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Comparison of Screened and Nonscreened Breast Cancer Patients in Relation to Age: A 2-Institution Study
Original Study
Comparison of Screened and Nonscreened Breast Cancer Patients in Relation to Age: A 2-Institution Study Israel Barco,1 Carol Chabrera,2 Marc García Font,3 Nuria Gimenez,4,5 Manel Fraile,6 Josep María Lain,7 Merce Piqueras,1 M Carmen Vidal,8 Merce Torras,9 Sonia González,10 Antoni Pessarrodona,11 Josep Barco,12,y Jordi Cassadó,11 Antonio García Fernández1,13 Abstract In this study we assessed the effect of a population screening program. A comparison was performed in the 50- to 69-year-old age group between 496 patients with breast cancer who participated on the screening program and 1325 who did not. The screened group showed significantly better results in all prognostic factors and in specific mortality than all nonscreened groups. Introduction: Screening programs for breast cancer aim to allow early diagnosis, and thus reduce mortality. The aim of this study was to assess the effect of a population screening program in a sample of women aged between 50 and 69 years in terms of recurrence, metastasis, biological profiles, and survival, and to compare their results with those of women of a wider age range who did not participate on the screening program. Patients and Methods: A prospective multicenter study in which 1821 patients with 1873 breast tumors who received surgery between 1999 and 2014 at MútuaTerrassa University Hospital and the Hospital of Terrassa in Barcelona were analyzed. A comparison was performed in the 50- to 69-year-old age group between those who participated on the screening program and those who did not. Results: The mean age of patients was 58 years. The mean follow-up was 72 months, and median follow-up 59 months. The screened group showed significantly better results in all prognostic factors and in specific mortality than all nonscreened groups. The specific mortality rate in the screened patients was 2.4% (12/496), local recurrence 2.8% (14/496), and metastasis at 10 years 3.6% (18/496). In the nonscreened group, younger women presented a higher rate of metastasis (16.4% [81/493]) and a shorter disease-free period (77.1% [380/493]). The age group older than 70 years had the highest number of T4 tumors (7.5% [30/403]) and the highest proportion of radical surgery (50.4% [203/403]). Conclusion: Patients in the screening program presented improved survival. We speculate that extending breast cancer screening programs to women younger than 50 and older than 70 years could bring about mortality benefits. Clinical Breast Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Breast neoplasm, Mortality, Recurrence, Screening, Survival
yThis author is dead. 1 Department of Gynaecology, Breast Unit, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 2 Department of Nursing, School of Health Science Tecnocampus Mataró-Maresme, Barcelona, Spain 3 Universitat Internacional de Catalunya, Barcelona, Spain 4 Research Unit, Research Foundation Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 5 Laboratory of Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain 6 Department of Nuclear Medicine (CTD), Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 7 Breast Unit, Department of Gynaecology, Hospital de Terrassa, Consorci Sanitari de Terrassa, Barcelona, Spain 8 Department of Nursing, Breastfeeding Promotion Programme, ASSIR Mollet, Institut Català de la Salut, Barcelona, Spain
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2015.04.007
9 Department of Nursing, Breast Unit, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 10 Department of Oncology, Breast Unit, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 11 Department of Gynaecology, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 12 Department of Gynaecology and Obstetrics, Clínica Sant Josep, Manresa, Spain 13 Breast Cancer Screening Unit, Vallès Occidental, Institut Català de la Salut, Terrassa, Barcelona, Spain
Submitted: Jan 18, 2015; Revised: Apr 2, 2015; Accepted: Apr 16, 2015 Address for correspondence: Nuria Gimenez, PhD, MD, Research Unit, Research Foundation Mútua Terrassa, Universitat de Barcelona, C/Sant Antoni, 19, E-08221 Terrassa, Barcelona, Spain Fax: þ34-93-581-29-59; e-mail contact: [email protected]
Clinical Breast Cancer Month 2015
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Breast Cancer Screening and Age: A 2-Institution Study Introduction The goal of breast cancer (BC) screening programs is to reduce mortality. Early diagnosis of the disease in the preclinical phase is directly related to tumor size, lesser nodal involvement, and a decreased risk of local and distant recurrence.1,2 The decrease in mortality due to BC recorded in the early 1990s was attributed to advances in adjuvant treatments and also to the implementation of screening programs; in fact, screening alone has been estimated to reduce BC mortality by between 0% and 75% (mean 46%).3-5 In a previous study by our group we reported a decline in mortality of 7% to 10% in patients aged 50 to 69 years who underwent screening compared with age-matched unscreened patients.6 It has been noted that the highest death rate from BC occurs in women who do not undergo screening.7 Mortality rates are especially high in women aged younger than 50 due to the rapid biological progression of the disease,8 and, to a lesser extent, in women aged older than 70 years due to late diagnosis.9 Patients who present with findings suspected to represent BC in the screening undergo additional confirmatory tests. Those who are negative for BC after additional testing are considered as false positives (FPs), and this is considered an adverse effect of the program.10 To optimize the balance between benefits and harms of mammography screening, it is important to keep the rate of FPs low, and at the same not to miss any true cases of BC.11 The aim of this study was to compare the results in different age groups of participants and nonparticipants in a population screening program, in terms of recurrence, metastasis, survival, and biological profiles, and also to calculate the rate of FP in our group.
Patients and Methods
2
-
Consecutive BC patients referred to the Breast Unit of the Mútua Terrassa University Hospital and the Hospital of Terrassa for surgical treatment of either primary or recurrent tumors were prospectively included between January 1, 1997 and January 31, 2014. All patients had been referred either from the regular public health care system (nonscreened group) and the rest of the patients were recruited from the Breast Cancer Screening Programme (BCSP) of the Generalitat de Catalunya, Vallès Occidental Section (Barcelona province). The BCSP was instituted May 2002 and included a population of approximately 500,000 inhabitants attending either of the 2 area public hospitals. Our BCSP is based on a target population of 49,847 women aged 50 to 69 years, for a cumulative grand total of 123,445 women. Under the BCSP, patients aged between 50 and 69 years undergo a mammography examination every 2 years. Patients with in situ carcinomas and those who were unfit for surgery were excluded from the study. Data regarding participation, BC cases, additional noninvasive testing, invasive testing (core biopsy, open biopsy), recall rates, and interval cancers were annually collected. Our database included the following variables: age, tumor size, histological type and grade, assessment of estrogen receptor, progesterone receptor, HER2, and nodal status, distant metastases, disease-free survival, and mortality. All patients were treated in accordance with the regularly updated protocol of the Breast Unit of the Mútua Terrassa University Hospital and Hospital of Terrassa, which follow local and international guidelines. At both hospitals, women with BC are followed by a multidisciplinary breast committee.
Clinical Breast Cancer Month 2015
We studied variations in patient prognosis between groups, defined as follows: 1 group of patients aged between 50 and 69 years who participated in the population screening program, and the other group of unscreened patients that was further subdivided into 3 subgroups (< 50 years, 50-69 years, and 70 years). The 50- to 69-year-old age group of unscreened patients consisted of those synchronic with the program, and those in the same age group before the BCSP was started. Variables considered were tumor size, histological type and grade, disease-free survival, all distant metastases, and specific visceral metastases, including liver, lung, or brain, and mortality. Mortality was considered per se (overall) and as specific mortality from BC when other causes of death had been excluded. Mortality figures were extracted from the mortality register at the centers and from the database of the Catalan Public Health Care System. Survival was determined as a function of the total number of cases over the natural year count from the date of surgery. The study was performed with the approval of our institution’s review board. Written informed consent was obtained in all cases before any invasive procedure and before surgery.
Statistics Time intervals were defined as the time elapsed from the diagnosis of cancer to the last uneventful control or to event occurrence: that is, local or distant recurrence, or death from BC or otherwise. Patients were “uncensored” when they had died or had a disease recurrence. All other patients were “censored.” Qualitative variables were expressed as “n” and percentages, and quantitative variables were expressed as their mean value and standard deviation. The c2 and Fisher exact tests were used to compare qualitative variables, and analyses of variance to compare mean values. Statistical significance was set at P < .05, with a 2-tailed approach. The KaplaneMeier analysis with ManteleCox log-rank tests were used to calculate and compare survival rates. A multivariate analysis was used to estimate the hazard ratios (HRs) based on the Cox proportional hazard method, adjusted for age, tumor size, and nodal status. Statistical analysis was performed using SPSS 17.0 (SPSS Inc, Chicago, IL).
Results The overall participation in the 6 previous rounds was 76.25% with a coverage of 80.5% and a total cumulative population of 154,065 women. The FP rate was 21.8% in the first round, which decreased progressively to a minimum of 8.5%. There were 14,884 recalls (9.6%) in the total of 6 rounds, which decreased gradually from a peak of 21.8% in the first round to a low of 8.5% in the fifth round. In the sixth round, the figure increased to 10.5%, coinciding with the introduction of digital mammography. Invasive tests White Core Needle Biopsy (WCNB) were performed in 11.7% of patients and surgical biopsies in 0.4% (Figure 1). Interval BC (IBC) makes an important surrogate indicator of the sensitivity and efficiency of screening programs. From a radiological perspective, we can consider “true” IBC: occult and minimal tumors, false-negative cases from mammography, and nonevaluable cases. IBCs were included in the screened group in the present study.
Israel Barco et al Figure 1 Recall Rate in Screening Program
The rate of interval breast tumors in our study was 15.6 (79/ 507). This corresponds to a rate of 0.6 per 1000 screened patients. We included 1822 patients with 1874 breast tumors who received surgery at the Mutua Terrassa University Hospital or at the Hospital of Terrassa. Some of the patients were participants in the early BC diagnosis program, which is now in its seventh round. Mean follow-up was 69 months (SD 52.5) and median 58 months. The actual minimum follow-up period was 1 month, and the maximum was 393 months. Of the patients, 12.0% had been followed for 12 months, 78.5% for 24 months, 67.3% for 36 months, 57.0% for 48 months, 49.2% for 60 months, 40.7% for 72 months, 33.9% for 84 months, 27.3% for 96 months, 22.8% for 108 months, and 18.3% for 10 years.
Patient Characteristics The general characteristics of the patients and BCs are shown in Table 1. As for the molecular subtype, the younger than 50 years subgroup showed a greater incidence of triple-negative (TN) BC than the screened group (P < .001). As for lymphovascular invasion, the screened group presented with a lower rate of lymphovascular invasion (P < .001). Tumor size for patients in the screened group was significantly smaller than in the 3 nonscreened subgroups. No significant differences were observed in tumor size between unscreened patients younger than 50 years and those aged 50 to 69 years. Patients aged older than 70 presented with larger tumors than the other 2 nonscreened subgroups. No significant difference in histologic type was found between groups. Of the patients older than 70 years, 20.5% (80 of 390) were synchronic with the screening program. Of them, 21.3% (17 of 80) were diagnosed with BC after discontinuing participation in the screening program. The screened group had a lower rate of positive lymph nodes and total axillary disease burden than the other 3 subgroups. The subgroups of patients younger than age 50 had a greater rate of positive nodes than the other 2 nonscreened subgroups.
A significant difference in stage at diagnosis was seen between the screened and the nonscreened groups, but not among the unscreened subgroups. The screened patients had a significantly greater incidence of conservative surgery than the other 3 subgroups. Patients older than 70 years had the greatest rate of radical surgery.
Mortality Participants in the screening program had a lower overall mortality than nonparticipants. Patients in the subgroup older than 70 years had a greater overall mortality than the rest of the subgroups. No significant differences were observed between the younger than 50 years group and the group aged 50 to 69 years who did not undergo screening (Table 2). The screened group had a lower rate of BC-specific mortality than any of the 3 nonscreened subgroups. No significant differences were found among the nonscreened subgroups. Compared with the corresponding unscreened patients, screened patients with luminal A and luminal B tumors had a significantly lower rate of specific mortality. Concerning HER2 tumors, screened patients had a significantly lower specific mortality rate than unscreened patients older than 50 years (P ¼ .009). Concerning TN tumors, screened patients had a lower specific mortality rate than unscreened patients (P ¼ .065).
Survival The mean specific survival in the younger than 50 years group was 63 months (SD 49) with a median of 44 months and range of 3 to 192 months. In the group aged 50 to 69 years, without screening, the mean was 67 months (SD 41 months), median 65 months, and range 7-165 months. In the age group older than 70 years, mean specific survival was 45 months (SD 39), median 36 months, and range 5 to 236 months. The median survival of the screened group was 46 months (SD 25) with a median of 39 months and range of 20 to 107 months (Figure 2).
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Breast Cancer Screening and Age: A 2-Institution Study Table 1 Baseline Characteristics and Distributions According to Tumor Group Nonscreened Groups <50 Years
50-69 Years
‡70 Years
Patients (Total n [ 1822), nb
493
442
390
496
Tumors (Total n [ 1874), nc
505
458
403
507
Molecular Subtype, nc
505
458
403
50-69 Years
195 (42.6)
182 (45.2)
246 (48.5)
Luminal B
189 (37.4)
178 (38.9)
143 (35.5)
201 (39.6)
Pure HER2
26 (5.1)
29 (6.3)
15 (3.7)
Triple-negative
77 (15.3)
56 (12.2)
63 (15.6)
505
458
403
18 (3.6) .399
42 (8.3)
223 (44.2)
183 (40.0)
171 (42.5)
No LVSI
252 (49.9)
254 (55.4)
223 (55.3)
386 (76.1)
Missing
30 (5.9)
21 (4.6)
9 (2.2)
15 (3.0)
458
.284
403
106 (20.9)
271 (53.7)
261 (57.0)
173 (42.9)
409 (80.7)
T2, n ¼ 640
203 (40.2)
162 (35.4)
187 (46.4)
88 (17.3)
T3, n ¼ 60
20 (3.9)
22 (4.8)
13 (3.2)
T4, n ¼ 59
11 (2.2)
13 (2.8)
30 (7.5)
505
458
466 (92.3)
415 (90.6)
373 (92.6)
Lobular carcinoma
29 (5.7)
37 (8.1)
28 (6.9)
Mixed ductal-lobular carcinoma
10 (2.0)
6 (1.3)
2 (0.5)
458
403
Lymph Node Statusc
505
5 (1.0) <.001
403
Ductal carcinoma
5 (1.0) 462 (91.1) 36 (7.1)
.217
9 (1.8)
262 (51.9)
271 (59.2)
255 (63.3)
243 (48.1)
187 (40.8)
148 (36.7)
140 (27.6) 80 (57.1)
87 (35.8)
69 (36.9)
55 (37.2)
44 (18.1)
30 (16.0)
17 (11.5)
112 (46.1)
88 (47.1)
76 (51.3)
458
403
3 Nodes positive Tumor Stage, nc
505
.001
367 (72.4)
<.001
19 (13.6) .525
41 (29.3)
<.001
507
I, n ¼ 821
176 (34.8)
187 (40.8)
132 (32.8)
325 (64.1)
IIA, n ¼ 555
160 (31.7)
134 (29.3)
144 (35.7)
117 (23.1)
IIB, n ¼ 213
76 (15.1)
57 (12.4)
47 (11.7)
III (IIIA þ IIIB þ IIIC), n ¼ 285
93 (18.4)
80 (17.5)
80 (19.8)
505
458
403
Surgery, nc
.422
507
Positive 2 Nodes positive
<.001
507
Negative 1 Node positive
.001
507
T1, n ¼ 1115
Histologic Type, nc
.008
507
Lymphovascular space invasion present
505
Total P
507
213 (42.2)
Size (T), nc
33 (6.5) .124
32 (6.3)
<.001
507
Radical
182 (36.0)
185 (40.4)
203 (50.4)
Conservative
323 (64.0)
273 (59.6)
200 (49.6)
<.001
424 (83.6)
<.001
380 (77.1)
330 (74.7)
315 (80.8)
.108
467 (94.1)
<.001
Disease-Free Perioda, n (%) Mean Months, Range
83 (16.4)
71 (3-249)
87 (3-280)
61 (3-408)
Median
56
72
48
55
SD
54
59
51
39
58 (3-172)
Metastasesa,b
493
442
5 Yearsa
63 (12.8)
49 (11.1)
43 (11)
.641
14 (2.8)
<.001
10 Yearsa
75 (15.2)a
70 (15.8)a
48 (12.3)
.310
18 (3.6)
<.001
>10 Yearsa
81 (16.4)
74 (16.7)
49 (12.6)
.180
19 (3.8)
<.001
493
442
390
Local Recurrencea,b
390
496
496
5 Yearsa
34 (6.9)
31 (7.0)
27 (6.9)
.997
9 (1.8)
<.001
10 Yearsa
50 (10.1)
54 (12.2)
34 (8.7)
.248
13 (2.6)
<.001
Total
58 (11.8)
66 (14.9)
38 (9.7)
.087
14 (2.8)a
<.001
Data are presented as n (%) except where otherwise stated. Abbreviation: LVSI ¼ Lymphovascular space invasion. a Statistically significant differences using the log-rank test between the screened group and nonscreened group. b Calculated on patients. c Calculated on tumors.
-
P
Luminal A
Lymphovascular, nc
4
Screened Group
Clinical Breast Cancer Month 2015
Israel Barco et al Table 2 Overall and Specific Mortality for Groups According to Age Nonscreened Groups
Screened Group
£50 Years
50-69 Years
‡70 Years
50-69 Years
493
442
390
496
66 (13.4)
78 (17.6)
5 Years
41 (8.3)
10 Yearsa
58 (11.8)
Patient n Overall Mortalitya
P
122 (31.3)
17 (3.4)
33 (7.5)
75 (19.2)
13 (2.6)
67 (15.2)
108 (27.7)
17 (3.4)
63 (12.8)
54 (12.2)
50 (12.8)
12 (2.4)
.001
5 Yearsa
39 (7.9)
24 (5.4)
39 (10)
9 (1.8)
.001
10 Yearsa
56 (11.4)
47 (10.6)
48 (12.3)
12 (2.4)
.001
a
Specific Mortalitya
.001
Specific Mortality Subtypes Luminal Aa
20/210 (9.5)
14/186 (7.5)
13/178 (7.3)
4/238 (1.7)
.030
Luminal Ba
24/182 (13.2)
23/171 (13.5)
17/136 (12.5)
6/200 (3.1)
.003
Pure HER2a Triple-negative P
3/26 (11.5)
6/29 (20.7)
5/15 (33.3)
0/18 (0.0)
.009
18/74 (24.3)
11/56 (19.6)
15/61 (24.6)
2/40 (5.0)
.065
.001
.001
<.001
.098
Data are presented as n (%) except where otherwise stated. a Statistically significant differences using the log-rank test.
Distant Metastases and Locoregional Recurrence In the screened group, the rate of occurrence of distant metastasis was significantly lower than in all other subgroups at 5 and 10 years and in the total study (Figure 3). In the nonscreened group, younger women had the highest rates of metastasis (Table 3).
Disease-Free Period The screened group included a significantly greater number of patients with a disease-free period than the other groups. In the nonscreened subgroups, similar to metastasis occurrence, the disease-free period was shorter in the subgroup younger than
50 years than in the subgroups aged 50 to 69 years and older than 70 years, but not with respect to the subgroup aged 50 to 69 years (Table 1).
Multivariate Analysis After modeling using the Cox analysis, age was shown to be a significant variable for overall mortality (P < .001) but not for specific mortality (P ¼ .248). Mortality differed according to whether patients had participated in the screening program. After adjusting for tumor size, nodal status, and age, the rate of specific mortality was lower in the screened group (HR, 0.33; 95%
Figure 2 (A) Overall Survival and (B) Specific Survival According to Age and Screened Group
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Breast Cancer Screening and Age: A 2-Institution Study Figure 3 Metastasis According to Age and Screened Group
confidence interval [CI], 0.18-0.63) than in the nonscreened group, and the overall mortality rate was lower (HR, 0.29; 95% CI, 0.170.50) in the screened group.
Discussion The purpose of BC screening programs is to reduce mortality from the disease. For years, attempts have been made to evaluate the effectiveness of BC screening. Often times, it has also been the subject of controversy, with reports showing a widely fluctuating decrease in mortality rate of between 0% and 80%.3-6,12 Such variability is puzzling, and it might be due to the differences in assessment methods or to differences in study samples.13 If screening allows diagnosis of the disease at an earlier stage, the most appropriate method to evaluate mortality gain would be to assess specific mortality rather than overall mortality.6 In the present study we found a decrease in BC-specific mortality of 12.4% in screened patients compared with unscreened patients of all age groups, and a reduction of 10% in the
unscreened group aged 50-69 years, figures that are similar to our previous work.6 Rates might seem lower than those reported in other series, but there was probably a certain amount of opportunistic screening in our population before the introduction of the BCSP. Moreover, a large proportion of our patients were aged between 40 and 50 years, or older than 70 years, thus outside of the program’s age range.14 For any screening program to be effective, a high rate (> 70%) of participation is required. In our experience, the overall rate of participation in the 6 rounds was 76.3% with a coverage of 80.5%. Until we master how to prevent BC, mass screening programs offer the possibility of early diagnosis in asymptomatic patients and reduce related mortality and morbidity. European guidelines for quality assurance in screening and diagnosis of BC11 recommend offering regular screening for patients aged 50 to 69 years. In our population, screened women had smaller tumors at the time of diagnosis, lower rates of lymph node involvement, and a lower clinical stage. These findings were associated with lower mortality, longer disease-free periods, and a greater rate of conservative surgery, and therefore, lower associated morbidity. However, the downside of early diagnosis programs is the occurrence of FPs: they increase recall rates, make additional tests mandatory, and cause added distress to the patient. It has been estimated that the total cumulative risk of a FP result is 20.4%.15 Most patients with positive screening results undergo additional noninvasive testing; only a small percentage of recalled patients require core biopsy, and even fewer require open biopsy.10 In our experience, it should be noted that recall rates were greater in the first rounds than in later ones, with a progressive decrease in cost and distress to patients. Previous opinion studies on women who undergo recall found that they favor a small improvement in diagnostic performance of BC despite increased emotional stress.16-18 Such attitudes might also encourage greater adherence to the program.6 Data regarding the ideal age for beginning and ending BC screening are controversial. Swedish population studies have shown a significant decrease in mortality in women younger than 50 years who undergo BC screening19-21 and evidence of downstaging.22 More recent series have also found benefits, especially in the 45- to 49-year-old subgroup.23 Most meta-analyses suggest that screening in this age reduces mortality, and that clearer benefits are
Table 3 Local Recurrence and Metastases and According to Organ Metastasesa
Local Recurrencea
Lunga
Livera
Braina
Lymph Nodea,b
Bonea
Age <50 Years (n ¼ 493)
81 (16.4%)
58 (11.8%)
40 (8.1%)
41 (8.3%)
25 (5.1%)
25 (5.1%)
47 (9.5%)
50-69 years nonscreened group (n ¼ 442)
74 (16.7%)
66 (14.9%)
40 (9.1%)
36 (8.1%)
15 (3.4%)
31 (7.0%)
36 (8.1%) 22 (5.6%)
70 years (n ¼ 390)
49 (12.6%)
38 (9.7%)
21 (5.4%)
22 (5.6%)
10 (2.6%)
11 (2.8%)
P for Nonscreened Groups
.180
.688
.121
.261
.135
.022
.102
Screened Group (n [ 496)
19 (3.8%)
14 (2.8%)
10 (2.0%)
11 (2.2%)
3 (0.6%)
4 (0.8%)
10 (2.0%)
<.001
<.001
<.001
<.001
<.001
<.001
<.001
P Total
Data are presented as n (%) except where otherwise stated. a Statistically significant differences using the log-rank test according to months without recurrence between the screened group and nonscreened group. b Statistically significant differences using the log-rank test according to months without recurrence among nonscreened subgroups.
6
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Clinical Breast Cancer Month 2015
Israel Barco et al obtained with longer follow-up periods.24-28 After a decade of follow-up, the reduction of risk is estimated at 17%.24 Because the incidence of BC has increased and approximately 25% of all deaths due to BC occur in the 40- to 49-year-old age group,29,30 it is possible that starting screening at age 45 could further decrease BC mortality due to BC. Earlier initiation of screening could also be justified on the grounds of a greater potential gain in years of life, and decreased psychological, social, and family impact. Mammography screening detects tumors with better final prognosis in patients either younger or older than 50 years compared with nonscreened women,31-35 and is an independent prognostic factor that confers real advantages for survival. However, it cannot be fully ruled out that enhanced mass screening programs would detect tumors with less aggressiveness that eventually are not lethal or even biologically relevant. Thus, we should always be aware of overdiagnosis as a counterpart of BCSP enthusiasm. As in other published series,36 we observed that most locally advanced tumors (T4) were found in the age group older than 70 years, probably because of increased personal and family neglect and to a decreased level of medical care. Patients in this age range often do not receive standard adjuvant chemotherapy, because of the existence of comorbidities, cognitive impairment, and poor social support,37 which might result in undertreatment and higher BC-specific mortality.38,39
Conclusion Our data confirm the usefulness of our screening program6 and we speculate that extending BCSPs to women younger than age 50 and older than 70 years could bring about mortality benefits.
Clinical Practice Points The aim of screening programs is to improve survival because of
early diagnosis and to increase the number of candidates suitable for conservative surgery. The screened group showed significantly better results than all nonscreened groups. In the nonscreened group, younger women presented a greater rate of metastasis and a shorter disease-free period, and the older than age 70 group had the highest number of T4 tumors and the highest proportion of radical surgery. These results confirm the usefulness of a screening program in patients aged 50 to 69 years. We speculate that extending BCSPs to women younger than 50 years and older than 70 years could bring about mortality benefits.
Acknowledgments We thank Manel Martori for helping us with the tables and graphs and, the staff of the Breast Cancer Screening Unit: Cristina Matarín, Pilar Cadenas, Sandra Carmona, and Xavier Fuentes and the staff of the Pathology Department: Francisca Perarnau, Maria Teresa Blanco, and Maribel Baldellon, for keeping our breast cancer database updated.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Baum M, Ravdin PM. Decision-making in early breast cancer: guidelines and decision tools. Eur J Cancer 2002; 38:745-9. 2. Silverstein MJ, Skinner KA, Lomis TJ. Predicting axillary nodal positivity in 2282 patients with breast carcinoma. World J Surg 2001; 25:767-72. 3. Kalager M, Zelen M, Langmark F, Adami HO. Effect of screening mammography on breast-cancer mortality in Norway. N Engl J Med 2010; 363:1203-10. 4. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005; 353:1784-92. 5. Vervoort MM, Draisma G, Fracheboud J, van de Poll-Franse LV, de Koning HJ. Trends in the usage of adjuvant systemic therapy for breast cancer in the Netherlands and its effect on mortality. Br J Cancer 2004; 91:242-7. 6. García A, Chabrera C, García M, et al. Mortality and recurrence patterns of breast cancer patients diagnosed under a screening programme versus comparable nonscreened breast cancer patients from the same population: analytical survey from 2002 to 2012. Tumour Biol 2014; 35:1945-53. 7. Spencer DB, Potter JE, Chung MA, Fulton J, Hebert W, Cady B. Mammographic screening and disease presentation of breast cancer patients who die of disease. Breast J 2004; 10:298-303. 8. Joyce KM, McInerney NM, Waters PS, Sweeney KJ, Barry K, Kerin MJ. Symptomatic breast cancer diagnosis and multimodal management in women aged 40 to 50 years; consequences of current mammographic screening programs. Clin Breast Cancer 2015; 15:e125-30. 9. Webb ML, Cady B, Michaelson JS, et al. A failure analysis of invasive breast cancer: most deaths from disease occur in women not regularly screened. Cancer 2014; 120:2839-46. 10. Hofvind S, Ponti A, Patnick J, et al. False-positive results in mammographic screening for breast cancer in Europe: a literature review and survey of service screening programmes. J Med Screen 2012; 19(suppl 1):57-66. 11. Perry N, Broeders M, de Wolf C, Törnberg S, Holland R, von Karsa L. European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition. Ann Oncol 2008; 19:614-22. 12. Autier P, Boniol M, Gavin A, Vatten LJ. Breast cancer mortality in neighbouring European countries with different levels of screening but similar access to treatment: trend analysis of WHO mortality database. BMJ 2011; 343:d4411. 13. Beckmann KR, Roder DM, Hiller JE, Farshid G, Lynch JW. Do breast cancer risk factors differ among those who do and do not undertake mammography screening? J Med Screen 2013; 20:208-19. 14. Tresserras R, Séculi E, Masuet C, Brugulat P. The practice of preventive mammography in Catalonia [Spain]: a step forward. Gac Sanit 2004; 18:321-5. 15. Salas D, Ibáñez J, Román R, et al. Effect of start age of breast cancer screening mammography on the risk of false-positive results. Prev Med 2011; 53:76-81. 16. Schwartz LM, Woloshin S, Sox HC, Welch H. US women’s attitudes to false positive mammography results and detection of ductal carcinoma in situ: cross sectional survey. BMJ 2000; 320:1635-40. 17. Ndkhlyudov L, Ross-Degnan D, Fletcher SW. Beliefs and expectations of women under 50 years old regarding screening mammography: a qualitative study. J Gen Intern Med 2003; 18:182-9. 18. Silverman E, Woloshin S, Schwartz LM, Byram SJ, Welch HG, Fischhoff B. Women’s views on breast cancer risk and screening mammography: a qualitative interview study. Med Decis Making 2001; 21:231-40. 19. Andersson I, Janzon L. Reduced breast cancer mortality in women under age 50: updated results from the Malmo Mammographic Screening Programme. J Natl Cancer Inst Monogr 1997; 22:63-7. 20. Bjurstam N, Björneld L, Duffy SW, et al. The Gothenburg breast screening trial: first results on mortality, incidence, and mode of detection for women ages 39-49 years at randomization. Cancer 1997; 80:2091-9. 21. Jonsson H, Törnberg S, Nyström L, Lenner P. Service screening with mammography in Sweden- evaluation of effects of screening on breast cancer mortality in age group 40-49 years. Acta Oncol 2000; 39:617-23. 22. Buseman S, Mouchawar J, Calonge N, Byers T. Mammography screening matters for young women with breast carcinoma: evidence of downstaging among 42-49year-old women with a history of previous mammography screening. Cancer 2003; 97:352-8. 23. Hellquist BN, Duffy SW, Abdsaleh S, et al. Effectiveness of population-based service screening with mammography for women ages 40 to 49 years: evaluation of the Swedish Mammography Screening in Young Women (SCRY) cohort. Cancer 2011; 117:714-22. 24. Kerlikowske K, Grady D, Rubin SM, Sandrock C, Ernster VL. Efficacy of screening mammography. A meta-analysis. JAMA 1995; 273:149-54. 25. Hendrick RE, Smith RA, Rutledge JH 3rd, Smart CR. Benefit of screening mammography in women aged 40-49: a new meta-analysis of randomized controlled trials. J Natl Cancer Inst Monogr 1997; 22:87-92. 26. Glasziou PP, Woodward AJ, Mahon CM. Mammographic screening trials for women aged under 50. A quality assessment and meta-analysis. Med J Aust 1995; 162:625-9. 27. Elwood JM, Cox B, Richardson AK. The effectiveness of breast cancer screening by mammography in younger women. Online J Curr Clin Trials 1993, Doc No 32. 28. Nystrom L, Andersson I, Bjurstam N, Frisell J, Nordenskjöld B, Rutqvist LE. Long-term effects of mammography screening: updated overview of the Swedish randomized trials. Lancet 2002; 359:909-19. 29. Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002 [published errata appear in 2002; 52:119, and 2002; 52:181-182]. CA Cancer J Clin 2002; 52:23-45.
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Breast Cancer Screening and Age: A 2-Institution Study 30. Feig SA. Mammographic screening of women aged 40-49 years: is it justified? Obstet Gynecol Clin North Am 1994; 21:587-606. 31. Curpen BN, Sickles EA, Sollitto RA, Ominsky SH, Galvin HB, Frankel SD. The comparative value of mammographic screening for women 40-49 years old versus women 50-64 years old. AJR Am J Roentgenol 1995; 164:1099-103. 32. Wazer DE, Gage I, Homer MJ, Krosnick SH, Schmid C. Age related differences in patients with nonpalpable breast carcinomas. Cancer 1996; 78:1432-7. 33. Thurfjell EL, Lindgren JA. Breast cancer survival rates with mammographic screening: similar favourable survival rates for women younger and those older than 50 years. Radiology 1996; 201:421-6. 34. Smart CR. Highlights of the evidence of benefit for women aged 40-49 years from the 14-year follow-up of the Breast Cancer Detection Demonstration Project. Cancer 1994; 74:296-300.
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35. Ck Chu, Smart CR, Tarone RE. Analysis of breast cancer mortality and stage distribution by age for the Health Insurance Plan clinical trial. J Natl Cancer Inst 1998; 80:1125-32. 36. McCarthy EP, Burns RB, Freund KM, et al. Mammography use, breast cancer stage at diagnosis, and survival among older women. J Am Geriatr Soc 2000; 48: 1226-33. 37. Patnaik JL, Byers T, Diguiseppi C, Denberg TD, Dabelea D. The influence of comorbidities on overall survival among older women diagnosed with breast cancer. J Natl Cancer Inst 2011; 103:1101-11. 38. Faulk RM, Sickles EA, Sollitto RA, Ominsky SH, Galvin HB, Frankel SD. Clinical efficacy of mammographic screening in the elderly. Radiology 1995; 194:193-7. 39. Bouchardy C, Rapiti E, Fioretta G, et al. Undertreatment strongly decreases prognosis of breast cancer in elderly women. J Clin Oncol 2003; 21:3580-7.
Comparison of Screened and Nonscreened Breast Cancer Patients in Relation to Age: A 2-Institution Study Israel Barco,1 Carol Chabrera,2 Marc García Font,3 Nuria Gimenez,4,5 Manel Fraile,6 Josep María Lain,7 Merce Piqueras,1 M Carmen Vidal,8 Merce Torras,9 Sonia González,10 Antoni Pessarrodona,11 Josep Barco,12,y Jordi Cassadó,11 Antonio García Fernández1,13 Abstract In this study we assessed the effect of a population screening program. A comparison was performed in the 50- to 69-year-old age group between 496 patients with breast cancer who participated on the screening program and 1325 who did not. The screened group showed significantly better results in all prognostic factors and in specific mortality than all nonscreened groups. Introduction: Screening programs for breast cancer aim to allow early diagnosis, and thus reduce mortality. The aim of this study was to assess the effect of a population screening program in a sample of women aged between 50 and 69 years in terms of recurrence, metastasis, biological profiles, and survival, and to compare their results with those of women of a wider age range who did not participate on the screening program. Patients and Methods: A prospective multicenter study in which 1821 patients with 1873 breast tumors who received surgery between 1999 and 2014 at MútuaTerrassa University Hospital and the Hospital of Terrassa in Barcelona were analyzed. A comparison was performed in the 50- to 69-year-old age group between those who participated on the screening program and those who did not. Results: The mean age of patients was 58 years. The mean follow-up was 72 months, and median follow-up 59 months. The screened group showed significantly better results in all prognostic factors and in specific mortality than all nonscreened groups. The specific mortality rate in the screened patients was 2.4% (12/496), local recurrence 2.8% (14/496), and metastasis at 10 years 3.6% (18/496). In the nonscreened group, younger women presented a higher rate of metastasis (16.4% [81/493]) and a shorter disease-free period (77.1% [380/493]). The age group older than 70 years had the highest number of T4 tumors (7.5% [30/403]) and the highest proportion of radical surgery (50.4% [203/403]). Conclusion: Patients in the screening program presented improved survival. We speculate that extending breast cancer screening programs to women younger than 50 and older than 70 years could bring about mortality benefits. Clinical Breast Cancer, Vol. -, No. -, --- ª 2015 Elsevier Inc. All rights reserved. Keywords: Breast neoplasm, Mortality, Recurrence, Screening, Survival
yThis author is dead. 1 Department of Gynaecology, Breast Unit, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 2 Department of Nursing, School of Health Science Tecnocampus Mataró-Maresme, Barcelona, Spain 3 Universitat Internacional de Catalunya, Barcelona, Spain 4 Research Unit, Research Foundation Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 5 Laboratory of Toxicology, Universitat Autònoma de Barcelona, Barcelona, Spain 6 Department of Nuclear Medicine (CTD), Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 7 Breast Unit, Department of Gynaecology, Hospital de Terrassa, Consorci Sanitari de Terrassa, Barcelona, Spain 8 Department of Nursing, Breastfeeding Promotion Programme, ASSIR Mollet, Institut Català de la Salut, Barcelona, Spain
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2015.04.007
9 Department of Nursing, Breast Unit, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 10 Department of Oncology, Breast Unit, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 11 Department of Gynaecology, Hospital Universitari Mútua Terrassa, Universitat de Barcelona, Barcelona, Spain 12 Department of Gynaecology and Obstetrics, Clínica Sant Josep, Manresa, Spain 13 Breast Cancer Screening Unit, Vallès Occidental, Institut Català de la Salut, Terrassa, Barcelona, Spain
Submitted: Jan 18, 2015; Revised: Apr 2, 2015; Accepted: Apr 16, 2015 Address for correspondence: Nuria Gimenez, PhD, MD, Research Unit, Research Foundation Mútua Terrassa, Universitat de Barcelona, C/Sant Antoni, 19, E-08221 Terrassa, Barcelona, Spain Fax: þ34-93-581-29-59; e-mail contact: [email protected]
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Breast Cancer Screening and Age: A 2-Institution Study Introduction The goal of breast cancer (BC) screening programs is to reduce mortality. Early diagnosis of the disease in the preclinical phase is directly related to tumor size, lesser nodal involvement, and a decreased risk of local and distant recurrence.1,2 The decrease in mortality due to BC recorded in the early 1990s was attributed to advances in adjuvant treatments and also to the implementation of screening programs; in fact, screening alone has been estimated to reduce BC mortality by between 0% and 75% (mean 46%).3-5 In a previous study by our group we reported a decline in mortality of 7% to 10% in patients aged 50 to 69 years who underwent screening compared with age-matched unscreened patients.6 It has been noted that the highest death rate from BC occurs in women who do not undergo screening.7 Mortality rates are especially high in women aged younger than 50 due to the rapid biological progression of the disease,8 and, to a lesser extent, in women aged older than 70 years due to late diagnosis.9 Patients who present with findings suspected to represent BC in the screening undergo additional confirmatory tests. Those who are negative for BC after additional testing are considered as false positives (FPs), and this is considered an adverse effect of the program.10 To optimize the balance between benefits and harms of mammography screening, it is important to keep the rate of FPs low, and at the same not to miss any true cases of BC.11 The aim of this study was to compare the results in different age groups of participants and nonparticipants in a population screening program, in terms of recurrence, metastasis, survival, and biological profiles, and also to calculate the rate of FP in our group.
Patients and Methods
2
-
Consecutive BC patients referred to the Breast Unit of the Mútua Terrassa University Hospital and the Hospital of Terrassa for surgical treatment of either primary or recurrent tumors were prospectively included between January 1, 1997 and January 31, 2014. All patients had been referred either from the regular public health care system (nonscreened group) and the rest of the patients were recruited from the Breast Cancer Screening Programme (BCSP) of the Generalitat de Catalunya, Vallès Occidental Section (Barcelona province). The BCSP was instituted May 2002 and included a population of approximately 500,000 inhabitants attending either of the 2 area public hospitals. Our BCSP is based on a target population of 49,847 women aged 50 to 69 years, for a cumulative grand total of 123,445 women. Under the BCSP, patients aged between 50 and 69 years undergo a mammography examination every 2 years. Patients with in situ carcinomas and those who were unfit for surgery were excluded from the study. Data regarding participation, BC cases, additional noninvasive testing, invasive testing (core biopsy, open biopsy), recall rates, and interval cancers were annually collected. Our database included the following variables: age, tumor size, histological type and grade, assessment of estrogen receptor, progesterone receptor, HER2, and nodal status, distant metastases, disease-free survival, and mortality. All patients were treated in accordance with the regularly updated protocol of the Breast Unit of the Mútua Terrassa University Hospital and Hospital of Terrassa, which follow local and international guidelines. At both hospitals, women with BC are followed by a multidisciplinary breast committee.
Clinical Breast Cancer Month 2015
We studied variations in patient prognosis between groups, defined as follows: 1 group of patients aged between 50 and 69 years who participated in the population screening program, and the other group of unscreened patients that was further subdivided into 3 subgroups (< 50 years, 50-69 years, and 70 years). The 50- to 69-year-old age group of unscreened patients consisted of those synchronic with the program, and those in the same age group before the BCSP was started. Variables considered were tumor size, histological type and grade, disease-free survival, all distant metastases, and specific visceral metastases, including liver, lung, or brain, and mortality. Mortality was considered per se (overall) and as specific mortality from BC when other causes of death had been excluded. Mortality figures were extracted from the mortality register at the centers and from the database of the Catalan Public Health Care System. Survival was determined as a function of the total number of cases over the natural year count from the date of surgery. The study was performed with the approval of our institution’s review board. Written informed consent was obtained in all cases before any invasive procedure and before surgery.
Statistics Time intervals were defined as the time elapsed from the diagnosis of cancer to the last uneventful control or to event occurrence: that is, local or distant recurrence, or death from BC or otherwise. Patients were “uncensored” when they had died or had a disease recurrence. All other patients were “censored.” Qualitative variables were expressed as “n” and percentages, and quantitative variables were expressed as their mean value and standard deviation. The c2 and Fisher exact tests were used to compare qualitative variables, and analyses of variance to compare mean values. Statistical significance was set at P < .05, with a 2-tailed approach. The KaplaneMeier analysis with ManteleCox log-rank tests were used to calculate and compare survival rates. A multivariate analysis was used to estimate the hazard ratios (HRs) based on the Cox proportional hazard method, adjusted for age, tumor size, and nodal status. Statistical analysis was performed using SPSS 17.0 (SPSS Inc, Chicago, IL).
Results The overall participation in the 6 previous rounds was 76.25% with a coverage of 80.5% and a total cumulative population of 154,065 women. The FP rate was 21.8% in the first round, which decreased progressively to a minimum of 8.5%. There were 14,884 recalls (9.6%) in the total of 6 rounds, which decreased gradually from a peak of 21.8% in the first round to a low of 8.5% in the fifth round. In the sixth round, the figure increased to 10.5%, coinciding with the introduction of digital mammography. Invasive tests White Core Needle Biopsy (WCNB) were performed in 11.7% of patients and surgical biopsies in 0.4% (Figure 1). Interval BC (IBC) makes an important surrogate indicator of the sensitivity and efficiency of screening programs. From a radiological perspective, we can consider “true” IBC: occult and minimal tumors, false-negative cases from mammography, and nonevaluable cases. IBCs were included in the screened group in the present study.
Israel Barco et al Figure 1 Recall Rate in Screening Program
The rate of interval breast tumors in our study was 15.6 (79/ 507). This corresponds to a rate of 0.6 per 1000 screened patients. We included 1822 patients with 1874 breast tumors who received surgery at the Mutua Terrassa University Hospital or at the Hospital of Terrassa. Some of the patients were participants in the early BC diagnosis program, which is now in its seventh round. Mean follow-up was 69 months (SD 52.5) and median 58 months. The actual minimum follow-up period was 1 month, and the maximum was 393 months. Of the patients, 12.0% had been followed for 12 months, 78.5% for 24 months, 67.3% for 36 months, 57.0% for 48 months, 49.2% for 60 months, 40.7% for 72 months, 33.9% for 84 months, 27.3% for 96 months, 22.8% for 108 months, and 18.3% for 10 years.
Patient Characteristics The general characteristics of the patients and BCs are shown in Table 1. As for the molecular subtype, the younger than 50 years subgroup showed a greater incidence of triple-negative (TN) BC than the screened group (P < .001). As for lymphovascular invasion, the screened group presented with a lower rate of lymphovascular invasion (P < .001). Tumor size for patients in the screened group was significantly smaller than in the 3 nonscreened subgroups. No significant differences were observed in tumor size between unscreened patients younger than 50 years and those aged 50 to 69 years. Patients aged older than 70 presented with larger tumors than the other 2 nonscreened subgroups. No significant difference in histologic type was found between groups. Of the patients older than 70 years, 20.5% (80 of 390) were synchronic with the screening program. Of them, 21.3% (17 of 80) were diagnosed with BC after discontinuing participation in the screening program. The screened group had a lower rate of positive lymph nodes and total axillary disease burden than the other 3 subgroups. The subgroups of patients younger than age 50 had a greater rate of positive nodes than the other 2 nonscreened subgroups.
A significant difference in stage at diagnosis was seen between the screened and the nonscreened groups, but not among the unscreened subgroups. The screened patients had a significantly greater incidence of conservative surgery than the other 3 subgroups. Patients older than 70 years had the greatest rate of radical surgery.
Mortality Participants in the screening program had a lower overall mortality than nonparticipants. Patients in the subgroup older than 70 years had a greater overall mortality than the rest of the subgroups. No significant differences were observed between the younger than 50 years group and the group aged 50 to 69 years who did not undergo screening (Table 2). The screened group had a lower rate of BC-specific mortality than any of the 3 nonscreened subgroups. No significant differences were found among the nonscreened subgroups. Compared with the corresponding unscreened patients, screened patients with luminal A and luminal B tumors had a significantly lower rate of specific mortality. Concerning HER2 tumors, screened patients had a significantly lower specific mortality rate than unscreened patients older than 50 years (P ¼ .009). Concerning TN tumors, screened patients had a lower specific mortality rate than unscreened patients (P ¼ .065).
Survival The mean specific survival in the younger than 50 years group was 63 months (SD 49) with a median of 44 months and range of 3 to 192 months. In the group aged 50 to 69 years, without screening, the mean was 67 months (SD 41 months), median 65 months, and range 7-165 months. In the age group older than 70 years, mean specific survival was 45 months (SD 39), median 36 months, and range 5 to 236 months. The median survival of the screened group was 46 months (SD 25) with a median of 39 months and range of 20 to 107 months (Figure 2).
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Breast Cancer Screening and Age: A 2-Institution Study Table 1 Baseline Characteristics and Distributions According to Tumor Group Nonscreened Groups <50 Years
50-69 Years
‡70 Years
Patients (Total n [ 1822), nb
493
442
390
496
Tumors (Total n [ 1874), nc
505
458
403
507
Molecular Subtype, nc
505
458
403
50-69 Years
195 (42.6)
182 (45.2)
246 (48.5)
Luminal B
189 (37.4)
178 (38.9)
143 (35.5)
201 (39.6)
Pure HER2
26 (5.1)
29 (6.3)
15 (3.7)
Triple-negative
77 (15.3)
56 (12.2)
63 (15.6)
505
458
403
18 (3.6) .399
42 (8.3)
223 (44.2)
183 (40.0)
171 (42.5)
No LVSI
252 (49.9)
254 (55.4)
223 (55.3)
386 (76.1)
Missing
30 (5.9)
21 (4.6)
9 (2.2)
15 (3.0)
458
.284
403
106 (20.9)
271 (53.7)
261 (57.0)
173 (42.9)
409 (80.7)
T2, n ¼ 640
203 (40.2)
162 (35.4)
187 (46.4)
88 (17.3)
T3, n ¼ 60
20 (3.9)
22 (4.8)
13 (3.2)
T4, n ¼ 59
11 (2.2)
13 (2.8)
30 (7.5)
505
458
466 (92.3)
415 (90.6)
373 (92.6)
Lobular carcinoma
29 (5.7)
37 (8.1)
28 (6.9)
Mixed ductal-lobular carcinoma
10 (2.0)
6 (1.3)
2 (0.5)
458
403
Lymph Node Statusc
505
5 (1.0) <.001
403
Ductal carcinoma
5 (1.0) 462 (91.1) 36 (7.1)
.217
9 (1.8)
262 (51.9)
271 (59.2)
255 (63.3)
243 (48.1)
187 (40.8)
148 (36.7)
140 (27.6) 80 (57.1)
87 (35.8)
69 (36.9)
55 (37.2)
44 (18.1)
30 (16.0)
17 (11.5)
112 (46.1)
88 (47.1)
76 (51.3)
458
403
3 Nodes positive Tumor Stage, nc
505
.001
367 (72.4)
<.001
19 (13.6) .525
41 (29.3)
<.001
507
I, n ¼ 821
176 (34.8)
187 (40.8)
132 (32.8)
325 (64.1)
IIA, n ¼ 555
160 (31.7)
134 (29.3)
144 (35.7)
117 (23.1)
IIB, n ¼ 213
76 (15.1)
57 (12.4)
47 (11.7)
III (IIIA þ IIIB þ IIIC), n ¼ 285
93 (18.4)
80 (17.5)
80 (19.8)
505
458
403
Surgery, nc
.422
507
Positive 2 Nodes positive
<.001
507
Negative 1 Node positive
.001
507
T1, n ¼ 1115
Histologic Type, nc
.008
507
Lymphovascular space invasion present
505
Total P
507
213 (42.2)
Size (T), nc
33 (6.5) .124
32 (6.3)
<.001
507
Radical
182 (36.0)
185 (40.4)
203 (50.4)
Conservative
323 (64.0)
273 (59.6)
200 (49.6)
<.001
424 (83.6)
<.001
380 (77.1)
330 (74.7)
315 (80.8)
.108
467 (94.1)
<.001
Disease-Free Perioda, n (%) Mean Months, Range
83 (16.4)
71 (3-249)
87 (3-280)
61 (3-408)
Median
56
72
48
55
SD
54
59
51
39
58 (3-172)
Metastasesa,b
493
442
5 Yearsa
63 (12.8)
49 (11.1)
43 (11)
.641
14 (2.8)
<.001
10 Yearsa
75 (15.2)a
70 (15.8)a
48 (12.3)
.310
18 (3.6)
<.001
>10 Yearsa
81 (16.4)
74 (16.7)
49 (12.6)
.180
19 (3.8)
<.001
493
442
390
Local Recurrencea,b
390
496
496
5 Yearsa
34 (6.9)
31 (7.0)
27 (6.9)
.997
9 (1.8)
<.001
10 Yearsa
50 (10.1)
54 (12.2)
34 (8.7)
.248
13 (2.6)
<.001
Total
58 (11.8)
66 (14.9)
38 (9.7)
.087
14 (2.8)a
<.001
Data are presented as n (%) except where otherwise stated. Abbreviation: LVSI ¼ Lymphovascular space invasion. a Statistically significant differences using the log-rank test between the screened group and nonscreened group. b Calculated on patients. c Calculated on tumors.
-
P
Luminal A
Lymphovascular, nc
4
Screened Group
Clinical Breast Cancer Month 2015
Israel Barco et al Table 2 Overall and Specific Mortality for Groups According to Age Nonscreened Groups
Screened Group
£50 Years
50-69 Years
‡70 Years
50-69 Years
493
442
390
496
66 (13.4)
78 (17.6)
5 Years
41 (8.3)
10 Yearsa
58 (11.8)
Patient n Overall Mortalitya
P
122 (31.3)
17 (3.4)
33 (7.5)
75 (19.2)
13 (2.6)
67 (15.2)
108 (27.7)
17 (3.4)
63 (12.8)
54 (12.2)
50 (12.8)
12 (2.4)
.001
5 Yearsa
39 (7.9)
24 (5.4)
39 (10)
9 (1.8)
.001
10 Yearsa
56 (11.4)
47 (10.6)
48 (12.3)
12 (2.4)
.001
a
Specific Mortalitya
.001
Specific Mortality Subtypes Luminal Aa
20/210 (9.5)
14/186 (7.5)
13/178 (7.3)
4/238 (1.7)
.030
Luminal Ba
24/182 (13.2)
23/171 (13.5)
17/136 (12.5)
6/200 (3.1)
.003
Pure HER2a Triple-negative P
3/26 (11.5)
6/29 (20.7)
5/15 (33.3)
0/18 (0.0)
.009
18/74 (24.3)
11/56 (19.6)
15/61 (24.6)
2/40 (5.0)
.065
.001
.001
<.001
.098
Data are presented as n (%) except where otherwise stated. a Statistically significant differences using the log-rank test.
Distant Metastases and Locoregional Recurrence In the screened group, the rate of occurrence of distant metastasis was significantly lower than in all other subgroups at 5 and 10 years and in the total study (Figure 3). In the nonscreened group, younger women had the highest rates of metastasis (Table 3).
Disease-Free Period The screened group included a significantly greater number of patients with a disease-free period than the other groups. In the nonscreened subgroups, similar to metastasis occurrence, the disease-free period was shorter in the subgroup younger than
50 years than in the subgroups aged 50 to 69 years and older than 70 years, but not with respect to the subgroup aged 50 to 69 years (Table 1).
Multivariate Analysis After modeling using the Cox analysis, age was shown to be a significant variable for overall mortality (P < .001) but not for specific mortality (P ¼ .248). Mortality differed according to whether patients had participated in the screening program. After adjusting for tumor size, nodal status, and age, the rate of specific mortality was lower in the screened group (HR, 0.33; 95%
Figure 2 (A) Overall Survival and (B) Specific Survival According to Age and Screened Group
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Breast Cancer Screening and Age: A 2-Institution Study Figure 3 Metastasis According to Age and Screened Group
confidence interval [CI], 0.18-0.63) than in the nonscreened group, and the overall mortality rate was lower (HR, 0.29; 95% CI, 0.170.50) in the screened group.
Discussion The purpose of BC screening programs is to reduce mortality from the disease. For years, attempts have been made to evaluate the effectiveness of BC screening. Often times, it has also been the subject of controversy, with reports showing a widely fluctuating decrease in mortality rate of between 0% and 80%.3-6,12 Such variability is puzzling, and it might be due to the differences in assessment methods or to differences in study samples.13 If screening allows diagnosis of the disease at an earlier stage, the most appropriate method to evaluate mortality gain would be to assess specific mortality rather than overall mortality.6 In the present study we found a decrease in BC-specific mortality of 12.4% in screened patients compared with unscreened patients of all age groups, and a reduction of 10% in the
unscreened group aged 50-69 years, figures that are similar to our previous work.6 Rates might seem lower than those reported in other series, but there was probably a certain amount of opportunistic screening in our population before the introduction of the BCSP. Moreover, a large proportion of our patients were aged between 40 and 50 years, or older than 70 years, thus outside of the program’s age range.14 For any screening program to be effective, a high rate (> 70%) of participation is required. In our experience, the overall rate of participation in the 6 rounds was 76.3% with a coverage of 80.5%. Until we master how to prevent BC, mass screening programs offer the possibility of early diagnosis in asymptomatic patients and reduce related mortality and morbidity. European guidelines for quality assurance in screening and diagnosis of BC11 recommend offering regular screening for patients aged 50 to 69 years. In our population, screened women had smaller tumors at the time of diagnosis, lower rates of lymph node involvement, and a lower clinical stage. These findings were associated with lower mortality, longer disease-free periods, and a greater rate of conservative surgery, and therefore, lower associated morbidity. However, the downside of early diagnosis programs is the occurrence of FPs: they increase recall rates, make additional tests mandatory, and cause added distress to the patient. It has been estimated that the total cumulative risk of a FP result is 20.4%.15 Most patients with positive screening results undergo additional noninvasive testing; only a small percentage of recalled patients require core biopsy, and even fewer require open biopsy.10 In our experience, it should be noted that recall rates were greater in the first rounds than in later ones, with a progressive decrease in cost and distress to patients. Previous opinion studies on women who undergo recall found that they favor a small improvement in diagnostic performance of BC despite increased emotional stress.16-18 Such attitudes might also encourage greater adherence to the program.6 Data regarding the ideal age for beginning and ending BC screening are controversial. Swedish population studies have shown a significant decrease in mortality in women younger than 50 years who undergo BC screening19-21 and evidence of downstaging.22 More recent series have also found benefits, especially in the 45- to 49-year-old subgroup.23 Most meta-analyses suggest that screening in this age reduces mortality, and that clearer benefits are
Table 3 Local Recurrence and Metastases and According to Organ Metastasesa
Local Recurrencea
Lunga
Livera
Braina
Lymph Nodea,b
Bonea
Age <50 Years (n ¼ 493)
81 (16.4%)
58 (11.8%)
40 (8.1%)
41 (8.3%)
25 (5.1%)
25 (5.1%)
47 (9.5%)
50-69 years nonscreened group (n ¼ 442)
74 (16.7%)
66 (14.9%)
40 (9.1%)
36 (8.1%)
15 (3.4%)
31 (7.0%)
36 (8.1%) 22 (5.6%)
70 years (n ¼ 390)
49 (12.6%)
38 (9.7%)
21 (5.4%)
22 (5.6%)
10 (2.6%)
11 (2.8%)
P for Nonscreened Groups
.180
.688
.121
.261
.135
.022
.102
Screened Group (n [ 496)
19 (3.8%)
14 (2.8%)
10 (2.0%)
11 (2.2%)
3 (0.6%)
4 (0.8%)
10 (2.0%)
<.001
<.001
<.001
<.001
<.001
<.001
<.001
P Total
Data are presented as n (%) except where otherwise stated. a Statistically significant differences using the log-rank test according to months without recurrence between the screened group and nonscreened group. b Statistically significant differences using the log-rank test according to months without recurrence among nonscreened subgroups.
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Clinical Breast Cancer Month 2015
Israel Barco et al obtained with longer follow-up periods.24-28 After a decade of follow-up, the reduction of risk is estimated at 17%.24 Because the incidence of BC has increased and approximately 25% of all deaths due to BC occur in the 40- to 49-year-old age group,29,30 it is possible that starting screening at age 45 could further decrease BC mortality due to BC. Earlier initiation of screening could also be justified on the grounds of a greater potential gain in years of life, and decreased psychological, social, and family impact. Mammography screening detects tumors with better final prognosis in patients either younger or older than 50 years compared with nonscreened women,31-35 and is an independent prognostic factor that confers real advantages for survival. However, it cannot be fully ruled out that enhanced mass screening programs would detect tumors with less aggressiveness that eventually are not lethal or even biologically relevant. Thus, we should always be aware of overdiagnosis as a counterpart of BCSP enthusiasm. As in other published series,36 we observed that most locally advanced tumors (T4) were found in the age group older than 70 years, probably because of increased personal and family neglect and to a decreased level of medical care. Patients in this age range often do not receive standard adjuvant chemotherapy, because of the existence of comorbidities, cognitive impairment, and poor social support,37 which might result in undertreatment and higher BC-specific mortality.38,39
Conclusion Our data confirm the usefulness of our screening program6 and we speculate that extending BCSPs to women younger than age 50 and older than 70 years could bring about mortality benefits.
Clinical Practice Points The aim of screening programs is to improve survival because of
early diagnosis and to increase the number of candidates suitable for conservative surgery. The screened group showed significantly better results than all nonscreened groups. In the nonscreened group, younger women presented a greater rate of metastasis and a shorter disease-free period, and the older than age 70 group had the highest number of T4 tumors and the highest proportion of radical surgery. These results confirm the usefulness of a screening program in patients aged 50 to 69 years. We speculate that extending BCSPs to women younger than 50 years and older than 70 years could bring about mortality benefits.
Acknowledgments We thank Manel Martori for helping us with the tables and graphs and, the staff of the Breast Cancer Screening Unit: Cristina Matarín, Pilar Cadenas, Sandra Carmona, and Xavier Fuentes and the staff of the Pathology Department: Francisca Perarnau, Maria Teresa Blanco, and Maribel Baldellon, for keeping our breast cancer database updated.
Disclosure The authors have stated that they have no conflicts of interest.
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