© 2004 Foundation for Promotion of Cancer Research
Improvement in the Prognosis of Japanese Breast Cancer Patients from 1946 to 2001—an Institutional Review
1 Department of Breast Surgery, 2 Department of Medical Oncology, 3 Department of Radiation Oncology and 4 Department of Breast Pathology, Cancer Institute Hospital, Tokyo, Japan
For reprints and all correspondence: Masataka Yoshimoto, Department of Breast Surgery, Cancer Institute Hospital, Kami-Ikebukuro 1-37-1, Toshima-ku, Tokyo 170-8455, Japan. E-mail: myoshimoto{at}jfcr.or.jp
Received February 21, 2004; accepted May 30, 2004
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Abstract |
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Background: Breast cancer has emerged as one of the most frequent malignancies among Japanese women; however, the long-term survival of Japanese breast cancer patients is uncertain.
Methods: We analyzed the chronological changes in the clinical and pathological characteristics, treatment procedures and the long-term prognosis of 15 416 Japanese women with 16 217 primary breast cancers treated in the Cancer Institute Hospital in Tokyo between 1946 and 2001.
Results: Our analysis revealed a chronological increase in the mean patient age, postmenopausal patients and non-invasive carcinomas. Operative procedures became less extensive, with approximately 45% of breast cancer patients in 2000–2001 receiving breast-conserving treatment. Radiotherapy to the regional lymph nodes decreased, while postoperative chemotherapy and hormonal treatments have become more frequent. The survival rate has improved steadily during the past 5 decades. The 10-year crude overall survival rate improved from 61% before 1960 to 83% in the 1990s.
Conclusions: The survival rate of Japanese women with breast cancer has dramatically improved during the past 5 decades.
Key Words: breast cancer • chronological change • survival • Japanese
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INTRODUCTION |
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Although Japan has one of the lowest breast cancer incidence rates in the world, recent increase in the incidence rate has made breast cancer one of the most frequent malignancies among Japanese women (1). The age-adjusted death rate due to breast cancer in Japan has increased (1), in contrast to the recent continuous reduction in breast cancer death rates in many developed countries (2–6). The effect of breast cancer screening programs and improvements in surgical procedures, chemotherapy and hormonal treatments on the long-term survival of Japanese breast cancer patients is unknown. This paper describes long-term chronological changes in Japanese breast cancer characteristics and therapeutic results from 1946 to 2001.
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SUBJECTS AND METHODS |
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PATIENTS
Data were obtained from the breast cancer database of the Cancer Institute Hospital in Tokyo. This database contains information regarding over 17 000 breast cancer patients from 1946 to the present. The database was designed according to the guideline laid down by the Japanese Breast Cancer Society and includes data regarding individual medical history, menstrual and pregnancy history, family history, breast cancer status and diagnosis, operative procedures, pathological records, biological markers, adjuvant treatment records, recurrence and survival. The recurrence and survival data were updated every year on the basis of the clinical follow-up examinations. In addition, information regarding patients with unknown prognoses was obtained every 5 years from the family register and death certificates, if necessary. The database includes all patients with breast cancer who were admitted to the Cancer Institute Hospital and had breast cancer surgery. Patients who underwent chemotherapy without surgery due to inoperable advanced breast cancer were not included in the database. Patients who underwent local excision in an outpatient clinic and were not admitted to the hospital because of a non-invasive breast cancer or a minimal invasive breast cancer before 1987, were not included in the database. However, the number of patients not included in the analysis is very small, compared to the total number of analyzed patients.
Although there were only three cases of primary breast cancer in 1946, the number of primary breast cancer patients has steadily increased. Almost 800 primary breast cancer patients were treated in 2001 (Fig. 1). From 1946 to 2001, we treated 15 523 patients with 16 326 primary breast cancers. The figures include 53 breast cancers in 51 male patients and 56 breast cancers in 56 non-Japanese patients. In the following analysis, male breast cancer patients and non-Japanese patients were excluded, and the data of 16 217 breast cancers in 15 416 Japanese women was reviewed. Among them, there were 801 bilateral breast cancers, of which 260 were simultaneous and 541 were heterogeneous.
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Our review encompasses chronological changes in clinical and pathological characteristics (age, menopausal status, clinical stage, lymph node involvement and histology), treatments (surgical procedures, radiotherapy, hormonal therapy and chemotherapy) and prognosis.
Clinical and pathological characteristics and surgical procedures were reviewed in 16 217 breast cancers, and therapeutic procedures (excluding surgical procedures) and therapeutic results were reviewed in 15 416 Japanese women with breast cancer. Survival times were calculated from the day on which first mastectomy was performed for breast cancer. Patients were grouped into six time periods: (1) 1946 to 1959, (2) 1960 to 1969, (3) 1970 to 1979, (4) 1980 to 1989, (5) 1990 to 1999 and (6) 2000 to 2001, and chronological changes were reviewed.
Data was adjusted according to the guidelines laid down by the Japanese Breast Cancer Society (14th Edition) for clinical and pathological recording of breast cancer (7). Regarding the histological classification, infiltrating carcinoma was classified into common and special types, and the former was classified into three subtypes: papillotubular carcinoma, solid-tubular carcinoma and scirrhous carcinoma. Papillotubular carcinoma is characterized by the projection of papillae into spaces and includes cribriform and comedo patterns. Solid-tubular carcinoma is a solid tumor mass consisting of tubular or trabecular structures and reveals expansive growth. Scirrhous carcinoma is characterized by cancer nest or cells accompanied by marked fibrosis.
STATISTICAL METHODS
Survival curves after surgery were estimated by the Kaplan–Meier method to determine cumulative survival times. P-values of less than 0.05 in 
2 tests were considered statistically significant.
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RESULTS |
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AGE AND MENOPAUSAL STATUS
Chronological changes in the distribution of patient age and menopausal status at the time of surgery for the first breast cancer are shown in Fig. 2 and Table 1.
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The age of the patients ranged from 20 to 90 years. The mean age was 48.0 years in 1946–1959, 47.8 years in 1960–1969, 49.2 years in 1970–1979, 50.7 years in 1980–1989, 52.5 years in 1990–1999 and 53.9 years in 2000–2001. The median age was 47 years in 1946–1959, 46 years in 1960–1969, 47 years in 1970–1979, 49 years in 1980–1989, 51 years in 1990–1999 and 53 years in 2000–2001. The mean and median age at the time of surgery has gradually and significantly increased (P < 0.0001); however, the age still remains normally distributed.
The menopausal status of breast cancer patients has changed significantly. The percentage of postmenopausal breast cancer patients, including artificial menopause, has increased from 40.6% in 1946–1959 to 55.4% in 2000–2001 (P < 0.0001) (Table 1).
CLINICAL STAGE
Chronological changes in stage distributions, node involvement and histological types are shown in Table 2.
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The proportion of Tis (including Paget disease) breast cancers has consistently increased over several decades. However, the proportion of early-stage breast cancer (Tis + stage I), which accounts for approximately 40% of all breast cancers, has not largely changed from the 1980s. The proportions of stage II, stage III and stage IV breast cancers have also not largely changed from the 1980s. The lack of a breast cancer screening program of our own may explain these findings.
NODE INVOLVEMENT
Axillary lymph node dissection usually encompasses level 1, 2 and 3 in Halsted or extended operations, level 1 and/or level 2 and 3 in modified operations and level 1 in breast-conserving operations. The mean number of examined axillary lymph nodes was 12.7 in 1946–1959, 13.0 in 1960–1969, 15.2 in 1970–1979, 21.2 in 1980–1989, 25.1 in 1990–1999 and 19.4 in 2000–2001. The increase in the number of dissected nodes up to 1999, according to our impression, may be merely due to more precise search after surgery. The recent decrease in the number of examined lymph nodes reflects the introduction of sentinel lymph node biopsy.
The percentage of node negative cases appears to have decreased from the 1980s (Table 2), but it is not actually the case. Since the great majority of the ‘not dissected’ cases were non-invasive carcinomas and minimal invasive breast cancers, the percentage of cases without lymph node involvement must have increased steadily even after the 1980s to over 60% of breast cancers in the 1990s and 2000s.
HISTOLOGY
The most important chronological change in histology was the increase in the percentage of non-invasive carcinomas (Table 2). The percentage of non-invasive carcinomas (including Paget's disease) has increased from 3.4% before 1959 to 13.5% in 2000–2001. Among invasive carcinomas, there has been a significant increase in solid-tubular carcinomas (P <0.0001) and a decrease in scirrhous carcinomas (P < 0.0001) (Table 2).
OPERATIVE PROCEDURES
Operative procedures for breast cancer have become less extensive over the past 5 decades (Fig. 3, Table 3). In 1974, pectoral muscle preserving modified radical mastectomies such as Patey's and Auchincloss's operations began to be performed. There was a rapid shift from radical mastectomies to modified radical mastectomies within several years. In 1986, breast-conserving surgery began to be performed. The number of patients receiving breast-conserving surgery has gradually increased. After 2000, 45% of the breast cancer patients had breast-conserving surgery (Fig. 3).
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Extensive operations are currently not performed, except for very rare cases. The number of parasternal and supraclavicular lymph node dissections and/or open biopsy has also reduced.
RADIOTHERAPY
Indications for postoperative radiotherapy have changed dramatically during the past 5 decades (Table 3). Prior to the advent of chemotherapy and hormonal treatments, radiotherapy was the only postoperative adjuvant treatment method. Before 1959, 82% of the patients received postoperative radiotherapy to the regional lymph nodes and/or chest wall. However, in the 1990s, only 1.6% of the patients received this type of radiotherapy. In 2000–2001, a slight increase was observed in the percentage of patients who received radiotherapy to the regional lymph nodes and chest wall, accompanied with recent worldwide re-evaluation.
Radiotherapy to the breast began to be performed after breast-conserving surgery was introduced. Since the indications for partial mastectomy have recently expanded considerably, there has been an increase in the percentage of patients who received radiotherapy to the conserved breast.
HORMONAL THERAPY
Before 1978, hormonal therapy was limited to surgical oophorectomy, adrenalectomy or radiation ablation of ovarian function that was performed in cases of advanced or inoperable breast cancer (Table 3). Tamoxifen was introduced in 1978 and was used extensively for hormone-receptor positive breast cancers. Aromatase inhibitors for postmenopausal patients and luteinizing hormone-releasing hormone (LH-RH) agonist for premenopausal patients were introduced in 1995 and 1997, respectively. Most patients who presently receive tamoxifen have taken it for 5 years or more. Almost all patients who receive LH-RH agonist also receive tamoxifen. Approximately 53% of breast cancer patients are currently treated with tamoxifen.
CHEMOTHERAPY
Mitomycin C (MMC) was introduced in clinical usage in 1959, cyclophosphamide (CPA) in 1961, 5-FU in 1969, L-phenylalanine mustard (L-PAM) in 1976, CMF (CPA, methotrexate and 5-FU) in 1978, CAF (CPA, doxorubicin and 5-FU) in 1978, docetaxel in 1997 and paclitaxel in 2001. Recently, over 40% of breast cancer patients have received postoperative adjuvant chemotherapy.
Adjuvant chemotherapy regimens have undergone a change from the old-fashioned single agent oral chemotherapy (5-fluorouracil (5-FU), cyclophosphamide (CPA) and/or L-phenylalanine mustard (L-PAM) tablets) to refined combination chemotherapy such as CMF or CAF (Table 3).
PROGNOSIS
Chronological changes in the crude overall survival curves by six-decade subgroups of 15 416 Japanese women with breast cancer from the day of first mastectomy are shown in Fig. 4. Survival curves have significantly improved in each decade. The 10-year cumulative overall survival rate was 61% in 1946–1959, 66% in 1960–1969, 72% in 1970–1979, 77% in 1980–1989, and 83% in 1990–1999. The improvement in survival in each decade was observed for both node-negative and node-positive patients. The 10-year cumulative overall survival rate for node-negative patients increased from 82% in 1946–1959 to 92% in 1990–1999. The 10-year cumulative overall survival rate for node-positive patients increased from 39% in 1946–1959 to 68% in 1990–1999.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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Although breast cancer continues to be a major cause of morbidity and mortality in women throughout the world, recent advancements in the diagnosis and treatment of breast cancer have vastly improved the prognosis in such patients (2,5,6). Peto et al. reported that breast cancer death rates in the United Kingdom and the United States started declining in the early 1990s (2). Decline in breast cancer death rates have also been reported in several countries (3–6). Researchers attribute this decline in breast cancer death rates to mammography screening programs that were implemented in the late 1980s (4,5) and to better treatments such as polychemotherapy regimens (e.g., CMF and CAF) and tamoxifen (3).
However, the age-adjusted death rate due to breast cancer among Japanese women has continued to rise until 2001 (1). The main reason for the rising breast cancer death rate in Japan is probably the rapid rise in the incidence rate of breast cancer in Japanese women, although the incidence rate is still much lower than that in Europe and the United States. The age-adjusted incidence rate of breast cancer in Japanese women has almost doubled during the past two decades (from 21.7 per 100 000 women in 1975 to 39.8 per 100 000 women in 1995) (1).
In this study, we examined the chronological changes in Japanese breast cancer characteristics and prognosis in a large series of patients. We found that the prognosis of Japanese breast cancer patients has steadily improved during the past 5 decades and that the 10-year overall survival rate after surgery has increased by approximately 5% each decade. Although several possible causes such as increased life expectancy of Japanese women could have partly contributed to the improved survival of breast cancer patients, we believe that the contribution of early breast cancer detection and improvements in chemotherapy and hormonal treatments has been the greatest.
In 2002, the breast cancer death rate per 100 000 Japanese women dropped to 14.9 from 15.0 (1) for the first time. The breast cancer death rate is expected to continue to decline in the next 10 years because of the advent of new anti-cancer drugs such as taxanes, herceptin and capecitabine, reliable evidence obtained from large-scale clinical trials (8,9) and vigorous breast cancer screening programs (4,5).
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Acknowledgments |
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We thank the physicians and staff of the Departments of Breast Surgery, Chemotherapy Treatment, Radiation Treatment, Cytology and Pathology. We thank the specialists and technical experts who utilize mammography, echography and cytology to detect breast cancer.
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References |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONReferences |
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1 Cancer Statistics in Japan—2001. Foundation for Promotion of Cancer Research.
2 Peto R, Boreham J, Clarke M, Davies C, Beral V. UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 2000;355:1822.[Web of Science][Medline]
3 Miller AB. Why is breast-cancer mortality declining? Lancet Oncol 2003;4:251–4.[CrossRef][Web of Science][Medline]
4 Otto SJ, Fracheboud J, Looman CW, Broeders MJ, Boer R, Hendriks JH, et al. Initiation of population-based mammography screening in Dutch municipalities and effect on breast-cancer mortality: a systemic review. Lancet 2003;361:1411–7.[CrossRef][Web of Science][Medline]
5 Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet 2002;361:1405–10.
6 Andersen LD, Remington P, Trentham-Dietz A, Reeves M. Assessing a decade of progress in cancer control. Oncologist 2002;7:200–4.
7 General Rules for Clinical and Pathological Recording of Breast Cancer. September 2000 (The 14th Edition), The Japanese Breast Cancer Society.
8 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet 1998;351:1451–67.[CrossRef][Web of Science][Medline]
9 Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomized trials. Lancet 1998;352:930–42.[CrossRef][Web of Science][Medline]
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