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Estrogen receptor-positive breast cancer in Japanese women: trends in incidence, characteristics, and prognosis
original article
Annals of Oncology 22: 1318–1325, 2011 doi:10.1093/annonc/mdq596 Published online 30 November 2010
Estrogen receptor-positive breast cancer in Japanese women: trends in incidence, characteristics, and prognosis H. Yamashita1*, H. Iwase2, T. Toyama1, S. Takahashi3, H. Sugiura1, N. Yoshimoto1, Y. Endo1, Y. Fujii1 & S. Kobayashi1 1
Oncology, Immunology, and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya; 2Department of Breast and Endocrine Surgery, Kumamoto University, Kumamoto; 3Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Received 27 June 2010; revised 23 August 2010; accepted 30 August 2010
Background: The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades.
original article
Patients and methods: We examined the characteristics of the tumors treated in three time periods between 1982 and 2010. Estrogen receptor (ER), progesterone receptor (PgR) and HER2 status were assessed by immunohistochemistry. Correlation of hormone receptor levels with clinicopathological factors and prognosis was analyzed in ER-positive, HER2-negative breast cancer in two age groups (£50 years versus >50 years). Results: The frequency of ER-positive breast cancer in women aged 50 years or younger increased greatly over the interval studied (1982–1991: 52.5%, 1992–2001: 72.6%, 2002–2010: 87.1%, P < 0.0001). The frequency of ERpositive tumors also significantly increased in women over 50 years of age (1982–1991: 69.4%, 1992–2001: 73.3%, 2002–2010: 78.6%, P = 0.029). In ER-positive, HER2-negative breast cancer, tumor grade was negatively correlated with expression levels of ER and PgR. Prognosis for patients with ER-positive, HER2-negative disease significantly improved over time, due to advances in adjuvant therapies. Conclusion: It is necessary to establish risk factors, both genetic and environmental, capable of predicting the risk of ER-positive breast cancer and thus enable the efficient selection of candidates for hormone receptor-targeted chemoprevention. Key words: breast cancer, estrogen receptor, HER2, incidence, Japanese, prognosis
introduction Currently, breast cancer is the most common cancer among women in Japan. Its incidence in Japanese women has doubled in all age groups over the past two decades, and the agestandardized incidence rates were estimated at 30.4/100 000 in 1984 and 62.0/100 000 in 2004 (Center for Cancer Control and Information Service, National Cancer Center, Japan http://ganjoho.jp/pro/statistics/en/gdball.html?1%2%1# Graph). Generally, the incidence remains only one-third of that seen in women in North American and European countries (Surveillance Epidemiology and End Results Cancer Statistics, USA, and Cancer Research, UK). However, the age-specific incidence in women <50 years of age is similar to that in the United States and the UK, and the peak age of age-specific incidence in Japanese women is 45 years old [1]. *Correspondence to: Dr H. Yamashita, Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel: +81-52-853-8231; Fax: +81-52-853-6440; E-mail: [email protected]
Parity is strongly associated with breast cancer risk in both premenopausal and postmenopausal women [2–4]. The Ministry of Health, Labor, and Welfare in Japan reported that the total fertility rate, which is the average number of children that would be born to a woman over her lifetime, has decreased since the 1970s from an estimated 2.16 in 1971 to an estimated 1.32 in 2006; in contrast, the incidence of breast cancer has been increasing. In addition, it is well known that obesity is associated with an increased risk of breast cancer among postmenopausal women. Interestingly, the average body mass index (BMI) in Japanese women in their 30s to 60s has reduced during the past decade, despite the fact that BMI tends to increase with age, and that in all age groups during the past decade the average height has increased while the average weight has remained unchanged (size-JPN 2004–2006, conducted by the Ministry of Economy, Trade, and Industry of Japan). Recent gene expression-based molecular classification has revealed that breast cancer is not one disease but a collection of several biologically different diseases [5, 6]. There are
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
large-scale molecular differences between estrogen receptor (ER)-positive and ER-negative breast cancers that reach far beyond the presence or absence of ER. The Breast Cancer Risk Assessment Tool (i.e., the Gail model) is used to predict the risk of breast cancer in Western countries, and the Gail model has identified populations at increased risk of ER-positive breast cancer in postmenopausal women [4, 7]. Moreover, genomewide association studies have identified genetic susceptibility loci for breast cancer by ER status [8–13]. To investigate the possible reasons for the recent increased incidence of breast cancer in Japan, we examined the characteristics of the tumors treated between 1982 and 2010, stratified by age group and ER status, as assessed by immunohistochemistry (IHC), and found that the recent notable increase of breast cancer incidence is mostly due an increase in the ER-positive subtype, especially in women aged 50 years or younger. We also analyzed the characteristics and prognosis in ER-positive, HER2-negative breast cancer, which is the most common and increasing subtype, by age group.
patients and methods patients and breast cancer samples The study included 1903 consecutive Japanese women with breast cancer, which were newly diagnosed at Nagoya City University Hospital between January 1982 and March 2010. The study protocol was approved by the institutional review boards and conformed with the guidelines of the 1996 Declaration of Helsinki. Stage (tumor–node–metastasis clinical classification) was classified according Union for International Cancer Control, sixth edition, 2002. All patients except for those with stage IV disease underwent surgical treatment (mastectomy or lumpectomy). Tumor samples of patients with stage IV disease were taken by core needle biopsies. Patients received adequate endocrine or chemotherapy for adjuvant or metastatic diseases.
immunohistochemical evaluation of ER, PgR, and HER2 status The ER, progesterone receptor (PgR), and HER2 status of the breast cancer tissues was assessed by IHC. One 4-lm section of each submitted paraffin block was stained first with hematoxylin–eosin to verify that an adequate number of carcinoma cells were present and that the fixation quality was adequate for IHC analysis. Serial sections (4 lm) were prepared from selected blocks and float-mounted on adhesive-coated glass slides, for staining of the expression of ER, PgR, and HER2 as described previously [14]. Primary antibodies included monoclonal mouse anti-human ERa antibody (1D5, DAKO, Glostrup, Denmark) at 1:100 dilution for ER, and monoclonal mouse anti-human PgR antibody (636, DAKO) at 1:100 dilution for PgR. The DAKO EnVision system (DAKO EnVision labeled polymer, peroxidase) was used as the detection system. Immunostained slides were scored after the entire slide was evaluated by light microscopy. Any brown nuclear staining in breast epithelium was counted as positive cells. The expression of ER and PgR was scored by assigning proportion and intensity scores, according to Allred’s procedure [15]. Tumors with ‡1% positive cells (proportion score ‡2) were evaluated as positive [16, 17]. Immunostaining of HER2 was evaluated using the same method as employed by the HercepTest (DAKO). To determine the HER2 expression score, the membrane staining pattern was estimated and scored on a scale of 0–3+. Scores 0 and 1+ were considered negative, and 3+ was considered positive. Tumors with a sore of 2+ were tested for gene amplification by
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FISH using the PathVysion assay (Vysis, Abbott Laboratories, Abbott Park, IL). A ratio of HER2 gene/chromosome 17 ‡ 2.0 was considered positive. Tumors were considered HER2 positive if IHC staining was 3+ or FISH positive [18].
statistical analysis To compare the hormone receptor and HER2 status among the three time periods (namely, 1982–1991, 1992–2001, and 2002–2010) and two age groups (£50 and >50 years of age), the chi-square test was used. Spearman’s rank correlation test was used to study relationships between clinicopathological factors and hormone receptor scores. Estimation of disease-free and overall survival was carried out using the Kaplan–Meier method, and differences between survival curves were assessed with the logrank test. Cox’s proportional hazards model was used for univariate and multivariate analyses of prognostic values.
results changes in the frequency of breast cancer according to ER and PgR status A total of 1903 Japanese women with breast cancer were treated and analyzed for ER status at the Nagoya City University Hospital between January 1982 and March 2010. We analyzed ER and PgR status by age group during the three study periods (Table 1). Surprisingly, the frequency of ER-positive breast cancer in women aged 50 years or younger increased greatly over the interval studied (1982–1991: 52.5%, 1992–2001: 72.6%, 2002–2010: 87.1%, P < 0.0001). The frequency of PgRpositive tumors also significantly increased in women aged 50 years or younger (1982–1991: 60.2%, 1992–2001: 72.3%, 2002– 2010: 81.3%, P < 0.0001). On the other hand, the frequency of ER-positive breast cancer significantly increased in women over 50 years of age (1982–1991: 69.4%, 1992–2001: 73.3%, 2002– 2010: 78.6%, P = 0.029), whereas the frequency of PgR-positive tumors was 60% in women over 50 years of age in all three study periods. When combined ER and PgR status was analyzed, during the three study periods, the proportion of ERpositive (+)/PgR-positive (+) tumors greatly increased in women aged 50 years or younger, whereas the proportion of ER-negative (2)/PgR+ and ER2/PgR2 tumors significantly decreased (P < 0.0001). The proportion of ER2/PgR+ and ER2/PgR2 tumors also decreased significantly over time in the >50 years of age group (P = 0.045). The frequency of noninvasive carcinoma (stage 0) increased significantly during the three study periods (1982–1991: 2.2%, 1992–2001: 3.1%, 2002–2010: 10.9%, P < 0.0001). However, there was no difference between the frequency of noninvasive carcinoma and invasive carcinoma with respect to ER status, and the ratios of ER-positive breast cancer were 78.7% in noninvasive carcinoma and 77.1% in invasive carcinoma. changes in the frequency of invasive breast cancer according to HER2 status HER2 status in invasive breast cancers was analyzed by age group between 1982 and 2010 (Table 2). The frequency of HER2-positive breast cancer was 10% over the three time periods in both age groups. When the combined ER and HER2 status was analyzed, the frequency of ER+/HER22 tumors increased greatly over the interval studied, especially in women
doi:10.1093/annonc/mdq596 | 1319
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Table 1. Hormone receptor status during the three study periods by age group Number of patients Number of patients 1903 Estrogen receptor (ER) status Total Positive 1470 Negative 433 £50 years Positive 574 Negative 154 >50 years Positive 896 Negative 279 Progesterone receptor (PgR) status Total Positive 1274 Negative 607 £50 years Positive 551 Negative 172 >50 years Positive 723 Negative 435 £50 years ER+/PgR+ 534 ER+/PgR2 37 ER2/PgR+ 18 ER2/PgR2 134 >50 years ER+/PgR+ 722 ER+/PgR2 161 ER2/PgR+ 9 ER2/PgR2 266
1982–1991, n (%)
1992–2001, n (%)
2002–2010, n (%)
P
223
490
1190
138 (61.9) 85 (38.1)
358 (73.1) 132 (26.9)
974 (81.8) 216 (18.2)
<0.0001*
52 (52.5) 47 (47.5)
130 (72.6) 49 (27.4)
392 (87.1) 58 (12.9)
<0.0001*
86 (69.4) 38 (30.6)
228 (73.3) 83 (26.7)
582 (78.6) 158 (21.4)
0.029*
132 (59.5) 90 (40.5)
305 (64.3) 169 (36.7)
837 (70.6) 348 (29.4)
0.0009*
59 (60.2) 39 (39.8)
128 (72.3) 49 (27.7)
364 (81.3) 84 (18.7)
<0.0001*
73 (58.9) 51 (41.1)
177 (59.6) 120 (40.4)
473 (64.2) 264 (35.8)
50 2 8 38
(51.0) (2.0) (8.2) (38.8)
121 8 7 41
(68.4) (4.5) (4.0) (23.2)
363 27 3 55
(81.0) (6.0) (0.7) (12.3)
<0.0001*
71 15 3 35
(57.3) (12.1) (2.4) (28.2)
179 39 4 75
(60.3) (13.1) (1.3) (25.3)
472 107 2 156
(64.0) (14.5) (0.3) (21.2)
0.045*
0.27
*P < 0.05 is considered significant.
aged 50 years or younger (1982–1991: 48.0%, 1992–2001: 69.8%, 2002–2010: 80.8%). In contrast, the frequency of ER2/HER22 tumors decreased greatly in women aged 50 years or younger (1982–1991: 39.8%, 1992–2001: 22.1%, 2002– 2010: 10.0%). The frequency of ER+/HER22 tumors slightly increased over time in women over 50 years of age (1982–1991: 66.9%, 1992–2001: 68.8%, 2002–2010: 72.4%).
clinicopathological characteristics in ER-positive, HER2-negative breast cancer We next examined correlations between clinicopathological factors and hormone receptor scores in ER-positive, HER2negative breast cancer (Table 3). Patient’s age was positively associated with expression levels of ER (P < 0.0001), and negatively correlated with expression levels of PgR (P < 0.0001). Tumor grade was negatively correlated with expression levels of ER (P = 0.0029) and PgR (P < 0.0001). ER and PgR Allred expression scores were compared between the two age groups (Figure 1). Although most tumors in women 50 years or younger showed high ER expression scores of ‡6, tumors with a score of 8 were found significantly less frequency compared with women over 50 years of age in whom
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70% of tumors had an ER expression score of 8 (Figure 1A). In contrast, in women aged 50 years or younger, most tumors had high PgR expression scores, especially scores of 7 and 8, whereas the distribution of PgR scores was evenly spread in tumors in women over 50 years of age (Figure 1B).
adjuvant therapies and prognosis in ER-positive, HER2-negatve breast cancer by age group We then analyzed the prognosis of patients with ER-positive, HER2-negative breast cancer treated between 1982 and 2006, by age group. Characteristics of patients and tumors are shown in Table 4. Kaplan–Meier analysis showed that disease-free and overall survival significantly improved over time in both age groups (Figure 2A–D). Indication and the choice of the drugs of adjuvant endocrine and chemotherapies have changed during the three time periods. Between 2002 and 2006, 57.6% of women aged 50 years or younger received endocrine therapy alone, and 34.3% received both endocrine and chemotherapy, whereas 60.9% of women over 50 years of age received endocrine therapy alone and 20.2% received both endocrine and chemotherapy (Tables 5 and 6). In women aged 50 years or younger, 25% of patients did not receive adjuvant endocrine
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original article
Annals of Oncology
Table 2. HER2 status in invasive carcinoma during the three study periods by age group Number of patients Number of patients HER2 status Total Negative Positive £50 years Negative Positive >50 years Negative Positive Estrogen receptor £50 years (ER)+/HER22 ER+/HER2+ ER2/HER2+ ER2/HER22 >50 years ER+/HER22 ER+/HER2+ ER2/HER2+ ER2/HER22
1724
1982–1991, n (%) 222
1992–2001, n (%) 470
2002–2010, n (%)
P
1032
1514 210
198 (89.2) 24 (10.8)
416 (88.5) 54 (11.5)
900 (87.2) 132 (12.8)
0.62
599 62
86 (87.8) 12 (12.2)
158 (91.9) 14 (8.1)
355 (90.8) 36 (9.2)
0.53
915 148
112 (90.3) 12 (9.7)
258 (86.6) 40 (13.4)
545 (85.0) 96 (15.0)
0.28
483 30 32 116
47 5 7 39
(48.0) (5.1) (7.1) (39.8)
120 4 10 38
(69.8) (2.3) (5.8) (22.1)
316 21 15 39
(80.8) (5.4) (3.8) (10.0)
<0.0001*
752 63 85 163
83 3 9 29
(66.9) (2.4) (7.3) (23.4)
205 15 25 53
(68.8) (5.0) (8.4) (17.8)
464 45 51 81
(72.4) (7.0) (8.0) (12.6)
0.024*
*P < 0.05 is considered significant.
Table 3. Correlations between clinicopathological factors and hormone receptor scores in estrogen receptor (ER)-positive, HER2-negative breast cancer
Tumor size Number of positive lymph nodes Tumor grade ER score Progesterone receptor score
Age
Tumor size
Number of positive lymph nodes
Tumor grade
ER score
20.033a 0.42b +0.039 0.40 +0.018 0.66 +0.404 <0.0001* 20.220 <0.0001*
+0.239 +0.068 20.052 20.081
+0.093 0.046* 20.052 0.26 +0.003 0.95
20.125 0.0029* 20.205 <0.0001*
+0.146 0.0004*
<0.0001* 0.10 0.21 0.0495*
a
Spearman’s correlation coefficient. P, Spearman’s rank correlation test. *P < 0.05 is considered significant.
b
Figure 1. Expression levels of estrogen receptor (ER) (A) and progesterone receptor (PgR) (B) assessed by Allred score in ER-positive, HER2-negative breast cancer by age group.
therapy between 1982 and 2001 (Table 5). Moreover, 71.7% of patients received tamoxifen for 2 years as adjuvant endocrine therapy between 1982 and 1991, whereas 65.7% received
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tamoxifen for 5 years plus luteinizing hormone-releasing hormone agonist for a minimum of 2 years between 2002 and 2006 (Table 5). Aromatase inhibitors, instead of tamoxifen, have been indicated as standard endocrine therapy since 2002, and 58% of patients over 50 years of age received aromatase inhibitors between 2002 and 2006 (Table 6). In addition, anthracyclines and taxanes have been indicated as standard chemotherapy for high-risk patients since 2002, although oral 5-fluorouracil derivatives were frequently administered for 2 years as adjuvant chemotherapy during 1980s and 1990s (Tables 5 and 6). Kaplan–Meier analysis showed that tumor size (Figure 3A– D) and lymph node status (Figure 4A–D) were strongly associated with disease-free and overall survival in both age groups. Tumor grade was significantly correlated with diseasefree and overall survival in women aged 50 years or younger (Figure 5A and B), whereas no association was observed between grade and survival in women over 50 years of age
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Table 4. Clinicopathological characteristics of patients and tumors in ER-positive, HER2-negative breast cancer between 1982 and 2006 Total, n (%) Number of patients 845 Age (mean 6 standard 56.8 6 13.3 deviation) Periods 1982–1991 127 (15.0) 1992–2001 308 (36.5) 2002–2006 410 (48.5) Tumor size (cm) £2 438 (51.8) 2–5 363 (43.0) >5 44 (5.2) Number of positive lymph nodes 0 466 (62.9) 1–3 178 (24.0) ‡4 97 (13.1) Tumor grade 1 248 (34.3) 2 370 (51.2) 3 105 (14.5) Progesterone receptor Positive 726 (86.6) Negative 112 (13.4)
£50 years, n (%)
>50 years, n (%)
331 43.7 6 5.1
514 65.3 6 9.5
46 (13.9) 113 (34.1) 172 (52.0)
81 (15.8) 195 (37.9) 238 (46.3)
158 (47.7) 146 (44.1) 27 (8.2)
280 (54.5) 217 (42.2) 17 (3.3)
184 (58.4) 85 (27.0) 46 (14.6)
282 (66.2) 93 (21.8) 51 (12.0)
104 (35.9) 149 (51.4) 37 (12.7)
144 (33.3) 221 (51.0) 68 (15.7)
314 (94.9) 17 (5.1)
412 (81.3) 95 (18.7)
Table 5. Adjuvant therapy in ER-positive, HER2-negative breast cancer in women aged 50 years or younger 1982–1991, n (%) Number of patients None Endocrine therapy alone Chemotherapy alone Combined Endocrine therapy None TAM alone LHRH agonist alone LHRH agonist + TAM AI TAM 2 AI Chemotherapy None Oral 5FU CMF Anthracyclins Taxanes Anthracyclins + taxanes
46 9 18 4 15
(19.6) (39.1) (8.7) (32.6)
1992–2001, n (%) 113 15 (13.3) 40 (35.4) 13 (11.5) 45 (39.8)
13 (28.3) 33 (71.7) 0 0 0 0
28 55 4 22 0 4
(24.8) (48.7) (3.5) (19.5)
27 (58.7) 18 (39.1) 0 1 (2.2) 0 0
55 35 11 7 5 0
(48.7) (31.0) (9.7) (6.2) (4.4)
(3.5)
2002–2006, n (%) 172 10 99 4 59
(5.8) (57.6) (2.3) (34.3)
14 26 4 113 14 1
(8.1) (15.1) (2.3) (65.7) (8.1) (0.6)
108 0 6 32 1 25
(62.8) (3.5) (18.6) (0.6) (14.5)
LHRH agonist, luteinizing hormone-releasing hormone agonist for a minimum of 2 years; tamoxifen (TAM) 2 aromatase inhibitors (AI), tamoxifen for 2–3 years followed by aromatase inhibitors for 3–2 years; 5FU, 5-fluorouracil derivatives for 2 years; CMF, cyclophosphamide, methotrexate, and fluorouracil; anthracyclins, AC (doxorubicin and cyclophosphamide), or FEC (fluorouracil, epirubocin, and cyclophosphamide); taxanes, docetaxel, or paclitaxel.
this younger age group. Multivariate analysis revealed that tumor size (P = 0.0007) and lymph node status (P < 0.0001) were prognostic factors for improved disease-free survival in women aged 50 years or younger. In women over 50 years of age, lymph node status (P < 0.0001) was the only prognostic factor for improved disease-free survival in multivariate analyses, although a significant association was found between disease-free survival and tumor size (P = 0.0006) and lymph node status (P < 0.0001) in univariate analysis.
discussion
Figure 2. Disease-free (A and C) and overall (B and D) survivals according to the three study periods in estrogen receptor-positive, HER2negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
(Figure 5C and D). Univariate analysis demonstrated that significant association between disease-free survival and tumor size (P < 0.0001), lymph node status (P < 0.0001) and tumor grade (P = 0.0031) was found in women aged 50 years or younger (Table 7). However, there was no association between disease-free survival and expression scores of ER and PgR in
1322 | Yamashita et al.
In this study, we have shown that the recent notable increase of breast cancer incidence is mostly due an increase in the ERpositive subtype, especially in women aged 50 years or younger. The Japanese Breast Cancer Society reported that, in Japan in 2006, there were 4899 women (81.1%) with ER-positive tumors among 6043 registered breast cancer patients under 50 years of age, and 10 152 women (73.3%) with ER-positive tumors among 13 783 registered breast cancer patients aged ‡50 years (Breast Cancer Statistics in Japan, 2006, conducted by the Japanese Breast Cancer Society). Almost 50% of newly diagnosed breast cancer patients in Japan were registered in this registration system in 2006. Although the incidence rates of ERpositive tumors in Japan seem lower than those in our present study, it may be because of different methods used for the
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Annals of Oncology
Table 6. Adjuvant therapy in ER-positive, HER2-negative breast cancer in women over 50 years of age
Number of patients None Endocrine therapy alone Chemotherapy alone Combined Endocrine therapy None TAM alone LHRH agonist alone LHRH agonist + TAM AI TAM 2 AI Chemotherapy None Oral 5FU CMF Anthracyclins Taxanes Anthracyclins + taxanes
1982–1991, n (%)
1992–2001, n (%)
2002–2006, n (%)
81 24 35 2 20
(29.6) (43.2) (2.5) (24.7)
195 31 124 3 37
(15.9) (63.6) (1.5) (19.0)
238 41 145 4 48
26 (32.1) 55 (67.9) 0 0 0 0
34 139 1 5 1 15
(17.4) (71.3) (0.5) (2.6) (0.5) (7.7)
45 27 0 9 138 19
(18.9) (11.3)
59 (72.8) 21 (25.9) 0 1 (1.2) 0 0
155 28 6 5 1 0
(79.5) (14.4) (3.1) (2.6) (0.5)
186 0 16 18 0 18
(78.2)
(17.2) (60.9) (1.7) (20.2)
(3.8) (58.0) (8.0)
(6.7) (7.6)
Figure 4 Disease-free (A and C) and overall (B and D) survivals according to number of positive lymph nodes in estrogen receptor-positive, HER2negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
(7.6)
LHRH agonist, luteinizing hormone-releasing hormone agonist for a minimum of 2 years; tamoxifen (TAM) – aromatase inhibitors (AI), tamoxifen for 2–3 years followed by aromatase inhibitors for 3–2 years; 5FU, 5-fluorouracil derivatives for 2 years; CMF, cyclophosphamide, methotrexate, and fluorouracil; anthracyclins, AC (doxorubicin and cyclophosphamide), or FEC (fluorouracil, epirubocin, and cyclophosphamide); taxanes, docetaxel, or paclitaxel.
Figure 5. Disease-free (A and C) and overall (B and D) survivals according to tumor grade in estrogen receptor-positive, HER2-negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
Figure 3. Disease-free (A and C) and overall (B and D) survivals according to tumor size in estrogen receptor-positive, HER2-negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
assessment of ER status. We evaluated tumors with ‡1% positive cells as positive for ER or PgR [16], whereas in 2006 most hospitals in Japan assessed tumors with ‡10% positive cells as positive for ER or PgR.
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Not only the incidence rates but also the frequencies of molecular subtypes of breast cancer differ greatly among ethnic groups [19, 20]. Genome-wide association studies have identified genetic susceptibility loci, such as fibroblast growth factor receptor 2 for breast cancer by ER status [8]. We have previously identified that genetic polymorphisms of ER (ERa), CYP19A1, COMT and p53 genes frequently occur in ERpositive premenopausal breast cancer patients compared with those in patients with ER-negative tumors [21]. It is necessary to establish genetic factors for predicting the risk of ER-positive breast cancer. In addition to genetic factors, it has been suggested that a change in environmental factors might also be having a notable effect on the increase of breast cancer incidence. Iwasaki and et al. [3] from the Japan Public Health
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Table 7. Univariate and multivariate analysis of factors predicting disease-free survival in ER-positive, HER2-negative breast cancer Factor £50 years Tumor size (£2, 2–5, >5 cm) Lymph node status (0, 1–3, ‡4) Tumor grade (1, 2, 3) ER (score) PgR (score) >50 years Tumor size (£ 2, 2–5, >5 cm) Lymph node status (0, 1–3, ‡4) Tumor grade (1, 2, 3) ER (score) PgR (score)
Univariate RR
95% CI
P
Multivariate RR
95% CI
P
2.34 3.13 1.84 0.94 0.94
1.63–3.35 2.31–4.25 1.23–2.74 0.79–1.11 0.83–1.06
<0.0001* <0.0001* 0.0031* 0.47 0.30
2.09 2.80 1.33
1.37–3.21 2.00–3.92 0.90–1.97
0.0007* <0.0001* 0.15
2.05 2.86 1.35 0.86 1.01
1.36–3.07 2.09–3.93 0.98–2.02 0.72–1.04 0.91–1.11
0.0006* <0.0001* 0.15 0.11 0.92
1.31 2.68
0.83–2.08 1.91–3.75
0.25 <0.0001*
*P < 0.05 is considered significant. RR, relative risk; CI, confidence interval; ER, estrogen receptor; PgR, progesterone receptor.
Center-Based Prospective Study reported that early age at menarche for premenopausal women, late age at natural menopause for postmenopausal women, and nulliparity and low parity for both premenopausal and postmenopausal women were significantly associated with an increased risk of breast cancer. The Life Span Study of the Radiation Effects Research Foundation in Hiroshima and Nagasaki showed an inverse association between the number of births and total period of breastfeeding and breast cancer risk [22]. Because the total fertility rate has been gradually decreasing since the 1970s in Japan, this decreased fertility might be one possible explanation for the increased incidence of breast cancer. Furthermore, increasing height, good nutrition, and a Westernized dietary life are all trends observed in Japan during the past two decades. Thus, changing lifestyles might increase breast cancer risk, especially in premenopausal Japanese women. We demonstrated that the frequencies of both ER+/PgR+ and ER+/HER22 tumors were significantly higher in women 50 years or younger than in women over 50 years of age between 2002 and 2010. Moreover, the expression levels of PgR were notably different in the ER-positive, HER2-negative subtype between the two age groups; most tumors showed high PgR expression scores in women 50 years or younger, whereas the distribution of PgR scores was similar in women over 50 years of age. We, and others previously, have reported that expression levels of PgR did not affect response to aromatase inhibitors given as primary endocrine therapy, although expression levels of PgR decreased in posttreatment tumors compared with the levels in pretreatment specimens regardless of the treatment response [23–25]. In contrast, it was recently identified that expression levels of ER and PgR were predictive for prognosis in postmenopausal patients who were treated with adjuvant endocrine therapy [26, 27]. Our present study demonstrated that expression levels of ER and PgR were strongly and negatively correlated with tumor grade in ERpositive, HER2-negative breast cancer. However, expression levels of neither ER nor PgR were not associated with disease-
1324 | Yamashita et al.
free survival in either age group, although tumor grade was significantly correlated with disease-free and overall survival in women 50 years or younger. Finally, we demonstrated that adjuvant therapies, both endocrine and chemotherapies, have been changed dramatically over the past two decades, and that prognosis in ER-positive, HER2-negative breast cancer has improved over time in both age groups. On the other hand, lymph node status and tumor size were strong prognostic factors regardless of the biological characteristics of the tumors. Recent meta-analysis of outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen indicated that aromatase inhibitors significantly lower recurrence rates compared with tamoxifen [28]. Furthermore, a TransATAC study showed that the risk of distant recurrence was higher for node-positive than node-negative patients and for patients with ‡4 positive nodes than patients with one to three positive nodes, regardless of recurrence scores [29]. It is considered that the characteristics of ER-positive, HER2-negative breast cancer are heterogeneous, and that standard chemotherapy does not improve prognosis for patients with highly endocrine responsive tumors, such as high levels of ER and PgR, low proliferation and low tumor grade [30]. It is necessary to establish new approaches for improving survival for node-positive, ER-positive breast cancer. In conclusion, the present study indicates that the recent notable increase of Japanese breast cancer incidence is mostly due to an increase in the ER-positive subtype, especially in women aged 50 years or younger. Moreover, prognosis in ERpositive, HER2-negative breast cancer has improved significantly over time due to advances in adjuvant therapies. It is necessary to establish risk factors, both genetic and environmental, capable of predicting the risk of ER-positive breast cancer and thus enable the efficient selection of candidates for hormone receptor-targeted chemoprevention. Furthermore, investigation of risk factors could lead to the identification of the mechanisms concerned in the development of ER-positive breast cancer.
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Annals of Oncology
funding The study had no sponsor or funding source.
disclosure The authors have declared no conflict of interest.
references 1. Tamaki Y, Kotsuma Y, Miyoshi Y, Noguchi S. Breast cancer risk assessment for possible tailored screening for Japanese women. Breast Cancer 2009; 16: 243–247. 2. Minami Y, Tsubono Y, Nishino Y et al. The increase of female breast cancer incidence in Japan: emergence of birth cohort effect. Int J Cancer 2004; 108: 901–906. 3. Iwasaki M, Otani T, Inoue M et al. Role and impact of menstrual and reproductive factors on breast cancer risk in Japan. Eur J Cancer Prev 2007; 16: 116–123. 4. Chlebowski RT, Anderson GL, Lane DS et al. Predicting risk of breast cancer in postmenopausal women by hormone receptor status. J Natl Cancer Inst 2007; 99: 1695–1705. 5. Perou CM, Sorlie T, Eisen MB et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752. 6. Sorlie T, Tibshirani R, Parker J et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003; 100: 8418–8423. 7. Colditz GA, Rosner BA, Chen WY et al. Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst 2004; 96: 218–228. 8. Garcia-Closas M, Chanock S. Genetic susceptibility loci for breast cancer by estrogen receptor status. Clin Cancer Res 2008; 14: 8000–8009. 9. Stacey SN, Manolescu A, Sulem P et al. Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 2007; 39: 865–869. 10. Zheng W, Long J, Gao YT et al. Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 2009; 41: 324–328. 11. Thomas G, Jacobs KB, Kraft P et al. A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 2009; 41: 579–584. 12. Milne RL, Benitez J, Nevanlinna H et al. Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042. J Natl Cancer Inst 2009; 101: 1012–1018. 13. Kirchhoff T, Chen ZQ, Gold B et al. The 6q22.33 locus and breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 2009; 18: 2468–2475. 14. Yamashita H, Nishio M, Toyama T et al. Low phosphorylation of estrogen receptor alpha (ERalpha) serine 118 and high phosphorylation of ERalpha serine 167 improve survival in ER-positive breast cancer. Endocr Relat Cancer 2008; 15: 755–763. 15. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998; 11: 155–168.
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original article 16. Hammond ME, Hayes DF, Dowsett M et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010; 28: 2784–2795. 17. Yamashita H, Ando Y, Nishio M et al. Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer. Breast Cancer 2006; 13: 74–83. 18. Wolff AC, Hammond ME, Schwartz JN et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 2007; 25: 118–145. 19. Lin CH, Liau JY, Lu YS et al. Molecular subtypes of breast cancer emerging in young women in Taiwan: evidence for more than just westernization as a reason for the disease in Asia. Cancer Epidemiol Biomarkers Prev 2009; 18: 1807–1814. 20. Setiawan VW, Monroe KR, Wilkens LR et al. Breast cancer risk factors defined by estrogen and progesterone receptor status: the multiethnic cohort study. Am J Epidemiol 2009; 169: 1251–1259. 21. Hamaguchi M, Nishio M, Toyama T et al. Possible difference in frequencies of genetic polymorphisms of estrogen receptor alpha, estrogen metabolism and P53 genes between estrogen receptor-positive and -negative breast cancers. Jpn J Clin Oncol 2008; 38: 734–742. 22. Land CE, Hayakawa N, Machado SG et al. A case-control interview study of breast cancer among Japanese A-bomb survivors. I. Main effects. Cancer Causes Control 1994; 5: 157–165. 23. Yamashita H, Takahashi S, Ito Y et al. Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer. Cancer Sci 2009; 100: 2028–2033. 24. Ellis MJ, Coop A, Singh B et al. Letrozole inhibits tumor proliferation more effectively than tamoxifen independent of HER1/2 expression status. Cancer Res 2003; 63: 6523–6531. 25. Dowsett M, Ebbs SR, Dixon JM et al. Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer—a study from the IMPACT trialists. J Clin Oncol 2005; 23: 2477–2492. 26. Viale G, Regan MM, Maiorano E et al. Prognostic and predictive value of centrally reviewed expression of estrogen and progesterone receptors in a randomized trial comparing letrozole and tamoxifen adjuvant therapy for postmenopausal early breast cancer: BIG 1-98. J Clin Oncol 2007; 25: 3846–3852. 27. Dowsett M, Allred C, Knox J et al. Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol 2008; 26: 1059–1065. 28. Dowsett M, Cuzick J, Ingle J et al. Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen. J Clin Oncol 2010; 28: 509–518. 29. Dowsett M, Cuzick J, Wale C et al. Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol 2010; 28: 1829–1834. 30. Goldhirsch A, Ingle JN, Gelber RD et al. Thresholds for therapies: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2009. Ann Oncol 2009; 20: 1319–1329.
doi:10.1093/annonc/mdq596 | 1325
Annals of Oncology 22: 1318–1325, 2011 doi:10.1093/annonc/mdq596 Published online 30 November 2010
Estrogen receptor-positive breast cancer in Japanese women: trends in incidence, characteristics, and prognosis H. Yamashita1*, H. Iwase2, T. Toyama1, S. Takahashi3, H. Sugiura1, N. Yoshimoto1, Y. Endo1, Y. Fujii1 & S. Kobayashi1 1
Oncology, Immunology, and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya; 2Department of Breast and Endocrine Surgery, Kumamoto University, Kumamoto; 3Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Received 27 June 2010; revised 23 August 2010; accepted 30 August 2010
Background: The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades.
original article
Patients and methods: We examined the characteristics of the tumors treated in three time periods between 1982 and 2010. Estrogen receptor (ER), progesterone receptor (PgR) and HER2 status were assessed by immunohistochemistry. Correlation of hormone receptor levels with clinicopathological factors and prognosis was analyzed in ER-positive, HER2-negative breast cancer in two age groups (£50 years versus >50 years). Results: The frequency of ER-positive breast cancer in women aged 50 years or younger increased greatly over the interval studied (1982–1991: 52.5%, 1992–2001: 72.6%, 2002–2010: 87.1%, P < 0.0001). The frequency of ERpositive tumors also significantly increased in women over 50 years of age (1982–1991: 69.4%, 1992–2001: 73.3%, 2002–2010: 78.6%, P = 0.029). In ER-positive, HER2-negative breast cancer, tumor grade was negatively correlated with expression levels of ER and PgR. Prognosis for patients with ER-positive, HER2-negative disease significantly improved over time, due to advances in adjuvant therapies. Conclusion: It is necessary to establish risk factors, both genetic and environmental, capable of predicting the risk of ER-positive breast cancer and thus enable the efficient selection of candidates for hormone receptor-targeted chemoprevention. Key words: breast cancer, estrogen receptor, HER2, incidence, Japanese, prognosis
introduction Currently, breast cancer is the most common cancer among women in Japan. Its incidence in Japanese women has doubled in all age groups over the past two decades, and the agestandardized incidence rates were estimated at 30.4/100 000 in 1984 and 62.0/100 000 in 2004 (Center for Cancer Control and Information Service, National Cancer Center, Japan http://ganjoho.jp/pro/statistics/en/gdball.html?1%2%1# Graph). Generally, the incidence remains only one-third of that seen in women in North American and European countries (Surveillance Epidemiology and End Results Cancer Statistics, USA, and Cancer Research, UK). However, the age-specific incidence in women <50 years of age is similar to that in the United States and the UK, and the peak age of age-specific incidence in Japanese women is 45 years old [1]. *Correspondence to: Dr H. Yamashita, Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel: +81-52-853-8231; Fax: +81-52-853-6440; E-mail: [email protected]
Parity is strongly associated with breast cancer risk in both premenopausal and postmenopausal women [2–4]. The Ministry of Health, Labor, and Welfare in Japan reported that the total fertility rate, which is the average number of children that would be born to a woman over her lifetime, has decreased since the 1970s from an estimated 2.16 in 1971 to an estimated 1.32 in 2006; in contrast, the incidence of breast cancer has been increasing. In addition, it is well known that obesity is associated with an increased risk of breast cancer among postmenopausal women. Interestingly, the average body mass index (BMI) in Japanese women in their 30s to 60s has reduced during the past decade, despite the fact that BMI tends to increase with age, and that in all age groups during the past decade the average height has increased while the average weight has remained unchanged (size-JPN 2004–2006, conducted by the Ministry of Economy, Trade, and Industry of Japan). Recent gene expression-based molecular classification has revealed that breast cancer is not one disease but a collection of several biologically different diseases [5, 6]. There are
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
original article
Annals of Oncology
large-scale molecular differences between estrogen receptor (ER)-positive and ER-negative breast cancers that reach far beyond the presence or absence of ER. The Breast Cancer Risk Assessment Tool (i.e., the Gail model) is used to predict the risk of breast cancer in Western countries, and the Gail model has identified populations at increased risk of ER-positive breast cancer in postmenopausal women [4, 7]. Moreover, genomewide association studies have identified genetic susceptibility loci for breast cancer by ER status [8–13]. To investigate the possible reasons for the recent increased incidence of breast cancer in Japan, we examined the characteristics of the tumors treated between 1982 and 2010, stratified by age group and ER status, as assessed by immunohistochemistry (IHC), and found that the recent notable increase of breast cancer incidence is mostly due an increase in the ER-positive subtype, especially in women aged 50 years or younger. We also analyzed the characteristics and prognosis in ER-positive, HER2-negative breast cancer, which is the most common and increasing subtype, by age group.
patients and methods patients and breast cancer samples The study included 1903 consecutive Japanese women with breast cancer, which were newly diagnosed at Nagoya City University Hospital between January 1982 and March 2010. The study protocol was approved by the institutional review boards and conformed with the guidelines of the 1996 Declaration of Helsinki. Stage (tumor–node–metastasis clinical classification) was classified according Union for International Cancer Control, sixth edition, 2002. All patients except for those with stage IV disease underwent surgical treatment (mastectomy or lumpectomy). Tumor samples of patients with stage IV disease were taken by core needle biopsies. Patients received adequate endocrine or chemotherapy for adjuvant or metastatic diseases.
immunohistochemical evaluation of ER, PgR, and HER2 status The ER, progesterone receptor (PgR), and HER2 status of the breast cancer tissues was assessed by IHC. One 4-lm section of each submitted paraffin block was stained first with hematoxylin–eosin to verify that an adequate number of carcinoma cells were present and that the fixation quality was adequate for IHC analysis. Serial sections (4 lm) were prepared from selected blocks and float-mounted on adhesive-coated glass slides, for staining of the expression of ER, PgR, and HER2 as described previously [14]. Primary antibodies included monoclonal mouse anti-human ERa antibody (1D5, DAKO, Glostrup, Denmark) at 1:100 dilution for ER, and monoclonal mouse anti-human PgR antibody (636, DAKO) at 1:100 dilution for PgR. The DAKO EnVision system (DAKO EnVision labeled polymer, peroxidase) was used as the detection system. Immunostained slides were scored after the entire slide was evaluated by light microscopy. Any brown nuclear staining in breast epithelium was counted as positive cells. The expression of ER and PgR was scored by assigning proportion and intensity scores, according to Allred’s procedure [15]. Tumors with ‡1% positive cells (proportion score ‡2) were evaluated as positive [16, 17]. Immunostaining of HER2 was evaluated using the same method as employed by the HercepTest (DAKO). To determine the HER2 expression score, the membrane staining pattern was estimated and scored on a scale of 0–3+. Scores 0 and 1+ were considered negative, and 3+ was considered positive. Tumors with a sore of 2+ were tested for gene amplification by
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FISH using the PathVysion assay (Vysis, Abbott Laboratories, Abbott Park, IL). A ratio of HER2 gene/chromosome 17 ‡ 2.0 was considered positive. Tumors were considered HER2 positive if IHC staining was 3+ or FISH positive [18].
statistical analysis To compare the hormone receptor and HER2 status among the three time periods (namely, 1982–1991, 1992–2001, and 2002–2010) and two age groups (£50 and >50 years of age), the chi-square test was used. Spearman’s rank correlation test was used to study relationships between clinicopathological factors and hormone receptor scores. Estimation of disease-free and overall survival was carried out using the Kaplan–Meier method, and differences between survival curves were assessed with the logrank test. Cox’s proportional hazards model was used for univariate and multivariate analyses of prognostic values.
results changes in the frequency of breast cancer according to ER and PgR status A total of 1903 Japanese women with breast cancer were treated and analyzed for ER status at the Nagoya City University Hospital between January 1982 and March 2010. We analyzed ER and PgR status by age group during the three study periods (Table 1). Surprisingly, the frequency of ER-positive breast cancer in women aged 50 years or younger increased greatly over the interval studied (1982–1991: 52.5%, 1992–2001: 72.6%, 2002–2010: 87.1%, P < 0.0001). The frequency of PgRpositive tumors also significantly increased in women aged 50 years or younger (1982–1991: 60.2%, 1992–2001: 72.3%, 2002– 2010: 81.3%, P < 0.0001). On the other hand, the frequency of ER-positive breast cancer significantly increased in women over 50 years of age (1982–1991: 69.4%, 1992–2001: 73.3%, 2002– 2010: 78.6%, P = 0.029), whereas the frequency of PgR-positive tumors was 60% in women over 50 years of age in all three study periods. When combined ER and PgR status was analyzed, during the three study periods, the proportion of ERpositive (+)/PgR-positive (+) tumors greatly increased in women aged 50 years or younger, whereas the proportion of ER-negative (2)/PgR+ and ER2/PgR2 tumors significantly decreased (P < 0.0001). The proportion of ER2/PgR+ and ER2/PgR2 tumors also decreased significantly over time in the >50 years of age group (P = 0.045). The frequency of noninvasive carcinoma (stage 0) increased significantly during the three study periods (1982–1991: 2.2%, 1992–2001: 3.1%, 2002–2010: 10.9%, P < 0.0001). However, there was no difference between the frequency of noninvasive carcinoma and invasive carcinoma with respect to ER status, and the ratios of ER-positive breast cancer were 78.7% in noninvasive carcinoma and 77.1% in invasive carcinoma. changes in the frequency of invasive breast cancer according to HER2 status HER2 status in invasive breast cancers was analyzed by age group between 1982 and 2010 (Table 2). The frequency of HER2-positive breast cancer was 10% over the three time periods in both age groups. When the combined ER and HER2 status was analyzed, the frequency of ER+/HER22 tumors increased greatly over the interval studied, especially in women
doi:10.1093/annonc/mdq596 | 1319
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Table 1. Hormone receptor status during the three study periods by age group Number of patients Number of patients 1903 Estrogen receptor (ER) status Total Positive 1470 Negative 433 £50 years Positive 574 Negative 154 >50 years Positive 896 Negative 279 Progesterone receptor (PgR) status Total Positive 1274 Negative 607 £50 years Positive 551 Negative 172 >50 years Positive 723 Negative 435 £50 years ER+/PgR+ 534 ER+/PgR2 37 ER2/PgR+ 18 ER2/PgR2 134 >50 years ER+/PgR+ 722 ER+/PgR2 161 ER2/PgR+ 9 ER2/PgR2 266
1982–1991, n (%)
1992–2001, n (%)
2002–2010, n (%)
P
223
490
1190
138 (61.9) 85 (38.1)
358 (73.1) 132 (26.9)
974 (81.8) 216 (18.2)
<0.0001*
52 (52.5) 47 (47.5)
130 (72.6) 49 (27.4)
392 (87.1) 58 (12.9)
<0.0001*
86 (69.4) 38 (30.6)
228 (73.3) 83 (26.7)
582 (78.6) 158 (21.4)
0.029*
132 (59.5) 90 (40.5)
305 (64.3) 169 (36.7)
837 (70.6) 348 (29.4)
0.0009*
59 (60.2) 39 (39.8)
128 (72.3) 49 (27.7)
364 (81.3) 84 (18.7)
<0.0001*
73 (58.9) 51 (41.1)
177 (59.6) 120 (40.4)
473 (64.2) 264 (35.8)
50 2 8 38
(51.0) (2.0) (8.2) (38.8)
121 8 7 41
(68.4) (4.5) (4.0) (23.2)
363 27 3 55
(81.0) (6.0) (0.7) (12.3)
<0.0001*
71 15 3 35
(57.3) (12.1) (2.4) (28.2)
179 39 4 75
(60.3) (13.1) (1.3) (25.3)
472 107 2 156
(64.0) (14.5) (0.3) (21.2)
0.045*
0.27
*P < 0.05 is considered significant.
aged 50 years or younger (1982–1991: 48.0%, 1992–2001: 69.8%, 2002–2010: 80.8%). In contrast, the frequency of ER2/HER22 tumors decreased greatly in women aged 50 years or younger (1982–1991: 39.8%, 1992–2001: 22.1%, 2002– 2010: 10.0%). The frequency of ER+/HER22 tumors slightly increased over time in women over 50 years of age (1982–1991: 66.9%, 1992–2001: 68.8%, 2002–2010: 72.4%).
clinicopathological characteristics in ER-positive, HER2-negative breast cancer We next examined correlations between clinicopathological factors and hormone receptor scores in ER-positive, HER2negative breast cancer (Table 3). Patient’s age was positively associated with expression levels of ER (P < 0.0001), and negatively correlated with expression levels of PgR (P < 0.0001). Tumor grade was negatively correlated with expression levels of ER (P = 0.0029) and PgR (P < 0.0001). ER and PgR Allred expression scores were compared between the two age groups (Figure 1). Although most tumors in women 50 years or younger showed high ER expression scores of ‡6, tumors with a score of 8 were found significantly less frequency compared with women over 50 years of age in whom
1320 | Yamashita et al.
70% of tumors had an ER expression score of 8 (Figure 1A). In contrast, in women aged 50 years or younger, most tumors had high PgR expression scores, especially scores of 7 and 8, whereas the distribution of PgR scores was evenly spread in tumors in women over 50 years of age (Figure 1B).
adjuvant therapies and prognosis in ER-positive, HER2-negatve breast cancer by age group We then analyzed the prognosis of patients with ER-positive, HER2-negative breast cancer treated between 1982 and 2006, by age group. Characteristics of patients and tumors are shown in Table 4. Kaplan–Meier analysis showed that disease-free and overall survival significantly improved over time in both age groups (Figure 2A–D). Indication and the choice of the drugs of adjuvant endocrine and chemotherapies have changed during the three time periods. Between 2002 and 2006, 57.6% of women aged 50 years or younger received endocrine therapy alone, and 34.3% received both endocrine and chemotherapy, whereas 60.9% of women over 50 years of age received endocrine therapy alone and 20.2% received both endocrine and chemotherapy (Tables 5 and 6). In women aged 50 years or younger, 25% of patients did not receive adjuvant endocrine
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original article
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Table 2. HER2 status in invasive carcinoma during the three study periods by age group Number of patients Number of patients HER2 status Total Negative Positive £50 years Negative Positive >50 years Negative Positive Estrogen receptor £50 years (ER)+/HER22 ER+/HER2+ ER2/HER2+ ER2/HER22 >50 years ER+/HER22 ER+/HER2+ ER2/HER2+ ER2/HER22
1724
1982–1991, n (%) 222
1992–2001, n (%) 470
2002–2010, n (%)
P
1032
1514 210
198 (89.2) 24 (10.8)
416 (88.5) 54 (11.5)
900 (87.2) 132 (12.8)
0.62
599 62
86 (87.8) 12 (12.2)
158 (91.9) 14 (8.1)
355 (90.8) 36 (9.2)
0.53
915 148
112 (90.3) 12 (9.7)
258 (86.6) 40 (13.4)
545 (85.0) 96 (15.0)
0.28
483 30 32 116
47 5 7 39
(48.0) (5.1) (7.1) (39.8)
120 4 10 38
(69.8) (2.3) (5.8) (22.1)
316 21 15 39
(80.8) (5.4) (3.8) (10.0)
<0.0001*
752 63 85 163
83 3 9 29
(66.9) (2.4) (7.3) (23.4)
205 15 25 53
(68.8) (5.0) (8.4) (17.8)
464 45 51 81
(72.4) (7.0) (8.0) (12.6)
0.024*
*P < 0.05 is considered significant.
Table 3. Correlations between clinicopathological factors and hormone receptor scores in estrogen receptor (ER)-positive, HER2-negative breast cancer
Tumor size Number of positive lymph nodes Tumor grade ER score Progesterone receptor score
Age
Tumor size
Number of positive lymph nodes
Tumor grade
ER score
20.033a 0.42b +0.039 0.40 +0.018 0.66 +0.404 <0.0001* 20.220 <0.0001*
+0.239 +0.068 20.052 20.081
+0.093 0.046* 20.052 0.26 +0.003 0.95
20.125 0.0029* 20.205 <0.0001*
+0.146 0.0004*
<0.0001* 0.10 0.21 0.0495*
a
Spearman’s correlation coefficient. P, Spearman’s rank correlation test. *P < 0.05 is considered significant.
b
Figure 1. Expression levels of estrogen receptor (ER) (A) and progesterone receptor (PgR) (B) assessed by Allred score in ER-positive, HER2-negative breast cancer by age group.
therapy between 1982 and 2001 (Table 5). Moreover, 71.7% of patients received tamoxifen for 2 years as adjuvant endocrine therapy between 1982 and 1991, whereas 65.7% received
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tamoxifen for 5 years plus luteinizing hormone-releasing hormone agonist for a minimum of 2 years between 2002 and 2006 (Table 5). Aromatase inhibitors, instead of tamoxifen, have been indicated as standard endocrine therapy since 2002, and 58% of patients over 50 years of age received aromatase inhibitors between 2002 and 2006 (Table 6). In addition, anthracyclines and taxanes have been indicated as standard chemotherapy for high-risk patients since 2002, although oral 5-fluorouracil derivatives were frequently administered for 2 years as adjuvant chemotherapy during 1980s and 1990s (Tables 5 and 6). Kaplan–Meier analysis showed that tumor size (Figure 3A– D) and lymph node status (Figure 4A–D) were strongly associated with disease-free and overall survival in both age groups. Tumor grade was significantly correlated with diseasefree and overall survival in women aged 50 years or younger (Figure 5A and B), whereas no association was observed between grade and survival in women over 50 years of age
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Table 4. Clinicopathological characteristics of patients and tumors in ER-positive, HER2-negative breast cancer between 1982 and 2006 Total, n (%) Number of patients 845 Age (mean 6 standard 56.8 6 13.3 deviation) Periods 1982–1991 127 (15.0) 1992–2001 308 (36.5) 2002–2006 410 (48.5) Tumor size (cm) £2 438 (51.8) 2–5 363 (43.0) >5 44 (5.2) Number of positive lymph nodes 0 466 (62.9) 1–3 178 (24.0) ‡4 97 (13.1) Tumor grade 1 248 (34.3) 2 370 (51.2) 3 105 (14.5) Progesterone receptor Positive 726 (86.6) Negative 112 (13.4)
£50 years, n (%)
>50 years, n (%)
331 43.7 6 5.1
514 65.3 6 9.5
46 (13.9) 113 (34.1) 172 (52.0)
81 (15.8) 195 (37.9) 238 (46.3)
158 (47.7) 146 (44.1) 27 (8.2)
280 (54.5) 217 (42.2) 17 (3.3)
184 (58.4) 85 (27.0) 46 (14.6)
282 (66.2) 93 (21.8) 51 (12.0)
104 (35.9) 149 (51.4) 37 (12.7)
144 (33.3) 221 (51.0) 68 (15.7)
314 (94.9) 17 (5.1)
412 (81.3) 95 (18.7)
Table 5. Adjuvant therapy in ER-positive, HER2-negative breast cancer in women aged 50 years or younger 1982–1991, n (%) Number of patients None Endocrine therapy alone Chemotherapy alone Combined Endocrine therapy None TAM alone LHRH agonist alone LHRH agonist + TAM AI TAM 2 AI Chemotherapy None Oral 5FU CMF Anthracyclins Taxanes Anthracyclins + taxanes
46 9 18 4 15
(19.6) (39.1) (8.7) (32.6)
1992–2001, n (%) 113 15 (13.3) 40 (35.4) 13 (11.5) 45 (39.8)
13 (28.3) 33 (71.7) 0 0 0 0
28 55 4 22 0 4
(24.8) (48.7) (3.5) (19.5)
27 (58.7) 18 (39.1) 0 1 (2.2) 0 0
55 35 11 7 5 0
(48.7) (31.0) (9.7) (6.2) (4.4)
(3.5)
2002–2006, n (%) 172 10 99 4 59
(5.8) (57.6) (2.3) (34.3)
14 26 4 113 14 1
(8.1) (15.1) (2.3) (65.7) (8.1) (0.6)
108 0 6 32 1 25
(62.8) (3.5) (18.6) (0.6) (14.5)
LHRH agonist, luteinizing hormone-releasing hormone agonist for a minimum of 2 years; tamoxifen (TAM) 2 aromatase inhibitors (AI), tamoxifen for 2–3 years followed by aromatase inhibitors for 3–2 years; 5FU, 5-fluorouracil derivatives for 2 years; CMF, cyclophosphamide, methotrexate, and fluorouracil; anthracyclins, AC (doxorubicin and cyclophosphamide), or FEC (fluorouracil, epirubocin, and cyclophosphamide); taxanes, docetaxel, or paclitaxel.
this younger age group. Multivariate analysis revealed that tumor size (P = 0.0007) and lymph node status (P < 0.0001) were prognostic factors for improved disease-free survival in women aged 50 years or younger. In women over 50 years of age, lymph node status (P < 0.0001) was the only prognostic factor for improved disease-free survival in multivariate analyses, although a significant association was found between disease-free survival and tumor size (P = 0.0006) and lymph node status (P < 0.0001) in univariate analysis.
discussion
Figure 2. Disease-free (A and C) and overall (B and D) survivals according to the three study periods in estrogen receptor-positive, HER2negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
(Figure 5C and D). Univariate analysis demonstrated that significant association between disease-free survival and tumor size (P < 0.0001), lymph node status (P < 0.0001) and tumor grade (P = 0.0031) was found in women aged 50 years or younger (Table 7). However, there was no association between disease-free survival and expression scores of ER and PgR in
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In this study, we have shown that the recent notable increase of breast cancer incidence is mostly due an increase in the ERpositive subtype, especially in women aged 50 years or younger. The Japanese Breast Cancer Society reported that, in Japan in 2006, there were 4899 women (81.1%) with ER-positive tumors among 6043 registered breast cancer patients under 50 years of age, and 10 152 women (73.3%) with ER-positive tumors among 13 783 registered breast cancer patients aged ‡50 years (Breast Cancer Statistics in Japan, 2006, conducted by the Japanese Breast Cancer Society). Almost 50% of newly diagnosed breast cancer patients in Japan were registered in this registration system in 2006. Although the incidence rates of ERpositive tumors in Japan seem lower than those in our present study, it may be because of different methods used for the
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Table 6. Adjuvant therapy in ER-positive, HER2-negative breast cancer in women over 50 years of age
Number of patients None Endocrine therapy alone Chemotherapy alone Combined Endocrine therapy None TAM alone LHRH agonist alone LHRH agonist + TAM AI TAM 2 AI Chemotherapy None Oral 5FU CMF Anthracyclins Taxanes Anthracyclins + taxanes
1982–1991, n (%)
1992–2001, n (%)
2002–2006, n (%)
81 24 35 2 20
(29.6) (43.2) (2.5) (24.7)
195 31 124 3 37
(15.9) (63.6) (1.5) (19.0)
238 41 145 4 48
26 (32.1) 55 (67.9) 0 0 0 0
34 139 1 5 1 15
(17.4) (71.3) (0.5) (2.6) (0.5) (7.7)
45 27 0 9 138 19
(18.9) (11.3)
59 (72.8) 21 (25.9) 0 1 (1.2) 0 0
155 28 6 5 1 0
(79.5) (14.4) (3.1) (2.6) (0.5)
186 0 16 18 0 18
(78.2)
(17.2) (60.9) (1.7) (20.2)
(3.8) (58.0) (8.0)
(6.7) (7.6)
Figure 4 Disease-free (A and C) and overall (B and D) survivals according to number of positive lymph nodes in estrogen receptor-positive, HER2negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
(7.6)
LHRH agonist, luteinizing hormone-releasing hormone agonist for a minimum of 2 years; tamoxifen (TAM) – aromatase inhibitors (AI), tamoxifen for 2–3 years followed by aromatase inhibitors for 3–2 years; 5FU, 5-fluorouracil derivatives for 2 years; CMF, cyclophosphamide, methotrexate, and fluorouracil; anthracyclins, AC (doxorubicin and cyclophosphamide), or FEC (fluorouracil, epirubocin, and cyclophosphamide); taxanes, docetaxel, or paclitaxel.
Figure 5. Disease-free (A and C) and overall (B and D) survivals according to tumor grade in estrogen receptor-positive, HER2-negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
Figure 3. Disease-free (A and C) and overall (B and D) survivals according to tumor size in estrogen receptor-positive, HER2-negative breast cancer by age group (A and B, £50 years; C and D, >50 years).
assessment of ER status. We evaluated tumors with ‡1% positive cells as positive for ER or PgR [16], whereas in 2006 most hospitals in Japan assessed tumors with ‡10% positive cells as positive for ER or PgR.
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Not only the incidence rates but also the frequencies of molecular subtypes of breast cancer differ greatly among ethnic groups [19, 20]. Genome-wide association studies have identified genetic susceptibility loci, such as fibroblast growth factor receptor 2 for breast cancer by ER status [8]. We have previously identified that genetic polymorphisms of ER (ERa), CYP19A1, COMT and p53 genes frequently occur in ERpositive premenopausal breast cancer patients compared with those in patients with ER-negative tumors [21]. It is necessary to establish genetic factors for predicting the risk of ER-positive breast cancer. In addition to genetic factors, it has been suggested that a change in environmental factors might also be having a notable effect on the increase of breast cancer incidence. Iwasaki and et al. [3] from the Japan Public Health
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Table 7. Univariate and multivariate analysis of factors predicting disease-free survival in ER-positive, HER2-negative breast cancer Factor £50 years Tumor size (£2, 2–5, >5 cm) Lymph node status (0, 1–3, ‡4) Tumor grade (1, 2, 3) ER (score) PgR (score) >50 years Tumor size (£ 2, 2–5, >5 cm) Lymph node status (0, 1–3, ‡4) Tumor grade (1, 2, 3) ER (score) PgR (score)
Univariate RR
95% CI
P
Multivariate RR
95% CI
P
2.34 3.13 1.84 0.94 0.94
1.63–3.35 2.31–4.25 1.23–2.74 0.79–1.11 0.83–1.06
<0.0001* <0.0001* 0.0031* 0.47 0.30
2.09 2.80 1.33
1.37–3.21 2.00–3.92 0.90–1.97
0.0007* <0.0001* 0.15
2.05 2.86 1.35 0.86 1.01
1.36–3.07 2.09–3.93 0.98–2.02 0.72–1.04 0.91–1.11
0.0006* <0.0001* 0.15 0.11 0.92
1.31 2.68
0.83–2.08 1.91–3.75
0.25 <0.0001*
*P < 0.05 is considered significant. RR, relative risk; CI, confidence interval; ER, estrogen receptor; PgR, progesterone receptor.
Center-Based Prospective Study reported that early age at menarche for premenopausal women, late age at natural menopause for postmenopausal women, and nulliparity and low parity for both premenopausal and postmenopausal women were significantly associated with an increased risk of breast cancer. The Life Span Study of the Radiation Effects Research Foundation in Hiroshima and Nagasaki showed an inverse association between the number of births and total period of breastfeeding and breast cancer risk [22]. Because the total fertility rate has been gradually decreasing since the 1970s in Japan, this decreased fertility might be one possible explanation for the increased incidence of breast cancer. Furthermore, increasing height, good nutrition, and a Westernized dietary life are all trends observed in Japan during the past two decades. Thus, changing lifestyles might increase breast cancer risk, especially in premenopausal Japanese women. We demonstrated that the frequencies of both ER+/PgR+ and ER+/HER22 tumors were significantly higher in women 50 years or younger than in women over 50 years of age between 2002 and 2010. Moreover, the expression levels of PgR were notably different in the ER-positive, HER2-negative subtype between the two age groups; most tumors showed high PgR expression scores in women 50 years or younger, whereas the distribution of PgR scores was similar in women over 50 years of age. We, and others previously, have reported that expression levels of PgR did not affect response to aromatase inhibitors given as primary endocrine therapy, although expression levels of PgR decreased in posttreatment tumors compared with the levels in pretreatment specimens regardless of the treatment response [23–25]. In contrast, it was recently identified that expression levels of ER and PgR were predictive for prognosis in postmenopausal patients who were treated with adjuvant endocrine therapy [26, 27]. Our present study demonstrated that expression levels of ER and PgR were strongly and negatively correlated with tumor grade in ERpositive, HER2-negative breast cancer. However, expression levels of neither ER nor PgR were not associated with disease-
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free survival in either age group, although tumor grade was significantly correlated with disease-free and overall survival in women 50 years or younger. Finally, we demonstrated that adjuvant therapies, both endocrine and chemotherapies, have been changed dramatically over the past two decades, and that prognosis in ER-positive, HER2-negative breast cancer has improved over time in both age groups. On the other hand, lymph node status and tumor size were strong prognostic factors regardless of the biological characteristics of the tumors. Recent meta-analysis of outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen indicated that aromatase inhibitors significantly lower recurrence rates compared with tamoxifen [28]. Furthermore, a TransATAC study showed that the risk of distant recurrence was higher for node-positive than node-negative patients and for patients with ‡4 positive nodes than patients with one to three positive nodes, regardless of recurrence scores [29]. It is considered that the characteristics of ER-positive, HER2-negative breast cancer are heterogeneous, and that standard chemotherapy does not improve prognosis for patients with highly endocrine responsive tumors, such as high levels of ER and PgR, low proliferation and low tumor grade [30]. It is necessary to establish new approaches for improving survival for node-positive, ER-positive breast cancer. In conclusion, the present study indicates that the recent notable increase of Japanese breast cancer incidence is mostly due to an increase in the ER-positive subtype, especially in women aged 50 years or younger. Moreover, prognosis in ERpositive, HER2-negative breast cancer has improved significantly over time due to advances in adjuvant therapies. It is necessary to establish risk factors, both genetic and environmental, capable of predicting the risk of ER-positive breast cancer and thus enable the efficient selection of candidates for hormone receptor-targeted chemoprevention. Furthermore, investigation of risk factors could lead to the identification of the mechanisms concerned in the development of ER-positive breast cancer.
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Annals of Oncology
funding The study had no sponsor or funding source.
disclosure The authors have declared no conflict of interest.
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