Health Q2

Original Study

Type of Breast Cancer Diagnosis, Screening, and Survival

Carla Cedolini,1 Serena Bertozzi,1 Ambrogio P. Londero,2 Sergio Bernardi,3,4

Luca Seriau,1 Serena Concina,1 Federico Cattin,1 Andrea Risaliti1

Abstract Organized, invitational breast cancer screening in our population succeeded in detecting early-stage tumors, which have been consequently treated more frequently with breast and axillary conservative surgery, com- plementary breast irradiation, and eventual hormonal therapy. The diagnosis of invasive cancer with screening in our population resulted in a survival gain at 5 years from the diagnosis. Introduction: Breast cancer screening is known to reduce mortality. In the present study, we analyzed the prevalence of breast cancers detected through screening, before and after introduction of an organized screening, and we evaluated the overall survival of these patients in comparison with women with an extrascreening imaging-detected breast cancer or those with palpable breast cancers. Materials and Methods: We collected data about all women who underwent a breast operation for cancer in our department between 2001 and 2008, focusing on type of tumor diagnosis, tumor characteristics, therapies administered, and patient outcome in terms of overall survival, and re- currences. Data was analyzed by R (version 2.15.2), and P < .05 was considered significant. Results: Among the 2070 cases of invasive breast cancer we considered, 157 were detected by regional mammographic screening (group A), 843 by extrascreening breast imaging (group B: 507 by mammography and 336 by ultrasound), and 1070 by extra- screening breast objective examination (group C). The 5-year overall survival in groups A, B, and C were, respectively, 99% (95% CI, 98%-100%), 98% (95% CI, 97%-99%), and 91% (95% CI, 90%-93%), with a significant difference between the first 2 groups and the third (P < .05) and a trend between groups A and B (P ¼ .081). Conclusion: The diagnosis of invasive breast cancer with screening in our population resulted in a survival gain at 5 years from the diagnosis, but a longer follow-up is necessary to confirm this data.

Clinical Breast Cancer, Vol. 14, No. 4, 235-40 ª 2014 Elsevier Inc. All rights reserved. Keywords: Breast cancer, Breast cancer screening, Invasive breast cancer, Mammographic screening, Overall survival

Introduction Because of the detection of early-stage tumors, breast cancer

screening reduced breast cancer mortality in Europe by 25%-31% in patients who were invited for screening and by 38%-48% in those who were actually screened during the last decade of the twentieth century and the first decade of the twenty-first.1 In our region of Italy, an organized breast cancer screening was firstly intro- duced in 2005, but despite the high compliance of invited women

1Clinic of Surgery 2Clinic of Obstetrics and Gynecology University of Udine, Udine, Italy 3Department of Surgery, Ospedale Civile di Latisana, Udine, Italy 4Department of Surgery, AOU “Santa Maria della Misericordia,” Udine, Italy

Submitted: Feb 17, 2013; Revised: Jan 23, 2014; Accepted: Feb 12, 2014; Epub: Feb 20, 2014

Address for correspondence: Dr Carla Cedolini, Clinic of Surgery, University of Udine, Italy p.le SSMM Misericordia 15, 33100 Udine, Italy E-mail contact: [email protected]

1526-8209/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.02.004

(which progressively increased after the screening introduction), a high prevalence still exists of women who have their breast cancer diagnosed by extrascreening objective examination or imaging.2,3

In the present study, analyzed, among breast cancer patients treated in our department, the prevalence of breast cancers detected through the invitational screening, and the overall survival of these patients in comparison with that of women with an extrascreening imaging-detected breast cancer or those with palpable breast cancers.

Materials and Methods We collected retrospective data for about 2811 women who

underwent a breast operation following breast cancer diagnosis or suspicion in our clinic between January 2001 and April 2008, in order to have a follow-up of � 5 years for every patient. Then, we excluded women with a diagnosis of benign lesion (471 patients), intralobular neoplasia (22 patients), or intraductal neoplasia (248 patients). Intraductal neoplasia represented the 17.6% of screen- detected and the 14.4% of extrascreening imaging-detected breast

Clinical Breast Cancer August 2014 - 235

Table 1 Description of the Population in the Different Groups

Characteristic

Method of Cancer Detection

PScreening Imaging Palpable Lesion

Age, years (SD) 61.6 (�5.77) 60.01 (�11.25) 61.2 (�15.14) .104 BMI, kg/m2 (SD) 27.47 (�5.55) 25.84 (�4.76) 25.49 (�4.8) <.05

Patients, % (no./total) Patients, % (no./total) Patients, % (no./total)

Tobacco smokera 7.9 (12/151) 4.7 (32/685) 5.7 (49/858) .256

Familial history of breast cancera 28.6 (10/35) 28.7 (48/167) 36.3 (89/245) .234

Estroprogestinic therapya 20.0 (7/35) 28.1 (43/153) 25.1 (54/215) .579

Menopausea 97.9 (137/140) 83.8 (607/724) 75.7 (738/975) <.05

Surgical treatment (first procedure)

Conservative 84.1 (132/157) 75.6 (637/843) 47.4 (507/1070) <.05

Mastectomy 15.9 (25/157) 24.4 (206/843) 52.6 (563/1070) <.05

Axilla surgery

CALND 33.8 (53/157) 49.5 (417/843) 80.0 (856/1070) <.05

SLNB 65.6 (103/157) 47.1 (397/843) 15.0 (160/1070) <.05

None 0.6 (1/157) 3.4 (29/843) 5.0 (54/1070) <.05

Surgical treatment (second procedure)b

Nothing 76.5 (101/132) 68.9 (439/637) 72.0 (365/507) .172

Conservative 15.2 (20/132) 14.8 (94/637) 10.1 (51/507) <.05

Mastectomy 8.3 (11/132) 16.3 (104/637) 17.9 (91/507) <.05

Neoadjuvant therapy 5.7 (9/157) 0.5 (4/843) 16.0 (171/1070) <.05

Adjuvant therapya

Radiotherapy 76.3 (119/156) 63.6 (510/802) 48.9 (496/1015) <.05

Chemotherapy 26.3 (41/156) 36.3 (290/799) 51.1 (518/1013) <.05

Hormonal therapy 85.3 (133/156) 83.3 (663/796) 73.2 (742/1013) <.05

Abbreviations: BMI ¼ body mass index; CALND ¼ complete axillary lymph node dissection; SLNB ¼ sentinel lymph node biopsy. aSample size varies because of incomplete data. bSample size varies because only conservative treatment were eventually treated by a second procedure.

Breast Cancer Screening and Survival

236 -

lesions, while it accounted for only the 2.5% of palpable lesions; therefore, we decided to exclude it from data analysis because of its better prognosis and its consequently probable influence on the survival analysis. In fact, it is well-known that the screening benefit of mortality reduction is accompanied by the harm of overdiagnosis, defined as the detection at screening of a cancer that would not have otherwise become clinically evident in the woman’s lifetime.4,5

Finally, the study population included 2070 women affected by invasive breast cancer.

Collected data included the following patients characteristics: age at diagnosis, body mass index (BMI), familial history of breast cancer, fertility status, eventual use of estroprogestinic therapies. Tumor characteristics were considered as follows: histological type, TNM classification and stage, nuclear grading, Mib1/Ki-67 prolif- eration index, hormone receptors status including estrogen receptor (ER), progesteron receptor (PR) and Her2/neu expression, eventual involvement of extraaxillary lymph nodes (internal mammary chain or subclavear ones), and other microscopic features evaluated in the new classification by Veronesi et al.6 such as multifocality, extensive intraductal component, perivascular invasion, peritumoral inflam- mation, lymph node extracapsular invasion or blanched lymph nodes. Moreover, the therapeutic management was investigated, including conservative versus radical, breast and axillary surgery,

Clinical Breast Cancer August 2014

eventual neoadjuvant therapies, adjuvant breast irradiation, endo- crine or chemotherapy administered.

Then, the study population was divided into 3 groups as follows: group A) screen-detected breast cancers (including lesions detected by mammography, ultrasound or breast objective examination within the biyearly, organized, regional screening program); group B) extrascreening imaging-detected breast cancers (including lesions detected by mammography or ultrasound, which the women un- derwent spontaneously, for example in case of familial history of breast cancer out from the age range of the screening, or yearly within the interval between 2 screening invitations, or even simply for personal choice); group C) cancers detected by extrascreening breast objective examination (including palpable mass, cutis retraction, breast ulceration, nipple discharge, and mastitis carcinomatosa).

Data was analyzed by R (version 2.15.2), considering significant P < .05. Monovariate analysis was performed by 1-way Anova or t test in case of continuous variables, chi-square test or Fisher exact test in case of categorical variables. Some data are presented as proportions with relative 95% confidence interval where appro- priate. Overall survival was considered to be the main outcome, and Kaplan-Meyer curve was drown to compare the overall survival among the 3 groups. Moreover, also the incidence of locoregional and distant recurrences was compared among the 3 groups.

Table 2 TNM Staging and Grading in the Different Groups

Screening Imaging Palpable Lesion

PPatients, % (no./total) Patients, % (no./total) Patients, % (no./total)

TNM classification

T1 87.9 (138/157) 88.1 (743/843) 55 (588/1070) <.05

T2 11.5 (18/157) 10.4 (88/843) 34.6 (370/1070) <.05

T3 0.6 (1/157) 0.4 (3/843) 2.6 (28/1070) <.05

T4 0 (0/157) 1.1 (9/843) 7.9 (84/1070) <.05

N0 75.2 (118/157) 75.7 (638/843) 58.8 (629/1070) <.05

N1 22.3 (35/157) 18.6 (157/843) 22.8 (244/1070) .078

N2 0.6 (1/157) 2.6 (22/843) 9.2 (98/1070) <.05

N3 1.9 (3/157) 3.1 (26/843) 9.3 (99/1070) <.05

TNM stagea

I 64.3 (101/157) 70 (577/824) 30.4 (307/1010) <.05

II 33.1 (52/157) 22.9 (189/824) 41.4 (418/1010) <.05

III 2.5 (4/157) 6.2 (51/824) 25 (253/1010) <.05

IV 0 (0/157) 0.8 (7/824) 3.2 (32/1010) <.05

Gradinga

G1 21.7 (34/157) 16.5 (137/828) 6.6 (68/1023) <.05

G2 56.7 (89/157) 64 (530/828) 58 (593/1023) <.05

G3 21.7 (34/157) 19.4 (161/828) 35.4 (362/1023) <.05

Abbreviation: TNM ¼ tumor, node, metastases. aSample size varies because of incomplete data.

Carla Cedolini et al

Results Among 2070 considered invasive breast cancers operated in our

Clinic between January 2001 and April 2008, 247 were detected by the regional, organized, mammographic screening (group A), 1176 by extrascreening breast imaging (group B: 768 by mammography and 408 by ultrasound), and 1393 by extrascreening breast objective examination (group C). Interventions made in patients with breast cancer diagnosed through screening began in 2006. Before and after screening introduction the number of operations for invasive breast cancer has not changed (respectively 21.6 vs. 21.5 interventions/ month). After the introduction of screening 20% of invasive cancers were diagnosed by screening and significantly decreased the preva- lence of cancers diagnosed by physical examination of the breast (56.0% antescreening vs. 44.5% postscreening period, P < .05).

If we compare patients characteristics in the 3 groups [Table 1], despite the similar mean age at diagnosis (about 61 years old), women in their fertile age were more frequently diagnosed to have a breast cancer by extrascreening objective examination (24.3%) than by breast screening (2.1%) or extrascreening breast imaging (16.2%). And, considering that breast screening in our region is offered to women between 50 and 69 years of age, it does not surprise that almost the totality of screen-detected breast cancers (97.9%) is diagnosed after menopause.

Taking into consideration the surgical treatment, the majority of screen-detected breast cancers were treated with breast conser- vative surgery (77.1% excluding 15.9% of primary mastectomies and 7.0% of radicalization mastectomies) and sentinel lymph node biopsy (65.6%). Women of group B and C underwent only breast conservative surgery in the 63.2% and 38.9% of cases respectively,

and sentinel lymph node biopsy in the 47.1% and 15.0% of cases respectively, and these prevalence resulted significantly different among the 3 groups (P < .05).

For what concerns nonsurgical treatments, group C has a significantly higher prevalence of both neoadjuvant therapy (16.0%, P < .05) and adjuvant chemotherapy (51.1%, P < .05), probably due to the significantly higher prevalence of advanced stage at diagnosis (stage III in the 25.0% of cases and stage IV in the 3.2%, P < .05) [Table 2], and a significantly lower prevalence of hormonal therapy (73.2%, P < .05), which correlates with the higher prev- alence of triple-negative cancers (Basal-like 14.9%, P < .05) [Table 3]. On the other hand, group A and B were more likely to receive breast irradiation after conservative surgery and adjuvant hormonal therapy when appropriate.

No significant difference was there among the 3 groups about the histological type, but in group C there was a significantly higher prevalence of tumor characteristics that are commonly recognized to negatively influence breast cancer prognosis [Table 2 and 3], such as greater tumor size (T3 and T4 respectively 2.6% and 7.9%, P < .05), greater lymph node involvement (N2 and N3 9% each, P < .05) higher nuclear grading (G3 35.4%, P < .05), higher Mib1/Ki-67 proliferation index (> 20% in the 49.7% of cases, P < .05), pres- ence of multifocality/multicentricity (19.6%, P < .05), lymphovas- cular invasion (16.9%, P < .05) and peritumoral inflammation (7.0%, P < .05), luminal B (41.3%, P < .05), luminal Her (11.1%, P < .05), basal-like (14.9%, P < .05) and Her2-enriched (8.2%, P < .05) molecular subtypes, extracapsular invasion of lymph node metastasis (12.4%, P < .05) and blanched lymph nodes (6.2%, P < .05).

Clinical Breast Cancer August 2014 - 237

Table 3 Tumor Characteristics in the Different Groups

Screening Imaging Palpable Lesion

PPatients, % (no./total) Patients, % (no./total) Patients, % (no./total)

Histological type

Ductal invasive carcinoma 80.9 (127/157) 74.1 (625/843) 73.8 (790/1070) .158

Ductal and lobular invasive carcinoma 5.7 (9/157) 9.1 (77/843) 8.8 (94/1070) .377

Lobular invasive carcinoma 10.8 (17/157) 12.7 (107/843) 13.3 (142/1070) .683

Other invasive carcinoma 2.5 (4/157) 4 (34/843) 4.1 (44/1070) .638

Tumor characteristicsa

ER positivity 89.2 (140/157) 87.5 (704/805) 80.2 (808/1007) <.05

PR positivity 67.5 (106/157) 78.7 (634/806) 67.7 (682/1007) <.05

Ki-67/Mib-1 >20 15.8 (24/152) 32.3 (149/462) 49.7 (319/642) <.05

Comedo-like necrosis 10.2 (16/157) 10.2 (86/843) 5 (54/1070) <.05

Multifocality 16.6 (26/157) 25.3 (213/843) 19.6 (210/1070) <.05

Extensive intraductal component 33.8 (53/157) 38.3 (323/843) 24 (257/1070) <.05

Lymphovascular invasion 7.6 (12/157) 7 (59/843) 16.9 (181/1070) <.05

Peritumoral inflammation 4.5 (7/157) 4.2 (35/843) 7 (75/1070) <.05

Molecular subtypea

Basal-like 6.5 (10/154) 9.9 (48/484) 14.9 (103/693) <.05

HER enriched 4.5 (7/154) 4.3 (21/484) 8.2 (57/693) <.05

Luminal A 66.2 (102/154) 44.4 (215/484) 24.5 (170/693) <.05

Luminal B 20.1 (31/154) 35.3 (171/484) 41.3 (286/693) <.05

Luminal HER 2.6 (4/154) 6 (29/484) 11.1 (77/693) <.05

Lymph node characteristics

Isolated tumor cells 3.2 (5/157) 2.4 (20/843) 1.4 (15/1070) .153

Micrometastasis 6.4 (10/157) 4.9 (41/843) 4.2 (45/1070) .446

Lymph node extracapsular invasion 2.5 (4/157) 4.4 (37/843) 12.4 (133/1070) <.05

Blanched lymph nodes 1.3 (2/157) 2.1 (18/843) 6.2 (66/1070) <.05

Internal mammary chain metastasis 3.8 (6/157) 2 (17/843) 1.5 (16/1070) .126

Local recurrences during follow-up 1.3 (2/157) 3.6 (30/843) 9.3 (99/1070) <.05

Distant metastases during follow-upa 1.3 (2/157) 5.1 (43/841) 13.4 (142/1059) <.05

Abbreviations: ER ¼ estrogen receptor; HER ¼ human epidermal growth factor receptor; PR ¼ progesterone receptor. aSample size varies because of incomplete data.

Breast Cancer Screening and Survival

238 -

Locoregional and distant recurrences were significantly more prevalent (P < .05) in group C (respectively 9.3% and 13.4%) than in group A (respectively 1.3% and 1.3%) and B (respectively 3.6% and 5.1%) [Table 3].

The 5-years overall survival in group A, B and C resulted respectively 99% (95% CI, 98%-100%), 98% (95% CI, 97%- 99%), and 91% (95% CI, 90%-93%), with a significant difference among the 3 groups (P < .05) [Fig. 1A], even considering only patients operated after screening introduction [Fig. 1B]. In partic- ular comparing group to group overall survival had a significant difference among the first 2 groups and the third (A or B vs. C) (P < .05) and a trend between group A and B (A vs. B)(P ¼ .081).

Discussion Breast cancer screening in our population succeeded in detecting

early-stage tumors with favorable tumor characteristics, which have been consequently treated more frequently with breast and axillary conservative surgery, complementary breast irradiation and eventual hormonal therapy. Women with a screen-detected breast cancer had

Clinical Breast Cancer August 2014

a significantly higher 5-years overall survival than women who had their breast cancer diagnosed by extrascreening objective examina- tion or imaging, as well as a significantly lower prevalence of locoregional and distant recurrences.

In accordance with the most published studies about this argument, our findings confirm the association of screening with both smaller tumor size and less lymph node metastases at pre- sentation,7,8 and support a survival improvement of breast cancer patients after breast screening introduction.1,8-19

However, there is much skepticism about the effective role of mammographic screening on breast cancer mortality. In fact, it is very difficult to determine how much of the observed reduction in mortality can be attributed exclusively to the screening, rather than to improved breast cancer management or to changes in risk fac- tors.20-26 In addiction, it is still debated whether the estimated effect of routine mammography on breast cancer mortality is thus highly dependent on study design.27-29

Moreover, a great number of women in our population under- went regular breast imaging controls out from the screening program,

Figure 1 Overall Survival in the 3 Groups: A) Considering The Whole Study Population; B) Considering Only Breast Cancers Diagnosed Since the Screening Introduction

0 1 2 3 4 5 6

70%

80%

90%

100%

Follow-up time, y

Follow-up time, y

O ve

ra ll

su rv

iv al

P < .05 Screening Imaging Palpable lesion

0 1 2 3 4 5 6

70%

80%

90%

100%

O ve

ra ll

su rv

iv al

P < .05 Screening Imaging Palpable lesion

A

B

Carla Cedolini et al

and the earlier detection of breast cancer in these cases may be explained just by the increased women awareness about this topic.

Furthermore, it is not possible to exclude that, even if the screening would have diagnosed group C cancers, their unfavorable biologic behavior would have anyway correlated with a worse prognosis. In this perspective, an analysis of interval cancers would be more helpful, defined as breast cancers that occur in the age-specific screening population during the interval between 2 consequent screening invitations.30 In fact, interval cancers repre- sent a group of very biologically aggressive tumors with a rapid grow and worse prognostic factors, and their incidence may be a good indicator of screening effectiveness.

The weakness of this study lays in its retrospective design and the limited number of patients if compared with other multicentric international studies.

Conclusion In conclusion, breast cancer screening in our population resulted

in a significant survival gain at 5 years from the diagnosis, but a longer follow up should be necessary to confirm this data, and further studies are required in order to evaluate interval cancers in order to better assess breast screening effectiveness in our population.

Clinical Practice Points

� Organized, invitational breast cancer screening significantly in- creased the detection rate of early-stage tumors in our popula- tion, and resulted in a survival gain at 5 years from the diagnosis.

� Women who had their breast cancers diagnosed by both orga- nized, invitational mammographic screening and extra-screening breast imaging had a significantly higher 5-years overall survival rate than those who had their cancer diagnosed by breast objective examination.

� Independently by the age group, regular breast imaging had an important impact on a prompt breast cancer diagnosis, and consequently to its prognosis.

� Anyway, further studies are required in order to better investigate the characteristics of cancers diagnosed by objective examination, and especially interval cancers detected between two consequent screening calls.

Disclosure The authors have stated that they have no conflicts of interest.

References 1. Broeders M, Moss S, Nyström L, et al. The impact of mammographic screening on

breast cancer mortality in Europe: a review of observational studies. J Med Screen 2012; 19(Suppl 1):14-25.

2. Driul L, Bernardi S, Bertozzi S, Schiavon M, Londero A, Petri R. New surgical trends in breast cancer treatment: conservative interventions and oncoplastic breast surgery. Minerva Ginecol 2013; 65:289-96.

3. Busolin A, Clagnan E, Franzo A, Tillati S, Zanier L. I programmi di screening oncologici in Friuli Venezia Giulia dal 1999 al 2010. Technical report, Servizio Epidemiologico - Direzione Centrale Salute, Integrazione Sociosanitaria e Politiche Sociali - Regione Friuli Venezia Giulia. 2011.

4. Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012; 367:1998-2005.

5. Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 2012; 380:1778-86.

Clinical Breast Cancer August 2014 - 239

Breast Cancer Screening and Survival

240 -

6. Arnone P, Zurrida S, Viale G, Dellapasqua S, Montagna E, Arnaboldi P, et al. The TNM classification of breast cancer: need for change. Updates Surg 2010; 62:75-81.

7. Nagtegaal ID, Duffy SW. Reduction in rate of node metastases with breast screening: consistency of association with tumor size. Breast Cancer Res Treat 2013; 137:653-63.

8. Paci E, Duffy SW, Giorgi D, Zappa M, Crocetti E, Vezzosi V, et al. Quantification of the effect of mammographic screening on fatal breast cancers: The Florence Programme 1990-96. Br J Cancer 2002; 87:65-9.

9. Paci E, EUROSCREENWG. Summary of the evidence of breast cancer service screening outcomes in Europe and first estimate of the benefit and harm balance sheet. J Med Screen 2012; 19(Suppl 1):5-13.

10. Otto SJ, Fracheboud J, Verbeek ALM, et al. Mammography screening and risk of breast cancer death: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2012; 21:66-73.

11. Paap E, Holland R, den Heeten GJ, et al. A remarkable reduction of breast cancer deaths in screened versus unscreened women: a case-referent study. Cancer Causes Control 2010; 21:1569-73.

12. Puliti D, Miccinesi G, Collina N, et al. Effectiveness of service screening: a case- control study to assess breast cancer mortality reduction. Br J Cancer 2008; 99: 423-7.

13. Roder D, Houssami N, Farshid G, et al. Population screening and intensity of screening are associated with reduced breast cancer mortality: evidence of ef- ficacy of mammography screening in Australia. Breast Cancer Res Treat 2008; 108:409-16.

14. Allgood PC, Warwick J, Warren RML, Day NE, Duffy SW. A case-control study of the impact of the East Anglian breast screening programme on breast cancer mortality. Br J Cancer 2008; 98:206-9.

15. Gabe R, Tryggvadóttir L, Sigfússon BF, Olafsdóttir GH, Sigurdsson K, Duffy SW. A case-control study to estimate the impact of the Icelandic population-based mammography screening program on breast cancer death. Acta Radiol 2007; 48: 948-55.

16. Swedish Organised Service Screening Evaluation Group. Reduction in breast cancer mortality from organized service screening with mammography: 1. Further confirmation with extended data. Cancer Epidemiol Biomarkers Prev 2006; 15:45-51.

Clinical Breast Cancer August 2014

17. Gorini G, Zappa M, Miccinesi G, Paci E, Costantini AS. Breast cancer mortality trends in two areas of the province of Florence, Italy, where screening programmes started in the 1970s and 1990s. Br J Cancer 2004; 90:1780-3.

18. Fielder HM, Warwick J, Brook D, et al. A case-control study to estimate the impact on breast cancer death of the breast screening programme in Wales. J Med Screen 2004; 11:194-8.

19. Tabár L, Vitak B, Chen HH, Yen MF, Duffy SW, Smith RA. Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality. Cancer 2001; 91:1724-31.

20. 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.

21. 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.

22. Jones AL. Reduction in mortality from breast cancer. BMJ 2005; 330:205-6. 23. 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. 24. Autier P, Héry C, Haukka J, Boniol M, Byrnes G. Advanced breast cancer

and breast cancer mortality in randomized controlled trials on mammography screening. J Clin Oncol 2009; 27:5919-23.

25. Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. JAMA 2009; 302:1685-92.

26. Jørgensen KJ, Zahl PH, Gøtzsche PC. Breast cancer mortality in organised mammography screening in Denmark: comparative study. BMJ 2010; 340:c1241.

27. Olsen AH, Njor SH, Lynge E. Estimating the benefits of mammography screening: the impact of study design. Epidemiology 2007; 18:487-92.

28. Paap E, Verbeek ALM, Puliti D, Paci E, Broeders MJM. Breast cancer screening case-control study design: impact on breast cancer mortality. Ann Oncol 2011; 22: 863-9.

29. Demissie K, Mills OF, Rhoads GG. Empirical comparison of the results of ran- domized controlled trials and case-control studies in evaluating the effectiveness of screening mammography. J Clin Epidemiol 1998; 51:81-91.

30. Heidinger O, Batzler WU, Krieg V, et al. The incidence of interval cancers in the german mammography screening program: results from the population-based cancer registry in north rhine-westphalia. Dtsch Arztebl Int 2012; 109:781-7.