Japanese Journal of Clinical Oncology 33:61-67 (2003)
© 2003 Foundation for Promotion of Cancer Research
Long-term Results of Breast-conserving Treatment for Early-stage Breast Cancer in Japanese Women from Multicenter Investigation
1 National Shikoku Cancer Center, Matsuyama, 2 Cancer Institute, Tokyo, 3 Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka, 4 Osaka National Hospital, Osaka, 5 Saitama Cancer Center, Ina, Saitama, 6 Mitsui Memorial Hospital, Tokyo, 7 St. Luke’s International Hospital, Tokyo, 8 Gunma University, Maebashi, 9 Aichi Cancer Center Hospital, Nagoya, 10 Keio University, Tokyo, 11 Kure National Hospital, Kure, Hiroshima, 12 National Cancer Center Central Hospital, Tokyo, 13 University of Tokushima, Tokushima, 14 Niigata Cancer Center Hospital, Niigata, 15 Urayasu Hospital of Juntendo University School of Medicine, Urayasu, Chiba, 16 Fukuyama National Hospital, Fukuyama, Hiroshima, 17 Tokyo Women’s Medical University, Tokyo and 18 Sapporo National Hospital, Sapporo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Background: Although many clinical data regarding breast-conserving treatment have already been reported from European and North American countries, few clinical data with long-term follow-up have been reported from Japan.
Method: We collected information on therapeutic and possible or developed prognostic factors and follow-up data for Japanese women who had received breast-conserving treatment consisting of wide excision of the primary tumor, axillary dissection and radiotherapy for unilateral breast cancer considered suitable for breast-conserving treatment from 18 Japanese major breast cancer treating hospitals; 1561 patients were registered.
Results: The median follow-up period was 77 months. Five-year disease-free and overall survival rates were 89.4 and 95.9%, respectively. The 5-year local recurrence-free rate was 96.3%. The patients with histologically positive margins (P < 0.0001) or estrogen receptor negative tumor (P = 0.0340) or younger than 40 years old (P < 0.0001) developed statistically significantly more local recurrences. Adjuvant endocrine therapy was essential for the estrogen receptor positive patients to have a lower local recurrence rate. Endocrine therapy did not change the local recurrence rate among estrogen receptor negative patients at all. Multivariate analysis showed histological margin status and the combination of estrogen receptor status and endocrine therapy were independent prognostic factors for local recurrence.
Conclusion: The 5-year local recurrence rate of Japanese breast cancer patients who were treated with breast-conserving treatment using radiotherapy was 3.7%. Independent prognostic factors for local recurrence were histological margin status and the combination of estrogen receptor status and adjuvant endocrine therapy.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Many prospective randomized controlled trials (RCTs) have demonstrated that breast-conserving treatment with radiotherapy (BCT) provided survival identical with that after mastectomy. At present BCT is considered one of the standard primary therapies for patients with breast cancer at an early stage. The long-term results of BCT have already been reported from many institutions, mainly in North American and European countries. In contrast, Japanese surgeons had been very skeptical about BCT until the results of RCTs comparing BCT and mastectomy conducted in the Western countries were reported (1–6), and BCT was not performed in Japan until the early 1980s. BCT became established in Japan in July 1989 when the Japanese BCT Study Group (JBSG) was set up with the support of the Japanese Ministry of Health and Welfare. Now that more than 10 years have passed since the introduction of BCT in Japan, the JBSG has collected data on patients treated with BCT from the members of JBSG to determine the long-term results of BCT and prognostic and predictive factors for local recurrence (LR) in Japanese patients.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Questionnaire forms were sent to members of JBSG in April 2000 to collect data on patients treated with BCT. Women with a unilateral breast cancer 3 cm or smaller who had been treated with wide excision or quadrantectomy, axillary lymph node dissection and postoperative radiotherapy (RT) to the conserved breast between July 1989 and May 1995 were considered eligible. Patients who had received preoperative systemic treatment or radiotherapy and those with a past history of breast cancer were excluded. The members of JBSG were asked to present the data on all eligible patients treated primarily at their institutions when completing the questionnaire form.
The patients’ and tumor characteristics that were requested on the questionnaire form were as follows: age at operation, tumor size by palpation, pathological lymph node status, estrogen and progesterone receptor status, histological margin status and histological type of the primary tumor. The measurement methods and cutoff levels of the hormone receptors were not standardized, but dependent on each institution. The method of judgment of histological margin status was also not standardized. The day of the definitive surgery, dose of radiation to the whole breast, radiation boost, postoperative adjuvant systemic therapy [chemotherapy and/or endocrine therapy (ET)], patients’ current status of disease including subsequent contralateral breast cancer and survival and the day of the last follow-up or death were also requested. The acceptance of completed questionnaires was closed in September 2000.
LR was defined as the reappearance of the malignant tumor in the conserved breast. Recurrence appearing in the regional lymph nodes was not considered as LR. Disease-free and overall survival and LR-free and contralateral breast cancer free rates were measured from the day of the definitive surgery and calculated using the Kaplan–Meier method. LR was considered as an event in disease-free survival, but subsequent contralateral breast cancer was not counted as an event for it. Patients who had died without LR or contralateral breast cancer were censored at the day of death in LR free and contralateral breast cancer free rates. Death from any cause was considered as an event for disease-free and overall survival. The LR after regional and/or distant recurrence was considered as an event in LR free rate. The difference in LR free and contralateral breast cancer free rates and overall survival were analyzed with the log rank test statistically in univariate analyses. Multivariate analyses for LR free rate and overall survival were performed using Cox’s proportional hazards model including the variables that were statistically significant in univariate analyses. All the statistical analyses were performed with StatView 5.0 (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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The number of patients registered was 1561. The mean age was 49.1 years (range: 21–93 years). The mean of the largest diameters by palpation of the primary tumors was 1.69 cm (range: 0–8.5 cm). Twenty-two patients were ineligible because the tumor sizes were >3 cm and data on the tumor size were not obtained in an additional 41 patients. However, all of them were included in the subsequent analyses if their follow-up data were obtained. Of the patients, 1191 (76.3%) were pathologically node negative and 354 (22.7%) were positive. Pathological lymph node status was not obtained in 16 cases (1.0%). The mean number of lymph nodes dissected was 13.8 (range: 0–50). In 26 patients the reported number of dissected lymph nodes was nil; those patients were regarded as node negative. The mean number of lymph nodes with metastases was 0.55 (range: 0–29). Of the patients, 1267 had invasive ductal carcinoma (81.2%), 76 had ductal carcinoma in situ (DCIS) (4.9%) and only 18 (1.2%) had invasive lobular carcinoma; 97 patients (6.2%) had tumors of other histological types. Estrogen receptor (ER) was positive in 671 cases (43.0%) and negative in 457 (29.3%). Progesterone receptor (PgR) was positive in 548 cases (35.1%) and negative in 410 (26.3%). Histological margins were positive in 297 cases (19.0%) and negative in 1223 (78.3%) (Table 1). The radiation dose to the whole breast was 50 Gy or more in 731 cases (46.8%) and <50 Gy in 472 cases (30.2%). The mean and median doses to the whole breast were 48.6 and 50 Gy, respectively. A boost to the tumor bed was received by 308 patients (19.7%). Postoperative adjuvant chemotherapy was received by 435 cases. Almost half of them (210 cases) received oral fluorouracil or its derivatives, 145 cases had a combination of cyclophosphamide, methotrexate and fluorouracil and only 12 had anthracycline-containing combination chemotherapy. Postoperative adjuvant ET was given to 923 patients (59.1%) (Table 2). It was not possible to specify what agents were used because the questionnaire did not ask specifically for the agents used in the ET. However, the agent used was believed to be tamoxifen because Japanese patients with breast cancer were given only tamoxifen as adjuvant ET before 1995.
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Among the registered 1561 cases, follow-up data regarding survival were not obtained in eight cases. All the analyses regarding clinical outcome were performed thereafter excluding these eight cases. Status of LR was not reported in 42 cases of the remaining 1553 cases (three cases were reported as unknown and data were not given in 39 cases.). Thirty-four cases out of 42 had developed recurrence at site(s) other than the conserved breast. These 42 cases were censored at the day of the last follow-up or death in the analysis of LR free rate. Information on subsequent contralateral breast cancer was not given in 405 cases out of 1553 (six cases were reported as unknown and data were not given in 399 cases); 44 of these cases had developed recurrence. These 405 were censored in the same fashion as the LR in the analysis of contralateral breast cancer free rate. Another five cases out of 1553 with follow-up data regarding survival were reported to have had contralateral breast cancer before the breast-conserving treatment. All the five cases had not developed distant metastasis. These cases were included in the analyses of disease-free and overall survival and LR free rate, but not of contralateral breast cancer free rate.
The median follow-up period of the 1553 cases with follow-up data was 77 months (range: 1–133 months): 191 patients (12.3%) developed recurrences; 77 cases (5.0%) had LRs; 85 cases (5.5%) were dead at the time of data collection, among whom 67 had died of breast cancer. The 5- and 7-year disease-free survival rates were 89.4 and 86.0%, respectively (Fig. 1). The corresponding overall survival rates were 95.9 and 94.4%, respectively (Fig. 2), and the corresponding LR free rates were 96.3 and 94.6%, respectively (Fig. 3).
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The results of univariate analyses using the log rank test in terms of LR are shown in Table 3. Age at operation (<40 vs
40 years P < 0.0001), ER status (positive vs negative, P = 0.0340) and histological margin status (negative vs positive, P < 0.0001) were statistically significantly associated with LR, whereas tumor size, systemic adjuvant treatments, PgR status and a boost to the tumor bed were not significantly associated with LR. However, pathological lymph node status (negative vs positive, P = 0.0683) and radiation boost to the tumor bed in the cases with positive histological margins (performed vs not performed, P = 0.0788) (data not shown in Table 3) were marginally associated with LR. On the other hand, adjuvant ET was associated with a reduced risk of LR only in the patients with hormone receptor positive tumors. Namely, among ER-positive patients the 5-year LR free rate was 98.9% for patients with ET and 94.8% for patients without ET (P = 0.0004) (Fig. 4A). ET did not reduce the LR rate in those with ER-negative tumors (Fig. 4B) and the LR rate of ER-negative patients was identical with that of ER-positive patients without ET (P = 0.7655). Therefore, ER was considered as a pure predictive factor for an effect of ET on LR but not a prognostic factor.
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Multivariate analysis including age at operation, histological margin status and the combination of ER status and ET revealed that the last two variables were independent prognostic factors for LR [margin negative versus positive: hazard ratio (HR) = 2.387, 95% confidence interval (CI) 1.318–4.310, P = 0.004, ER-positive and treated with ET versus ER-negative or not treated with ET: HR = 3.876, 95% CI 1.733–8.696, P = 0.001] and age was marginally significant (
40 vs <40 years: HR = 1.942, 95% CI 0.989–3.817, P = 0.054) (Table 4).
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The analyses regarding LR were performed also after excluding the 42 cases without data on LR. The results were essentially the same as those described above except that the 5-year LR rate became 3.8% and age at operation became statistically significant even on multivariate analysis (
40 vs <40 years: HR = 2.009, 95% CI 1.023–3.946, P = 0.043). Thirty-seven contralateral breast cancers were observed subsequently. Postoperative ET reduced contralateral tumors statistically significantly (5-year contralateral breast cancer free rate: 99.2% for ET vs 97.3% for no ET, P = 0.006) but chemotherapy did not. When the 405 cases without data on subsequent contralateral breast cancer were excluded from the analysis, the statistical significance of ET disappeared (5-year contralateral breast cancer free rate: 98.8% for ET vs 96.9% for no ET, P = 0.079).
We analyzed the data on overall survival to identify prognostic factors. The results of univariate analyses are shown in Table 3. A statistically significant difference was observed in tumor size (P = 0.0017), ER and PgR status (P = 0.0018 and < 0.0001, respectively), lymph node status (P < 0.0001) and adjuvant chemotherapy (P = 0.0108). Interestingly, adjuvant chemotherapy was negatively associated with overall survival, probably because the patients with more advanced disease tended to have adjuvant chemotherapy. On multivariate analysis only tumor size, lymph node status and ER status were included because ER and PgR status are strongly correlated mutually and adjuvant chemotherapy tended to be performed in patients with more advanced disease, namely a larger tumor and/or positive nodes. As shown in Table 5, all the three variables were demonstrated to be independent prognostic factors for overall survival.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Although BCT consisting of partial mastectomy, axillary dissection and RT is now regarded as one of the standard treatments for patients with early-stage breast cancer based on the evidence obtained by several RCTs, in European and North American countries BCT was started before the publication of the results of the RCTs mentioned above (1–6). Therefore, many clinical data regarding BCT had already reported been from those countries. On the other hand, in Japan BCT was started only after the data on RCTs comparing BCT and mastectomy were reported. Therefore, few long-term results of BCT have been reported from Japan. We intended to clarify the long-term clinical results of BCT and determine prognostic factors for LR in Japanese patients with early-stage breast cancer.
In this series, the 5-year LR free rate was 96.3%. On the other hand, the 5-year LR free rate has been reported to be 90–93% in European and North American countries (7–11). This seems to be higher than that in the present study. A possible explanation is the difference in the volume of the excised breast tissue. Although most Japanese surgeons excised the tumor with surrounding macroscopically normal breast tissue of width 2 cm, the volume of the tissue excised in European and North American hospitals was thought to be much smaller according to their reports. Another explanation is the difference in frequency of use of adjuvant systemic therapies: adjuvant systemic therapies were not performed as frequently in those hospitals as in the Japanese hospitals in the present study because the patients in the present study were treated more recently. Actually, a more recent report from the USA showed a very low LR rate (12). On the other hand, it is known that the prognosis of Japanese patients with breast cancer is better than that of Caucasian patients generally (13). There is a possibility that the rates of LR might be truly different between Japanese and Caucasian patients.
The present study revealed three prognostic factors for LR, namely histological margin status, age at operation and the combination of ER status and postoperative ET. The first two factors are well known prognostic factors for LR after BCT (7,12,14–16). It is plausible that the positive histological margins indicate a high possibility of the existence of tumor cells in the conserved breast. On the other hand, the reasons for the higher incidence of LR in younger patients are still not well understood, although Kurtz et al. reported a higher incidence of major stromal reaction, histological grade 3 and very extensive DCIS in younger patients (17). Tamoxifen is known to reduce the incidence of LR according to the results of an NSABP B-14 trial (18). In that study the incidence of recurrence in the ipsilateral breast was reduced from 14.7 to 4.3% at 10 years by administration of tamoxifen in ER-positive and node-negative patients. However, it is not known whether tamoxifen is effective in reducing LR of patients with an ER-negative tumor. After Inaji et al. (19) and Yamakawa et al. (20) reported higher expression rates of pS2 protein, which is associated with ER expression, in the intraductal component of invasive breast cancer than in the invasive component, many Japanese doctors administered tamoxifen to patients treated conservatively to reduce LR even if the invasive component did not have hormone receptors. The NASBP B-23 trial is a trial in which the effect of tamoxifen was evaluated in patients with an ER-negative tumor in the adjuvant setting (21). Although its results were expected to provide an answer to the issue, the LR rate of the control arm (the no tamoxifen arm) was too low to evaluate the effect of tamoxifen on LR. However, tamoxifen did not appear to affect LR according to the data of NSABP-B23. The present study suggests that tamoxifen is not effective at all in the ER-negative population in terms of LR. Also, the LR rate of ER-positive patients who were not treated with tamoxifen was identical with that of ER-negative patients regardless of tamoxifen administration. Therefore, ER is thought to be a pure predictive factor of tamoxifen in the effect of prevention of LR and not a prognostic factor. However, since the present study is a retrospective one, this result must be confirmed in large prospective studies.
The present study also evaluated the effect of tamoxifen on contralateral breast cancer and confirmed the published results, namely that tamoxifen reduces the incidence of contralateral breast cancer. The 1998 Oxford overview showed that longer durations of tamoxifen administration are associated with a greater reduction in the risk of contralateral tumors (22). In the present study, the questionnaire did not ask about the duration of tamoxifen. However, tamoxifen was usually administered for 1 or 2 years before 1995 in Japan. The percentage reduction of contralateral cancer in the present study was much larger than those of 1 or 2 years of tamoxifen in the Oxford overview, which were 13 and 26%, respectively. The difference might be explained by chance, but there might be some unknown reasons.
We analyzed the survival data to identify prognostic factors. Multivariate analysis revealed that the conventional prognostic factors, which were tumor size, lymph node status and ER status, were statistically significant. These factors were not necessarily prognostic for LR. This finding has already been reported by other investigators (12). It is well known that the survival of patients who develop LR is worse than that of patients without LR (23). However, it is still not well understood whether LR is a cause of distant metastasis, although Fisher et al. regarded LR as a marker of risk of distant metastasis, not a cause (24). One of the reasons for the difference in survival between the two patient groups might be the existence of common prognostic and/or predictive factors between overall survival and LR free rate, e.g. ER status.
In conclusion, the 5-year LR rate of Japanese breast cancer patients who were treated with BCT using RT was 3.7%. Independent prognostic factors for LR were the combination of ER status and adjuvant ET and histological margin status.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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This study was supported by a Grant-in-Aid for research of cancer treatment from the Ministry of Health, Labor and Welfare of Japan (No. 13–10).
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FOOTNOTES |
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+ For reprints and all correspondence: Shozo Ohsumi, Department of Surgery, National Shikoku Cancer Center, 13 Hori-no-uchi, Matsuyama, Ehime 790-0007, Japan. E-mail: sosumi@shikoku-cc.go.jp
Abbreviations: RCT, prospective randomized controlled trial; BCT, breast-conserving treatment; JBSG, Japanese BCT Study Group; LR, local recurrence; RT, radiotherapy; ET, endocrine therapy; DCIS, ductal carcinoma in situ; ER, estrogen receptor; PgR, progesterone receptor; HR, hazard ratio; CI, confidence interval
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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1 Blichert-Toft M, Rose C, Andersen JA, Overgaard M, Axelsson CK, Andersen KW, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group. J Natl Cancer Inst Monogr 1992;11:19–25.[Medline]
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17 Kurtz JM, Jacquemier J, Amalric R, Brandone H, Ayme Y, Hans D, et al. Why are local recurrences after breast-conserving therapy more frequent in younger patients? J Clin Oncol 1990;8:591–8.[Abstract]
18 Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996;88:1529–42.
19 Inaji H, Koyama H, Motomura K, Noguchi S, Tsuji N, Wada A. Immunohistochemical survey of pS2 expression in intraductal lesions associated with invasive ductal carcinoma of the breast. Int J Cancer 1993;55:883–6.[Web of Science][Medline]
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21 Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol 2001;19:931–42.
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Received July 5, 2002; accepted November 13, 2002
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