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Improved survival in metastatic breast cancer 1985–2016
The Breast 31 (2017) 46e50
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Improved survival in metastatic breast cancer 1985e2016 € ran Tejler c Marie Sundquist a, *, Lars Brudin b, Go a
Kalmar County Breast Centre, Surgery, County Hospital, Kalmar, Sweden Dep of Physiology, County Hospital, Kalmar, Sweden c €stervik Hospital, Sweden Kalmar County Breast Centre, Surgery, Va b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2016 Accepted 10 October 2016 Available online 2 November 2016
Purpose: In the last 25 years new treatment options in breast cancer have evolved. We wanted to determine whether the survival of; patients with metastatic breast cancer have improved during this period. Methods: Patients consecutively diagnosed with disseminated breast cancer 1985e2014 in the County of Kalmar, Sweden, were identified and followed to 2016. Survival was calculated for each successive 5 year interval. Separate analyses were performed for pts with ER and/or PR and HER2 positive tumours resp. Results: Median survival of the 784 patients increased successively from 13 to 33 months. Five year survival increased from 10 to 27%. Patients with high grade primary tumours had the shortest post recurrence survival time but their median survival increased significantly by time from 12 to 30 months, 3 year survival from 16 to 38% and 5 year from 5 to 20%. Median survival for patients with grade 2 tumours was 2 years and did not improve. Only 47 patients had grade 1 tumours and their median survival of 4 years did not change. Median survival for HER2 positive patients treated before the introduction of trastuzumab in year 2000 was 14 months and after 2000 29 months, 5 year survival improved from 2 to 31%. Conclusions: Survival in metastatic breast cancer improved 1985e2016. For the first time a significant increase in survival time for patients with metastasis from fast-growing grade 3 tumours was seen. The most striking improvement was achieved in the HER2 positive subset. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Metastatic Survival Prognosis
1. Introduction Approximately one third of patients with primary breast cancer will eventually develop disseminated disease [1]. Disease-free interval is known to vary from months to decades. Mortality due to breast cancer occurs up to 40 years after primary diagnosis [2]. Systemic breast cancer is essentially incurable. Few per cent of patients diagnosed with distant metastasis die without signs of breast cancer [3]. The clinical course of patients with distant metastases is however highly variable. Some die within months after detection of dissemination but some live with a high quality of life for ten or more years. In the last 25 years several new treatment options in breast cancer have evolved. The taxanes were introduced in the nineties,
* Corresponding author. E-mail addresses: [email protected] (M. Sundquist), lars.brudin@ ltkalmar.se (L. Brudin), [email protected] (G. Tejler). http://dx.doi.org/10.1016/j.breast.2016.10.005 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
as were dose dense regimens of anthracyclines. Aromatase inhibitors came into use in the metastatic setting in 1997 and fulvestrant in 2005. The first immunologic treatment in breast cancer, trastuzumab, became available year 2000. We wanted to determine whether the survival of patients with metastatic breast cancer has improved during this period. Approximately 30e40% of patients with recurrences restricted to the preserved breast, ipsilateral chest wall or axillary nodes remain free of distant disease during an observation time of 7e10 years [4e6]. In the present study the outcomes of patients with truly disseminated disease was explored. Patients with loco regional recurrence or a new primary in the contra lateral breast without signs of distant metastasis were excluded from the investigation. Further, we wanted to assess predictors of disease development in metastatic breast cancer. Disease free interval [7,8], steroid receptor level [9], age [10,11], S-phase fraction [12,13], histological grade [5,7,12,14,15], histological type [16] and tumour HER2 expression [17] have been associated with survival after dissemination.
M. Sundquist et al. / The Breast 31 (2017) 46e50
2. Patients and methods 2.1. Patients All patients with a diagnosis of disseminated breast cancer established between 1985 and 2014 in the county of Kalmar with 240 000 inhabitants were identified from the patient's registry. Patient and tumour data were retrieved from patient records and the pathology database. Patients with recurrences exclusively within the ipsilateral chest wall or mammary and axillary region were excluded as were tumours occurring in the contralateral breast. If distant metastases were diagnosed before or within 3 months from the diagnosis of the primary breast tumour it was classified as primary distant metastatic, de novo, disease. To ensure the comparability of patients between time periods histological grading and receptor assessments were validated. 2.2. Pathology Histological type and grade had been routinely assessed in the primary tumour and when possible in the metastases since 1985. Nottingham histological grade (NHG) was assessed according to the protocol of Elston/Ellis [18]. Validation of grading of the primary tumours was performed in 1999 and 2010 [19,20]. There was no significant change in the distribution of NHG 1, 2 and 3 in the primary tumours over the time periods. In 50 patients diagnosed with metastasis before 1990 and in approximately 1 patient each year thereafter it was not possible to grade the primary tumour. The primary tumour characteristics have been used in the investigation. 2.3. Hormone receptor determination Before 2000 hormone receptor status were determined using 2 different cytosol assays. Until 1989 isoelectric focusing (IF) on polyacrylamide gel and thereafter an enzyme immunoassay (EIA) was used [21,22]. For ER, studies have shown that results with these techniques correlate well with those obtained using methods based on ultra-centrifugation, dextran-coated charcoal and immunohistochemistry [21e24]. The cytosol receptor values were normalized to DNA content as measured by Burton [25]. Cut-off values defined approximately 70% of the tumours as ER and/or PR positive. Year 2000 and onwards tumour tissue was analysed for ER and PR status using immunohistochemistry. The fractions of ER and PR positive nuclei were determined and classified into four groups (0e10%, 11e50%, 51e75%, and >75%). Tumours with more than 10% positively staining nuclei were considered positive. The cytosol and IHC assays defined approximately the same proportion of tumours as positive [26] indicating the comparability of patients of different cohorts. 2.4. HER2 assessment HER2 status was assessed in the primary tumours from 1996 and onwards using IHC and subsequently FISH. A polyclonal rabbit anti human antibody against the HER-2 protein was used (Dako A 0485). Only samples with distinct staining in more than 75% of the entire membrane and in more than 75% of the tumour cell were judged as overexpressed. FISH analysis was performed using the FDA-approved Path-Vysions HER-2 DNA ProbeKit. Signal ratios (HER2:CEP17) of 2 were classified as amplified. 2.5. Adjuvant treatments In 1981 endocrine adjuvant therapy was introduced as
47
postmenopausal patients with oestrogen receptor positive tumours were offered two years of adjuvant tamoxifen, which in 1995 was extended to five years. From 2004 postmenopausal women with high grade tumours or node positivity were offered aromatase inhibitors either for 5 years or for 3 years followed by 2 years of tamoxifen. From 1989 endocrine therapy with tamoxifen was used also for premenopausal patients with hormone receptor positive disease and in the early nineties 2 years of LHRH agonist treatment was added for this group of patients. In 1981 also adjuvant chemotherapy was introduced when premenopausal patients with node positive disease received six months of CMF therapy. In the nineties adjuvant therapy with anthracycline containing regimens were introduced and used also for postmenopausal patient with node positive disease. From 2004 patients with high risk disease received adjuvant taxanes sequenced with anthracycline based therapy. From 2006 patients with HER2 amplified tumours were given trastuzumab for 1 year after chemotherapy. Only 11 of the patients with HER2 positive primary tumours had received trastuzumab in the adjuvant setting. 2.6. Data analysis and statistics Survival curves were constructed and median survival in months from the date of diagnosis of distant metastasis was determined for each successive interval of five years 1985e2014 for the cohort as a whole and by grade. The percentage of patients surviving more than 2, 3, and 5 and 10 years after the first metastatic event was determined for each group. In our hospitals the aromatase inhibitors came into use in the metastatic setting in 1997 and trastuzumab (Herceptin) in 2000. Fulvestrant (Faslodex) was introduced in 2005. Separate analyses were performed for patients with ER/PR positive and HER2 positive tumours, respectively, to determine whether the survival changed according to if distant disease was detected before or after the introduction of the new therapies. Significances were determined using Cox regression. Univariate survival distributions were estimated using the product limit method of Kaplan and Meier [27]. Death rates and tests of the statistical significance of relationship between study parameters and survival were computed using Cox's proportional hazards method [28]. Statistical analysis was computed using STATISTICA for Windows [29]. 3. Results Median disease-free interval (DFI) increased significantly over the time periods from 1, 8 to almost 6 years, p for trend <0.001. The median survival of the 784 patients in the whole study population increased significantly from 13 months to 15, 16, 20, 23 and 33 respectively for each successive five-year period from 1985 to 2014, p ¼ 0.009 (Fig. 1). Grade and hormone receptor status of the primary tumour were significantly correlated to survival after first metastatic event in the whole cohort of patients, p < 0.001 for both parameters. 3.1. Survival according to grade For patients with grade 3 tumours (N ¼ 411) the median survival improved gradually over time from 12 to 14, 15, 17, 17 and 30 months, for the six periods (Table 2, Fig. 2). The percentage of patients surviving more than three years improved from 16 to 38% and the five year survival increased from 3 to 17% (Table 1). The median survival for patients with grade 2 tumours (N ¼ 229) was 23 months and did not change significantly. Only 47 patients had grade 1 tumours with a median survival of 39 months and no
48
M. Sundquist et al. / The Breast 31 (2017) 46e50
3.2. Hormone receptor positive tumours Four hundred and forty eight patients had ER/PR positive tumours. The first half of the cohort (<2000) was compared to the second half and the percentages of patients surviving more than 2, 3 and 5 years respectively were calculated. Forty-seven percent of patients diagnosed before 2000 survived more than 2 years and 32% more than 3 years and 14% more than 5 years. Corresponding figures for patients diagnosed 2000 and later were 57, 39 and 19%, respectively (Table 2). When comparing the 91 patients treated with fulvestrant (a selective oestrogen receptor down-regulator; SERD) after it became available 2005 with earlier diagnosed ER/PR positive patients who would have been subjected to treatment with this substance had it been available, there was a significant difference in survival time in favour of fulvestrant (Cox regression; HR ¼ 0.62 (CI 0.47e0.84); p < 0.002). There was no corresponding increase in survival time for patients that received aromatase inhibitors in the metastatic setting. However, aromatase inhibitors were introduced in the adjuvant setting 2004. 3.3. HER2 positive tumours
Fig. 1. Cumulative survival of 784 patients diagnosed with metastatic breast cancer by successive time periods.
Forty-six patients with HER2þ tumours were treated before year 2000 and 69 patients from year 2000 and onwards. Two-year survival for patients with HER2þ tumours improved from 20 to 52%, three-year from 11 to 40 and five-year survival from 2 to 31% (Table 2, Fig. 3). Ninety of the HER2 positive tumours were of grade 3. In this subset 48% of patients diagnosed in 2000 or later survived more than two years, 34% more than three years and 28% more than five years and 13% more than 10 years, as compared to 12, and 3, 3, 3%, respectively for those diagnosed before the year 2000. Almost all patients diagnosed with metastases 2000 and later received trastuzumab but also 2 of patients diagnosed before 2000. 3.4. Triple negative tumours Seventy two patients with assessment of HER2 status had tumours that lacked ER, PR and HER2 (triple negative). Their median survival was 10 months and did not improve in the last half of the period as compared to the first. Only 23% survived 2 years or longer. 4. Discussion
Fig. 2. Two, 3, 5 and 10 year survival for pts with grade 3 tumours by period of diagnosis of metastatic disease. Table 1 DFI by time period and percentage of de novo cases. Recurrence period
N
De novo n (% of total)a
DFI - median (range)b
<1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 Total
124 147 160 129 152 72 784
29 (23.4) 19 (12.9) 23 (14.4) 21 (16.3) 28 (18.4) 6 (8.3) 126 (16.1)
1.83 3.02 4.24 4.88 4.08 5.99 3.50
a b
(0.27e13.8) (0.30e15.6) (0.34e31.7) (0.33e22.5) (0.33e24.2) (0.27e30.0) (0.27e31.7)
Up to three months from diagnosis. De novo excluded.
significant change over time. One third of the grade 1 patients survived for more than 5 years with metastatic disease and 20% for more than 10 years.
Our results support a trend shift towards improved survival for patients diagnosed with disseminated breast cancer. Powles concluded in 1980 that there had been no improvement in survival from first metastasis, and survival may even have been shortened in some patients given chemotherapy [30]. Patel found no increase in survival times from first recurrence 1942e75 [31]. Patanaphan reported the median survival after diagnosis of distant metastases 1969e77 to be less than 11 months after diagnosis of disseminated disease [32]. Debonis found no improvement in survival times of patients with metastatic breast cancer for five-year intervals diagnosed 1955e1980 [33]. Giordano et al. found that survival for patients with recurrent breast cancer improved from 1974 to 2000 [34]. However, in their report patients with exclusively loco regional recurrences were included. Tevaarwerk et al. found in 2013 no evidence of improved survival when reviewing 3447 patients having recurred after participating in adjuvant chemotherapy trials [35]. Giuliani and Bonetti concluded in 2015 that the OS of women with metastatic BC had not improved in the last years [36]. However, their study included only 70 patients diagnosed during 7 years. Chia et al. demonstrated in 2007 in a population-based study a significant successive improvement in survival time for patients
M. Sundquist et al. / The Breast 31 (2017) 46e50
49
Table 2 Post-recurrence survival (months) for patients presenting at different time periods with metastatic breast cancer calculated from the Kaplan-Meier curves using the total cohort and different subgroups. Q1 and Q3 are the lower and upper quartiles, respectively. Recurrence period
n
Survival (months and %) Median
Q1eQ3
2 yrs
3 yrs
5 yrs
10 yrs
All
ER/PR Neg Pos
Grade 1
2
3
HER2 Neg Pos
HER2 Pos and grade 3
<1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 Total
124 147 160 129 152 72 784
13 16 16 20 23 33 18
4e31 6e35 7e36 7e45 6e48 18e55 7e41
31 38 36 43 49 64 42
20 24 25 29 36 37 29
10 13 9 15 17 27 14
3 3 2 4 7 e 4
<2000 2000 <2000 2000 Total
119 92 192 256 563
11 12 22 30 19
4e23 5e32 9e42 13e50 7e42
23 29 47 57 43
14 19 32 39 29
8 14 14 19 15
3 4 4 5 5
<1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 <1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 <1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 Total
2 6 13 12 11 3 7 34 52 52 57 27 63 72 90 64 83 39 687
e 46 33 17 70 e 25 23 23 24 22 33 12 14 15 17 17 30 20
e 36e96 7e55 6e45 43e e 13e85 7e51 9e41 12e35 6e46 18e 5e27 5e27 6e27 6e47 5e41 18e 7e42
e 100 62 50 82 e 43 47 46 50 44 69 27 31 26 33 45 57 44
e 67 38 33 82 e 29 38 33 23 32 35 16 10 17 30 30 38 29
e 33 15 17 55 e 29 21 10 10 4 30 3 4 6 16 19 17 15
e 17 8 8 45 e 14 6 2 2 2 e 2 1 1 5 6 e 4
<2000 2000 <2000 2000 Total
85 239 46 69 439
22 24 14 29 22
10e49 8e45 6e22 8e69 9e47
47 51 20 52 48
34 33 11 40 33
18 16 2 31 18
7 3 2 14 6
<2000 2000 Total
34 56 90
13 21 16
4e19 7e62 5e35
12 48 35
3 34 23
3 28 18
3 13 8
diagnosed med metastatic breast cancer 1995e2001. The improvements in survival over time periods were associated to the introduction of new therapeutic agents [37]. Weide et al. reported 2014 a prolongation of survival in metastatic breast cancer but restricted to hormone receptor and Her2 positive tumours [38]. Our results confirm the improvements with regard to ER/PR and Her2 positive tumours but we can also demonstrate for the first time a considerable improvement in survival time for patients with dissemination of tumours of high malignancy grade. Rapidly proliferating cells are more sensitive to chemotherapy than tumours with less mitotic activity. An increasing range of cytotoxic treatment options with different clinical activities like anthracyclines, taxanes, vinorelbine, capecitabine and eribulin have contributed to increased survival in pts with high grade tumours. The improved survival for patients with HER2 positive tumours is attributable most of all to the availability of trastuzumab but the availability of new and efficacious cytotoxic agents may have contributed as well. The prolongation of the disease-free interval by time periods is likely to be an effect of the increased use of adjuvant therapies.
Anthracycline based therapies became more common after 1990 and taxanes were introduced 2004. Endocrine treatments were given for 2 years in the first and 5e7 years in the last period when also the aromatase inhibitors had been introduced. 5. Conclusion Survival in metastatic breast cancer improved 1985e2015. Although patients with high grade tumours had the shortest survival after detection of metastases their relative improvement was increased as compared to patients with grade 1 or 2 tumours. The most striking improvement was achieved in the HER2 positive subset which parallels the introduction of trastuzumab. Unlike other series, we did not see an improvement in survival linked to the introduction of aromatase inhibitors in the metastatic setting, but we did observe such as improvement linked to the introduction of fulvestrant. For patients with ER/PR positive tumours the introduction of new endocrine treatments represented a significant improvement in survival time after diagnosis of metastatic disease. Notwithstanding these results, the improvements seen in the
50
M. Sundquist et al. / The Breast 31 (2017) 46e50
Fig. 3. Cumulative survival of patients with HER2 positive tumours diagnosed with metastatic breast cancer before and after the introduction of trastuzumab in 2000. N ¼ 46 þ 69.
metastatic breast cancer setting are still small and slow in comparison for example with what has been seen in the early setting. Median overall survival is still of only a few years and the disease is far from being a chronic one. Continuous efforts are needed in many fields, such as basic research, drug development, guidelines implementation, education and awareness, among others. The fact that the more substantial improvements are seen with the introduction of new efficacious therapies, stresses the crucial importance of access to best care for all metastatic breast cancer patients. Conflict of interest statement None declared. References [1] Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparisons between different polychemotherapy regimens for early breast cancer: metaanalyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet 4e10 February 2012;379(9814):432e44. [2] Brenner H, Hakulinen T. Are patients diagnosed with breast cancer before age 50 years ever cured? J Clin Oncol 2004;22(3):432e8. [3] Garne JP. Cure in Breast Cancer following treatment for distant metastases. € 1961-1992. Malmo €: Thesis. 1996. p. 158e73. Invasive breast Cancer Malmo [4] van Tienhoven G, Voogd AC, Peterse JL, Nielsen M, Andersen KW, Mignolet, et al. Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group. Eur J Cancer 1999;35(1):32e8. [5] Buchanan CL, Dorn PL, Fey J, Giron G, Naik A, Mendez J, et al. Locoregional recurrence after mastectomy: incidence and outcomes. J Am Coll Surg 2006;203(4):469e74. [6] Schmoor C, Sauerbrei W, Bastert G, Schumacher M. Role of isolated locoregional recurrence of breast cancer: results of four prospective studies. J Clin Oncol 2000;18(8):1696e708. [7] Alanko A, Heinonen E, Scheinin TM, Tolppanen EM, Vihko R. Oestrogen and progesterone receptors and disease-free interval in primary breast cancer. Br J Cancer 1984;50(5):667e72. [8] Jubelirer SJ, Wilson R, Summers L, Richardson S. Prognostic factors determining survival in breast cancer patients presenting with metastatic disease. W V Med J 1990;86(1):7e9. [9] Shek LL, Godolphin W, Spinelli JJ. Oestrogen receptors, nodes and stage as predictors of post-recurrence survival in 457 breast cancer patients. Br J
Cancer 1987;56(6):825e9. [10] Clark GM, Sledge GW, Osborne CK, McGuire WL. Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients. J Clin Oncol 1987;5(1):55e61. [11] Alexieva-Figusch J, Van Putten WL, van Gilse HA, Blonk-vd Wijst J, Klijn JG. Sequential treatment of metastatic breast cancer with tamoxifen after megestrol acetate therapy and vice versa (a retrospective study). Med Oncol Tumor Pharmacother 1985;2(2):69e75. [12] Stål O, Carstensen JM, Wingren S, Rutqvist LE, Skoog L, Klintenberg C, et al. Relationship of DNA ploidy and S-phase fraction to survival after first recurrence of breast cancer. Acta Oncol 1994;33(4):423e9. €ntoft O, Nordenskjo € ld B. [13] Hatschek T, Carstensen J, Fagerberg G, Stål O, Gro Influence of S-phase fraction on metastatic pattern and post-recurrence survival in a randomized mammography screening trial. Breast Cancer Res Treat 1989;14(3):321e7. €kinen J. Survival after first recurrence in breast [14] Hietanen P, Miettinen M, Ma cancer. Eur J Cancer Clin Oncol 1986;22(8):913e9. [15] Blanco G, Holli K, Heikkinen M, Kallioniemi OP, Taskinen P. Prognostic factors in recurrent breast cancer: relationships to site of recurrence, disease-free interval, female sex steroid receptors, ploidy and histological malignancy grading. Br J Cancer 1990;62(1):142e6. [16] Pater JL, Mores D, Loeb M. Survival after recurrence of breast cancer. Can Med Assoc J 1981;124(12):1591e5. [17] Horiguchi J, Iino Y, Takei H, Maemura M, Takeyoshi I, Yokoe T, et al. c-erbB-2 status is an independent predictor of survival after first recurrence. Int J Oncol 1998;12(1):123e8. [18] Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 2002;41(3A):154e61. [19] Sundquist M, Thorstenson S, Brudin L, Nordenskjold B. South east Swedish breast Cancer study group applying the Nottingham prognostic index to a Swedish breast cancer population. Breast Cancer Res Treat 1999 Jan;53(1):1e8. [20] Blamey RW, Hornmark-Stenstam B, Ball G, Blichert-Toft M, Cataliotti L, Fourquet A, et al. Ellis I ONCOPOOL e a European database for 16,944 cases of breast cancer. Eur J Cancer January 2010;46(1):56e71. [21] Wrange O, Nordenskjold B, Silfversward C, Granberg PO, Gustafsson JA. Isoelectric focusing of estradiol receptor protein from human mammary carcinoma - a comparison to sucrose gradient analysis. Eur J Cancer 1976;12:695e700. [22] Wrange O, Nordenskjold B, Gustafsson JA. Cytosol estradiol receptor in human mammary carcinoma: an assay based on isoelectric focusing in polyacrylamide gel. Anal Biochem 1978;85:461e75. [23] Ferno M, Borg A, Sellberg G. Enzyme immuno assay of the estrogen receptor in breast cancer biopsy samples. A comparison with isoelectric focusing. Acta Radiol Oncol 1986;25:171e5. [24] Ferno M, Borg A, Norgren A. A comparison of two steroid receptor assays in breast cancer: dextran coated charcoal and isoelectric focusing. Anticancer Res 1983;3:243e6. [25] Burton K. A study of the conditions and mechanism of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J 1956;62:315e23. n L, Stål O. Ferno € M for the South and South-East [26] Grabau GA, Bendahl PO, Ryde Swedish Breast Cancer groups. The prevalence of immunohistochemically determined oestrogen receptor positivity in primary breast cancer is dependent on the choice of antibody and method of heat-induced epitope retrieval e prognostic implications? Acta Oncol 2013;52:1657e66. [27] Kaplan EL, Meijer P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457e81. [28] Cox DR. Regression models and life tables. J R Stat Soc Ser B Methodol 1972;34:187e220. [29] Stat SI. Computer program manual. Tulsa OK: Stat Soft, inc; 1995. [30] Powles TJ, Coombes RC, Smith IE, Jones JM, Ford HT, Gazet JC. Failure of chemotherapy to prolong survival in a group of patients with metastatic breast cancer. Lancet 1980;1(8168 PT 1):580e2. [31] Patel JK, Nemoto T, Vezeridis M, Petrelli N, Suh O, Dao TL. Does more intense palliative treatment improve overall survival in metastatic breast cancer patients? Cancer 1986;57(3):567e70. [32] Patanaphan V, Salazar OM, Poussin-Rosillo H. Prognosticators in recurrent breast cancer. A 15-year experience with irradiation. Cancer 1984;54(2):228e34. [33] Debonis D, Terz JJ, Eldar S, Hill LR. Survival of patients with metastatic breast cancer diagnosed between 1955 and 1980. J Surg Oncol 1991;48(3):158e63. [34] Giordano SH, Buzdar AU, Smith TL, Kau SW, Yang Y, Hortobagyi GN. Is breast cancer survival improving? Cancer 2004;100(1):44e52. [35] Tevaarwerk AJ, Gray R, 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 March 15, 2013:1140e8. [36] Giuliani J, Bonetti A. Trends in survival for patients with metastatic breast cancer: is survival improving? Tumori 2015;101(4):347e52. [37] Weide R, Feiten S, Friesenhahn V, Heymanns J, Kleboth K, Thomalla J, et al. Metastatic breast cancer: prolongation of survival in routine care is restricted to hormone-receptor and Her2-positive tumors. SpringerPlus 2014;3:535. [38] 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(5):973e9.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Improved survival in metastatic breast cancer 1985e2016 € ran Tejler c Marie Sundquist a, *, Lars Brudin b, Go a
Kalmar County Breast Centre, Surgery, County Hospital, Kalmar, Sweden Dep of Physiology, County Hospital, Kalmar, Sweden c €stervik Hospital, Sweden Kalmar County Breast Centre, Surgery, Va b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2016 Accepted 10 October 2016 Available online 2 November 2016
Purpose: In the last 25 years new treatment options in breast cancer have evolved. We wanted to determine whether the survival of; patients with metastatic breast cancer have improved during this period. Methods: Patients consecutively diagnosed with disseminated breast cancer 1985e2014 in the County of Kalmar, Sweden, were identified and followed to 2016. Survival was calculated for each successive 5 year interval. Separate analyses were performed for pts with ER and/or PR and HER2 positive tumours resp. Results: Median survival of the 784 patients increased successively from 13 to 33 months. Five year survival increased from 10 to 27%. Patients with high grade primary tumours had the shortest post recurrence survival time but their median survival increased significantly by time from 12 to 30 months, 3 year survival from 16 to 38% and 5 year from 5 to 20%. Median survival for patients with grade 2 tumours was 2 years and did not improve. Only 47 patients had grade 1 tumours and their median survival of 4 years did not change. Median survival for HER2 positive patients treated before the introduction of trastuzumab in year 2000 was 14 months and after 2000 29 months, 5 year survival improved from 2 to 31%. Conclusions: Survival in metastatic breast cancer improved 1985e2016. For the first time a significant increase in survival time for patients with metastasis from fast-growing grade 3 tumours was seen. The most striking improvement was achieved in the HER2 positive subset. © 2016 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Metastatic Survival Prognosis
1. Introduction Approximately one third of patients with primary breast cancer will eventually develop disseminated disease [1]. Disease-free interval is known to vary from months to decades. Mortality due to breast cancer occurs up to 40 years after primary diagnosis [2]. Systemic breast cancer is essentially incurable. Few per cent of patients diagnosed with distant metastasis die without signs of breast cancer [3]. The clinical course of patients with distant metastases is however highly variable. Some die within months after detection of dissemination but some live with a high quality of life for ten or more years. In the last 25 years several new treatment options in breast cancer have evolved. The taxanes were introduced in the nineties,
* Corresponding author. E-mail addresses: [email protected] (M. Sundquist), lars.brudin@ ltkalmar.se (L. Brudin), [email protected] (G. Tejler). http://dx.doi.org/10.1016/j.breast.2016.10.005 0960-9776/© 2016 Elsevier Ltd. All rights reserved.
as were dose dense regimens of anthracyclines. Aromatase inhibitors came into use in the metastatic setting in 1997 and fulvestrant in 2005. The first immunologic treatment in breast cancer, trastuzumab, became available year 2000. We wanted to determine whether the survival of patients with metastatic breast cancer has improved during this period. Approximately 30e40% of patients with recurrences restricted to the preserved breast, ipsilateral chest wall or axillary nodes remain free of distant disease during an observation time of 7e10 years [4e6]. In the present study the outcomes of patients with truly disseminated disease was explored. Patients with loco regional recurrence or a new primary in the contra lateral breast without signs of distant metastasis were excluded from the investigation. Further, we wanted to assess predictors of disease development in metastatic breast cancer. Disease free interval [7,8], steroid receptor level [9], age [10,11], S-phase fraction [12,13], histological grade [5,7,12,14,15], histological type [16] and tumour HER2 expression [17] have been associated with survival after dissemination.
M. Sundquist et al. / The Breast 31 (2017) 46e50
2. Patients and methods 2.1. Patients All patients with a diagnosis of disseminated breast cancer established between 1985 and 2014 in the county of Kalmar with 240 000 inhabitants were identified from the patient's registry. Patient and tumour data were retrieved from patient records and the pathology database. Patients with recurrences exclusively within the ipsilateral chest wall or mammary and axillary region were excluded as were tumours occurring in the contralateral breast. If distant metastases were diagnosed before or within 3 months from the diagnosis of the primary breast tumour it was classified as primary distant metastatic, de novo, disease. To ensure the comparability of patients between time periods histological grading and receptor assessments were validated. 2.2. Pathology Histological type and grade had been routinely assessed in the primary tumour and when possible in the metastases since 1985. Nottingham histological grade (NHG) was assessed according to the protocol of Elston/Ellis [18]. Validation of grading of the primary tumours was performed in 1999 and 2010 [19,20]. There was no significant change in the distribution of NHG 1, 2 and 3 in the primary tumours over the time periods. In 50 patients diagnosed with metastasis before 1990 and in approximately 1 patient each year thereafter it was not possible to grade the primary tumour. The primary tumour characteristics have been used in the investigation. 2.3. Hormone receptor determination Before 2000 hormone receptor status were determined using 2 different cytosol assays. Until 1989 isoelectric focusing (IF) on polyacrylamide gel and thereafter an enzyme immunoassay (EIA) was used [21,22]. For ER, studies have shown that results with these techniques correlate well with those obtained using methods based on ultra-centrifugation, dextran-coated charcoal and immunohistochemistry [21e24]. The cytosol receptor values were normalized to DNA content as measured by Burton [25]. Cut-off values defined approximately 70% of the tumours as ER and/or PR positive. Year 2000 and onwards tumour tissue was analysed for ER and PR status using immunohistochemistry. The fractions of ER and PR positive nuclei were determined and classified into four groups (0e10%, 11e50%, 51e75%, and >75%). Tumours with more than 10% positively staining nuclei were considered positive. The cytosol and IHC assays defined approximately the same proportion of tumours as positive [26] indicating the comparability of patients of different cohorts. 2.4. HER2 assessment HER2 status was assessed in the primary tumours from 1996 and onwards using IHC and subsequently FISH. A polyclonal rabbit anti human antibody against the HER-2 protein was used (Dako A 0485). Only samples with distinct staining in more than 75% of the entire membrane and in more than 75% of the tumour cell were judged as overexpressed. FISH analysis was performed using the FDA-approved Path-Vysions HER-2 DNA ProbeKit. Signal ratios (HER2:CEP17) of 2 were classified as amplified. 2.5. Adjuvant treatments In 1981 endocrine adjuvant therapy was introduced as
47
postmenopausal patients with oestrogen receptor positive tumours were offered two years of adjuvant tamoxifen, which in 1995 was extended to five years. From 2004 postmenopausal women with high grade tumours or node positivity were offered aromatase inhibitors either for 5 years or for 3 years followed by 2 years of tamoxifen. From 1989 endocrine therapy with tamoxifen was used also for premenopausal patients with hormone receptor positive disease and in the early nineties 2 years of LHRH agonist treatment was added for this group of patients. In 1981 also adjuvant chemotherapy was introduced when premenopausal patients with node positive disease received six months of CMF therapy. In the nineties adjuvant therapy with anthracycline containing regimens were introduced and used also for postmenopausal patient with node positive disease. From 2004 patients with high risk disease received adjuvant taxanes sequenced with anthracycline based therapy. From 2006 patients with HER2 amplified tumours were given trastuzumab for 1 year after chemotherapy. Only 11 of the patients with HER2 positive primary tumours had received trastuzumab in the adjuvant setting. 2.6. Data analysis and statistics Survival curves were constructed and median survival in months from the date of diagnosis of distant metastasis was determined for each successive interval of five years 1985e2014 for the cohort as a whole and by grade. The percentage of patients surviving more than 2, 3, and 5 and 10 years after the first metastatic event was determined for each group. In our hospitals the aromatase inhibitors came into use in the metastatic setting in 1997 and trastuzumab (Herceptin) in 2000. Fulvestrant (Faslodex) was introduced in 2005. Separate analyses were performed for patients with ER/PR positive and HER2 positive tumours, respectively, to determine whether the survival changed according to if distant disease was detected before or after the introduction of the new therapies. Significances were determined using Cox regression. Univariate survival distributions were estimated using the product limit method of Kaplan and Meier [27]. Death rates and tests of the statistical significance of relationship between study parameters and survival were computed using Cox's proportional hazards method [28]. Statistical analysis was computed using STATISTICA for Windows [29]. 3. Results Median disease-free interval (DFI) increased significantly over the time periods from 1, 8 to almost 6 years, p for trend <0.001. The median survival of the 784 patients in the whole study population increased significantly from 13 months to 15, 16, 20, 23 and 33 respectively for each successive five-year period from 1985 to 2014, p ¼ 0.009 (Fig. 1). Grade and hormone receptor status of the primary tumour were significantly correlated to survival after first metastatic event in the whole cohort of patients, p < 0.001 for both parameters. 3.1. Survival according to grade For patients with grade 3 tumours (N ¼ 411) the median survival improved gradually over time from 12 to 14, 15, 17, 17 and 30 months, for the six periods (Table 2, Fig. 2). The percentage of patients surviving more than three years improved from 16 to 38% and the five year survival increased from 3 to 17% (Table 1). The median survival for patients with grade 2 tumours (N ¼ 229) was 23 months and did not change significantly. Only 47 patients had grade 1 tumours with a median survival of 39 months and no
48
M. Sundquist et al. / The Breast 31 (2017) 46e50
3.2. Hormone receptor positive tumours Four hundred and forty eight patients had ER/PR positive tumours. The first half of the cohort (<2000) was compared to the second half and the percentages of patients surviving more than 2, 3 and 5 years respectively were calculated. Forty-seven percent of patients diagnosed before 2000 survived more than 2 years and 32% more than 3 years and 14% more than 5 years. Corresponding figures for patients diagnosed 2000 and later were 57, 39 and 19%, respectively (Table 2). When comparing the 91 patients treated with fulvestrant (a selective oestrogen receptor down-regulator; SERD) after it became available 2005 with earlier diagnosed ER/PR positive patients who would have been subjected to treatment with this substance had it been available, there was a significant difference in survival time in favour of fulvestrant (Cox regression; HR ¼ 0.62 (CI 0.47e0.84); p < 0.002). There was no corresponding increase in survival time for patients that received aromatase inhibitors in the metastatic setting. However, aromatase inhibitors were introduced in the adjuvant setting 2004. 3.3. HER2 positive tumours
Fig. 1. Cumulative survival of 784 patients diagnosed with metastatic breast cancer by successive time periods.
Forty-six patients with HER2þ tumours were treated before year 2000 and 69 patients from year 2000 and onwards. Two-year survival for patients with HER2þ tumours improved from 20 to 52%, three-year from 11 to 40 and five-year survival from 2 to 31% (Table 2, Fig. 3). Ninety of the HER2 positive tumours were of grade 3. In this subset 48% of patients diagnosed in 2000 or later survived more than two years, 34% more than three years and 28% more than five years and 13% more than 10 years, as compared to 12, and 3, 3, 3%, respectively for those diagnosed before the year 2000. Almost all patients diagnosed with metastases 2000 and later received trastuzumab but also 2 of patients diagnosed before 2000. 3.4. Triple negative tumours Seventy two patients with assessment of HER2 status had tumours that lacked ER, PR and HER2 (triple negative). Their median survival was 10 months and did not improve in the last half of the period as compared to the first. Only 23% survived 2 years or longer. 4. Discussion
Fig. 2. Two, 3, 5 and 10 year survival for pts with grade 3 tumours by period of diagnosis of metastatic disease. Table 1 DFI by time period and percentage of de novo cases. Recurrence period
N
De novo n (% of total)a
DFI - median (range)b
<1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 Total
124 147 160 129 152 72 784
29 (23.4) 19 (12.9) 23 (14.4) 21 (16.3) 28 (18.4) 6 (8.3) 126 (16.1)
1.83 3.02 4.24 4.88 4.08 5.99 3.50
a b
(0.27e13.8) (0.30e15.6) (0.34e31.7) (0.33e22.5) (0.33e24.2) (0.27e30.0) (0.27e31.7)
Up to three months from diagnosis. De novo excluded.
significant change over time. One third of the grade 1 patients survived for more than 5 years with metastatic disease and 20% for more than 10 years.
Our results support a trend shift towards improved survival for patients diagnosed with disseminated breast cancer. Powles concluded in 1980 that there had been no improvement in survival from first metastasis, and survival may even have been shortened in some patients given chemotherapy [30]. Patel found no increase in survival times from first recurrence 1942e75 [31]. Patanaphan reported the median survival after diagnosis of distant metastases 1969e77 to be less than 11 months after diagnosis of disseminated disease [32]. Debonis found no improvement in survival times of patients with metastatic breast cancer for five-year intervals diagnosed 1955e1980 [33]. Giordano et al. found that survival for patients with recurrent breast cancer improved from 1974 to 2000 [34]. However, in their report patients with exclusively loco regional recurrences were included. Tevaarwerk et al. found in 2013 no evidence of improved survival when reviewing 3447 patients having recurred after participating in adjuvant chemotherapy trials [35]. Giuliani and Bonetti concluded in 2015 that the OS of women with metastatic BC had not improved in the last years [36]. However, their study included only 70 patients diagnosed during 7 years. Chia et al. demonstrated in 2007 in a population-based study a significant successive improvement in survival time for patients
M. Sundquist et al. / The Breast 31 (2017) 46e50
49
Table 2 Post-recurrence survival (months) for patients presenting at different time periods with metastatic breast cancer calculated from the Kaplan-Meier curves using the total cohort and different subgroups. Q1 and Q3 are the lower and upper quartiles, respectively. Recurrence period
n
Survival (months and %) Median
Q1eQ3
2 yrs
3 yrs
5 yrs
10 yrs
All
ER/PR Neg Pos
Grade 1
2
3
HER2 Neg Pos
HER2 Pos and grade 3
<1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 Total
124 147 160 129 152 72 784
13 16 16 20 23 33 18
4e31 6e35 7e36 7e45 6e48 18e55 7e41
31 38 36 43 49 64 42
20 24 25 29 36 37 29
10 13 9 15 17 27 14
3 3 2 4 7 e 4
<2000 2000 <2000 2000 Total
119 92 192 256 563
11 12 22 30 19
4e23 5e32 9e42 13e50 7e42
23 29 47 57 43
14 19 32 39 29
8 14 14 19 15
3 4 4 5 5
<1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 <1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 <1990 1990e1994 1995e1999 2000e2004 2005e2009 2010 Total
2 6 13 12 11 3 7 34 52 52 57 27 63 72 90 64 83 39 687
e 46 33 17 70 e 25 23 23 24 22 33 12 14 15 17 17 30 20
e 36e96 7e55 6e45 43e e 13e85 7e51 9e41 12e35 6e46 18e 5e27 5e27 6e27 6e47 5e41 18e 7e42
e 100 62 50 82 e 43 47 46 50 44 69 27 31 26 33 45 57 44
e 67 38 33 82 e 29 38 33 23 32 35 16 10 17 30 30 38 29
e 33 15 17 55 e 29 21 10 10 4 30 3 4 6 16 19 17 15
e 17 8 8 45 e 14 6 2 2 2 e 2 1 1 5 6 e 4
<2000 2000 <2000 2000 Total
85 239 46 69 439
22 24 14 29 22
10e49 8e45 6e22 8e69 9e47
47 51 20 52 48
34 33 11 40 33
18 16 2 31 18
7 3 2 14 6
<2000 2000 Total
34 56 90
13 21 16
4e19 7e62 5e35
12 48 35
3 34 23
3 28 18
3 13 8
diagnosed med metastatic breast cancer 1995e2001. The improvements in survival over time periods were associated to the introduction of new therapeutic agents [37]. Weide et al. reported 2014 a prolongation of survival in metastatic breast cancer but restricted to hormone receptor and Her2 positive tumours [38]. Our results confirm the improvements with regard to ER/PR and Her2 positive tumours but we can also demonstrate for the first time a considerable improvement in survival time for patients with dissemination of tumours of high malignancy grade. Rapidly proliferating cells are more sensitive to chemotherapy than tumours with less mitotic activity. An increasing range of cytotoxic treatment options with different clinical activities like anthracyclines, taxanes, vinorelbine, capecitabine and eribulin have contributed to increased survival in pts with high grade tumours. The improved survival for patients with HER2 positive tumours is attributable most of all to the availability of trastuzumab but the availability of new and efficacious cytotoxic agents may have contributed as well. The prolongation of the disease-free interval by time periods is likely to be an effect of the increased use of adjuvant therapies.
Anthracycline based therapies became more common after 1990 and taxanes were introduced 2004. Endocrine treatments were given for 2 years in the first and 5e7 years in the last period when also the aromatase inhibitors had been introduced. 5. Conclusion Survival in metastatic breast cancer improved 1985e2015. Although patients with high grade tumours had the shortest survival after detection of metastases their relative improvement was increased as compared to patients with grade 1 or 2 tumours. The most striking improvement was achieved in the HER2 positive subset which parallels the introduction of trastuzumab. Unlike other series, we did not see an improvement in survival linked to the introduction of aromatase inhibitors in the metastatic setting, but we did observe such as improvement linked to the introduction of fulvestrant. For patients with ER/PR positive tumours the introduction of new endocrine treatments represented a significant improvement in survival time after diagnosis of metastatic disease. Notwithstanding these results, the improvements seen in the
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M. Sundquist et al. / The Breast 31 (2017) 46e50
Fig. 3. Cumulative survival of patients with HER2 positive tumours diagnosed with metastatic breast cancer before and after the introduction of trastuzumab in 2000. N ¼ 46 þ 69.
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