Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
Geurts SME, van Dijck JAAM, de Vegt F, Paquay Y, Siesling S,
Verbeek ALM, Tjan-Heijnen VCG. Huge decreases in the risk of
breast cancer relapse over the last three decades. OA
Epidemiology 2013 Apr 19;1(1):1.
m p e ti n g i n te re st s: n o n e d e cl a re d . C o n fl ic t o f in te re st s: n o n e d e cl a re d . a u th o rs c o n tr ib u te d t o c o n ce p ti o n a n d d e si g n , m a n u sc ri p t p re p a ra ti o n , re a d a n d a p p ro v e d t h e f in a l m a n u sc ri p t. a u th o rs a b id e b y t h e A ss o ci a ti o n f o r M e d ic a l E th ic s (A M E ) e th ic a l ru le s o f d is cl o su re .miology
Apr 19;1(1):
Huge decreases in the risk of breast cancer relapse over the last three decades
1
Geurts SME1*, van Dijck JAAM1, de Vegt F1, Paquay Y2, Siesling S3,4, Verbeek ALM1, Tjan-Heijnen
2
VCG5
3 4
1
Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands 5
2
Department of Surgery, Hospital Bernhoven, Oss, The Netherlands 6
3
Comprehensive Cancer Centre the Netherlands, Utrecht, The Netherlands 7
4
Health Technology and Services Research, Twente University, Enschede, The Netherlands 8
5
Department of Internal Medicine, GROW – School for Oncology and Developmental Biology, 9
Division of Medical Oncology, Maastricht University Medical Centre, Maastricht, The Netherlands 10
11
*Corresponding author
12
Sandra M.E. Geurts, PhD 13
Department for Health Evidence 14
Radboud University Medical Centre 15 PO Box 9101 16 6500 HB Nijmegen 17 The Netherlands 18
E-mail address: S.Geurts@ebh.umcn.nl 19
20
Manuscript type: Original article 21
All authors contributed to conception and design, manuscript preparation, read and approved the final 22
version of the manuscript. 23
Conflict of interests: none declared 24
ABSTRACT
25 26
PURPOSE: To evaluate local and systemic breast cancer control by comparing the risk of relapse in
27
breast cancer patients in 2003-2004 with 1972-1979 and 1980-1986. 28
METHODS: 8570 Women diagnosed with invasive breast cancer in 2003-2004 were selected from
29
the population-based Netherlands Cancer Registry and compared with 133 patients treated in 1972-30
1979 and 174 in 1980-1986. Five-year risk of relapse was calculated by the Kaplan-Meier method. 31
Cox-proportional hazards models were applied to adjust for tumor size, nodal status and age at 32
diagnosis. 33
RESULTS: Patients diagnosed in 2003-2004 had smaller tumors and less advanced nodal stage than
34
patients diagnosed in 1972-1986. In 1972-1979, 1980-1986 and 2003-2004, treatment included 35
mastectomy in 94%, 72% and 47%; post-mastectomy radiotherapy in 75%, 70% and 30%; 36
chemotherapy in 9%, 14% and 37%; and hormonal therapy in 3%, 3% and 42% of patients, 37
respectively. Five-year risk of locoregional and distant recurrence decreased from 37% and 34% to 38
15%, respectively. The 5-year risk of second primary breast cancer did not differ and was 1%, 4% and 39
2%, respectively. The improved relapse-free survival in patients diagnosed in 2003-2004 as compared 40
with 1972-1979 hardly changed after adjustment (HR=0.38, 95% CI:0.28-0.52). 41
CONCLUSIONS: Over the last decades, local breast cancer therapies became less rigorous, whereas
42
systemic therapy use has increased. Simultaneously, the risk of breast cancer relapse has tremendously 43
decreased. Future novel therapies may lead to such small additional decreases in recurrence rates, that 44
the long term side effects in breast cancer survivors become more important. 45
46
KEYWORDS: Breast neoplasms; Epidemiology; Recurrence; Survival analysis; Netherlands
INTRODUCTION
48 49
The breast cancer relapse rate is the key outcome when evaluating local and systemic disease 50
control achieved by primary breast cancer management. Changing relapse rates may have implications 51
for patient management and post-treatment follow-up. In contrast to breast cancer mortality, 52
population-based studies on the time trend in relapse-free survival are rare, and generally focus on 53
locoregional recurrence1,2, second primary breast cancer3,4or distant metastasis5,6separately, instead of
54
studying overall time trends on relapse-free survival. Relapse rate estimates derived from randomized 55
controlled trials (RCT) may differ from daily practice, as trials are usually carried out in specialized 56
clinics. Patients and physicians participating in a trial are likely to be more motivated and patient care 57
is expected to be of higher quality.7,8For that reason, population-based outcome research is of pivotal
58
importance to assess the real impact of innovations after translation in daily practice. 59
The purpose of this population-based cohort study is to determine the risk of relapse in breast 60
cancer patients treated with curative intent diagnosed in 2003-2004 and in 1972-1986. 61
PATIENTS AND METHODS
62 63
Two cohorts of female breast cancer patients operated for invasive non-metastatic breast 64
cancer were available. The oldest cohort comprised 307 patients consecutively diagnosed from 1972 to 65
1986 in the St Anna hospital in Oss, the Netherlands. Occurrences of relapse and death were registered 66
in 1993. A recent population-based cohort was selected from the Netherlands Cancer Registry and 67
comprised 8570 patients diagnosed in 2003 or 2004 in 53 hospitals in the Netherlands. The 68
Netherlands Cancer Registry has registered all primary tumors since 1984, but does not routinely 69
register cancer recurrences.9Based on pathological notification through an automated pathology
70
archive, trained registration clerks gathered data from the patients’ files. Information about relapse and 71
death was retrieved until December 31, 2009, corresponding with at least five years of follow-up since 72
diagnosis. Only first occurrence of either locoregional recurrence or distant metastasis was registered. 73
74
Patients diagnosed in 1972-1986 were staged according to the TNM classification of 1977.10
75
In 2003-2004 the TNM classification of 2002 was used.11Staging of tumor size (T) was similar for
76
both periods, but categorization of patients by lymph node status (N) differed between 1977 and 2002 77
(Table 1). Nodal status was, therefore, categorized as N0, i.e. no lymph node metastases, versus N1-3, 78
i.e. at least 1 lymph node metastasis. Patients with unknown pathological TNM stage were classified 79
according to their clinical TNM stage. 80
Of patients who had a second primary breast cancer diagnosed within three months of the first 81
breast cancer, the tumor with the highest Nottingham Prognostic Index12was included for further
82
analyses. 83
Breast cancer relapse was defined as a local or regional recurrence, distant metastasis or 84
second primary breast cancer.13Relapses diagnosed within three months were considered to be
85 diagnosed simultaneously. 86 87 Data analyses 88
To examine the time trend in patient, tumor and treatment characteristics and breast cancer 89
relapse rates, the historical cohort was divided in two groups. Analyses were consequently reported for 90
three periods: 1972-1979, 1980-1986 and 2003-2004. The utilization of radiotherapy was stratified by 91
type of surgery. 92
Five-year relative survival by age, sex and calendar year was calculated using the method 93
described by Dickman.14Five-year risk of relapse were calculated using the Kaplan-Meier method.
94
Relapse was defined as a second primary breast cancer, locoregional recurrence or distant metastasis. 95
Date of surgery was defined as the starting point of follow-up. When locoregional recurrence was 96
considered as event of interest, patients’ follow-up was censored at date of last follow-up, distant 97
metastasis or death. For risk of distant metastasis patients were censored at last follow-up date, 98
occurrence of a local or regional recurrence or death. We therefore also calculated risk of locoregional 99
recurrence or distant metastasis. Patients with second primary breast cancer were censored at time of 100
last follow-up or death. Patients with synchronous bilateral breast cancer at primary diagnosis were 101
excluded from the risk of second primary breast cancer analyses. 102
The hazard ratio of five-year risk of relapse in 1980-1986 and 2003-2004 versus 1972-1979 103
was adjusted for age at diagnosis, tumor size, nodal status and tumor histology using Cox-proportional 104
hazards modeling. 105
The SAS system was used to perform the analyses (release 9.2; SAS Institute Inc., Cary, NC, 106
USA). 107
RESULTS
108 109
Patient and tumor characteristics
110
Patient, tumor and treatment characteristics by period of diagnosis are presented in Table 2. 111
Over the last decades, tumor size decreased. The mean tumor size per tumor stage did not differ 112
between the periods (data not shown). The use of breast conserving surgery has increased over time, 113
from 2% in 1972-1979 and 26% in 1980-1986 to 53% in 2003-2004. Radiotherapy after breast 114
conserving surgery was standard practice irrespective of period of diagnosis. Radiotherapy after 115
mastectomy decreased from 75% in 1972-1979 and 70% in 1980-1986 to 30% in 2003-2004. Women 116
aged below 50 years more often received chemotherapy compared with women aged 50 years or over, 117
but for both increasing over time: 15% versus 5% in 1972-1979, 36% versus 5% in 1980-1986 and 118
72% versus 24% in 2003-2004, respectively. A similar but smaller trend was observed for hormonal 119
therapy: 7% versus 0% in 1972-1979, 2% versus 3% in 1980-1986 and 48% versus 39% in 2003-2004, 120
respectively. Pathological examination of lymph nodes was not performed for 26% of patients with 121
cN0 and 9% of patients with cN1-3 in the years 1972-1979, whereas these proportions were 5% and 122
7%, respectively, in 1980-1986, and 2% in total in 2003-2004. 123
124
Relative survival
125
Survival data were available for 132 patients (99%) diagnosed in 1972-1979, for 168 patients 126
(96%) diagnosed in 1980-1986 and for 8570 patients (100%) diagnosed in 2003 or 2004. Follow-up 127
for survival was at least 5 years for all but 3 patients diagnosed in 1972-1979 and 27 patients 128
diagnosed in 1980-1986. Five-year relative survival increased from 75% (95% CI: 65%-83%) to 87% 129
(95% CI: 79%-94%) and 93% (95% CI: 92%-93%) for the years 1972-1979, 1980-1986 and 2003-130 2004, respectively. 131 132 Relapse-free survival 133
Follow-up for occurrences of relapse was available for 113 patients (85%) diagnosed in 1972-134
1979, for 166 patients (95%) diagnosed in 1980-1986 and for 8417 patients (98%) diagnosed in 2003 135
or 2004. Four patients diagnosed in 1972-1979 died without signs of relapse within 5 years after 136
diagnosis. Ten patients diagnosed between 1980 and 1986 were lost to follow-up. In the 2003-2004 137
cohort, 749 patients were lost to follow-up for relapse within 4 years after diagnosis, of whom 254 138
died within 3 months after the last follow-up date. Five-year risk of relapse decreased from 38% (95% 139
CI: 29%-48%) in 1972-1979 and 35% (95% CI: 28%-43%) in 1980-1986 to 16% (95% CI: 15%-17%) 140
in 2003-2004. The 5-year risk of second primary breast cancer was similar for all periods: 1% (95% 141
CI: 0%-3%:), 4% (95% CI: 1%-7%:) and 2% (95% CI: 2%-3%), respectively (Figure 1). Five-year 142
risk of locoregional recurrence or distant metastasis decreased over the three periods: from 37% (95% 143
CI: 28%-47%) to 34% (95% CI: 27%-41%) to 15% (95% CI: 14%-15%) (Figure 2). Considering the 144
first site of relapse, 5-year risk of locoregional recurrence was 24% (95% CI: 16%-33%), 14% (95% 145
CI: 9%-19%) and 4% (95% CI: 3%-4%) for the years 1972-1979, 1980-1986 and 2003-2004, 146
respectively. For patients diagnosed in 2003-2004, 5-year risk of locoregional recurrence after breast 147
conserving surgery was 3% (95% CI: 3%-4%) and 5% (95% CI: 5%-6%) after mastectomy. The 5-148
year risk of distant metastasis as first event was 27% (95% CI: 18%-35%), 28% (95% CI: 21%-35%) 149
and 12% (95% CI: 11%-13%), for the years 1972-1979, 1980-1986 and 2003-2004, respectively. 150
Risk of relapse was lower in 2003-2004 compared with 1972-1979 (HR=0.35, 95% CI: 0.26-151
0.47), also after adjustment for tumor size, nodal status and age at diagnosis (HR=0.38, 95% CI: 0.28-152
0.52, Table 3). Smaller tumor size and no lymph node involvement were associated with a lower 153
relapse rate. 154
DISCUSSION
155 156
This study among 8877 Dutch breast cancer patients treated with curative intent showed a 157
decrease in 5-year risk of relapse from 38% in 1972-1979 and 35% in 1980-1986 to 16% in 2003-158
2004. This impressive improvement equals a risk reduction of 1% per year. The increasing use of 159
systemic therapy in clinical practice has, to a large extent, contributed to the improved breast cancer 160
outcome at a population level. Especially, since this improvement was largely independent of tumor 161
size, nodal status and age. In contrast to systemic therapy, the strategy with respect to local treatment 162
became less aggressive. Apparently, the less aggressive local approach could safely be implemented 163
and possibly may have been facilitated by the availability and increased use of systemic therapy. 164
165
In the Netherlands, breast cancer screening was introduced in 1989. Previous studies showed 166
that both a more early diagnosis and the use of systemic treatment are effective in preventing breast 167
cancer relapse.13,15,16Discerning the impact of changed breast cancer therapy from that of a more early
168
diagnosis goes beyond the scope of this study. Nevertheless, we attempted to evaluate the effect of a 169
more early diagnosis by adjusting period-specific breast cancer relapse for age at diagnosis, tumor size 170
and nodal status. Increasing tumor size and a positive lymph node status were associated with an 171
increased risk of recurrence. Adjustment for these factors changed the period effect only slightly. 172
Lymph node staging has, however, changed with the introduction of the sentinel node biopsy 173
procedure in 1993.17As accurate staging became increasingly important for treatment planning,
174
pathological lymph node examination was intensified. This may explain the incomplete correction for 175
lymph node status in the present study. The stage migration caused by intensified lymph node 176
examination was, however, to some extent prevented to occur by the introduction of a new TNM 177
classification in 2002.18We decided not to adjust for treatment for several reasons. First, adjustment
178
for stage includes part of the treatment effect. Furthermore, not only frequency of use changed, but the 179
treatments themselves have changed over the years as well. In addition, we expect an interaction 180
between therapy and tumor stage. Unfortunately, we were not able to consider other important 181
prognostic factors, like the mitotic activity index,19,20tumor grade, hormonal receptor status, HER2
and resection margin. The differences in histology between the periods may reflect changes in 183
pathological assessment and classification rather than true changes. The period effect (HR=0.38) after 184
adjustment for tumor characteristics and patient’s age therefore includes the issues described above. 185
186
The 5-year risk of locoregional recurrence as first event decreased from 24% in the 1970s to 187
14% in the 1980s and was only 4% in 2003-2004. This trend was also observed in previous Dutch 188
studies.1,2We can therefore conclude that current treatment, despite the increased use of breast
189
conserving therapy, has resulted in a good local control. In the late 1980s, a positive resection margin 190
was identified as an important risk factor for local recurrence. This had led to more careful breast 191
imaging before surgery, routine pathological assessment of the resection margins and re-excision in 192
case of a positive margin.21In addition, adjuvant treatment13and a lower tumor stage16were associated
193
with a decreased risk of locoregional recurrence. Breast cancer treatment is currently changing from 194
maximal tolerable to optimally needed.22We recognize the importance of preventing overtreatment,
195
yet, it is important to monitor relapse rates closely to prevent underuse of (axillary) surgery or 196
radiotherapy.23
197 198
The occurrence of distant metastases has markedly decreased between the 1980s and 2003-199
2004, which was also observed in Canada5and Sweden6. This decrease may be attributable to a more
200
early detection at initial diagnosis and the increased use of systemic therapy in primary breast cancer 201
treatment. In addition, more and more effective chemotherapeutic options have become available.13
202
The risk of distant metastasis is expected to decrease further because other systemic treatment options 203
become available, e.g. trastuzumab24, and more patients are advised to be treated with systemic
204
therapy. As prognosis improves, the impact of more and more aggressive systemic therapy on survival 205
time will become smaller, whereas the attention for long term toxic side effects will increase. 206
Implementation of new systemic treatment options should therefore be preceded by a careful 207
We observed no large difference in risk of second primary breast cancer between the 1970s, 210
1980s and 2000s, despite the increase in breast cancer incidence in the general population. In the 211
United States, second primary breast cancer rate decreased since 1985.3,4The increased risk may have
212
been counterbalanced by the use of systemic therapy for the primary tumour.13,25In addition,
213
contralateral prophylactic mastectomy (CPM) in patients at high risk of developing a second breast 214
cancer is increasingly performed. In the United States, the CPM rate increased from 0.4% in 1998 to 215
4.7% in 2007.26In the future, increased use of systemic therapy and CPM might further
216
counterbalance the increasing population risk of breast cancer.27
217 218
The trends in breast cancer treatment observed in our study was also observed in previous 219
Dutch studies28-31and in other countries.5,32-37Nowadays, treatment strategies are quite similar for
220
different countries, although the use of breast conserving therapy (BCS) in China was only 30% in 221
1994-2007.38Notably, radiotherapy following BCS is standard practice in the Netherlands,28-30but
222
underused in the United States39and in Korea40even though numerous studies have shown a survival
223
benefit from adjuvant radiotherapy after BCS.41Radiotherapy after mastectomy has decreased in the
224
Netherlands, which was in line with guideline recommendations.42In contrast, the use of
post-225
mastectomy radiotherapy was lower and increased over time in the United States43and Korea40. Of
226
patients diagnosed in 2003-2004 in the Netherlands, 37% received chemotherapy and 42% hormonal 227
therapy. Similar rates were observed in Australia32and Sweden36.
228 229
This population- and hospital-based study reflects changes in breast cancer management in 230
practice. We studied risk of relapse in total, and for the different sites separately, providing a complete 231
overview of trends in relapse. A limitation of this study is that in patients diagnosed in 2003-2004, 232
only first occurrence of locoregional recurrence or distant metastasis was registered. Site-specific risk 233
estimates for locoregional recurrence and distant metastasis were, therefore, underestimated in this 234
study. Another limitation of this study is the use of only one hospital as a historical control. Findings 235
were, however, in line with previous Dutch studies1,2,28-30, suggesting good representativeness of our
236
data. 237
238
CONCLUSION
239 240
This hospital and population based study demonstrates a huge improvement in breast cancer 241
outcome when comparing the patients diagnosed in the nineteen seventies to those diagnosed in the 242
early twenties. Moreover, as since 2004 the number of patients selected for systemic therapy has 243
further increased, it is likely that outcome for current patients is even better. On the one hand, this 244
implies that there may still be room to reduce the extent of locoregional breast treatment. On the other 245
hand, however, it may be time to reconsider the indications for systemic therapy. When the benefit of 246
systemic therapy is only 1-2% for subgroups of patients, preventing long-term toxicities in cancer 247
survivors may become equally or more important than preventing locoregional recurrences. This is, in 248
our opinion, an important challenge for clinical practice and future clinical trials. 249
ACKNOWLEDGEMENTS
251
The authors thank the registrars of the Netherlands Cancer Registry, the scientific staff of the 252
Netherlands Cancer Registry and Dr P Luning for the patient registration. This study was supported by 253
a grant from the Dutch Cancer Society, The Netherlands (Grant No. KUN 2008-4086), no 254
involvement. 255
256
CONFLICTS OF INTEREST STATEMENT
257
The authors declare no conflicts of interest 258
259 260
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367 368
No. at risk
0 1 2 3 4 5 5-year risk (95% CI)
1972-1979 111 108 99 92 85 80 0.01 (0.00-0.03)
1980-1986 166 163 150 141 129 121 0.04 (0.01-0.07)
2003-2004 8303 8142 7821 7480 7191 6883 0.02 (0.02-0.03)
369
FIGURE 1 Risk of second primary breast cancer in non-metastatic breast cancer patients for the years
370 1972-1979 (....), 1980-1986 (---) and 2003-2004 (—). 371 372 373 374 375 376 377 No. at risk
0 1 2 3 4 5 5-year risk (95% CI)
1972-1979 113 100 82 78 71 68 0.37 (0.28 -0.47)
1980-1986 166 150 133 116 108 101 0.34 (0.27 -0.41)
2003-2004 8417 8034 7548 7110 6659 4820 0.15 (0.14 -0.15)
378
FIGURE 2 Risk of locoregional recurrence or distant metastasis in non-metastatic breast cancer
379
patients for the years 1972-1979 (....), 1980-1986 (---) and 2003-2004 (—). 380
TABLE 1 TNM in 1977 and in 2002: pathological classification of breast cancer
382 383
Sources: American Joint Committee for Cancer Staging and End-Results Reporting 197710and
384
American Joint Committee on Cancer 2002 11
385 386 387
TABLE 2 Patient, tumor and treatment characteristics of non-metastatic breast cancer patients by
388
period of diagnosis, n (%) 389
390
* In case the pathological status was unknown the clinical status was taken 391
392
TABLE 3 Cox-proportional hazard models for risk of breast cancer relapse by period of diagnosis
i n 1977 an d i n 20 02: p at h ol og ic al c la ss if ic at ion o f b re as t c anc er 1977 2002 F P F P 2.01 -5 c m 2.01 -5 c m > 5 c m > 5 c m T um or of a ny s iz e w it h di re ct e x te n si o n t o che st w al l o r s k in T um or of a ny s iz e w it h di re ct e x te n si o n t o che st w al l o r s k in N o m et as ta ti c i p si la te ra l ax il la ry node s N o r eg iona l l y m p h node m et as ta si s M ov ab le i p si la te ra l a x il la ry m et as ta ti c node s no t f ixe d to one anot h er o r o the r s tr uc tu re s M et as ta si s in 1 -3 ip si la te ra l a xi ll ar y l y m p h node (s ), an d/ or i n ip si la te ra l i n te rna l m a m m ar y node s w it h m ic ros co p ic m et as ta si s de te ct ed b y s ent ine l lym p h node d is se ct ion b ut n ot c li n ic al ly app ar ent Ip si la te ra l a x il la ry node s c o nt ai ni ng m et as ta ti c tum or a nd f ixe d to one a no the r o r t o ot h er s tr u ct ur es M et as ta si s in 4 -9 i p si la te ra l a xi ll ar y l y m p h node s or i n cl ini ca ll y app ar ent i p si la te ra l int er n al m a m m ar y l ym p h node (s ) in t he a b se nc e of a x il la ry l ym p h node m et as ta si s Ip si la te ra l s u p ra cl av ic u la r o r i n fr ac la v ic ul ar n ode s con ta in ing t um or or oe d em a of t he a rm M et as ta si s in 10 o r m or e i p si la te ra l a x il la ry l ym p h node s; o r i n cl ini ca ll y a p p ar ent i p si la te ra l i nt er na l m am m ar y l ym p h node s in the p re se nc e of on e o r m or e p o si ti v e a xi ll ar y l y m p h node s; or i n m or e tha n 3 axi ll ar y l y m p h node s w it h c li ni ca ll y ne g at iv e, m ic ro sc o p ic m et as ta si s in int er n al m am m ar y l ym p h node s; o r i n i p si la te ra l su p ra cl av ic ul ar l y m p h node s an Joi n t C om m it te e f o r C an ce r S ta g in g a nd E nd -R es ul ts R ep o rt in g 1977 10 and A m er ic an Joi nt C om m it te e on C an ce r 20 02 11
TABLE 2 Patient, tumor and treatment characteristics of non-metastatic breast cancer patients by period of diagnosis, n (%) Period of diagnosis Characteristics 1972-1979 N=133 1980-1986 N=174 2003-2004 N=8570 Patient
Age at diagnosis, median (range) years 50 (27-76) 57 (29-82) 58 (20-96)
Age at diagnosis < 50 years 61 (46) 53 (40) 2265 (26) \HDUV 57 (43) 116 (67) 6305 (74) Unknown 15 (11) 5 (3) -Tumor Tumor size* T1 57 (43) 72 (41) 4962 (58) T2 45 (39) 72 (41) 3152 (37) T3 12 (9) 14 (8) 317 (4) T4 19 (14) 16 (9) 134 (2) Unknown - - 5 (0) Nodal status* N0 78 (59) 105 (60) 5074 (59) N1 31 (23) 43 (25) 2355 (27) N2 4 (3) 7 (4) 740 (9) N3 19 (14) 18 (10) 380 (4) Unknown 1 (1) - 21 (0) Histology Ductal 73 (55) 142 (82) 6711 (78) Lobular 30 (23) 19 (11) 984 (11) Other 29 (22) 13 (7) 875(10) Unknown 1 (1) -
-Bilateral breast cancer
Yes 2 (2) 1 (1) 119 (1)
No 130 (98) 171 (98) 8451 (99)
Unknown 1 (1) 2 (1)
-Treatment
Surgery
Breast conserving surgery (BCS) 2 (2) 45 (26) 4553 (53)
Mastectomy 125 (94) 125 (72) 4012 (47)
Unknown 6 (5) 4 (2) 5 (0)
Radiotherapy after BCS
Yes 1 (50) 43 (96) 4417 (97)
No 1 (50) 2 (4) 136 (3)
Radiotherapy after mastectomy
Yes 86 (75) 87 (70) 1197 (30)
Chemotherapy
Yes 12 (9) 25 (14) 3181 (37)
No 111 (83) 149 (86) 5389 (63)
Unknown 10 (8) -
-Chemotherapy in patients aged < 50 years
Yes 9 (15) 34 (36) 137 (72) No 48 (79) 19 (64) 628 (27) Unknown 4 (7) - -&KHPRWKHUDS\LQSDWLHQWVDJHG\HDUV Yes 3 (5) 6 (5) 1544 (24) No 51 (89) 110 (95) 4761 (76) Unknown 3 (5) - -Hormonal therapy Yes 4 (3) 5 (3) 3571 (42) No 120 (90) 169 (97) 4999 (58) Unknown 9 (7) -
-Hormonal therapy in patients aged < 50 years
Yes 4 (7) 1 (2) 1098 (48) No 54 (89) 52 (98) 1167 (52) Unknown 3 (5) - -+RUPRQDOWKHUDS\LQSDWLHQWVDJHG\HDUV Yes 0 (0) 3 (3) 2473 (39) No 54 (95) 113 (97) 3832 (61) Unknown 3 (5) -
TABLE 3 Cox-proportional hazard models for risk of breast cancer relapse by period of diagnosis
1
Variables Hazard ratio (95% confidence interval)
Model 1 Period 1972-1979 Reference 1980-1986 0.92 (0.62-1.37) 2003-2004 0.35 (0.26-0.47) Model 2 Period 1972-1979 Reference 1980-1986 0.85 (0.57-1.27) 2003-2004 0.38 (0.28-0.52)
Tumor size T1 Reference
T2 1.85 (1.65-2.08)
T3 2.80 (2.27-3.46)
T4 4.38 (3.17-6.06)
Nodal status N0 Reference
N1-N3 1.81 (1.62-2.03)
Age at diagnosis years Reference
< 50 years 1.08 (0.96-1.21)
2 3
