Prognosis and Pathology of Screen-Detected Carcinomas

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1 Prognosis and Pathology of Screen-Detected Carcinomas How Different Are They? Iris D. Nagtegaal, MD, PhD 1 ; Prue C. Allgood, PhD 3 ; Stephen W. Duffy, MSc 3 ; Olive Kearins 2 ; E. O. Sullivan, BSc 2 ; Nancy Tappenden, MPH 2 ; Matthew Wallis, MB, ChB, FRCR 4 ; and Gill Lawrence, PhD 2 BACKGROUND: It has been observed that screen-detected breast cancers have a better prognosis than symptomatic tumors, even after taking pathological tumor attributes into account. This has led to the hypothesis that screendetected tumors are substantially biologically different from symptomatic cancers. METHODS: The pathology and survival by detection mode was investigated in 21,382 breast cancers diagnosed in women aged years in the West Midlands, United Kingdom, between 1988 and Tumor attributes were compared using chi-square tests and logistic regression. Survival was analyzed using Cox regression. RESULTS: Screen-detected cancers were significantly smaller, better differentiated, and less likely to be node-positive than symptomatic cancers (P <.001 in all cases). In addition, a higher proportion of screen-detected cancers were hormone receptor-positive, and a higher proportion were tubular carcinomas (P <.001). Survival was substantially better in screen-detected breast cancers (86% at 10 yearsvs 70% for interval cancers and 58% for cancers in women unexposed to screening). Adjustment for age, tumor size, nodal status, grade, histological type, and year of diagnosis accounted for 64% (interval cancers) and 68% (unexposed women) of these survival differences, respectively. Overall survival improved with time. Approximately half of this improvement was due to the increase over time in the proportion of tumors that were screendetected. CONCLUSION: The majority of the difference in prognosis between screen-detected and symptomatic breast cancers is due to the differences in routinely measured pathological features (size, type, grade, and nodal status), leaving a small residual difference to be accounted for by other biological differences. Cancer 2011;117: VC 2010 American Cancer Society. KEYWORDS: breast cancer, prognosis, pathology, screen-detected, survival. The introduction of population-wide breast cancer screening programs has been accompanied by a decrease in breast cancer-related mortality 1,2 and by an increase in the incidence of breast cancer, notably of early-stage tumors. 3 It has been suggested that the latter may constitute overdiagnosis (ie, the detection of tumors that would not have caused problems during the lifetime of the affected women) or possibly the less extreme phenomenon of length bias, whereby slow-growing tumors have a longer window of opportunity for screen detection and are therefore overrepresented in screen-detected cancers. 4,5 Both hypotheses are consistent with biological differences between screen-detected and symptomatic cancers. 5,6 It is clear that for breast screening to work, it must detect cancers at an earlier stage. 7 Several reports indicate that breast cancers detected by screening have more favorable pathological features compared with symptomatic breast cancers, some of which may be due to a stage shift, and some to underlying biological differences In addition to stage shift and length bias or overdiagnosis, there is an artificial increase in survival due to lead time (if screening detects a tumor on average 3 years earlier than symptoms would have arisen, 3 years are added to the survival time regardless of the eventual outcome). Between screening rounds, breast cancers occur symptomatically in women with a previous negative screen. These tumors, usually called interval cancers, have a worse prognosis than screen-detected carcinomas, although it is sometimes better than that of subjects unexposed to screening. 11,12 They are likely to constitute a mixture of aggressive tumors that Corresponding author: Prue C. Allgood, PhD, CR-UK Centre for EMS, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, United Kingdom; Fax: (011) ; p.allgood@qmul.ac.uk 1 Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 2 West Midlands Cancer Intelligence Unit, Birmingham, United Kingdom; 3 CR-UK Center for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, London, United Kingdom; 4 Cambridge Breast Screening Unit and National Institute for Health Research, Cambridge Biomedical Research Center, Addenbrooke s Hospital Cambridge, United Kingdom We thank Rosie Day at the West Midlands Cancer Intelligence Unit for extracting the data from the cancer registration database. DOI: /cncr.25613, Received: May 20, 2010; Accepted: July 28, 2010, Published online November 2, 2010 in Wiley Online Library (wileyonlinelibrary.com) 1360 Cancer April 1, 2011

2 Breast Cancer Differences/Nagtegaal et al have developed rapidly to the symptomatic phase and less aggressive tumors that have been missed at the previous screening. In the present study, we used a database of more than 21,000 breast cancers recorded on the West Midlands Cancer Intelligence Unit s cancer registration database to address the following issues to a level of detail and precision that has not been possible in smaller tumor series: 1. What are the typical pathological features of screen-detected breast cancers and how do these differ from interval cancers and tumors in women unexposed to screening? 2. What are the implications of these differences for prognosis? 3. To what extent can the better survival of screendetected breast cancers be attributed to shifts in nodal status, tumor size, and other routinely measured histological factors, and what remains to be explained by biological and other differences? 4. What changes in tumor attributes and in survival have occurred over the period of observation, and to what extent are these changes attributable to screening or to other factors? MATERIALS AND METHODS Patients In collaboration with the National Health Service Breast Screening Programme, the West Midlands Cancer Intelligence Unit collected screening history, pathological data, and follow-up data on cancers diagnosed in women aged years in the West Midlands, United Kingdom, from 1988 to From 2002 to 2004, the dataset was expanded to include women aged years, and with an extension of the upper age limit for invitation to 70 years, nonnegligible screening was being performed in women aged years. In the present study, to avoid complications in screening history classification caused by the staggered rollout of the upper age limit extension, only data for the 21,382 breast cancers diagnosed in women aged were included. The data were available for 9259 screen-detected breast cancers, 5413 interval cancers, and 6710 cancers in women not recently exposed to screening. In the early years of the program, the latter group mainly comprised women who had not yet been invited, whereas in the later years it was mainly made up of nonattenders. The group as a whole is referred to as unexposed for purposes of brevity. Follow-up was available through April 12, Pathology Data Invasive status (invasive, microinvasive, in situ), differentiation grade, vascular invasion, nodal status, tumor size, and tumor type (according to ICD-O3 morphology classification) were recorded from the pathology reports. In addition, estrogen receptor (ER) and progesterone receptor (PR) status were collected, although the majority of these data were not available until 2002 and 2004, respectively. Statistics Data were analyzed using the Stata software package. 13 Associations among the various parameters were analyzed using chi-square tests and logistic regression. 14 Trends over time were also analyzed using logistic regression. Survival analyses were performed using Cox regression, with the time of diagnosis as the entry date and breast cancerrelated death as outcome, 15 yielding relative hazards of breast cancer death and 95% confidence intervals on these. The extent to which screening effects on survival could be attributable to other factors was calculated by comparison of adjusted and unadjusted Cox regression analyses using the method of Freedman et al. 16 Cumulative survival was calculated using Kaplan-Meier survival curves. 15 P.05 was considered statistically significant. RESULTS Tumor Attributes and Mode of Detection A total of 21,382 breast cancers diagnosed in women aged years were studied: 43.3% were screen-detected, 25.3% were interval cancers, and 31.4% occurred in women unexposed to screening. Between the 3 groups, there were substantial differences in tumor attributes (Table 1). Screen-detected breast cancers were lower grade (better differentiated), less likely to be node-positive, more likely to be ER- or PR positive, and smaller than tumors in the 2 symptomatic groups (P <.001 in all cases). The women unexposed to screening were more likely to have larger tumors than those with interval cancers and were more likely to have nodal status, histological grade, and undetermined ER and PR status. More in situ carcinomas were present in the screen-detected group (15.5% vs 3.6% and 3.2%, respectively, P <.001). The histological type of tumors differed significantly (P < Cancer April 1,

3 Table 1. Frequencies of Pathological Attributes for Women Aged Years With Screen- Detected Tumors, Interval Tumors, and Tumors Occurring in Women Unexposed to Screening Factor % Screen- Detected n59259 % Interval n55413 % Unexposed n56710 Invasive status <.001 Invasive Microinvasive In situ Differentiation grade a <.001 Grade Grade Grade Unknown Nodal status a <.001 Negative Positive Unknown Tumor size a < mm >5 to 10 mm >10 to 15 mm >15 to 20 mm >20 to 50 mm >50 mm Tumor type a <.001 IDC ILC IDC and ILC Tubular Cribriform Medullary Mucinous SRCC Neuroendocrine Papillary Micropapillary Apocrine Metaplastic Rare types Paget Sarcoma Phylloides Not known ER status a <.001 Negative Positive Unknown PR status a <.001 Negative Positive Unknown IDC indicates invasive ductal carcinoma; ILC, invasive lobular carcinoma; SSRC, signet ring cell carcinoma; ER, estrogen receptor; PR, progesterone receptor. a Invasive tumors only. P 1362 Cancer April 1, 2011

4 Breast Cancer Differences/Nagtegaal et al Table 2. Pathological Features of In Situ Carcinomas by Detection Mode Factor % Screen- Detected n5989 % Interval n5113 % Unexposed n597 Tumor size a < mm >5 to 10 mm >10 to 15 mm >15 to 20 mm >20 to 50 mm >50 mm Tumor type <.001 DCIS LCIS DCIS and LCIS Intraductal papillary Cytonuclear grade.6 Low Intermediate High DCIS indicates ductal carcinoma in situ; LCIS, lobular carcinoma in situ. a 43% missing data. P Table 3. Annual Percentage Changes in Odds From Logistic Regression Modeling of Invasive Tumors Over the Entire Study Period ( ) Tumor Characteristics Overall Invasive tumors 6% a 10% a 5% a Node-positive b 3% a 7% a 0.8% Grade 3 cancer 4% a 10% a þ1% Size 10 mm þ2% a þ3% þ1% Size >50 mm 3% a 7% a þ4% Lobular carcinoma þ3% a þ4% a % Tubular carcinoma þ2% a þ8% a 4% a a Trend significant with p <.05. b Only patients with known nodal status were considered. Figure 1. Proportion of all breast tumors (in situ and invasive) diagnosed over time for women screened and women not screened is shown..001) by detection mode. Most tumors were invasive ductal carcinoma without further specification. In the screendetected group, there was a higher proportion of tubular carcinoma (8.4% vs 2.0% and 2.1% respectively) and a lower proportion of ductal carcinoma. Rare tumor types included acinar cell carcinoma (n ¼ 2), clear cell adenocarcinoma (n ¼ 4), and inflammatory carcinoma (n ¼ 15). Inflammatory carcinoma was mostly diagnosed symptomatically (n ¼ 1, n ¼ 9, and n ¼ 5 for screendetected cancers, interval cancers, and cancers in women unexposed to screening, respectively). The sarcomas consisted of fibrosarcomas (n ¼ 2), leiomyosarcomas (n ¼ 1), osteosarcomas (n ¼ 1), and sarcomas not otherwise specified (n.o.s.) (n ¼ 5). The in situ carcinomas that were screen-detected were smaller (Table 2) and more often ductal carcinoma in situ. Although there was a trend towards a higher cytonuclear grade for all modes of detection there was no significant difference between detection modes (P ¼.6). In situ interval cancers had the largest proportion of intraductal papillary tumors. Trends Over Time Changes in detection mode with time are shown in Figure 1. In 1988, 5.9% of all breast cancers were diagnosed in women exposed to screening (screen-detected or interval Cancer April 1,

5 Figure 2. Mode of detection data are shown for (A) node positivity in invasive breast tumors, (B) grade 3 invasive breast tumors, (C) lobular invasive breast tumors, (D) invasive breast tumors 10 mm, (E) tubular invasive breast tumors, and (F) invasive breast tumors >50 mm. cancers), whereas in 1997, 78.1% of all breast cancers were diagnosed in women who had been exposed to screening. This figure rose slightly each year and was 81.9% for all breast cancers in This was contemporaneous with considerable changes in the distribution of pathological features in invasive cancers (Table 3). We determined the trends in time during the starting phase of the program ( ) and during the continuation 1364 Cancer April 1, 2011

6 Breast Cancer Differences/Nagtegaal et al Figure 3. Kaplan-Meier survival curve for women aged years diagnosed with invasive breast tumors is shown. phase ( ) using logistic regression with year as a continuous variable. Overall, there were reductions with time in the proportion of invasive breast cancers, node-positive cancers, grade 3 cancers, and large (pt3) invasive tumors >50 mm; these were much more pronounced during the starting phase of the program. Overall and during the early years there was a 2% and 8% annual increase, respectively, in the proportion of tubular carcinomas, whereas during the later years there was a 4% annual decrease. When evaluating trends in time for the different detection modes (screen-detected, interval, women unexposed to screening; Figure 2), changes in interval cancers and cancers in women unexposed to screening were remarkably similar for node positivity, poor differentiation, and small tumors (<10 mm). For screen-detected cancers, node positivity and poor differentiation were always significantly lower and small tumors were always significantly higher than for the other two detection modes. Large tumors (pt3) with diameter >50 mm were consistently more often present in the unexposed group compared with both interval and screen-detected cancers. Tubular carcinoma was consistently higher in the screen-detected group, but with time an increase in lobular carcinoma was present in all 3 groups. Within the detection modes, proportions of small tumors and tubular carcinomas remained constant, indicating that the overall increases were due to the increase in the proportion of screen-detected tumors. Survival Women with screen-detected cancers had a better prognosis than women with interval cancers and cancers in women with no screening (Figure 3). Ten-year survival rates for invasive breast cancer were 85.5%, 69.8%, and 57.7%, respectively (P <.001), with an overall rate of 71.6%. These differences are also reflected in the unadjusted Cox regression model (Table 4) for invasive breast tumors only, in which the hazard ratios for interval cancers and cancers in women unexposed to screening were 2.3 and 3.4, respectively, for breast cancer-related death. In the adjusted model, after correction for nodal status, tumor size, differentiation grade, tumor type, age, and year of diagnosis, this difference was smaller but was still present, with hazard ratios of 1.26 and 1.54, respectively. When adjusted for age, tumor size, and node status only, the hazard ratios for interval cancers and cancers in women who had not been screened were 1.56 and 2.04, respectively, compared with screen-detected cancers (complete results are available from the authors). The Freedman statistics for the proportion of the survival differences for invasive cancers explained by age, tumor size, and node status were 47% for the difference in survival between screen-detected and interval cancers and 42% for the difference between screen-detected cancers and cancers in women unexposed to screening. Additional adjustment for grade, tumor type, and year of diagnosis accounted for a further 17% and 26%, respectively, bringing the total proportions explained to 64% and 68%, respectively. When evaluating screening status and year of diagnosis only, the Freedman proportions explained for interval cancers and cancers in women unexposed to screening were 0.03% and 4.8%, respectively, suggesting that the better prognosis of screen-detected cancers was not simply due to the strong confounding with year of diagnosis. On the other hand, for year of diagnosis, the Freedman statistic for the proportion of the year of diagnosis effect explained by confounding with detection mode was 34%, which means that a substantial part of the increase in survival by year of diagnosis is explained by the increase in the proportion of screen-detected cancers. This finding is consistent with the predicted 10-year survival rates from the Cox regression model, including year of diagnosis and detection mode in 1990 and 1997, respectively (Table 5). Expected survival rates increased during these 7 years for all detection modes, but most of the change in overall survival was due to the increased proportion of screendetected cases (a 2% increase) and the improved survival of the symptomatic cancers (a 3% increase). Ten-year survival for women with screen-detected cancers and women unexposed to screening increased over time, but the survival of women with interval cancers decreased by 1.5%. Cancer April 1,

7 Table 4. Unadjusted and Adjusted Cox Regression Model for Breast Cancer Survival After Invasive Carcinoma Factor Unadjusted HR n519,411 Adjusted HR n510,245 HR 95% CI P HR 95% CI P Histological type <.001 Screen-detected Interval < Unexposed < Nodal status <.001 Negative Positive < Unknown < Tumor size < mm >5 to 10 mm >10 to 15 mm >15 to 20 mm < >20 to 50 mm < >50 mm < Differentiation grade <.001 Grade Grade < Grade < Age, y < < Tumor type Ductal carcinoma Lobular carcinoma < Tubular carcinoma < Other carcinoma < Other malignancy Vascular invasion a <.001 No Yes < Year of diagnosis < <.001 HR indicates hazard ratio; CI, confidence interval. a 43.4% missing data. DISCUSSION In this study, of more than 21,000 breast cancers diagnosed in women aged years since the initiation of breast screening in the West Midlands, we found more favorable tumor size, nodal status, grade, and hormone receptor status in screen-detected breast cancers than in symptomatic cancers, as one might expect from the results of other studies Of the screen-detected invasive cancers, 30% were 10 mm compared with 11% of interval cancers and 9.8% of cancers in women unexposed to screening. Also, as expected, 17,22 there was a higher proportion of in situ tumors among screen-detected cancers. Screen-detected invasive tumors had a higher proportion of tubular cancers (8.4% vs 2% in the symptomatic tumors), and a lower proportion of ductal cancers (76.0% vs 78.6% and 79.8%). Interval cancers contained a higher proportion of lobular cancers. Screen-detected in situ cancers had a significantly higher proportion of ductal carcinoma in situ. The proportion of screen-detected tumors, including both in situ and invasive, rose from 5.9% in 1988 to 43.5% in 1996 and 55.0% in The proportion of tumors in women exposed to screening (screen-detected plus interval cancers) rose from 5.9% in 1988 to 76.1% in 1366 Cancer April 1, 2011

8 Breast Cancer Differences/Nagtegaal et al Table 5. Predicted Survival by Detection Mode and Year of Diagnosis (Invasive Tumors Only) Detection Mode Percentage of Cases Year Survival Percentage of Cases 10-Year Survival Percentage of Cases 10-Year Survival Screen-detected Interval Unexposed to screening Total All data are expressed as percentages (%) and were derived using Cox regression and 81.9% in During the start-up phase of the screening program ( ), dramatic reductions were observed in invasive tumors in the proportions of node-positive, grade 3 and large (>50 mm) tumors, along with substantial increases in small (10 mm) tumors, tubular carcinomas, and lobular carcinomas. In the continuation phase, after 1996, these trends were either absent, reversed, or much attenuated. Further investigation of the trends showed that the changes in the proportions of tubular and small tumors were largely due to the increase in the proportion of screen-detected cancers. Within both the screen-detected and the symptomatic tumors, the proportion of small tumors remained roughly constant over time, but the proportion of tubular cancers declined in the continuation phase. The slow development of tubular carcinoma implies a long lead time and suggests that many of the asymptomatic tubular cancers were diagnosed during the early years of the program, when most of the screening episodes were prevalent screens. Screen-detected invasive breast cancers had substantially better survival than either interval cancers or cancers in women unexposed to screening, which is consistent with the findings of others. 11,12,18,19 Of this survival advantage, approximately 64%-68% could be explained by age, tumor size, nodal status, grade, tumor type, and year of diagnosis, whereas 42%-47% could be explained by age, tumor size, and nodal status only. Because only a small minority of cases had ER and PR data, we were unable to assess the impact of these confounding factors. These results suggest that the majority of the difference in prognosis of screen-detected cancers can be attributed to age and histological characteristics. The remaining 32%-36% of the survival difference between screendetected and symptomatic tumors may be partly due to effects of early detection, for which we have no data (eg, the number of nodes involved in node-positive tumors), partly due to lead time and partly due to length bias, which might be manifested by differences in biological features such as HER2/neu status and epithelial proliferation rate. Certainly, there were more ER- and PR-positive cases among the screen-detected tumors in the years for which these data were available. When considering possible biological differences between screen-detected and symptomatic breast cancers, it should be noted that any such difference is quantitative rather than qualitative. Screening does not exclusively single out ER-positive or well-differentiated tumors; rather, higher percentages of such tumors are represented in a screen-detected tumor series. It is also worth noting that there is evidence that histological grade may change as a tumor develops 23 (although these findings have been contested by some 24 ), so that a difference in grade between screen-detected and symptomatic invasive breast cancer may be an effect of early detection rather than length bias. This may also be the case for hormone receptor status. Ongoing studies are evaluating how much of the screening effect can be attributed to lead time and length bias. In the meantime, it is clear that the screening program in the West Midlands has brought about substantial changes in tumor attributes and improvements in survival, mainly due to a higher proportion of screendetected cases rather than to changes in prognosis within screen-detected cases. The better survival for women with screen-detected cancers explains much of the improved survival by year of diagnosis, rather than vice versa. Most of this survival can be accounted for by age and the routinely measured histological factors of tumor size, nodal status, grade, and tumor type, leaving approximately onequarter of the effect to be explained by lead time and unmeasured biological features. CONFLICT OF INTEREST DISCLOSURES Supported by Cancer Research UK and the Breast Cancer Research Trust. Iris Nagtegaal was supported by a fellowship from the Dutch Cancer Society. Cancer April 1,

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