

Fischer’s exact test was used to compare various prevalence rates among the groups. The unpaired t test was employed to make intergroup comparisons in the numbers of cases and mean values. The significance level was set at less than 0.01 when multiple comparisons were required between two groups. All statistical processing was completed using the SAS software program (version 9.1.3; SAS Institute, Inc., Cary, NC).

Results

Patient backgrounds and clinicopathological characteristics

The age distribution of the patients is shown in Fig. 1. Young breast cancer patients, defined as those less than 35 years of age at diagnosis, were analyzed. The numbers of young and non-young patients were 2,982 (2.7 %) and 106,295 (97.0 %), respectively. Three hundred forty (0.3 %) patients were of unknown age. The median patient age was 58 years. The clinicopathological factors were compared between the young patients and the non-young patients (Table 1). Almost all of the young patients were premenopausal, and 64.1 % of the non-young patients were postmenopausal. The body mass indices of the young patients were lower than those of the non-young patients. According to the definition of the Japan society for the study of obesity, a BMI >25 was regarded as overweight; therefore, 10.4 % of the young patients and 22.8 % of the non-young patients were regarded as being overweight. On the other hand, 11.4 % of the young patients and 5.2 % of the non-young patients were regarded as being thin (BMI ≤18). A family history of breast cancer was found in 12.4 % of the young patients, which was higher than the 9.4 % observed in the non-young patients. Synchronous bilateral tumors and metachronous bilateral tumors were found in 1.8 % and 0.8 % of young patients, which were both lower than the rates of 4.1 % and 3.2 % observed in the non-young patients. More than 80 % of the young patients reported subjective symptoms by self detection, which was higher than the 67.3 % of non-young patients who reported similar symptoms. Asymptomatic tumors were detected on screening in only 8.4 % of the young patients, which was much lower than the rate of 20.7 % observed in the non-young patients. The young patients were more likely to be diagnosed with large tumors and advanced-stage tumors than the non-young patients. The mean tumor size was 2.9 cm in the young patients, which was larger than the 2.5 cm observed in the non-young patients (p < 0.0001). More than 12 % of the young patients had large tumors (>5 cm), which was higher than the rate of 6.8 % observed in the non-young patients. The distribution of histological subtypes is shown in Fig. 2. The histological tumor subtypes were classified in accordance with the classification of breast carcinoma issued by the Japanese Breast Cancer Society, which is a modified World Health Organization histological classification [9, 10]. The subtypes did not differ significantly between the young and non-young patients. Scirrhous carcinoma was the most frequent histological type in both the young and non-young patients. The frequency of solid-tubular carcinoma in the young patients tended to be higher than that observed in the non-young patients. Invasive lobular carcinoma rarely occurred in the young patients.
https://static-content.springer.com/image/art%3A10.1007%2Fs12282-013-0466-2/MediaObjects/12282_2013_466_Fig1_HTML.gif
Fig. 1

Distribution of age at diagnosis among patients registered between 2004 and 2008 with the Japanese Breast Cancer Society

Table 1

Comparison of the clinicopathological factors between young and non-young patients with breast cancer

 

Young patients (n = 2,982)

Non-young patients (n = 106,295)

p value

N

(%)

N

(%)

Menopausal status

 Pre-menopausal

2,898

97.2

35,037

33

<0.0001

 Post-menopausal

48

1.6

68,107

64.1

 

 Unknown

36

1.2

3,151

3.0

Body mass index (BMI)

 ≦18

339

11.4

5,524

5.2

<0.0001

 18< BMI ≦22

1,690

56.7

40,374

38.0

 

 22< BMI ≦25

514

17.2

30,842

29.0

 25<

310

10.4

24,209

22.8

 Unknown

129

4.3

5,346

5.0

Family history of breast cancer

 No

2,399

80.4

88,195

83.0

<0.0001

 Yes

370

12.4

9,967

9.4

 

 Unknown

213

7.1

8133

7.7

Method of detection

 Self-detection

2,482

83.2

71,517

67.3

<0.0001

 Screening (with symptoms)

107

3.6

5,233

4.9

 

 Screening (no symptoms)

251

8.4

22,028

20.7

 Other

99

3.3

6,352

6.0

 Unknown

43

1.4

1,165

1.1

Bilateral breast cancer

 No

2,904

97.4

98,610

92.8

<0.0001

 Synchronous

53

1.8

4,339

4.1

 

 Metachronous

25

0.8

3,346

3.2

Size of tumor

 ~2.0 cm

1,206

43.4

52,635

53.0

<0.0001

 2.1 ~ 5.0 cm

1,231

44.3

39,976

40.2

 

 ~5.1 cm

341

12.3

6,771

6.8

N

 N0

2,154

72.2

83,992

79

<0.0001

 N1

638

21.4

17,409

16.4

 

 N2

99

3.3

2,703

2.5

 N3

46

1.5

1,181

1.1

 Unknown

45

1.5

1,010

1.0

M

 M0

2,837

95.1

102,701

96.6

<0.0001

 M1

87

2.9

2,328

2.2

 

 Unknown

58

2

1,266

1.2

Stage

 0

298

10

9,380

8.8

<0.0001

 I

832

27.9

38,723

36.4

 

 II

1,172

43.9

38,185

39.8

 III

278

10.4

7,369

7.7

 IV

87

3.3

2,328

2.4

 Unknown

315

10.6

10,310

9.7

BMI body mass index

https://static-content.springer.com/image/art%3A10.1007%2Fs12282-013-0466-2/MediaObjects/12282_2013_466_Fig2_HTML.gif
Fig. 2

Distribution of the histological subtypes of breast cancer. DCIS ductal carcinoma in situ

Biological markers

The ER, PgR and HER2 expressions were compared between the young and non-young patients (Table 2). The status of ER and PgR was determined according to the immunohistochemical (IHC) technique using monoclonal antibodies. A cutoff level of between 2 and 3 was adopted on the Allred Score [11] or 10 % as a staining proportion [12]. Tumors that were immunohistochemically scored as 3+ or 2+ with a FISH-positive status were regarded as HER2-positive in the majority of individual participating institutions. Of the young patients, 70.8 % had ER-positive tumors, which was lower than the rate of 75.0 % observed in the non-young patients (p < 0.0001). The HER2-positive rate in the young patients was 16.3 %, which was higher than the 14.1 % observed in the non-young patients (p = 0.0032). The rate of so-called ‘triple-negative’ [(TN), ER-, PgR- and HER2-negative] tumors was 18.3 % in the young patients, which was higher than the 13.7 % observed in the non-young patients (p < 0.0001).
Table 2

Comparison of the hormone receptor and HER2 status between young and non-young patients with breast cancer

 

Young patients (n = 2,982)

Non-young patients (n = 106,295)

p value

N

(%)

N

(%)

ER

 Positive

2,110

70.8

79,699

75.0

<0.0001

 Negative

792

26.6

23,910

22.5

 

 Unknown

80

2.7

2,686

2.5

PgR

 Positive

1,892

63.5

64,728

60.9

0.0082

 Negative

999

33.5

38,539

36.3

 

 Unknown

91

3.1

3,028

2.9

HER2

 Positive

486

16.3

15,010

14.1

0.0032

 Negative

2,183

73.2

80,104

75.4

 

 Unknown

313

10.5

11,181

10.5

Triple negative

 Yes

487

18.3

12,998

13.7

<0.0001

 No

2,173

81.7

81,605

86.3

 

ER estrogen receptor, PgR progesterone receptor, HER2 human epidermal growth factor receptor 2

Surgical treatment

The types of surgery were compared between the young and non-young patients. Both the young and non-young patients were more likely to undergo breast-conserving therapy (BCT) than mastectomy, as shown in Table 3. The rate of BCT in the young patients was higher than that observed in the non-young patients (62.7 % vs. 57.0 %), although the rate of mastectomy in the young patients was lower than that observed in the non-young patients (35.1 % vs. 41.9 %, p < 0.0001, respectively). Axillary lymph node dissection was performed in 53.6 % of the young patients, which was higher than the rate of 51.1 % observed in the non-young patients (p < 0.0001).
Table 3

Comparison of the type of surgery between young and non-young patients with breast cancer

 

Young patients (n = 2,982)

Non-young patients (n = 106,295)

p value

N

(%)

N

(%)

Surgery for breast

 No

5

0.2

130

0.1

<0.0001

 Breast conservation

1,844

62.7

59,822

57.0

 

 Mastectomy

1,030

35.1

43,982

41.9

 Other

58

2.0

1,023

1.0

 Unknown

2

0.1

49

0.1

Axillary dissection

 No

168

5.7

7,338

7.0

<0.0001

 SNB alone

1,105

37.6

40,495

38.6

 

 Sampling alone

63

2.1

2,912

2.8

 More than level I

1,575

53.6

53,627

51.1

 Other

14

0.5

488

0.5

 Unknown

14

0.5

146

0.1

SNB sentinel node biopsy

Adjuvant therapy

The details of the neoadjuvant and adjuvant therapy were compared between the young and non-young patients, as shown in Tables 4, 5 and 6. The rate of neoadjuvant therapy was 24.7 % in the young patients, which was significantly higher than the 11.3 % observed in the non-young patients (p < 0.0001). Among the patients who received neoadjuvant therapy, 97.1 % and 89.8 % of the young and non-young patients received chemotherapy, 15.7 % and 16.9 % received hormone therapy and 11.9 % and 11.0 % received trastuzumab, respectively. Anthracyclines and taxans were primarily prescribed as neoadjuvant chemotherapy in both the young and non-young patients. LHRHa was prescribed as neoadjuvant hormone therapy in 12.4 % of the young patients, and AI was prescribed in 10.6 % of the non-young patients.
Table 4

Comparison of the adjuvant therapy between young and non-young patients with breast cancer

 

Young patients (n = 2,982)

Non-young patients (n = 106,295)

p value

N

(%)

N

(%)

Neoadjuvant therapy

 No

2,211

75.2

92,992

88.6

<0.0001

 Yes

725

24.7

11,912

11.3

 

 Unknown

3

0.1

102

0.1

Adjuvant therapy

 No

569

19.4

19,306

18.4

0.006

 Yes

2,326

79.1

84,678

80.6

 

 Unknown

44

1.5

1,022

1.0

Table 5

Comparison of the neoadjuvant therapy between young and non-young patients with breast cancer

 

Young patients (n = 725)

Non-young patients (n = 11,912)

p value

N

(%)

N

(%)

Chemotherapy

704

97.1

10,698

89.8

<0.0001

 Anthracyclines

636

87.7

9,002

75.6

 

 Taxanes

595

82.1

8,732

73.3

 Oral FU

33

4.6

714

6.0

 CMF

1

0.1

31

0.3

 Other

4

0.6

68

0.5

Hormone therapy

114

15.7

2,014

16.9

<0.0001

 Tamoxifen

33

4.6

533

4.5

 

 GnRH agonist

90

12.4

256

2.1

 AI

2

0.3

1,262

10.6

 MPA

15

2.1

257

2.2

Trastuzumab

 No

639

88.1

10,607

89.0

0.4488

 Yes

86

11.9

1,305

11.0

 

Oral FU oral furuorouracil (doxifluridine/tegafur-gimeracil-oteracil potassium/tegafur-uracil/capecitabine), CMF cyclophosphamide + methotorexate + 5-FU, Other irinotecan hydrochloride, gemcitabine hydrochloride, vinorelbine tartrate, GnRH agonist gonadotropin-releasing hormone agonist (goserelin acetate/leuprorelin acetate), AI aromatase inihibitors (anastrozole/exemestane/letrozole), MPA acetic acid medroxyprogesterone

Table 6

Comparison of the adjuvant therapy between young and non-young patients with breast cancer

 

Young patients (n = 2,326)

Non-young patients (n = 84,678)

p value

N

(%)

N

(%)

Chemotherapy

1,290

55.5

35,163

41.5

<0.0001

 Anthracyclines

1,013

43.6

24,893

29.4

 

 Taxanes

636

27.3

14,350

16.9

 Oral FU

162

7.0

5,262

6.2

 CMF

42

1.8

2,407

2.8

 Other

9

0.4

155

0.2

Hormone therapy

1,772

76.2

68,712

81.2

<0.0001

 Tamoxifen

1,576

67.8

28,696

33.9

 

 GnRH agonist

1,291

55.5

11,169

13.2

 AI

37

1.6

40,507

47.8

 MPA

7

0.3

168

0.2

Trastuzumab

 No

2,102

90.4

79,793

94.2

<0.0001

 Yes

224

9.6

4,885

5.8

Radiation therapy

 No

872

37.5

41,257

48.7

<0.0001

 Yes

1,441

62.0

43,112

50.9

 

 Unknown

13

0.6

309

0.4

Oral FU oral furuorouracil (doxifluridine/tegafur-gimeracil-oteracil potassium/tegafur-uracil/capecitabine), CMF cyclophosphamide + methotorexate + 5-FU, Other irinotecan hydrochloride, gemcitabine hydrochloride, vinorelbine tartrate, GnRH agonist gonadotropin-releasing hormone agonist (goserelin acetate/leuprorelin acetate), AI aromatase inihibitors (anastrozole/exemestane/letrozole), MPA acetic acid medroxyprogesterone

Table 6 shows a comparison of the adjuvant therapies. The young patients were more likely to be treated with chemotherapy, targeted therapy and radiation therapy, but not hormone therapy, compared to the non-young patients. Among the patients who received adjuvant therapy, 55.5 % and 41.5 % of the young and non-young patients received chemotherapy, 76.2 % and 81.2 % received hormone therapy and 9.6 % and 5.8 % received trastuzumab, respectively. In contrast to that observed for neoadjuvant therapy, adjuvant therapy primarily included hormone therapy rather than chemotherapy in both the young and non-young patients. Tamoxifen and LHRHa were most prescribed as adjuvant therapy in the young patients, while AI and tamoxifen were prescribed in the non-young patients.

Radiation therapy was performed in 62.0 % of the young patients, which was significantly higher than the rate of 50.9 % observed in the non-young patients (p < 0.0001). Radiotherapy was indicated for patients who underwent breast-conserving surgery, those with larger tumors and those with four or more positive lymph nodes at the time of surgery.

Discussion

We analyzed data obtained from a large number of breast cancer cases registered with the JBCS in order to characterize and advance our understanding of the features of young breast cancer patients. The median age of breast cancer patients was 58 years old and the percentage of young patients under 35 years of age was 2.7 % in this study. It has been established that a racial difference exists in the incidence rates and age distribution of breast cancer [13]. The age-adjusted breast cancer incidence rate for Japanese women was reported to be 73.4 per 100,000 women per year in 2007, which is still lower than the rate reported in Western countries [1]. In the US, the age-adjusted breast cancer incidence rate was 124.3 per 100,000 women per year in 2009, the median age at the diagnosis of breast cancer was 61 years of age, and the percentage of young patients under 35 years of age was 1.8 % [14]. In the 1990s, the Japanese age-adjusted breast cancer incidence rate was only 37.0–43.6 per 100,000 women per year, with the peak age at the diagnosis of breast cancer reported to range from 45–50 years of age and the percentage of young patients under 35 years of age ranged from 5–7 % [1, 15]. A rapid increase in the incidence rate was seen among middle and old age groups, especially among individuals from 45 to 64 years old; the percentage of young patients compared to all patients has shown a decreasing trend over the past 20 years [13, 15]. Early menarche, late child-bearing and a decreasing birthrate are the current trends among Japanese women, which are factors that appear to influence the present increasing rates of breast cancer in addition to changes in both foods and lifestyles from traditional Japanese customs to Western styles. As the Japanese have recently become more Westernized, the epidemiology of breast cancer might change from the previously observed patterns to Western patterns [16].

Features of the young Japanese patients’ backgrounds compared to those of the non-young patients included lower BMIs, more frequent family histories of breast cancer and fewer bilateral tumors. The rate of being overweight was 10.4 % among the young patients and 22.8 % among the non-young patients. According to surveillance data of the Ministry of Health, Labor and Welfare, the rate of overweight Japanese females (BMI >25) was 20.2 % in 2007 [17]. The rates of females who are overweight between the ages of 20–29 and 30–39 are 5.9 and 11.1 %, respectively. This rate increases with age and is highest at 29.5 % among females 60–69 years of age. The weight distribution of Japanese breast cancer patients corresponds to the weight distribution of common Japanese females. In this study, young patients more frequently had a family history of breast cancer, which highlights the possibility of hereditary breast cancer accompanied by the BRCA1/2 mutation and other genetic mutations. A younger age at diagnosis is one of the features of hereditary breast cancer, as well as TN subtype and bilateral tumors [18]. In this study, since the patients were still young and had been little influenced by age, there were few metachronous bilateral tumors in the young patients. It has also been reported that a young age at diagnosis of a first cancer is a risk factor for contralateral breast cancer [19]. In our study, the biological characteristics of breast cancer in the young patients included endocrine-unresponsive tumors such as ER-negative, HER2-positive and TN tumors. Young patients tend to have larger tumors and lymph node metastasis due to delays in detection and/or rapid growth. Young patients hardly notice small-sized tumors due to fact that they have dense breasts. From a viewpoint of morphologic classification, the frequency of solid tubular carcinoma in young patients is higher, and this type has a tendency to exhibit a rapid and expansive growth pattern and prevail in patients with TN breast cancer [20]. These results are similar to those of previous studies from Western and Asian countries [28, 13, 21]. Breast cancer in young women is likely mainly caused by either genetic mutations or hereditary factors rather than long-term hormonal, environmental or lifestyle effects, and the biological subtypes of breast cancer in young women tend to be similar and no substantial racial differences are observed.

In terms of trends in treatment choices among young patients, the rate of BCT was higher in the young patients than in the non-young patients, in spite of the young patients exhibiting larger tumor sizes. This is due to the high rate of administration of neoadjuvant chemotherapy in young patients. In Japan, the rate of BCT was over 50 % in 2009. However, the cosmetic results of BCT were not satisfactory for all patients, and knowledge of breast reconstruction became widespread; therefore, the rate of BCT has reached a ceiling [22]. Total mastectomy and immediate reconstruction may replace BCT, especially in young patients who feel severe breast loss or who worry about intramammary recurrence. In the US, females ≤40 years of age are significantly more likely to undergo mastectomy followed by breast reconstruction than BCT compared with older females [23]. As mentioned for adjuvant therapy, both anthracyclines and taxans were used in most of the young patients in this study. Trastuzumab was also used as adjuvant therapy. Both the pathological complete remission (pCR) rate and the survival rate of patients with breast cancer have dramatically improved because of progress in targeted therapy combined with chemotherapy during the last several years [24, 25]. A prognostic analysis of this cohort is now underway.

Preserving the ovarian function and maintaining fertility are also important issues for young patients who desire childbirth. GnRH agonists given with chemotherapy for early breast cancer have been reported to be associated with a low risk of long-term chemotherapy-induced amenorrhea and a high chance of pregnancy [26]. According to one report, of the 42 patients who attempted pregnancy, 71 % (n = 30) managed to achieve pregnancy, including 8 females ≥35 years of age. Although the use of GnRH agonists during chemotherapy is not yet considered to be the standard for protecting ovarian function, 12.4 % of the young patients were treated with a GnRH agonist together with neoadjuvant chemotherapy in the present study. It is important for young patients to make treatment choices based on both breast cancer subtype and personal preference with consideration for life planning, survivorship and long-term side effects. Our study has several limitations; neither the reasons for selecting the type of treatment, the timing and duration of hormone therapy, the subsequent ovarian function nor the disease prognosis was clearly elucidated in these cases. We could confirm that young patients with breast cancer are more likely to have advanced or endocrine-unresponsive tumors than non-young patients; therefore, young patients tended to be treated more aggressively with systemic therapy. Further prognostic analyses and cohort studies of long-term side effects are needed.

Acknowledgments

We wish to thank Mr. Naohito Fukui, the NPO Japan Clinical Research Support Unit staff and the Japanese Breast Cancer Society for their collaboration on this study and their ongoing development, maintenance and improvement of this registry. This work was supported by a research fund from the Japanese Breast Cancer Society.

Conflict of interest

The authors declare that they have no conflicts of interest.

Copyright information

© The Japanese Breast Cancer Society 2013