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Survival time according to the year of recurrence and subtype in recurrent breast cancer
The Breast 24 (2015) 588e593
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Survival time according to the year of recurrence and subtype in recurrent breast cancer Masahiro Nakano a, *, Mamiko Fujisue a, Rumiko Tashima b, Yasuhiro Okumura a, Yasuyuki Nishiyama a, Tomofumi Ohsako a, Yasuo Toyozumi c, Nobuyuki Arima c, Reiki Nishimura a a b c
Department of Breast and Endocrine Surgery, Kumamoto City Hospital, 1-1-60, Kotoh, Higashi-ku, Kumamoto 860-8505, Japan Department of Surgery, Kumamoto City Hospital, 1-1-60, Kotoh, Higashi-ku, Kumamoto 860-8505, Japan Department of Pathology, Kumamoto City Hospital, 1-1-60, Kotoh, Higashi-ku, Kumamoto 860-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 November 2014 Received in revised form 14 May 2015 Accepted 4 June 2015 Available online 20 June 2015
Background: Survival for patients with recurrent breast cancer has improved over time due to the introduction of modern systemic therapy. The aim of this study was to determine the impact of subtype and the year of recurrence on the survival times of recurrent breast cancer. Methods: Between 1979 and 2013, 813 patients who underwent initial treatment for primary breast cancer experienced recurrence. They were divided into two groups based on the year of recurrence; before 2000 and after 2001. Survival after recurrence was compared between these groups based on following criteria; subtypes, disease free interval (DFI), and dominant recurrent site. The median followup period after recurrence was 4.3 years. Results: Survival improved significantly in the after 2001 group, and a significant improvement in survival was only seen in the HER2-enriched subtype. Multivariate analysis revealed that DFI, ER, HER2 status, dominant recurrent site and the Ki-67 index value were significant prognostic factors. In the HER2-enriched subtype, the year of recurrence, DFI and dominant recurrent site were significant independent factors. In the other subtypes, these factors were not correlated with survival. Conclusion: Our study revealed that the survival rate of patients with only the HER2-enriched subtype significantly improved after recurrence. To prolong the survival time after recurrence of both luminal and triple negative subtypes, the development of novel targeting therapies to overcome refractory recurrent breast cancer is extremely important. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Survival after recurrence Subtype Disease free interval Metastatic disease
Introduction Metastatic breast cancer (MBC) is the leading cause of cancer death among females worldwide with over 400,000 dying each year [1]. Although the mortality of early stage breast cancer has certainly declined due to evidence-based multidisciplinary treatment [2e5], breast cancer heterogeneity often causes recurrence resulting in an incurable disease. Now, it is widely accepted that the intrinsic subtype is an important prognostic and predictive factor in breast cancer [6]. Current treatment algorithms are generally based on the
* Corresponding author. Tel.: þ81 96 365 1711; fax: þ81 96 365 1796. E-mail address: [email protected] (M. Nakano). http://dx.doi.org/10.1016/j.breast.2015.06.003 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
subtypes divided by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and the Ki-67 index value not only in adjuvant but also in metastatic settings [7,8]. Previous studies have reported that survival for MBC improved due to the introduction of modern systemic therapy [9e11]. Other studies were able to demonstrate an improvement in looking at the ER status [12,13]. However, the prolongation of survival according to Luminal-A, -B, -HER2, HER2-enriched and Triple Negative (TN) breast cancer subtypes is still unclear. Various newly developed drugs, such as taxanes, were approved in the late 1990s and third-generation aromatase inhibitors (AI) and trastuzumab, were approved in 2001 for clinical use in Japan resulting in a more favorable prognosis for MBC than previously expected [12]. However, there were few
M. Nakano et al. / The Breast 24 (2015) 588e593
studies that analyzed the survival time of MBC according to subtypes. We hypothesized that survival in ER positive and/or HER2 positive MBC would be longer due to the introduction of AI and trastuzumab and retrospectively analyzed patients who developed recurrent breast cancer after standard adjuvant treatment. The aim of this study was to determine the impact of subtype and the year of recurrence on the survival times of recurrent breast cancer.
Table 1 Patients characteristics. Year of recurrence: n (%)
Age ER
HER2
Materials and methods
Ki-67
Patients We retrospectively analyzed a total of 5542 primary breast cancer patients who were treated at Kumamoto City Hospital between January 1979 and December 2013. The follow-up period was at least 10 years after initial surgery and no patients were lost or excluded in this time period. However, there was no way to identify patients with recurrence after 10 years unless they visited our hospital for treatment. In order to avoid the possibility of not receiving information of patient recurrence or death of any cause, we contact them at least once a year so that we can accurately update our records. In this follow-up period, we identified 813 recurrent breast cancer and included current study. They were divided into two groups based on the year of recurrence; before 2000 group (n ¼ 381) and after 2001 group (n ¼ 432). The rationale for setting 2001 as the cut-off point was that 2001 was the year that AI and trastuzumab were approved in Japan. Survival after recurrence was then compared between the two groups based on the following criteria: subtypes (Luminal-A, -B, -HER2, HER2-enriched, TN); DFI (2, 2e5 and >5 years); and dominant recurrent site (soft tissue, bone and viscera). The subtypes were selected from primary tumor samples and the patients with unknown ER/PR, HER2 and Ki-67 values were omitted (n ¼ 344, 42.3%) The dominant recurrent site was categorized as follows: soft tissue dominant disease (local recurrence to the skin, chest wall, lymph nodes, or breast); bone dominant disease (bone metastases with or without soft tissue involvement); and visceral dominant disease (metastases to organs with or without bone or soft tissue involvement). The median follow-up period after recurrence was 4.3 years. Details of postoperative adjuvant therapy are described in our article [8]. This study was approved by the Ethics Committee at Kumamoto City Hospital.
589
DFI
Dominant recurrent site
median range positive negative unknown positive negative unknown 20% 21-50% 51% unknown <2 year 2-5 year >5 year soft tissue bone viscera unknown
Before 2000
After 2001
50 26-84 165 (43) 186 (59) 30 (8) 22 (6) 51 (13) 308 (81) 97 (25) 106 (28) 64 (17) 114 (30) 185 (49) 124 (33) 72 (18) 150 (40) 92 (24) 139 (36) 0 (0)
55 28-89 311 (72) 117 (27) 4 (1) 104 (24) 286 (66) 42 (10) 139 (32) 217 (50) 75 (17) 4 (1) 153 (35) 145 (34) 134 (31) 155 (36) 90 (21) 171 (40) 16 (3)
p value
<0.0001 <0.0001
0.056
0.0145
<0.0001
0.0006
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; DFI, disease free interval.
index value). The cut-off point for the Ki-67 index value was based on the guidelines of the European Society for Medical Oncology [17] and set at 20%.
Statistics The chi-square test and Fisher's exact test were used for the intergroup comparisons (Table 1). Survival after recurrence was defined as the interval from the date of diagnosis of recurrence to death from any cause. All patients who were still alive at the time of the last analysis (December 2013) were censored. Cumulative survival after recurrence was calculated using the KaplaneMeier method and tested using the log-rank test. Multivariate analysis of factors related to survival after recurrence was performed using the Cox proportional hazards regression model. All statistical analyses were carried out using JMP8 software (SAS Institute).
Histopathological analysis Factors investigated included the presence or absence of lymph node metastasis, nuclear grade, ER/PR status, the Ki-67 index value and HER2 overexpression at primary tumor. Immunohistochemistry (IHC) for ER, PR, Ki-67 and HER2 was done as previously described [14]. ER/PR status was assessed by enzyme immunoassay until the year 2000 and IHC after 2001 [15]. The proliferative activity was determined by IHC using the Ki-67 antibody (Dako), and evaluated based on the percentage of positive cells; 20%, 21e50% and >50% [16]. HER2 status was evaluated according to the guidelines of the American Society of Clinical Oncology/College of American Pathologists. We classified the subtypes as follows: Luminal A (ER positive, any PR, HER2 negative and a Ki-67 index value 20%); Luminal B (ER positive, any PR, HER2 negative and a Ki-67 index value >20%); LuminalHER2 (ER positive, any PR, HER2 positive and any Ki-67 index value); HER2-enriched (ER/PR negative, HER2 positive and any Ki-67 index value); and TN (ER/PR/HER2 negative and any Ki-67
Fig. 1. Survival after recurrence in all of the patients with recurrent breast cancer according to the year of recurrence. (HR, hazard ratio).
590
M. Nakano et al. / The Breast 24 (2015) 588e593
Results The distributions of patients according to the year of recurrence are presented in Table 1. The median age of patients with
recurrence in the after 2001 group was significantly higher than that of the before 2000 group. Over time, the proportion of patients with ER positive recurrent breast cancer increased and the proportion with visceral dominant metastases increased
Fig. 2. Survival after recurrence according to the year of recurrence in patients with (A) Luminal-A (n ¼ 102), (B) Luminal-B (n ¼ 168), (C) Luminal-HER2 (n ¼ 62), (D) HER2enriched (n ¼ 65) and (E) Triple Negative subtypes (n ¼ 72).
M. Nakano et al. / The Breast 24 (2015) 588e593
591
while the proportion with soft-tissue dominant disease decreased. Also over time the DFI for patients with recurrent breast cancer increased with higher proportion with a DFI >5 years. Comparing the survival period of 813 recurrent breast cancer patients, survival after recurrence significantly improved in the after 2001 group (p < 0.0001, HR: 0.65; Fig. 1). The median survival of each group was 25.9 and 45.3 months respectively. Survival in the after 2001 group was about twice as long as survival in the before 2000 group. We also analyzed survival after recurrence according to the subtypes (Luminal-A, -B, -HER2, HER2-enriched and TN) in only the patients with the subtype was known (n ¼ 469). The findings revealed that only the HER2-enriched subtype showed significant improvement in survival after recurrence (p ¼ 0.0003, HR: 0.30; Fig. 2D). No prolongation of survival was seen in any of the other four subtypes of the three groups (Fig. 2AeC and E). Next, we examined survival after recurrence according to DFI (within 2 years, 2e5 years and more than 5 years). Table 2 shows that survival after recurrence was longer in patients with longer DFI, probably because longer DFI indicates less aggressive breast cancer. However, patients with a shorter DFI of within 2 years and 2e5 years showed significant prolongations of survival after recurrence in the after 2001 group compared with the before 2000 group (p ¼ 0.0022, HR: 0.69 and p ¼ 0.0061, HR: 0.66; respectively), while there was no prolongation of survival in patients with a longer DFI of more than 5 years (Fig. 3AeC). Finally, we investigated survival after recurrence according to the dominant recurrent site (soft tissue, bone and viscera) and found that there was no difference in cases with bone metastasis, and that there was significant improvement in survival after recurrence in cases with soft tissue and visceral metastases (p ¼ 0.0017, HR: 0.64 and p < 0.0001, HR: 0.56; respectively; Fig. 4AeC). Multivariate analysis was performed to identify the independent factors for survival after recurrence (Table 2) and to evaluate them according to the subtypes (Table 3). DFI, ER and HER2 status, the Ki-67 index value and the dominant recurrent site were significant factors while the year of recurrence was not significant factor in all patients with recurrent breast cancer (Table 2). However, all of the items were significant independent factors in the HER2-enriched subtype, and HER2-enriched was the only subtype that year of recurrence significantly related to survival after recurrence (Table 3).
Table 2 Multivariate analysis for survival after recurrence. HR Year of Recurrence DFI
ER HER2 Ki-67
Dominant recurrent site
Before 2000 After 2001 <2 year 2-5 year >5 year positive negative positive negative 20% 21-50% 51% soft tissue bone viscera
1 0.884 1 0.488 0.424 1 1.477 1 1.703 1 1.574 1.877 1 1.826 2.022
95%CI
p value
0.669-1.184
0.401
0.369-0.642 0.299-0.593
<0.0001 <0.0001
1.119-1.946
0.006
1.288-2.269
0.0002
1.169-2.138 1.295-2.724
0.0026 0.0009
1.301-2.550 1.538-2.666
0.0006 <0.0001
Abbreviations: HR, hazard ratio; 95%CI, 95% confidence interval.
Fig. 3. Survival after recurrence according to the year of recurrence in patients with (A) disease free interval (DFI) 2years, (B) 2e5 years and (C) > 5 years.
592
M. Nakano et al. / The Breast 24 (2015) 588e593
Discussion
Fig. 4. Survival after recurrence according to the year of recurrence in patients with dominantly metastasized to (A) soft tissue, (B) bone and (C) viscera.
This study found that the survival time of patients with recurrent HER2-enriched breast cancer increased indicating that perhaps the introduction of trastuzumab played an important role in this result. In addition, there has been no trastuzumab equivalent for triple negative or ER positive breast cancer and the survival time in these cancer subtypes has not changed. Survival after recurrence has increased for HER2-enriched subtype even though the difference was not significant for Luminal-HER2 subtype. Trastuzumab influenced the prognosis of HR-negative and HER2-positive breast cancer but may have had a limited effect on HR-positive and HER2-positive breast cancer possibly due to cross-talk signaling between ER and HER2 [18]; and, breast cancer heterogeneity could be associated with the difficulty of treating patients with MBC according to the subtypes [19,20]. We also found that the survival time of patients with a shorter DFI (within 2 or 5 years) increased and that a longer DFI of more than 5 years did not significantly improve. ATAC trial demonstrated that in adjuvant settings, AI was more effective to suppress the recurrence within 5years from surgery than over 5 years compared to tamoxifen [21]. In addition, patients with HER2enriched subtype had frequently shorter DFI and showed a significant improvement in survival time when the new trastuzumab treatment was introduced. This finding suggests that survival in the shorter DFI group improved while survival in the longer DFI group did not change. Moreover, we found the survival time of patients with soft tissue and visceral metastases increased and that bone metastases did not increase. Bone metastases were more common in ER positive and HER2 negative breast cancer than other subtypes such as HER2 positive or triple negative [22,23]. Bone metastases were not so aggressive suggesting that it might have been difficult to detect a difference of the survival time over time. Many researchers agree that third-generation AI and HER2 targeting agent, trastuzumab are both useful in treating patients with MBC [24e27]. In fact, a few studies have shown that survival after recurrence has improved in Japan except in case with HR-negative and HER2-negative breast cancer [12]. On the other hand, some studies have concluded that survival in the past few decades has not improved at all [13,28]. We compared our findings with the findings of other studies. Shigematsu et al. [12] divided MBC into four groups (HR-positive/-negative and HER2-positve/-negative) and found that survival in all of the groups except HR-negative and HER2-negative improved. However, they did not determine the Ki67 index value which could be a reason why their findings were different from ours. Tevaarwerk et al. [13] found that survival improved in only the HR-negative and shorter DFI group which is consistent with our findings. The limitations of this study include: retrospective and the sample size per group was relatively small; it was difficult to identify some of the patients subtype in the before 2000 group. Moreover, dividing into five subtypes made the number of each sample smaller. So the statistical power was not sufficient for definitive conclusion. Further investigation with larger sample size is needed to confirm our findings. In conclusion, our findings suggest that the survival time after recurrence increased only in the HER2-enriched subtype despite the introduction of AI and trastuzumab. To prolong the survival time after recurrence of both Luminal and TN subtypes, we need to develop novel targeting therapies to effectively treat refractory recurrent breast cancer. Moreover, it might be effective to introduce chemotherapy in the earlier stage of patients with ER positive MBC.
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Table 3 Multivariate analysis for survival after recurrence according to the breast cancer subtypes. Luminal-A (n ¼ 102) HR Year of Recurrence DFI
Dominant recurrent site
Before 2000 After 2001 <2 year 2-5 year >5 year soft tissue bone viscera
1 1.252 1 0.991 0.795 1 1.100 1.031
Luminal-B (n ¼ 168) p value 0.513 0.983 0.578 0.799 0.932
HR 1 1.415 1 0.308 0.349 1 1.355 1.757
p value 0.184 <0.0001 <0.0001 0.223 0.019
Luminal-HER2 (n ¼ 62)
HER2-enriched (n ¼ 65)
Triple negative (n ¼ 72)
HR
HR
HR
1 0.814 1 1.009 0.582 1 1.695 1.637
p value 0.655 0.979 0.287 0.295 0.190
1 0.383 1 0.437 0.240 1 6.694 3.145
p value 0.015 0.029 0.030 0.003 0.004
1 0.986 1 0.435 0.530 1 2.618 2.253
p value 0.963 0.023 0.178 0.092 0.005
Abbreviations: HR, hazard ratio; DFI, disease free interval.
Conflict of interest statement None. Acknowledgment We would like to thank the staff at the Department of Pathology in Kumamoto City Hospital for their technical assistance and for collecting cancer tissue. References [1] Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69e90. [2] Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M, et al. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 2011;378:1707e16. [3] Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 2011;378: 771e84. [4] Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer Jr CE, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011;29: 3366e73. [5] Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, et al. Comparisons between different polychemotherapy regimens for early breast cancer: metaanalyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet 2012;379:432e44. [6] Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn HJ. Strategies for subtypesedealing with the diversity of breast cancer: highlights of the St. Gallen international expert consensus on the primary therapy of early breast Cancer 2011. Ann Oncol 2011;22:1736e47. [7] Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast Cancer 2013. Ann Oncol 2013;24:2206e23. [8] Nishimura R, Osako T, Nishiyama Y, Tashima R, Nakano M, Fujisue M, et al. Prognostic significance of Ki-67 index value at the primary breast tumor in recurrent breast cancer. Mol Clin Oncol 2014;2:1062e8. [9] Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 2007;110:973e9. [10] Dawood S, Broglio K, Gonzalez-Angulo AM, Buzdar AU, Hortobagyi GN, Giordano SH. Trends in survival over the past two decades among white and black patients with newly diagnosed stage IV breast cancer. J Clin Oncol 2008;26:4891e8. [11] Giordano SH, Buzdar AU, Smith TL, Kau SW, Yang Y, Hortobagyi GN. Is breast cancer survival improving? Cancer 2004;100:44e52. [12] Shigematsu H, Kawaguchi H, Nakamura Y, Tanaka K, Shiotani S, Koga C, et al. Significant survival improvement of patients with recurrent breast cancer in the periods 2001-2008 vs. 1992-2000. BMC Cancer 2011;11:118.
[13] Tevaarwerk AJ, Gray RJ, Schneider BP, Smith ML, Wagner LI, Fetting JH, et al. Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: little evidence of improvement over the past 30 years. Cancer 2013;119:1140e8. [14] Kai K, Nishimura R, Arima N, Miyayama H, Iwase H. p53 expression status is a significant molecular marker in predicting the time to endocrine therapy failure in recurrent breast cancer: a cohort study. Int J Clin Oncol 2006;11: 426e33. [15] Nishimura R, Osako T, Nishiyama Y, Tashima R, Nakano M, Fujisue M, et al. Evaluation of factors related to late recurrenceelater than 10 years after the initial treatmentein primary breast cancer. Oncology 2013;85:100e10. [16] 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: 747e54. [17] Senkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson A, Zackrisson S, et al. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24(Suppl. 6):vi7e23. [18] Massarweh S, Schiff R. Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res 2007;13: 1950e4. [19] Aurilio G, Disalvatore D, Pruneri G, Bagnardi V, Viale G, Curigliano 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;50:277e89. [20] Nishimura R, Osako T, Okumura Y, Tashima R, Toyozumi Y, Arima N. Changes in the ER, PgR, HER2, p53 and Ki-67 biological markers between primary and recurrent breast cancer: discordance rates and prognosis. World J Surg Oncol 2011;9:131. [21] Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:1135e41. [22] Lee SJ, Park S, Ahn HK, Yi JH, Cho EY, Sun JM, et al. Implications of bone-only metastases in breast cancer: favorable preference with excellent outcomes of hormone receptor positive breast cancer. Cancer Res Treat 2011;43:89e95. [23] Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, et al. Subtypes of breast cancer show preferential site of relapse. Cancer Res 2008;68:3108e14. [24] Bonneterre J, Thurlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, et al. Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 2000;18:3748e57. [25] Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, et al. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The exemestane study Group. J Clin Oncol 2000;18:1399e411. [26] Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the international Letrozole breast Cancer Group. J Clin Oncol 2003;21:2101e9. [27] Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783e92. [28] Largillier R, Ferrero JM, Doyen J, Barriere J, Namer M, Mari V, et al. Prognostic factors in 1,038 women with metastatic breast cancer. Ann Oncol 2008;19: 2012e9.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Survival time according to the year of recurrence and subtype in recurrent breast cancer Masahiro Nakano a, *, Mamiko Fujisue a, Rumiko Tashima b, Yasuhiro Okumura a, Yasuyuki Nishiyama a, Tomofumi Ohsako a, Yasuo Toyozumi c, Nobuyuki Arima c, Reiki Nishimura a a b c
Department of Breast and Endocrine Surgery, Kumamoto City Hospital, 1-1-60, Kotoh, Higashi-ku, Kumamoto 860-8505, Japan Department of Surgery, Kumamoto City Hospital, 1-1-60, Kotoh, Higashi-ku, Kumamoto 860-8505, Japan Department of Pathology, Kumamoto City Hospital, 1-1-60, Kotoh, Higashi-ku, Kumamoto 860-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 12 November 2014 Received in revised form 14 May 2015 Accepted 4 June 2015 Available online 20 June 2015
Background: Survival for patients with recurrent breast cancer has improved over time due to the introduction of modern systemic therapy. The aim of this study was to determine the impact of subtype and the year of recurrence on the survival times of recurrent breast cancer. Methods: Between 1979 and 2013, 813 patients who underwent initial treatment for primary breast cancer experienced recurrence. They were divided into two groups based on the year of recurrence; before 2000 and after 2001. Survival after recurrence was compared between these groups based on following criteria; subtypes, disease free interval (DFI), and dominant recurrent site. The median followup period after recurrence was 4.3 years. Results: Survival improved significantly in the after 2001 group, and a significant improvement in survival was only seen in the HER2-enriched subtype. Multivariate analysis revealed that DFI, ER, HER2 status, dominant recurrent site and the Ki-67 index value were significant prognostic factors. In the HER2-enriched subtype, the year of recurrence, DFI and dominant recurrent site were significant independent factors. In the other subtypes, these factors were not correlated with survival. Conclusion: Our study revealed that the survival rate of patients with only the HER2-enriched subtype significantly improved after recurrence. To prolong the survival time after recurrence of both luminal and triple negative subtypes, the development of novel targeting therapies to overcome refractory recurrent breast cancer is extremely important. © 2015 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Survival after recurrence Subtype Disease free interval Metastatic disease
Introduction Metastatic breast cancer (MBC) is the leading cause of cancer death among females worldwide with over 400,000 dying each year [1]. Although the mortality of early stage breast cancer has certainly declined due to evidence-based multidisciplinary treatment [2e5], breast cancer heterogeneity often causes recurrence resulting in an incurable disease. Now, it is widely accepted that the intrinsic subtype is an important prognostic and predictive factor in breast cancer [6]. Current treatment algorithms are generally based on the
* Corresponding author. Tel.: þ81 96 365 1711; fax: þ81 96 365 1796. E-mail address: [email protected] (M. Nakano). http://dx.doi.org/10.1016/j.breast.2015.06.003 0960-9776/© 2015 Elsevier Ltd. All rights reserved.
subtypes divided by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and the Ki-67 index value not only in adjuvant but also in metastatic settings [7,8]. Previous studies have reported that survival for MBC improved due to the introduction of modern systemic therapy [9e11]. Other studies were able to demonstrate an improvement in looking at the ER status [12,13]. However, the prolongation of survival according to Luminal-A, -B, -HER2, HER2-enriched and Triple Negative (TN) breast cancer subtypes is still unclear. Various newly developed drugs, such as taxanes, were approved in the late 1990s and third-generation aromatase inhibitors (AI) and trastuzumab, were approved in 2001 for clinical use in Japan resulting in a more favorable prognosis for MBC than previously expected [12]. However, there were few
M. Nakano et al. / The Breast 24 (2015) 588e593
studies that analyzed the survival time of MBC according to subtypes. We hypothesized that survival in ER positive and/or HER2 positive MBC would be longer due to the introduction of AI and trastuzumab and retrospectively analyzed patients who developed recurrent breast cancer after standard adjuvant treatment. The aim of this study was to determine the impact of subtype and the year of recurrence on the survival times of recurrent breast cancer.
Table 1 Patients characteristics. Year of recurrence: n (%)
Age ER
HER2
Materials and methods
Ki-67
Patients We retrospectively analyzed a total of 5542 primary breast cancer patients who were treated at Kumamoto City Hospital between January 1979 and December 2013. The follow-up period was at least 10 years after initial surgery and no patients were lost or excluded in this time period. However, there was no way to identify patients with recurrence after 10 years unless they visited our hospital for treatment. In order to avoid the possibility of not receiving information of patient recurrence or death of any cause, we contact them at least once a year so that we can accurately update our records. In this follow-up period, we identified 813 recurrent breast cancer and included current study. They were divided into two groups based on the year of recurrence; before 2000 group (n ¼ 381) and after 2001 group (n ¼ 432). The rationale for setting 2001 as the cut-off point was that 2001 was the year that AI and trastuzumab were approved in Japan. Survival after recurrence was then compared between the two groups based on the following criteria: subtypes (Luminal-A, -B, -HER2, HER2-enriched, TN); DFI (2, 2e5 and >5 years); and dominant recurrent site (soft tissue, bone and viscera). The subtypes were selected from primary tumor samples and the patients with unknown ER/PR, HER2 and Ki-67 values were omitted (n ¼ 344, 42.3%) The dominant recurrent site was categorized as follows: soft tissue dominant disease (local recurrence to the skin, chest wall, lymph nodes, or breast); bone dominant disease (bone metastases with or without soft tissue involvement); and visceral dominant disease (metastases to organs with or without bone or soft tissue involvement). The median follow-up period after recurrence was 4.3 years. Details of postoperative adjuvant therapy are described in our article [8]. This study was approved by the Ethics Committee at Kumamoto City Hospital.
589
DFI
Dominant recurrent site
median range positive negative unknown positive negative unknown 20% 21-50% 51% unknown <2 year 2-5 year >5 year soft tissue bone viscera unknown
Before 2000
After 2001
50 26-84 165 (43) 186 (59) 30 (8) 22 (6) 51 (13) 308 (81) 97 (25) 106 (28) 64 (17) 114 (30) 185 (49) 124 (33) 72 (18) 150 (40) 92 (24) 139 (36) 0 (0)
55 28-89 311 (72) 117 (27) 4 (1) 104 (24) 286 (66) 42 (10) 139 (32) 217 (50) 75 (17) 4 (1) 153 (35) 145 (34) 134 (31) 155 (36) 90 (21) 171 (40) 16 (3)
p value
<0.0001 <0.0001
0.056
0.0145
<0.0001
0.0006
Abbreviations: ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; DFI, disease free interval.
index value). The cut-off point for the Ki-67 index value was based on the guidelines of the European Society for Medical Oncology [17] and set at 20%.
Statistics The chi-square test and Fisher's exact test were used for the intergroup comparisons (Table 1). Survival after recurrence was defined as the interval from the date of diagnosis of recurrence to death from any cause. All patients who were still alive at the time of the last analysis (December 2013) were censored. Cumulative survival after recurrence was calculated using the KaplaneMeier method and tested using the log-rank test. Multivariate analysis of factors related to survival after recurrence was performed using the Cox proportional hazards regression model. All statistical analyses were carried out using JMP8 software (SAS Institute).
Histopathological analysis Factors investigated included the presence or absence of lymph node metastasis, nuclear grade, ER/PR status, the Ki-67 index value and HER2 overexpression at primary tumor. Immunohistochemistry (IHC) for ER, PR, Ki-67 and HER2 was done as previously described [14]. ER/PR status was assessed by enzyme immunoassay until the year 2000 and IHC after 2001 [15]. The proliferative activity was determined by IHC using the Ki-67 antibody (Dako), and evaluated based on the percentage of positive cells; 20%, 21e50% and >50% [16]. HER2 status was evaluated according to the guidelines of the American Society of Clinical Oncology/College of American Pathologists. We classified the subtypes as follows: Luminal A (ER positive, any PR, HER2 negative and a Ki-67 index value 20%); Luminal B (ER positive, any PR, HER2 negative and a Ki-67 index value >20%); LuminalHER2 (ER positive, any PR, HER2 positive and any Ki-67 index value); HER2-enriched (ER/PR negative, HER2 positive and any Ki-67 index value); and TN (ER/PR/HER2 negative and any Ki-67
Fig. 1. Survival after recurrence in all of the patients with recurrent breast cancer according to the year of recurrence. (HR, hazard ratio).
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Results The distributions of patients according to the year of recurrence are presented in Table 1. The median age of patients with
recurrence in the after 2001 group was significantly higher than that of the before 2000 group. Over time, the proportion of patients with ER positive recurrent breast cancer increased and the proportion with visceral dominant metastases increased
Fig. 2. Survival after recurrence according to the year of recurrence in patients with (A) Luminal-A (n ¼ 102), (B) Luminal-B (n ¼ 168), (C) Luminal-HER2 (n ¼ 62), (D) HER2enriched (n ¼ 65) and (E) Triple Negative subtypes (n ¼ 72).
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while the proportion with soft-tissue dominant disease decreased. Also over time the DFI for patients with recurrent breast cancer increased with higher proportion with a DFI >5 years. Comparing the survival period of 813 recurrent breast cancer patients, survival after recurrence significantly improved in the after 2001 group (p < 0.0001, HR: 0.65; Fig. 1). The median survival of each group was 25.9 and 45.3 months respectively. Survival in the after 2001 group was about twice as long as survival in the before 2000 group. We also analyzed survival after recurrence according to the subtypes (Luminal-A, -B, -HER2, HER2-enriched and TN) in only the patients with the subtype was known (n ¼ 469). The findings revealed that only the HER2-enriched subtype showed significant improvement in survival after recurrence (p ¼ 0.0003, HR: 0.30; Fig. 2D). No prolongation of survival was seen in any of the other four subtypes of the three groups (Fig. 2AeC and E). Next, we examined survival after recurrence according to DFI (within 2 years, 2e5 years and more than 5 years). Table 2 shows that survival after recurrence was longer in patients with longer DFI, probably because longer DFI indicates less aggressive breast cancer. However, patients with a shorter DFI of within 2 years and 2e5 years showed significant prolongations of survival after recurrence in the after 2001 group compared with the before 2000 group (p ¼ 0.0022, HR: 0.69 and p ¼ 0.0061, HR: 0.66; respectively), while there was no prolongation of survival in patients with a longer DFI of more than 5 years (Fig. 3AeC). Finally, we investigated survival after recurrence according to the dominant recurrent site (soft tissue, bone and viscera) and found that there was no difference in cases with bone metastasis, and that there was significant improvement in survival after recurrence in cases with soft tissue and visceral metastases (p ¼ 0.0017, HR: 0.64 and p < 0.0001, HR: 0.56; respectively; Fig. 4AeC). Multivariate analysis was performed to identify the independent factors for survival after recurrence (Table 2) and to evaluate them according to the subtypes (Table 3). DFI, ER and HER2 status, the Ki-67 index value and the dominant recurrent site were significant factors while the year of recurrence was not significant factor in all patients with recurrent breast cancer (Table 2). However, all of the items were significant independent factors in the HER2-enriched subtype, and HER2-enriched was the only subtype that year of recurrence significantly related to survival after recurrence (Table 3).
Table 2 Multivariate analysis for survival after recurrence. HR Year of Recurrence DFI
ER HER2 Ki-67
Dominant recurrent site
Before 2000 After 2001 <2 year 2-5 year >5 year positive negative positive negative 20% 21-50% 51% soft tissue bone viscera
1 0.884 1 0.488 0.424 1 1.477 1 1.703 1 1.574 1.877 1 1.826 2.022
95%CI
p value
0.669-1.184
0.401
0.369-0.642 0.299-0.593
<0.0001 <0.0001
1.119-1.946
0.006
1.288-2.269
0.0002
1.169-2.138 1.295-2.724
0.0026 0.0009
1.301-2.550 1.538-2.666
0.0006 <0.0001
Abbreviations: HR, hazard ratio; 95%CI, 95% confidence interval.
Fig. 3. Survival after recurrence according to the year of recurrence in patients with (A) disease free interval (DFI) 2years, (B) 2e5 years and (C) > 5 years.
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Discussion
Fig. 4. Survival after recurrence according to the year of recurrence in patients with dominantly metastasized to (A) soft tissue, (B) bone and (C) viscera.
This study found that the survival time of patients with recurrent HER2-enriched breast cancer increased indicating that perhaps the introduction of trastuzumab played an important role in this result. In addition, there has been no trastuzumab equivalent for triple negative or ER positive breast cancer and the survival time in these cancer subtypes has not changed. Survival after recurrence has increased for HER2-enriched subtype even though the difference was not significant for Luminal-HER2 subtype. Trastuzumab influenced the prognosis of HR-negative and HER2-positive breast cancer but may have had a limited effect on HR-positive and HER2-positive breast cancer possibly due to cross-talk signaling between ER and HER2 [18]; and, breast cancer heterogeneity could be associated with the difficulty of treating patients with MBC according to the subtypes [19,20]. We also found that the survival time of patients with a shorter DFI (within 2 or 5 years) increased and that a longer DFI of more than 5 years did not significantly improve. ATAC trial demonstrated that in adjuvant settings, AI was more effective to suppress the recurrence within 5years from surgery than over 5 years compared to tamoxifen [21]. In addition, patients with HER2enriched subtype had frequently shorter DFI and showed a significant improvement in survival time when the new trastuzumab treatment was introduced. This finding suggests that survival in the shorter DFI group improved while survival in the longer DFI group did not change. Moreover, we found the survival time of patients with soft tissue and visceral metastases increased and that bone metastases did not increase. Bone metastases were more common in ER positive and HER2 negative breast cancer than other subtypes such as HER2 positive or triple negative [22,23]. Bone metastases were not so aggressive suggesting that it might have been difficult to detect a difference of the survival time over time. Many researchers agree that third-generation AI and HER2 targeting agent, trastuzumab are both useful in treating patients with MBC [24e27]. In fact, a few studies have shown that survival after recurrence has improved in Japan except in case with HR-negative and HER2-negative breast cancer [12]. On the other hand, some studies have concluded that survival in the past few decades has not improved at all [13,28]. We compared our findings with the findings of other studies. Shigematsu et al. [12] divided MBC into four groups (HR-positive/-negative and HER2-positve/-negative) and found that survival in all of the groups except HR-negative and HER2-negative improved. However, they did not determine the Ki67 index value which could be a reason why their findings were different from ours. Tevaarwerk et al. [13] found that survival improved in only the HR-negative and shorter DFI group which is consistent with our findings. The limitations of this study include: retrospective and the sample size per group was relatively small; it was difficult to identify some of the patients subtype in the before 2000 group. Moreover, dividing into five subtypes made the number of each sample smaller. So the statistical power was not sufficient for definitive conclusion. Further investigation with larger sample size is needed to confirm our findings. In conclusion, our findings suggest that the survival time after recurrence increased only in the HER2-enriched subtype despite the introduction of AI and trastuzumab. To prolong the survival time after recurrence of both Luminal and TN subtypes, we need to develop novel targeting therapies to effectively treat refractory recurrent breast cancer. Moreover, it might be effective to introduce chemotherapy in the earlier stage of patients with ER positive MBC.
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Table 3 Multivariate analysis for survival after recurrence according to the breast cancer subtypes. Luminal-A (n ¼ 102) HR Year of Recurrence DFI
Dominant recurrent site
Before 2000 After 2001 <2 year 2-5 year >5 year soft tissue bone viscera
1 1.252 1 0.991 0.795 1 1.100 1.031
Luminal-B (n ¼ 168) p value 0.513 0.983 0.578 0.799 0.932
HR 1 1.415 1 0.308 0.349 1 1.355 1.757
p value 0.184 <0.0001 <0.0001 0.223 0.019
Luminal-HER2 (n ¼ 62)
HER2-enriched (n ¼ 65)
Triple negative (n ¼ 72)
HR
HR
HR
1 0.814 1 1.009 0.582 1 1.695 1.637
p value 0.655 0.979 0.287 0.295 0.190
1 0.383 1 0.437 0.240 1 6.694 3.145
p value 0.015 0.029 0.030 0.003 0.004
1 0.986 1 0.435 0.530 1 2.618 2.253
p value 0.963 0.023 0.178 0.092 0.005
Abbreviations: HR, hazard ratio; DFI, disease free interval.
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