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Originally published as JCO Early Release 10.1200/JCO.2006.10.3754 on May 21 2007 © 2007 American Society of Clinical Oncology. Poor Outcome of Hormone Receptor–Positive Breast Cancer at Very Young Age Is Due to Tamoxifen Resistance: Nationwide Survival Data in Korea—A Report From the Korean Breast Cancer Society
From the Department of Surgery, College of Medicine, University of Ulsan and Asan Medical Center; Department of Surgery, Yonsei University College of Medicine; Department of Surgery, Sungkyunkwan University School of Medicine; Department of Surgery, Seoul National University College of Medicine, Seoul; and the Center for Breast Cancer Research Institute and Hospital, National Cancer Center, Goyang-si, Korea Address reprint requests to Wonshik Han, MD, Department of Surgery, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul, Korea; e-mail: hanw{at}snu.ac.kr
Purpose: Breast cancer in very young women (age < 35 years) is uncommon and poorly understood. We sought to evaluate the prognosis and treatment response of these patients compared with women ages 35 to 50 years.
Patients and Methods: We analyzed data from 9,885 breast cancer patients age Results: One thousand four hundred forty-four patients (14.6%) were younger than age 35 and 8,441 (85.4%) patients were between 35 and 50 years of age. Younger patients had significantly higher T-stage and higher lymph node positivity and lower hormone receptor expression than older patients. Younger patients had a greater probability of death than older patients, regardless of tumor size or lymph node status. The survival difference was significant for patients with positive or unknown hormone receptor status (P < .0001), but not for patients with negative hormone receptor status. In a multivariate analysis, the interaction term of young age and hormone receptor positivity was significant for OS and BCSS with a hazard ratio for OS of 2.13 (95% CI, 1.52 to 2.98). The significant survival benefit from adjuvant hormone therapy after chemotherapy observed in older patients (hazard ratio for OS, 0.61; 95% CI, 0.47 to 0.79; P = .001) could not be seen in younger patients (P > .05). Conclusion: Younger patients (age < 35) showed worse prognosis than older patients (age, 35 to 50 years) only in the hormone receptor–unknown or hormone receptor–positive subgroups. Adjuvant tamoxifen therapy might provide less survival benefit when added to chemotherapy in very young breast cancer patients.
Breast cancer is uncommon in women younger than 35 years of age, with this group accounting for fewer than 4% of the total number of breast cancer cases diagnosed in Western countries.1,2 In Asian breast cancer patients, the proportion of patients in this age group was reported to be much higher, at up to 9.5% to 12%.3 Women younger than 35 years with breast cancer face some specific problems that are less relevant for older premenopausal patients, including the late effects of radiation therapy, pregnancy after breast cancer, and interpersonal, family, and professional relations.4 Hence, special consideration should be given to patients in this age group. However, the biology, outcome, and response to adjuvant therapy of the disease in patients of this age group remain controversial with few well-designed studies investigating this minority group of women. Although there have been conflicting results, many studies have shown that young breast cancer patients have worse outcomes compared with older premenopausal or postmenopausal patients.3,5-9 A population-based retrospective study showed that young women who did not receive adjuvant chemotherapy had a significantly increased risk of dying, and the risk increased with younger age at diagnosis.10 In an analysis of 3,700 premenopausal patients involved in International Breast Cancer Study Group trials,11 younger patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy alone had an increased risk of relapse and death than older patients, especially if their tumors expressed estrogen receptors (ERs). Another large analysis on 7,631 patients who were treated with chemotherapy alone showed markedly increased risks of relapse for young patients with ER–positive tumors compared with older patients.4 Therefore, it has been proposed that the endocrine effects of chemotherapy alone are insufficient for young women with ER–positive breast cancer. As yet, however, there is limited evidence that young breast cancer patients gain a survival benefit from adjuvant tamoxifen after chemotherapy. The purpose of our study was to examine whether breast cancer in very young patients is associated with worse outcomes than in older patients using nationwide data from the Korean Breast Cancer Society registry and national death statistics. The most common limitations of previous studies were the small numbers of young patients enrolled and, although showing differences in recurrence-free survival, an inability to detect overall survival differences. In a subgroup analysis, we sought to determine whether the survival difference between age groups is only in ER–positive breast cancers, as indicated by previous data,4,11,12 and moreover, whether young patients with hormone receptor–positive breast cancers benefit from tamoxifen treatment after chemotherapy.
Breast Cancer Registry The Korean Breast Cancer Society has prospectively collected breast cancer data since 1996. Nationwide, 102 general hospitals with at least 400 beds, including 41 university hospitals and 61 surgical training hospitals, have voluntarily participated in this program.13 From 2001, the Online Korean Breast Cancer Registration Program was launched, so physicians from each participating hospital could input the data into the web-based database themselves. Newly diagnosed biopsy-proven primary breast cancer patients from individual hospitals were recruited. Retrospective data collection back to 1992 was also allowed in case a participating hospital had its own breast cancer database before 1996 and the private database contained all the essential items for this registry described herein. Before the online system, all data were sent from individual hospitals in the form of a recorded cancer registration sheet. Essential items were the patients' unique Korean resident's registration number as identifier, sex, age, surgical method used, and cancer stage based on the American Joint Committee on Cancer classification. For patients diagnosed before 2002, stages were uniformly adjusted according to the fifth edition of American Joint Committee on Cancer staging. Optional items were symptoms and signs, operative and histopathologic findings, laboratory and image findings, biologic markers (such as expression of ER, progesterone receptor [PgR], and human epidermal growth factor receptor 2 [HER2]), and adjuvant treatment (such as radiation therapy, hormone therapy, and chemotherapy). This registry is estimated to include about 35.2% of all newly developed breast cancer patients in Korea between 1992 and 2001.
Patients and Follow-Up
Hormone Receptors and Hormone Therapies
Statistical Analysis
Patient Characteristics Of the 9,885 patients analyzed, 1,444 (14.6%) were younger than 35 years, and 8,441 (85.4%) were between 35 and 50 years. The age distributions of patients in each group are presented in Table 1. The group of younger patients (age < 35 years) had tumors classed as higher T stage (T1 v  T2) and had higher lymph node positivity than older patients (both P < .001). The younger group also had significantly lower ER (P = .002) and PgR expression (P < .001). The proportion of patients who underwent breast conservation surgery was greater for the younger group (P = .011). Adjuvant chemotherapy and hormone therapy data were available for 6,248 (63.2%) and 5,567 patients (56.3%), respectively. The proportion of patients who received adjuvant chemotherapy was greater in the younger group than in the older group (P = .039). The proportion of patients who received adjuvant hormone therapy was greater in the older group than in the younger group (P < .001; Table 1). There was no difference in the ratio of use of toremifene to tamoxifen between the younger and the older age group (data not shown).
Univariate Survival Analyses: Younger (age < 35 years) Versus Older (age 35 years) Age GroupThe median follow-up for this cohort of patients was 63.3 months. The 5-year overall survival rate was 81.5% for younger patients and 89.4% for older patients (log-rank P < .0001; Fig 1A). The 5-year BCSS was 83.0% for younger patients and 90.2% for older patients (P < .0001; Fig 2A). When we analyzed the patient groups according to hormone receptor status, the younger group showed worse overall survival than the older group if hormone receptor status was positive or unknown (P < .0001). The hazard ratio for overall survival was greatest for hormone receptor–positive patients (Figs 1C and 1D). However, in the subgroup with hormone receptor–negative tumors, the two age groups showed no significant overall survival difference (P = .3094; Fig 1B). Similar findings could be seen in the analysis for BCSS (Figs 2B, 2C, and 2D).
The overall survival difference between age groups is significant for patients with lymph node–positive disease (P < .0001) and for patients with lymph node–negative disease (P = .0118; Figs 1E and 1F). The BCSS difference between age groups is significant for patients with lymph node–positive disease (P < .0001), while there was borderline significance for patients with lymph node–negative disease (P = .0635; Figs 2E and 2F). The overall survival and BCSS difference between age groups is also significant for patients with tumor size  2 cm (P = .0001) and for patients with tumor size more than 2 cm (P < .0001; data not shown). It could be argued that the marked survival difference in patients with ER–positive disease between the two groups is due to the lower use of hormone therapy in the younger group. Of patients with positive or unknown hormone receptor status, the overall survival and BCSS difference according to age was significant both for the patient subgroup that received hormone therapy and the subgroup that did not (Fig 1G, 1H, 2G, and 2H).
Multivariate Survival Analysis
Benefit of Hormone Therapy After Chemotherapy for Each Age Group For patients with positive or unknown hormone receptor status, hormone therapy after chemotherapy added significant survival benefit in patients between 35 and 50 years of age, with a hazard ratio of 0.61 for overall survival (95% CI, 0.47 to 0.79; P = .0016; Fig 3A) and 0.63 for BCSS (95% CI, 0.49 to 0.83; P = .0065; Fig 3B). In these patients, the absolute difference between treatment group in 5-year overall survival and BCSS was 3.63% and 2.93%, respectively. It was 31.9% reduction in overall death and 29.1% reduction in breast cancer death in 5 years. However, there was no significant additional benefit from hormone therapy in patients younger than 35 years (hazard ratio = 0.84; 95% CI, 0.55 to 1.28 for OS; and hazard ratio = 0.91 for BCSS; 95% CI, 0.58 to 1.42; Figs 3C and 3D). The results were similar for patients with hormone receptor–positive tumors (Figs 3E, 3F, 3G, and 3H).
The results of this large, multi-institution analysis confirmed that younger premenopausal patients (age < 35 years) had worse overall survival than older pre- and perimenopausal patients (between 35 and 50 years of age) regardless of lymph node status or tumor size. The more important finding was that the survival difference according to age was observed only in patients with hormone receptor–positive tumors and not in those with hormone receptor–negative tumors. This finding is consistent with several recent analyses involving large numbers of subjects.4,11,12 To our knowledge, the number of very young patients included in this study (n = 1,444) is larger than in any previous single patient series, and even larger than previous meta-analyses. The most common weaknesses of previous studies included the small number of very young patients and insufficient statistical power. Owing to the large number of subjects, we could calculate overall survival differences between age groups, even in subgroup analyses. Unexpectedly, the survival difference according to age in patients with hormone receptor–positive disease was significant in patients who received hormone therapy as well as in those who did not. This finding showed that the reduced prescribing of hormone therapy for younger patients does not explain the survival difference in hormone receptor–positive patients. It indicates that very young patients may not benefit from hormone therapy, even in cases of hormone receptor–positive disease (solid lines in Figs 1G and 1H). This finding is in contrast to the results of Colleoni et al,12 which showed a large difference in disease-free survival between very young patients (age < 35 years) who received hormone therapy and those who did not in the supplementary analysis with small number of subjects. Aebi et al11 suggested that the endocrine effects of chemotherapy alone are insufficient for younger patients and that additional endocrine therapies should be considered in their analysis of young premenopausal patients with CMF chemotherapy only. Therefore, we sought to determine the benefits of hormone therapy after adjuvant chemotherapy in each age group. In our study, adjuvant hormone therapy was associated with markedly less added survival benefit in very young patients (age < 35 years), when compared with the significant benefit in patients between 35 and 50 years of age. In this study, most hormone therapy involved selective estrogen-receptor modifiers, such as tamoxifen and toremifene, so this finding indicates that the use of selective estrogen-receptor modifiers as adjuvant hormone therapy might be less effective for improving the survival of very young breast cancer patients after chemotherapy. The Early Breast Cancer Trialists' Collaborative Group overview in 1998 found that there is unequivocal benefit to be gained from the use of tamoxifen in the adjuvant setting in premenopausal ER–positive women, regardless of whether chemotherapy had been administered.14 In that study, however, all patients younger than 50 years were classified together, and there was no subgroup analysis for very young women younger than 35 years. Although the biology of breast cancer in younger patients is largely unknown, there have been reports that breast cancer that develops at a young age expresses high-proliferation molecular markers.15,16 According to recent gene expression-profiling studies, ER–positive tumors with high proliferation17,18 tend to be aggressive. In the study of Paik et al, 19 the percentage of women with a high recurrence score, of which high expression levels of proliferation regulatory genes are mainly responsible, was greater in the younger group, and a high recurrence score was significantly associated with poor outcome after tamoxifen treatment. Further study is required to answer the question of whether breast cancer in younger patients has such a molecular profile. Crosstalk between ER and growth factor receptor pathways has been considered as a cause for endocrine therapy resistance in breast cancer.20 It is possible that HER2 overexpression could account for the apparent tamoxifen resistance seen in young women of this study. The distribution of HER2 expression in this cohort was not significantly different between the younger and older age group when hormone receptor status was positive (Table 3). It is consistent with the result of Colleoni et al.16 The survival difference between age group was significant in either case when HER2 was less expressed (0 or 1+) or more expressed (2+ or 3+; data not shown). In a multivariate Cox model including HER2 status, the combination of younger age and hormone receptor–positive tumors was still a significant prognostic factor for overall survival and BCSS (data not shown). These results suggest that HER2 status may not be a major factor that affects the tamoxifen resistance of very young breast cancer patients.
If very young patients with ER–positive disease have a worse prognosis even after chemotherapy and tamoxifen therapy, the last therapeutic strategy currently available is ovarian function suppression with or without aromatase inhibitors. However, the effect of this treatment after chemotherapy in premenopausal patients is unclear and is currently under study in several randomized trials.21 Patients most likely to benefit from ovarian function suppression are women who have no amenorrhea after chemotherapy or who resume menses after completion of chemotherapy. The proportion of women who continue to menstruate is greater in younger premenopausal women, and this might contribute to the poor outcome associated with young age endocrine-responsive cancer treated with chemotherapy alone.4 The results of this study should be interpreted with caution because the adjuvant hormone therapy was not randomly assigned and treatment duration was not investigated. Goldhirsch et al4 highlighted that factors affecting the success of endocrine therapy in very young women are complex, involving issues such as treatment duration, induced menopausal symptoms, and issues of sexual functioning and family planning. It is possible that more younger women ceased tamoxifen therapy before completion of the 5-year course of treatment than older women due to menopausal symptoms, sexual dysfunction, or desire for pregnancy. The lack of consensus about hormone receptor assay methods and the cutoff criteria for determining receptor positivity is another limitation of this analysis. Another confounding factor that could affect use of adjuvant tamoxifen is that, historically, fewer premenopausal patients were prescribed tamoxifen despite hormone receptor–positive status compared with patients who have been diagnosed more recently. In our study, among the younger women, 18.2% of women diagnosed with hormone receptor–positive disease before January 1999 were not prescribed adjuvant hormone therapy, compared with 12.5% of women diagnosed after January 1999 (P < .001). All of the patients enrolled in this study were Korean and virtually all of them were ethnically homogenous Far East Asian. It is possible that the tamoxifen resistance of very young breast cancer patients seen here can be limited to this ethnic group and similar findings may not be found in Western women. The high PgR expression rate seen in this cohort could be a unique finding to Asian breast cancer. Previous reports showed that the proportion of ER–negative and PgR–positive tumors seems to be higher in the Asian population, especially in premenopausal women.22,23 Age younger than 35 years was adopted as one of the important factors to categorize risk in the 2003 and 2005 St Gallen consensus meetings.24,25 We propose that the increased risk associated with a young age should be reconsidered with respect to the response to hormone therapy as well as chemotherapy. We await the results of ongoing randomized trials of premenopausal women with hormone receptor–positive breast cancer.
The author(s) indicated no potential conflicts of interest.
Conception and design: Wonshik Han Administrative support: Sei Hyun Ahn Provision of study materials or patients: Sei Hyun Ahn, Byung Ho Son, Seok Won Kim, Seung Il Kim, Joon Jeong, Seung Sang Ko, Wonshik Han Collection and assembly of data: Wonshik Han Data analysis and interpretation: Wonshik Han Manuscript writing: Wonshik Han Final approval of manuscript: Sei Hyun Ahn, Wonshik Han
The Korean Breast Cancer Society thanks the following members who participated in this national study: S.H. Ahn, J.W. Bae, Y.T. Bae, J.W. Baek, J.G. Bong, K.H. Cha, E.S. Chang, IT. Chang, S.S. Chang, J.W. Cho, S.H. Cho, Y.U. Cho, J.W. Choi, K.J. Choi, M.S. Choi, S.I. Choi, S.Y. Choi, G.S. Goo, S.H. Han, W. Han, S.J. Hong, J.Y. Hwang, T.I. Hyun, Y.J. Jegal, M.G. Im, Y.G. Joh, S.Y. Jun, B.W. Jung, J. Jung, J.H. Jung, K.H. Jung, P.J. Jung, S.H. Jung, S.S. Jung, Y.H. Jung, Y.S. Jung, D.H. Kang, H.J. Kang, Y.I. Kang, Y.J. Kang, J.H. Keum, D.Y. Kim, H.J. Kim, J.G. Kim, J.H. Kim, J.S. Kim, J.S. Kim, K.C. Kim, SC. Kim, S.H. Kim, S.I. Kim, S.J. Kim, S.W. Kim, S.W. Kim, S.Y. Kim, S.Y. Kim, Y.S. Kim, B.K. Ko, S.S. Ko, S.H. Koh, B.H. Koo, J.Y. Koo, B.S. Kwak, C.H. Lee, C.H. Lee, D.H. Lee, D.S. Lee, E.S. Lee, G.S. Lee, H.D. Lee, H.S. Lee, J.C. Lee, J.H. Lee, J.K. Lee, J.S. Lee, J.Y. Lee, K.M. Lee, K.P. Lee, K.S. Lee, K.Y. Lee, M.H. Lee, R.A. Lee, SC. Lee, S.J. Lee, S.K. Lee, W. Lee, Y.H. Lee, J.W. Leu, C.H. Lim, C.W. Lim, B.I. Moon, Y.S. Nam, S.J. Nam, D.Y. Noh, W.C. Noh, S.J. Oh, S.S. Oh, W.K. Pae, I.W. Paik, N.S. Paik, B.G. Park, B.W. Park, C.H. Park, H.B. Park, H.Y. Park, J.H. Park, K.H. Park, S.J. Park, S.T. Park, S.W. Park, W.C. Park, Y.K. Park, Y.K. Park, H.S. Seo, K.H. Seo, Y.J. Seo, Y.S. Sin, B.H. Son, G.S. Son, B.J. Song, K.H. Song, Y.J. Song, Y.J. Suh, J.M. Won, D.H. Woo, D.H. Yang, J.H. Yang, K.Y. Yoo, S.Y. Yoo, H.S. Yoon, J.H. Yoon, and S.O. Yoon.
published online ahead of print at www.jco.org on May 21, 2007. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to determine the differences in clinicopathologic features between pairs of groups. All statistical analyses were carried out using SPSS, version 12.0 (SPSS Inc, Chicago, IL). 
