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Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence
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Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence Y. Okumura a, R. Nishimura a, K. Nakatsukasa b, A. Yoshida c, N. Masuda d, M. Tanabe e, T. Shien f, S. Tanaka g, N. Arima h, Y. Komoike i, T. Taguchi b, T. Iwase e, H. Inaji i, M. Ishitobi i,*, Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society a
Dept. of Breast & Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan Dept. of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan c Dept. of Breast Surgery, St. Luke’s International Hospital, Tokyo, Japan d Dept. of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan e Division of Breast Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan f Dept. of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan g Section of Breast and Endocrine Surgery, Department of General and Gastroenterological Surgery, Osaka Medical College, Osaka, Japan h Dept. of Pathology, Kumamoto City Hospital, Kumamoto, Japan i Dept. of Breast and Endocrine Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan b
Accepted 19 January 2015 Available online - - -
Abstract Introduction: Changes in the biological marker status between primary and recurrent tumors are observed in breast cancer. However, their clinical significance is still uncertain, especially for patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery. Patients and methods: A total of 117 patients with IBTR without distant metastases were enrolled in this study. All patients were examined for estrogen receptor (ER), HER2, and Ki-67 in both the primary tumors and paired IBTR. We evaluated the impact of changes in these biomarkers between primary tumors and IBTR on the prognosis after IBTR. Results: There were no associations of changes in the ER, HER2 status with distant disease-free survival (DDFS) after surgical resection of IBTR, whereas the change in the Ki-67 status between the primary tumors and IBTR was significantly correlated with DDFS (unadjusted: p ¼ 0.0094; adjusted: p ¼ 0.013). Patients in the “increased or remained high” Ki-67 group had a significantly shorter DDFS than those in the “decreased or remained low” Ki-67 group (5-year DDFS: 55.5 vs. 79.3%, respectively, p ¼ 0.0084 by log-rank test). Conclusion: An increased or persistently high Ki-67 status in the IBTR was significantly correlated with a poorer prognosis after IBTR. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer; Ipsilateral breast tumor recurrence; Ki-67
Introduction
* Corresponding author. Present address: 1-3-3 Nakamichi, Higashinariku, Osaka 537-8511, Japan. Tel.: þ81 6 6972 1181; fax: þ81 6 6981 8055. E-mail address: [email protected] (M. Ishitobi).
Treatment decision-making for recurrent breast cancer is usually based on biomarkers such as estrogen receptors (ER) and HER2 of the primary tumors.1,2 However, prior
http://dx.doi.org/10.1016/j.ejso.2015.01.030 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
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Y. Okumura et al. / EJSO xx (2015) 1e5
studies reported on changes in the ER and HER2 status between primary and recurrent tumors in breast cancer.3e11 A recent meta-analysis demonstrated that rates of changes in the ER and HER2 status were 20 and 8%, respectively.12 Several studies suggested the negative impact of these changes on the prognosis, probably due to inappropriate targeted therapies for metastatic breast cancer.5,8,11 For these reasons, recent guidelines recommended evaluating the ER and HER2 status of recurrent tumors to decide on treatment planning of targeted therapies if clinically feasible.1,13 In contrast, there is limited information regarding the change in the biomarker status and its prognostic impact between the primary tumors and ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery. Furthermore, few studies have evaluated the prognostic relevance of the change in Ki-67 status between the primary and recurrent tumors in breast cancer,6,10 and no definitive conclusions have been made. We previously demonstrated the prognostic significance of the breast cancer subtype of IBTR based on immunohistochemical staining of ER,
HER2, and Ki-67.14 In this study, we evaluated the change in the ER, HER2, and Ki-67 status between the primary tumors and IBTR and its prognostic value using paired samples of primary tumors and IBTR. Patients and methods We previously analyzed the prognostic significance of the breast cancer subtype of IBTR among 187 patients with IBTR without distant metastases between 1989 and 2008 from eight institutions in Japan.14 Among 187 patients, there were 117 (62.6%) patients for whom information on ER, HER2, and Ki-67 of both the primary tumors and IBTR were available. These 117 patients were enrolled in this study. This study was approved by the ethics committee of each institution. Inclusion and exclusion criteria were described previously.14 Patients who underwent definitive surgery for IBTR until 2008 in the participating institutions were included. Patient characteristics are shown in Table 1. The ER status was determined by immunohistochemistry,
Table 1 Patient characteristics (n ¼ 117). Characteristics Age Tumor size (mm) Lymph node status
Histological grade
Lymphovascular invasion
Margin status
Breast cancer subtype
Radiotherapy
Preoperative therapy Postoperative therapy
Disease-free interval (months) Recurrence type
Surgical method a b c d
Median (range) Median (range) Negative Positive Unknown 1 2 3 Unknown Negative Positive Unknown Negative Positive Unknown Luminal Aa Luminal Bb HER2c Triple-negatived No Yes Unknown No Yes Chemotherapy Endocrine therapy Targeted therapy Median (range) True recurrence New primary tumor Unknown Repeat lumpectomy Total Mastectomy
Primary lesion (n ¼ 117)
Recurrent lesion (n ¼ 117)
48 (26e78) 19 (0e6) 72 38 7 21 37 43 16 50 57 10 99 13 5 53 23 9 32 57 59 1 111 6 40 73 3 43.5 (2.9e125.6)
51 (29e84) 15 (0e11) 19 5 93 20 32 46 19 63 44 10 80 9 28 38 31 22 26 91 26 0 114 3 28 67 7 67 45 5 67 50
Estrogen receptor (ER)-positive, Ki-67 < 20%, and HER2-negative. ER-positive and Ki-67 20% or HER2-positive or both. HER2-positive and ER-negative. ER and HER2-negative.
Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
Y. Okumura et al. / EJSO xx (2015) 1e5
and tumors with 10% positively stained tumor cells were classified as positive. The HER2 status was considered positive if immunohistochemistry was 3þ or fluorescence in situ hybridization (her-2/neu to chromosome 17 ratio) was >2.0. The ER and HER2 status was evaluated at each institution. Proliferation activity was assessed by immunostaining with the Ki-67 antibody (Dako). Ki-67 was centrally evaluated by one pathologist (N.A.), from whom all patient data were masked. The proportion of proliferating cells was determined by counting at least 500 tumor cells in hot spots. Two cut-off values of Ki-67 (20 and 50%) were used.6,15 Patterns of change in the Ki-67 status and histological grade from the primary tumors to IBTR were categorized into 2 groups: “increased or remained high” or “decreased or remained low”. “Increase or remained high” Ki-67 was as follows: <20 to 20e50%, <20 to >50%, 20e50 to >50%, 20e50 to 20e50%, or >50 to >50%. “Decreased or remained low” Ki-67 was as follows: >50 to 20e50%, >50 to <20%, 20e50 to <20%, or <20 to <20% (Table 2). “Increase or remained high” histological grade was as follows: 1 to 2, 1 to 3, 2 to 3, 2 to 2, or 3 to 3. “Decreased or remained low” histological grade was as follows: 3 to 2, 3 to 1, 2 to 1, or 1 to 1 (Table 2). Breast cancer subtypes were defined as follows: triplenegative (ER and HER2-negative), HER2 (HER2positive and ER-negative), luminal A (ER-positive, Ki67-low, and HER2-negative), and luminal B (ER-positive and Ki-67-high or HER2-positive or both). In this study, the cut-off value of the Ki-67 index was 20%.14 Distant disease-free survival (DDFS) was defined as the period from the date of surgery for IBTR to the date of
Table 2 Estrogen receptor, HER2, Ki-67 status, and histologic grade between primary breast cancer and ipsilateral breast tumor recurrence. Primary tumor
Ipsilateral breast tumor recurrence
ERa Negative Positive Total HER2 Negative Positive Total Ki-67 <20% 20e50% >50% Total Histological grade 1 2 3 Total
Negative 35 13 48 Negative 82 2 84 <20% 50b 11b 0b 61 1 10b 7b 1b 18
a b c
Estrogen receptor. Decreased or remained low. Increased or remained high.
Positive 6 63 69 Positive 14 19 33 20e50% 20c 23c 2b 45 2 6c 15c 9b 30
Total 41 76 117 96 21 117
>50% 3c 7c 1c 11 3 4c 12c 27c 43
73 41 3 117 20 34 37 91
3
appearance of distant metastases. The DDFS was calculated using the KaplaneMeier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. In the multivariate analyses, covariates for adjustment were the breast cancer subtype of IBTR (luminal A vs. others), disease-free interval (less than 2 years vs. 2 years or longer), tumor size of IBTR (2 cm or smaller vs. larger than 2 cm), lymphovascular invasion of IBTR (negative vs. positive), and tumor location (same vs. different quadrant). We conducted exploratory analyses on the association of the change in the Ki-67 status with DDFS according to the recurrence type (true recurrence vs. new primary tumor). True recurrences were defined as tumors occurring in the same quadrant as the primary tumors. New primary tumors were defined as tumors occurring in a different quadrant than the primary tumors. All statistical tests and p-values were two-tailed, and p-values of <0.05 were considered significant. Results ER, HER2, Ki-67, and the histological grade of the primary tumors and IBTR are shown in Table 2. Changes in the ER, HER2, and Ki-67 status between the primary tumors and IBTR were observed in 16.2, 13.7, and 36.8%, respectively. Of the 117 patients, 54 (46.2%) patients were defined as an “increased or remained high” Ki-67 group and 63 (53.8%) patients were defined as a “decreased or remained low” Ki-67 group. With a median follow-up of 4.8 years, 40 (34.2%) of the 117 patients had distant recurrences. There were no associations of changes in the ER, HER2 status, or histological grade with DDFS (ER: p ¼ 0.38, HER2: p ¼ 0.51, histological grade: p ¼ 0.59). In contrast, a change in the Ki-67 status between the primary tumors and IBTR was significantly correlated with DDFS. Patients in the “increased or remained high” Ki-67 group had a significantly shorter DDFS than those in the “decreased or remained low” Ki67 group (5-year DDFS: 55.5 vs. 79.3%, respectively, p ¼ 0.0084 by log-rank test) (Fig. 1). This significance remained after adjusting with other clinicopathological factors (p ¼ 0.013) (Table 3). In the exploratory analyses, the change in the Ki-67 status was significantly correlated with DDFS in women with true recurrence (p ¼ 0.036), but was not significantly correlated in women with new primary tumors (p ¼ 0.29) (Table 3). Discussion We analyzed the association of changes in the ER, HER2, and Ki-67 status between primary tumors and IBTR with DDFS. We observed that patients with a persistently high or upgraded Ki-67 status had a significantly poorer prognosis. Previous studies on the prognostic relevance of the change in Ki-67 status between primary and recurrent tumors reported inconsistent results.6,10
Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
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classified the recurrence type using the tumor location. The tumor location is the most frequently used16e21; IBTR located in the same quadrant as the primary tumor was defined as true recurrence, and IBTR located in a different quadrant from the primary tumor was defined as a new primary tumor. We defined quadrants as the upper outer, upper inner, lower inner, and lower outer. This definition has a limitation regarding the interpretation of the results in our study. In our study, there was no association between changes in the ER and HER2 status with DDFS. Several studies have reported the prognostic significance of changes in the ER and HER2 status.5,8,11 In these studies, it was mentioned that a poor prognosis among patients with changes in the ER or HER2 status might be due to inadequate targeted therapy. A randomized controlled trial showed that adjuvant hormone therapy reduced recurrence in patients with surgically resected locoregional recurrences,22 whereas no evidence has been reported that adjuvant trastuzumab reduces recurrence in this clinical setting. In our study, most (97.1%, 67 of 69) patients with ERpositive IBTR received hormone therapy after IBTR resection. A possible explanation for there being no association of the change in the ER status between primary and recurrent tumors with the prognosis in our study might be that adjuvant treatment was modified according to the receptor status of recurrent tumors.7 It has been established that there is a strong correlation between the Ki-67 status and histological grade.23 In our study, there was no association between changes in the histological grade and DDFS, whereas there was a significant correlation with changes in the Ki-67 status. Reasons for there being no association between changes in the histological grade with DDFS might be the high frequency of missing data (22.2% (26/117)) and lack of central evaluation. The small sample size is a limitation of our study. In addition, there was a no ideal cut-off of Ki-67.24 In this study, we used 2 cut-offs, which were also used in previous studies.6,15 Regarding ER positivity and treatment
Figure 1. Distant disease-free survival after ipsilateral breast tumor recurrence according to patterns of change in Ki-67 between primary breast cancer and ipsilateral breast tumor recurrence.
Nishimura et al.6 reported that high Ki-67 in primary tumors, irrespective of high or low Ki-67 in recurrent tumors, was significantly correlated with a lower survival rate. Ibrahim et al.10 reported that patients with high Ki-67 in recurrent tumors showed significantly lower survival rates, irrespective of high or low Ki-67 in primary tumors. This inconsistency may be due to different patient populations (i.e., only patients with IBTR in our study compared with patients with locoregional or distant metastases in other studies). IBTR was thought to be separate from other types of recurrence because it encompasses 2 types of disease: true recurrence and a new primary tumor. In general, patients with new primary tumors have a better prognosis than those with true recurrence.16e19 Because true recurrence and a new primary tumor are associated with different prognoses, these 2 types were separately analyzed. Importantly, the prognostic significance of a change in the Ki-67 status was only seen in patients with true recurrence. This finding may provide important information for a better understanding of the biology of IBTR. To date, there has been no standard classification of new primary tumors and true recurrence. In this study, we
Table 3 Change in Ki-67 status between primary breast cancer and ipsilateral breast tumor recurrence and its prognostic significance. Unadjusted c
HR All patients (n ¼ 117) Ki-67 Decreased or remained low vs. increased or remained high True recurrence (n ¼ 67)b Ki-67 Decreased or remained low vs. increased or remained high New primary tumor (n ¼ 45)b Ki-67 Decreased or remained low vs. increased or remained high
Adjusted d
95%CI
P-value
HRc
95%CId
P-value
a
0.43
0.22e0.81
0.0094
0.30
0.11e0.78
0.013
0.38
0.17e0.85
0.018
0.30
0.079e0.93
0.036
0.37
0.095e1.26
0.11
0.40
0.052e2.10
0.29
a
Covariates for adjustment were: breast cancer subtype of ipsilateral breast tumor recurrence (IBTR), disease-free interval, tumor size of IBTR, lymphovascular invasion of IBTR, and tumor location. b Covariates for adjustment were breast cancer subtype of IBTR, disease-free interval, tumor size of IBTR, and lymphovascular invasion of IBTR. c Hazard ratio. d Confidence interval. Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
Y. Okumura et al. / EJSO xx (2015) 1e5
decisions, a 1% cut-off was introduced in 2010 by the American Society of Clinical Oncology recommendations.25 This cut-off is widely used at present. Therefore, to be consistent with the introduction detailing the influence of changes in the ER and HER2 status on therapeutic decisions, it would be better to consider a 1% cut-off for defining ER positivity rather than 10%. However, a 10% cut-off of ER was used in our study because patients who underwent definitive surgery for IBTR until 2008 were included in our study. In conclusion, a change in the Ki-67 status between the primary tumor and IBTR was significantly correlated with the prognosis after IBTR. Further research and validation studies are needed.
Acknowledgments This study was supported in part by Grants-in-Aid for Scientific Research from the Japanese Breast Cancer Society. The authors declare that the study sponsor had no role in the study design, collection, analysis, and interpretation of data, writing of the manuscript, nor decision to submit the manuscript for publication. Conflict of interest statement All authors have no conflicts of interest.
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9. Montagna E, Bagnardi V, Rotmensz N, et al. Breast cancer subtypes and outcome after local and regional relapse. Ann Oncol 2012;23: 324–31. 10. Ibrahim T, Farolfi A, Scarpi E, et al. Hormonal receptor, human epidermal growth factor receptor-2, and Ki67 discordance between primary breast cancer and paired metastases: clinical impact. Oncology 2013;84:150–7. 11. Dieci MV, Barbieri E, Piacentini F, et al. Discordance in receptor status between primary and recurrent breast cancer has a prognostic impact: a single-institution analysis. Ann Oncol 2013;24:101–8. 12. Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer 2014;50:277–89. 13. Cardoso F, Costa A, Norton L, et al. 1st International consensus guidelines for advanced breast cancer (ABC 1). Breast 2012;21:242–52. 14. Ishitobi M, Okumura Y, Arima N, et al. Breast cancer subtype and distant recurrence after ipsilateral breast tumor recurrence. Ann Surg Oncol 2013;20:1886–92. 15. Nishimura R, Osako T, Okumura Y, Hayashi M, Toyozumi Y, Arima N. Ki-67 as a prognostic marker according to breast cancer subtype and a predictor of recurrence time in primary breast cancer. Exp Ther Med 2010;1:747–54. 16. Haffty BG, Carter D, Flynn SD, et al. Local recurrence versus new primary: clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting. Int J Radiat Oncol Biol Phys 1993;27:575– 83. 17. Smith TE, Lee D, Turner BC, Carter D, Haffty BG. True recurrence vs. new primary ipsilateral breast tumor relapse: an analysis of clinical and pathologic differences and their implications in natural history, prognoses, and therapeutic management. Int J Radiat Oncol Biol Phys 2000;48:1281–9. 18. Komoike Y, Akiyama F, Iino Y, et al. Analysis of ipsilateral breast tumor recurrences after breast-conserving treatment based on the classification of true recurrences and new primary tumors. Breast Cancer 2005;12:104–11. 19. Yi M, Buchholz TA, Meric-Bernstam F, et al. Classification of ipsilateral breast tumor recurrences after breast conservation therapy can predict patient prognosis and facilitate treatment planning. Ann Surg 2011;253:572–9. 20. Freedman GM, Anderson PR, Hanlon AL, Eisenberg DF, Nicolaou N. Pattern of local recurrence after conservative surgery and whole-breast irradiation. Int J Radiat Oncol Biol Phys 2005;61:1328–36. 21. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomized controlled equivalence trial. Lancet Oncol 2013;14: 1269–77. 22. Waeber M, Castiglione-Gertsch M, Dietrich D, et al. Adjuvant therapy after excision and radiation of isolated postmastectomy locoregional breast cancer recurrence: definitive results of a phase III randomized trial (SAKK 23/82) comparing tamoxifen with observation. Ann Oncol 2003;14:1215–21. 23. Spyratos F, Ferrero-Po€us M, Trassard M, et al. Correlation between MIB-1 and other proliferation markers: clinical implications of the MIB-1 cutoff value. Cancer 2002;94:2151–9. 24. Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in Breast Cancer: recommendations from the International Ki67 in Breast Cancer Working Group. J Natl Cancer Inst 2011;103:1656–64. 25. 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;28:2784–95.
Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
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Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence Y. Okumura a, R. Nishimura a, K. Nakatsukasa b, A. Yoshida c, N. Masuda d, M. Tanabe e, T. Shien f, S. Tanaka g, N. Arima h, Y. Komoike i, T. Taguchi b, T. Iwase e, H. Inaji i, M. Ishitobi i,*, Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society a
Dept. of Breast & Endocrine Surgery, Kumamoto City Hospital, Kumamoto, Japan Dept. of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan c Dept. of Breast Surgery, St. Luke’s International Hospital, Tokyo, Japan d Dept. of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan e Division of Breast Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan f Dept. of Breast and Endocrine Surgery, Okayama University Hospital, Okayama, Japan g Section of Breast and Endocrine Surgery, Department of General and Gastroenterological Surgery, Osaka Medical College, Osaka, Japan h Dept. of Pathology, Kumamoto City Hospital, Kumamoto, Japan i Dept. of Breast and Endocrine Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan b
Accepted 19 January 2015 Available online - - -
Abstract Introduction: Changes in the biological marker status between primary and recurrent tumors are observed in breast cancer. However, their clinical significance is still uncertain, especially for patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery. Patients and methods: A total of 117 patients with IBTR without distant metastases were enrolled in this study. All patients were examined for estrogen receptor (ER), HER2, and Ki-67 in both the primary tumors and paired IBTR. We evaluated the impact of changes in these biomarkers between primary tumors and IBTR on the prognosis after IBTR. Results: There were no associations of changes in the ER, HER2 status with distant disease-free survival (DDFS) after surgical resection of IBTR, whereas the change in the Ki-67 status between the primary tumors and IBTR was significantly correlated with DDFS (unadjusted: p ¼ 0.0094; adjusted: p ¼ 0.013). Patients in the “increased or remained high” Ki-67 group had a significantly shorter DDFS than those in the “decreased or remained low” Ki-67 group (5-year DDFS: 55.5 vs. 79.3%, respectively, p ¼ 0.0084 by log-rank test). Conclusion: An increased or persistently high Ki-67 status in the IBTR was significantly correlated with a poorer prognosis after IBTR. Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer; Ipsilateral breast tumor recurrence; Ki-67
Introduction
* Corresponding author. Present address: 1-3-3 Nakamichi, Higashinariku, Osaka 537-8511, Japan. Tel.: þ81 6 6972 1181; fax: þ81 6 6981 8055. E-mail address: [email protected] (M. Ishitobi).
Treatment decision-making for recurrent breast cancer is usually based on biomarkers such as estrogen receptors (ER) and HER2 of the primary tumors.1,2 However, prior
http://dx.doi.org/10.1016/j.ejso.2015.01.030 0748-7983/Ó 2015 Elsevier Ltd. All rights reserved. Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
2
Y. Okumura et al. / EJSO xx (2015) 1e5
studies reported on changes in the ER and HER2 status between primary and recurrent tumors in breast cancer.3e11 A recent meta-analysis demonstrated that rates of changes in the ER and HER2 status were 20 and 8%, respectively.12 Several studies suggested the negative impact of these changes on the prognosis, probably due to inappropriate targeted therapies for metastatic breast cancer.5,8,11 For these reasons, recent guidelines recommended evaluating the ER and HER2 status of recurrent tumors to decide on treatment planning of targeted therapies if clinically feasible.1,13 In contrast, there is limited information regarding the change in the biomarker status and its prognostic impact between the primary tumors and ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery. Furthermore, few studies have evaluated the prognostic relevance of the change in Ki-67 status between the primary and recurrent tumors in breast cancer,6,10 and no definitive conclusions have been made. We previously demonstrated the prognostic significance of the breast cancer subtype of IBTR based on immunohistochemical staining of ER,
HER2, and Ki-67.14 In this study, we evaluated the change in the ER, HER2, and Ki-67 status between the primary tumors and IBTR and its prognostic value using paired samples of primary tumors and IBTR. Patients and methods We previously analyzed the prognostic significance of the breast cancer subtype of IBTR among 187 patients with IBTR without distant metastases between 1989 and 2008 from eight institutions in Japan.14 Among 187 patients, there were 117 (62.6%) patients for whom information on ER, HER2, and Ki-67 of both the primary tumors and IBTR were available. These 117 patients were enrolled in this study. This study was approved by the ethics committee of each institution. Inclusion and exclusion criteria were described previously.14 Patients who underwent definitive surgery for IBTR until 2008 in the participating institutions were included. Patient characteristics are shown in Table 1. The ER status was determined by immunohistochemistry,
Table 1 Patient characteristics (n ¼ 117). Characteristics Age Tumor size (mm) Lymph node status
Histological grade
Lymphovascular invasion
Margin status
Breast cancer subtype
Radiotherapy
Preoperative therapy Postoperative therapy
Disease-free interval (months) Recurrence type
Surgical method a b c d
Median (range) Median (range) Negative Positive Unknown 1 2 3 Unknown Negative Positive Unknown Negative Positive Unknown Luminal Aa Luminal Bb HER2c Triple-negatived No Yes Unknown No Yes Chemotherapy Endocrine therapy Targeted therapy Median (range) True recurrence New primary tumor Unknown Repeat lumpectomy Total Mastectomy
Primary lesion (n ¼ 117)
Recurrent lesion (n ¼ 117)
48 (26e78) 19 (0e6) 72 38 7 21 37 43 16 50 57 10 99 13 5 53 23 9 32 57 59 1 111 6 40 73 3 43.5 (2.9e125.6)
51 (29e84) 15 (0e11) 19 5 93 20 32 46 19 63 44 10 80 9 28 38 31 22 26 91 26 0 114 3 28 67 7 67 45 5 67 50
Estrogen receptor (ER)-positive, Ki-67 < 20%, and HER2-negative. ER-positive and Ki-67 20% or HER2-positive or both. HER2-positive and ER-negative. ER and HER2-negative.
Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
Y. Okumura et al. / EJSO xx (2015) 1e5
and tumors with 10% positively stained tumor cells were classified as positive. The HER2 status was considered positive if immunohistochemistry was 3þ or fluorescence in situ hybridization (her-2/neu to chromosome 17 ratio) was >2.0. The ER and HER2 status was evaluated at each institution. Proliferation activity was assessed by immunostaining with the Ki-67 antibody (Dako). Ki-67 was centrally evaluated by one pathologist (N.A.), from whom all patient data were masked. The proportion of proliferating cells was determined by counting at least 500 tumor cells in hot spots. Two cut-off values of Ki-67 (20 and 50%) were used.6,15 Patterns of change in the Ki-67 status and histological grade from the primary tumors to IBTR were categorized into 2 groups: “increased or remained high” or “decreased or remained low”. “Increase or remained high” Ki-67 was as follows: <20 to 20e50%, <20 to >50%, 20e50 to >50%, 20e50 to 20e50%, or >50 to >50%. “Decreased or remained low” Ki-67 was as follows: >50 to 20e50%, >50 to <20%, 20e50 to <20%, or <20 to <20% (Table 2). “Increase or remained high” histological grade was as follows: 1 to 2, 1 to 3, 2 to 3, 2 to 2, or 3 to 3. “Decreased or remained low” histological grade was as follows: 3 to 2, 3 to 1, 2 to 1, or 1 to 1 (Table 2). Breast cancer subtypes were defined as follows: triplenegative (ER and HER2-negative), HER2 (HER2positive and ER-negative), luminal A (ER-positive, Ki67-low, and HER2-negative), and luminal B (ER-positive and Ki-67-high or HER2-positive or both). In this study, the cut-off value of the Ki-67 index was 20%.14 Distant disease-free survival (DDFS) was defined as the period from the date of surgery for IBTR to the date of
Table 2 Estrogen receptor, HER2, Ki-67 status, and histologic grade between primary breast cancer and ipsilateral breast tumor recurrence. Primary tumor
Ipsilateral breast tumor recurrence
ERa Negative Positive Total HER2 Negative Positive Total Ki-67 <20% 20e50% >50% Total Histological grade 1 2 3 Total
Negative 35 13 48 Negative 82 2 84 <20% 50b 11b 0b 61 1 10b 7b 1b 18
a b c
Estrogen receptor. Decreased or remained low. Increased or remained high.
Positive 6 63 69 Positive 14 19 33 20e50% 20c 23c 2b 45 2 6c 15c 9b 30
Total 41 76 117 96 21 117
>50% 3c 7c 1c 11 3 4c 12c 27c 43
73 41 3 117 20 34 37 91
3
appearance of distant metastases. The DDFS was calculated using the KaplaneMeier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. In the multivariate analyses, covariates for adjustment were the breast cancer subtype of IBTR (luminal A vs. others), disease-free interval (less than 2 years vs. 2 years or longer), tumor size of IBTR (2 cm or smaller vs. larger than 2 cm), lymphovascular invasion of IBTR (negative vs. positive), and tumor location (same vs. different quadrant). We conducted exploratory analyses on the association of the change in the Ki-67 status with DDFS according to the recurrence type (true recurrence vs. new primary tumor). True recurrences were defined as tumors occurring in the same quadrant as the primary tumors. New primary tumors were defined as tumors occurring in a different quadrant than the primary tumors. All statistical tests and p-values were two-tailed, and p-values of <0.05 were considered significant. Results ER, HER2, Ki-67, and the histological grade of the primary tumors and IBTR are shown in Table 2. Changes in the ER, HER2, and Ki-67 status between the primary tumors and IBTR were observed in 16.2, 13.7, and 36.8%, respectively. Of the 117 patients, 54 (46.2%) patients were defined as an “increased or remained high” Ki-67 group and 63 (53.8%) patients were defined as a “decreased or remained low” Ki-67 group. With a median follow-up of 4.8 years, 40 (34.2%) of the 117 patients had distant recurrences. There were no associations of changes in the ER, HER2 status, or histological grade with DDFS (ER: p ¼ 0.38, HER2: p ¼ 0.51, histological grade: p ¼ 0.59). In contrast, a change in the Ki-67 status between the primary tumors and IBTR was significantly correlated with DDFS. Patients in the “increased or remained high” Ki-67 group had a significantly shorter DDFS than those in the “decreased or remained low” Ki67 group (5-year DDFS: 55.5 vs. 79.3%, respectively, p ¼ 0.0084 by log-rank test) (Fig. 1). This significance remained after adjusting with other clinicopathological factors (p ¼ 0.013) (Table 3). In the exploratory analyses, the change in the Ki-67 status was significantly correlated with DDFS in women with true recurrence (p ¼ 0.036), but was not significantly correlated in women with new primary tumors (p ¼ 0.29) (Table 3). Discussion We analyzed the association of changes in the ER, HER2, and Ki-67 status between primary tumors and IBTR with DDFS. We observed that patients with a persistently high or upgraded Ki-67 status had a significantly poorer prognosis. Previous studies on the prognostic relevance of the change in Ki-67 status between primary and recurrent tumors reported inconsistent results.6,10
Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
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classified the recurrence type using the tumor location. The tumor location is the most frequently used16e21; IBTR located in the same quadrant as the primary tumor was defined as true recurrence, and IBTR located in a different quadrant from the primary tumor was defined as a new primary tumor. We defined quadrants as the upper outer, upper inner, lower inner, and lower outer. This definition has a limitation regarding the interpretation of the results in our study. In our study, there was no association between changes in the ER and HER2 status with DDFS. Several studies have reported the prognostic significance of changes in the ER and HER2 status.5,8,11 In these studies, it was mentioned that a poor prognosis among patients with changes in the ER or HER2 status might be due to inadequate targeted therapy. A randomized controlled trial showed that adjuvant hormone therapy reduced recurrence in patients with surgically resected locoregional recurrences,22 whereas no evidence has been reported that adjuvant trastuzumab reduces recurrence in this clinical setting. In our study, most (97.1%, 67 of 69) patients with ERpositive IBTR received hormone therapy after IBTR resection. A possible explanation for there being no association of the change in the ER status between primary and recurrent tumors with the prognosis in our study might be that adjuvant treatment was modified according to the receptor status of recurrent tumors.7 It has been established that there is a strong correlation between the Ki-67 status and histological grade.23 In our study, there was no association between changes in the histological grade and DDFS, whereas there was a significant correlation with changes in the Ki-67 status. Reasons for there being no association between changes in the histological grade with DDFS might be the high frequency of missing data (22.2% (26/117)) and lack of central evaluation. The small sample size is a limitation of our study. In addition, there was a no ideal cut-off of Ki-67.24 In this study, we used 2 cut-offs, which were also used in previous studies.6,15 Regarding ER positivity and treatment
Figure 1. Distant disease-free survival after ipsilateral breast tumor recurrence according to patterns of change in Ki-67 between primary breast cancer and ipsilateral breast tumor recurrence.
Nishimura et al.6 reported that high Ki-67 in primary tumors, irrespective of high or low Ki-67 in recurrent tumors, was significantly correlated with a lower survival rate. Ibrahim et al.10 reported that patients with high Ki-67 in recurrent tumors showed significantly lower survival rates, irrespective of high or low Ki-67 in primary tumors. This inconsistency may be due to different patient populations (i.e., only patients with IBTR in our study compared with patients with locoregional or distant metastases in other studies). IBTR was thought to be separate from other types of recurrence because it encompasses 2 types of disease: true recurrence and a new primary tumor. In general, patients with new primary tumors have a better prognosis than those with true recurrence.16e19 Because true recurrence and a new primary tumor are associated with different prognoses, these 2 types were separately analyzed. Importantly, the prognostic significance of a change in the Ki-67 status was only seen in patients with true recurrence. This finding may provide important information for a better understanding of the biology of IBTR. To date, there has been no standard classification of new primary tumors and true recurrence. In this study, we
Table 3 Change in Ki-67 status between primary breast cancer and ipsilateral breast tumor recurrence and its prognostic significance. Unadjusted c
HR All patients (n ¼ 117) Ki-67 Decreased or remained low vs. increased or remained high True recurrence (n ¼ 67)b Ki-67 Decreased or remained low vs. increased or remained high New primary tumor (n ¼ 45)b Ki-67 Decreased or remained low vs. increased or remained high
Adjusted d
95%CI
P-value
HRc
95%CId
P-value
a
0.43
0.22e0.81
0.0094
0.30
0.11e0.78
0.013
0.38
0.17e0.85
0.018
0.30
0.079e0.93
0.036
0.37
0.095e1.26
0.11
0.40
0.052e2.10
0.29
a
Covariates for adjustment were: breast cancer subtype of ipsilateral breast tumor recurrence (IBTR), disease-free interval, tumor size of IBTR, lymphovascular invasion of IBTR, and tumor location. b Covariates for adjustment were breast cancer subtype of IBTR, disease-free interval, tumor size of IBTR, and lymphovascular invasion of IBTR. c Hazard ratio. d Confidence interval. Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030
Y. Okumura et al. / EJSO xx (2015) 1e5
decisions, a 1% cut-off was introduced in 2010 by the American Society of Clinical Oncology recommendations.25 This cut-off is widely used at present. Therefore, to be consistent with the introduction detailing the influence of changes in the ER and HER2 status on therapeutic decisions, it would be better to consider a 1% cut-off for defining ER positivity rather than 10%. However, a 10% cut-off of ER was used in our study because patients who underwent definitive surgery for IBTR until 2008 were included in our study. In conclusion, a change in the Ki-67 status between the primary tumor and IBTR was significantly correlated with the prognosis after IBTR. Further research and validation studies are needed.
Acknowledgments This study was supported in part by Grants-in-Aid for Scientific Research from the Japanese Breast Cancer Society. The authors declare that the study sponsor had no role in the study design, collection, analysis, and interpretation of data, writing of the manuscript, nor decision to submit the manuscript for publication. Conflict of interest statement All authors have no conflicts of interest.
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Please cite this article in press as: Okumura Y, et al., Change in estrogen receptor, HER2, and Ki-67 status between primary breast cancer and ipsilateral breast cancer tumor recurrence, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.01.030