Individually tailored screening of breast cancer with genes, tumour phenotypes, clinical attributes, and conventional risk factors.

BACKGROUND: We demonstrated how to comprehensively translate the existing and updated scientific evidence on genomic discovery, tumour phenotype, clinical features, and conventional risk factors in association with breast cancer to facilitate individually tailored screening for breast cancer. METHODS: We proposed an individual-risk-score-based approach that translates state-of-the-art scientific evidence into the initiators and promoters affecting onset and subsequent progression of breast tumour underpinning a novel multi-variable three-state temporal natural history model. We applied such a quantitative approach to a population-based Taiwanese women periodical screening cohort. RESULTS: Risk prediction for pre-clinical detectable and clinical-detected breast cancer was made by the two risk scores to stratify the underlying population to assess the optimal age to begin screening and the inter-screening interval for each category and to ascertain which high-risk group requires an alternative image technique. The risk-score-based approach significantly reduced the interval cancer rate as a percentage of the expected rate in the absence of screening by 30% and also reduced 8.2% false positive cases compared with triennial universal screening. CONCLUSION: We developed a novel quantitative approach following the principle of translational research to provide a roadmap with state-of-the-art genomic discovery and clinical parameters to facilitate individually tailored breast cancer screening.

Dermatomyositis is associated with an increased risk of cardiovascular and cerebrovascular events: a Taiwanese population-based longitudinal follow-up study.

BACKGROUND: While the chronic inflammation related to autoimmune diseases is known to be associated with an increased cardiovascular risk, much less is known about cerebrovascular risks. OBJECTIVES: The present population-based, age- and sex-matched follow-up study was undertaken to investigate the risks of acute myocardial infarction (AMI) and ischaemic stroke in patients with dermatomyositis (DMS). METHODS: In total 907 patients with DMS were enrolled and compared with a non-DMS control group consisting of 4535 age- and sex-matched, randomly sampled subjects without DMS. The AMI-free and ischaemic stroke-free survival curves were generated using the Kaplan-Meier method. Cox proportional hazard regression was used to estimate the DMS-associated risks of AMI and ischaemic stroke. RESULTS: During the 2-year follow-up period, 14 patients with DMS (1.5%) and 18 patients in the non-DMS control group (0.4%) suffered AMIs. The crude hazard ratio (HR) for suffering an AMI in patients with DMS compared with subjects in the non-DMS group was 3.96 [95% confidence interval (CI) 1.97-7.96, P = 0.0001], while the adjusted HR was 3.37 (95% CI 1.67-6.80, P = 0.0007), after taking into account demographic characteristics and cardiovascular comorbidities. During the same follow-up period, 46 patients (5.1%) and 133 subjects in the control group (2.9%) developed ischaemic strokes. The crude HR for developing an ischaemic stroke in patients with DMS compared with subjects in the non-DMS group was 1.78 (95% CI 1.27-2.49, P = 0.0007), and the adjusted HR was 1.67 (95% CI, 1.19-2.34, P = 0.0028). CONCLUSIONS: These findings suggest that DMS is associated with an increased risk of cardiovascular and cerebrovascular events.

Increased risk of trigeminal neuralgia after hypertension: a population-based study.

OBJECTIVE: Very few studies have explored the temporal relationship between hypertension and trigeminal neuralgia (TN). The aim of this population-based follow-up study was to investigate whether hypertension is associated with a higher risk of developing TN. METHODS: A total of 138,492 persons with at least 2 ambulatory visits with the principal diagnosis of hypertension in 2001 were enrolled in the hypertension group. The nonhypertension group consisted of 276,984 age- and sex-matched, randomly sampled subjects without hypertension. The 3-year TN-free survival rate and the cumulative incidence of TN were calculated using the Kaplan-Meier method. Cox proportional hazard regression was used to estimate the hazard ratio of TN. RESULTS: In the hypertension group, 121 patients developed TN during follow-up, while, in the nonhypertension group, 167 subjects developed TN. The crude hazard ratio for the hypertension group was 1.52 (95% confidence interval [CI] 1.20-1.92; p = 0.0005), while, after adjustment for demographic characteristics and medical comorbidities, the adjusted hazard ratio was 1.51 (95% CI 1.19-1.90; p = 0.0006). CONCLUSIONS: This study shows a significantly increased risk of developing TN after hypertension. Further studies are needed to elucidate the underlying mechanism of the association between hypertension and TN.

A population-based study investigating the association between metabolic syndrome and hepatitis B/C infection (Keelung Community-based Integrated Screening study No. 10).

OBJECTIVES: We aimed to assess the association between metabolic syndrome (MS) and hepatitis B/C virus infection using a large population-based study. DESIGN AND METHODS: A population-based cross-sectional study design was adopted with a total of 53,528 subjects being enrolled from the integrated multiple diseases screening program in Keelung, Taiwan. Evidence of past hepatitis B/C infection, acquired during childhood or as a young adult, was identified during the two-stage liver cancer screening part of the process. Information on biochemical markers and anthropometric measures related to MS, such as fasting blood sugar, triglyceride and high-density lipoprotein (HDL), abdominal circumference and blood pressure (BP), were collected routinely while screening for hypertension, type 2 diabetes, and hyperlipidemia. Logistic regression was used to estimate odds ratios and related 95% confidence intervals for the associations between MS and hepatitis B/C infection. RESULTS: High blood pressure (SBP > or = 135 mmHg or DBP > or = 85 mmHg) (adjusted odd ratio: 0.89 (0.83-0.94)) and high triglyceride (> or = 150 mg/dl) (adjusted odds ratio: 0.65 (0.60-0.69)) were, after adjusting for gender and age, inversely associated with being HBsAg positive (P<0.05). The likelihood of developing MS was lower in the HBsAg positive than the HBsAg negative (adjusted odds ratio: 0.84 (0.76-0.93)). A positive association between being anti-HCV positive and having low serum HDL (male <40 mg/dl, female <50 mg/dl) was also noted (adjusted odds ratio: 1.61 (1.37-1.88) after controlling for gender and age). High triglyceride was inversely associated with being anti-HCV positive (adjusted odds ratio: 0.63 (0.55-0.71). CONCLUSIONS: There is an inverse association between MS and hepatitis B virus infection whereas the association was heterogeneous for HCV infection with a positive association with abnormal serum HDL but an inverse association with hypertriglyceridemia.

Mammographic tumor features can predict long-term outcomes reliably in women with 1-14-mm invasive breast carcinoma.

BACKGROUND: The radiologic images of 1-14-mm invasive breast carcinomas can be classified into 5 separate categories. The use of these mammographic indicators to predict patient outcome has important prognostic and therapeutic implications. METHODS: To verify the results of previous studies conducted with smaller numbers of patients, the authors studied the 24-year survival of 714 women with 1-14-mm invasive breast carcinoma according to mammographic prognostic factors. The association of mammographic features with lymph node status, histologic malignancy grade, and 24-year survival in 714 women with invasive breast carcinomas that measured 1-14 mm also was evaluated. Adjustments were made for tumor characteristics and treatment factors in the survival analysis. RESULTS: The most common mammographic feature was a stellate lesion with no associated calcifications (420 women; 59%). Patients with stellate lesions had excellent long-term survival (95%). Casting-type calcifications were observed in 52 women (7%) and were associated significantly with a positive lymph node status (odds ratio [OR], 3.29; 95% confidence interval [95% CI], 1.41-7.67), poorer histologic grade (OR, 7.04; 95% CI, 3.77-13.16), and an increased risk of death from breast carcinoma (HR, 9.19; 95% CI, 4.18-20.17). Except for women who had tumors with associated casting-type calcifications, all other women with tumors < 10 mm in size had excellent survival regardless of lymph node status, histologic grade, or treatment. For women who had casting-type calcifications, survival was poorer even in the group with tumors that measured 1-9 mm (72% at 20 years). For women with 10-14-mm tumors, the 20-year survival rate was 52% for those who had casting calcifications and 86-100% those for those who had other mammographic features. CONCLUSIONS: The subgroup of women who had small invasive breast carcinomas accompanied by casting-type calcifications had an unexpectedly poor prognosis for this tumor-size category. The process of neoductgenesis offers a possible explanation for the unexpectedly poor outcome. There is a need to develop treatment protocols for this group and to reevaluate the present TNM classification system for mammographically detected 1-14-mm breast carcinomas. After excluding women who had tumors associated with casting-type calcifications, the remaining women had an extremely good prognosis when they were treated with surgery alone. Due to their already excellent survival, adjuvant therapeutic regimens are unlikely to offer further benefit for these patients.

Number needed to screen: lives saved over 20 years of follow-up in mammographic screening.

OBJECTIVE: To estimate the number needed to screen with mammography to save one life, based on a stated amount of screening activity and long-term follow-up for breast cancer death. SETTING: A randomised controlled trial of mammographic screening for breast cancer, with 77,080 women invited to screening and 55,985 not invited. The invited group was offered screening for seven years. Follow-up continued for a total of just over 20 years. METHODS: Number needed to screen for seven years to save one life over 20 years was calculated by dividing the number screened (not the number invited) by the total number of lives saved. Similarly, we calculated the number of mammographic examinations required to save one life. RESULTS: We estimate that the number of women needed to screen for seven years to save one life over 20 years is 465 (95% CI 324-819). The number of mammographic examinations needed to save one life was 1499 (95% CI 1046-2642). CONCLUSIONS: The number needed to screen to save one life is smaller than has been reported in the past. Mammographic screening is effective in absolute terms as well as relative. Long-term follow-up allowed us to estimate the absolute benefit with greater accuracy.

Assessing progression and efficacy of treatment for diabetic retinopathy following the proliferative pathway to blindness: implication for diabetic retinopathy screening in Taiwan.

AIMS: The natural history and treatment efficacy of diabetic retinopathy (DR) play important roles in the evaluation of screening. Therefore, the natural history of DR and rates of transition after treatment (including metabolic control and laser photocoagulation) from no diabetic retinopathy (NDR) to blindness were quantified. METHODS: We studied a cohort of 795 patients with diabetes mellitus (DM) receiving fundus examination in the ophthalmology out-patient department of one medical centre between 1 January 1990 and 31 December 1992 in Taiwan. Follow-up data until 31 December 1998 were collected by chart review. Two multistate Markov models were proposed to assess the efficacy of the treatment regime in reducing progression to blindness. RESULTS: The average times spent in states (i) no diabetic retinopathy (NDR), (ii) background diabetic retinopathy (BDR), (iii) preproliferative diabetic retinopathy (PPDR), and (iv) proliferative retinopathy (PDR) were 10.86 years, 8.33 years, 1.67 years, and 2.17 years, respectively. Early detection of PPDR may lead to a 60% reduction in PDR and an 83% reduction in blindness. Simulated results based on these parameters show that an annual screening programme, a biennial screening regime and a 4-yearly screening regime can lead to 54% (95% confidence interval (CI): 44-62%), 51% (95% CI: 41-59%), and 46% (95% CI: 36-54%) reductions in blindness, respectively. CONCLUSIONS: Assessing the progression of DR following the proliferative pathway in this study suggests that screening for DR is worthwhile and that a 4-year interscreening interval for patients as yet without DR may be justified.

The Swedish Two-County Trial of mammographic screening: cluster randomisation and end point evaluation.

BACKGROUND: The Swedish Two-County Trial has been criticised on the grounds of the cluster randomisation and alleged bias in classification of cause of death. PATIENTS AND METHODS: In the Two-County Trial, 77 080 women were randomised to regular invitation to screening (active study population, ASP) and 55 985 to no invitation (passive study population, PSP), in 45 geographical clusters. After approximately 7 years, the PSP was invited to screening and the trial closed. We analysed data using hierarchical statistical models to take account of cluster randomisation, and performed a conservative analysis assuming a systematic difference between ASP and PSP in baseline breast cancer mortality in one of the counties. We also analysed deaths from causes other than breast cancer and from all causes among breast cancer cases diagnosed in the ASP and PSP. RESULTS: Taking account of the cluster randomisation there was a significant 30% reduction in breast cancer mortality in the ASP. Conservatively, assuming a systematic difference between ASP and PSP clusters in baseline breast cancer mortality, there was a significant 27% reduction in mortality in the ASP. Ignoring classification of cause of death, there was a significant 13% reduction in all-cause mortality in breast cancer cases in the ASP. CONCLUSIONS: Breast cancer mortality is a valid end point and mammographic screening does indeed reduce mortality from breast cancer. The criticisms of the Swedish Two-County Trial are unfounded.

Quantifying the potential problem of overdiagnosis of ductal carcinoma in situ in breast cancer screening.

The relevance of detection of ductal carcinoma in situ (DCIS) in a breast cancer screening programme, and the extent of overdiagnosis of non-progressive lesions, remains controversial. It was the purpose of this paper to estimate the incidence of non-progressive, 'overdiagnosed' DCIS. We defined non-progressive DCIS (DCIS(0)) as DCIS which could not have progressed to invasive disease if left untreated. Progressive DCIS (DCIS(1)) was defined as DCIS which has the propensity to progress to invasive disease. We fitted a Markov process model of the incidence of progressive and non-progressive DCIS, the transition of the former to preclinical invasive disease and the subsequent progression to clinical symptomatic cancer. We used data from the Swedish Two-County Trial and from service screening programmes in the UK, Netherlands, Australia and the USA to estimate the incidence of progressive and non-progressive DCIS, and the detection rates of each at the first and subsequent screening. Average incidence of non-progressive DCIS was 1.11 per 100000 per year. Average incidence of progressive DCIS was 2.1 per 1000 per year. At prevalence screen, 37% of DCIS cases were estimated to be non-progressive. A woman attending prevalence screen has a 19 times greater chance of having a progressive DCIS or an invasive tumour diagnosed than of having a non-progressive DCIS diagnosed. At incidence screen, only 4% of DCIS cases were estimated to be non-progressive. A woman attending an incidence screen has a 166 times higher probability of having a progressive DCIS or invasive lesion diagnosed than of having a non-progressive DCIS diagnosed. There is an element of overdiagnosis of DCIS in breast cancer screening, but the phenomenon is small in both relative and absolute terms.

The relative contributions of screen-detected in situ and invasive breast carcinomas in reducing mortality from the disease.

We aimed to quantify the benefits of detecting ductal carcinoma in situ (DCIS) and of downwards stage-shifting within invasive tumours in mammographic screening. Using data from the Swedish Two-County Trial of breast cancer screening, we examined the 20-year death rates from invasive tumours of stage II or worse, invasive tumours of stage I and DCIS. We then used these rates and their respective incidences in invited (active study population, ASP) and control (passive study population, PSP) arms of the trial, to estimate the numbers of deaths avoided by downward stage-shifting the larger stage II or worse tumours to stage I and the stage I cancers to DCIS. We also studied the association between the mortality reduction achieved and the proportion of DCIS cases detected in the randomised trials of breast cancer screening. In the Swedish Two County Trial, 141 breast cancer deaths were avoided in the ASP compared with the PSP at approximately 20 years of follow-up. Of these, 65% (91/141) were avoided as a result of stage-shifting from invasive stage II or worse to invasive stage I, and 5% (7/141) as a result of stage-shifting from invasive stage I to DCIS. If we assumed that 10% of stage II or worse tumours avoided were shifted not to stage I, but to DCIS, the estimated number of deaths prevented by shifting from invasive disease to in situ was 17, which is 12% of all deaths prevented. When the results of all the randomised trials of breast cancer screening were reviewed, there was no clear association between the percentage of DCIS cases diagnosed and the observed mortality reduction. We conclude that compared with downward stage-shifting of invasive tumours, detection of DCIS plays a small part in saving lives from breast cancer. Treatment decisions in DCIS, as in invasive carcinoma, should take full account of histopathological, clinical and radiological attributes of the tumour.

A case-cohort study for the disease natural history of adenoma-carcinoma and de novo carcinoma and surveillance of colon and rectum after polypectomy: implication for efficacy of colonoscopy.

The disease natural history of colorectal neoplasm regarding two opposing theories, adenoma-carcinoma sequence and de novo carcinoma theory, is controversial and rarely quantified. The aims of this study are therefore to estimate the dwelling times of adenoma-carcinoma sequence by adenoma size and histological type, taking de novo carcinoma into account. The efficacy of polypectomy was therefore estimated making allowance for two pathways. A case-cohort design, underpinning a cohort with 13 908 subjects (including 10 496 normal subjects, 2652 polyps, 760 colorectal cancers) who underwent the first examination of colonoscopy between 1979 and 1998, was devised to estimate parameters associated with two opposing theories by randomly selecting 305 normal subjects, 300 patients with polyps, and 116 colorectal cancers from the cohort. All the 2652 polyps were linked to national cancer registry to ascertain 25 invasive carcinomas after polypectomy. For the five-state model associated with adenoma size, dwelling times of small (0.6-1 cm) and large adenoma (>1 cm) are 7.75 and 5.27 years for the model without considering de novo, and 17.48 and 15.90 years for the model taking de novo carcinoma into account. Similar findings are observed for the model associated with histological type. The estimated proportions of de novo carcinoma are 31.87% from the model by adenoma size and 27.81% from the model by histological type. Compared to size less than 5 mm, patients with adenoma size between 6 and 10 mm and patients with adenoma size larger than 1 cm have 2.17-fold (0.67-10.74) and 4.25-fold (1.23-14.70), respectively, for the risk of malignant transformation. There are similar findings for the model by histological type. The estimates of overall efficacy of colonoscopy in reducing CRC is 73% for the model allowing for de novo carcinoma and 88% for the model without considering de novo carcinoma theory. The efficacy of diminutive adenoma and small adenoma increases with follow-up years, whereas the efficacy of large adenoma decreases with follow-up years. In conclusion, about 30% of cancers arising from de novo sequence are demonstrated. This finding, together with the adenoma-carcinoma sequence associated with adenoma size and histological type, is important for the estimation of dwelling times, the efficacy of colonoscopy, and the surveillance of polyp after polypectomy.

All-cause mortality among breast cancer patients in a screening trial: support for breast cancer mortality as an end point.

BACKGROUND: It has recently been suggested that all-cause mortality is a more appropriate end point than disease specific mortality in cancer screening trials, and that disease specific mortality is biased in favour of screening. This suggestion is based partly on supposed inconsistencies between all-cause mortality results and disease specific results in cancer screening trials, and alleged increases in deaths from causes other than breast cancer among breast cancer cases diagnosed among women invited to screening. METHODS: We used data from the Swedish Two-County Trial of mammographic screening for breast cancer, in which 77 080 women were randomised to an invitation to screening and 55 985 to no invitation. We estimated relative risks (RRs) (invited v control) of death from breast cancer, death from other causes within the breast cancer cases, and death from all causes within the breast cancer cases. RRs were adjusted for age and took account of the longer follow up of breast cancer cases in the invited group due to lead time. RESULTS: There was a significant 31% reduction in breast cancer mortality in the invited group (RR 0.69, 95% confidence interval (CI) 0.58-0.80; p<0.001). There was no significant increase in deaths from other causes among breast cancer cases in the invited group (RR 1.12, 95% CI 0.96-1.31; p=0.14). A significant 19% reduction in deaths from all causes was observed among breast cancer cases in the group invited to screening (RR 0.81, 95% CI 0.72-0.90; p<0.001). A more conservative estimation gave a significant 13% reduction (RR 0.87, 95% CI 0.78-0.97; p=0.01). These findings are consistent with the magnitude of the reduction in breast cancer mortality. CONCLUSIONS: Invitation to screening was associated with a reduction in deaths from all causes among breast cancer cases, consistent with high participation rates in screening. There is no significant evidence of bias in cause of death classification in the Two-County Trial, and as breast cancer mortality is the targeted clinical outcome in breast cancer screening, it is the appropriate end point in a breast cancer screening trial. All-cause mortality is a poor and inefficient surrogate for breast cancer mortality.

Prevalence, incidence, and mortality of PD: a door-to-door survey in Ilan county, Taiwan.

BACKGROUND: The reported prevalence and incidence rates of PD were significantly lower in China than those in Western countries. People in China and Taiwan have a similar ethnic background. OBJECTIVE: To investigate the prevalence, incidence, and mortality rate of PD in Taiwan. METHOD: The authors conducted a population-based survey using a two-stage door-to-door approach for patients aged 40 years or older in Ilan, Taiwan. Patients were diagnosed with PD by having at least two of the four cardinal signs of parkinsonism and exclusion of seconddary parkinsonism. To identify new cases of PD after the survey, patients with negative results of parkinsonism in the first stage were matched to the information on clinical diagnosis of PD from the Bureau of National Health Insurance toward the end of December 31, 1997. All cases of PD were linked to the Taiwan mortality registration to ascertain causes of deaths until December 31, 1999. RESULTS: The participation rate was 88.1% among the 11,411 contacted individuals. Thirty-seven cases of PD were identified. The age-adjusted prevalence rate of PD for all age groups was 130.1 per 100,000 population after being adjusted to the 1970 US census, assuming no cases of PD would be found among those younger than 40 years of age. Of 9972 non-PD subjects in the first screen, 15 new cases of PD were ascertained. The age-adjusted incidence rate was 10.4 per 100,000 population for all age groups. The case fatality rate of PD after a 7-year follow-up was 40.4% (21 deaths in 52 patients with PD). The relative risk of death for PD cases versus non-PD cases was 3.38 (95% CI: 2.05-4.34). The 5-year cumulative survival rate in PD cases (78.85%) was statistically lower than that in non-PD cases (92.84%). CONCLUSION: The prevalence and incidence rates of PD in Taiwan were much higher than those reported in China, but closer to those in Western countries. These results suggest that environmental factors may be more important than racial factors in the pathogenesis of PD.

A computer simulation model for cost-effectiveness analysis of mass screening for Type 2 diabetes mellitus.

The cost-effectiveness analysis of mass screening for Type 2 diabetes mellitus (DM) was performed to elucidate whether, who and how often it should be conducted in Taiwan. A series of Markov process was developed to model the disease natural history of Type 2 DM. A hypothetical cohort with 30,000 residents aged over 30 years in Taiwan was randomly assigned to three arms of screening regimes, biennial, five-yearly and the control group. A Monte Carlo computer simulation was performed to calculate effectiveness of two screening regimes compared with the control group. Direct costs and utilities were incorporated to each corresponding state to calculate the incremental costs per life-years gained and per quality-adjusted life-years (QALYs) for biennial and five-yearly screening regimes. The incremental costs for biennial screening regime were estimated at $26,750 per life-year gained, and $17,833 per QALY. The corresponding figures for five-yearly screening regime were $10,531 per life-year gained and $17,113 per QALY. The incremental costs per life-year gained and per QALY increase with age, ranging from $17,238 for aged 30-39 years to $54,700 for aged over 70 years and from $9193 to 36,467, respectively. In conclusion, mass screening for Type 2 DM, especially in younger subjects, with 5-year inter-screening interval is cost-effective in Taiwan.

Beyond randomized controlled trials: organized mammographic screening substantially reduces breast carcinoma mortality.

BACKGROUND: The efficacy of mammographic screening in the reduction of breast carcinoma mortality has been demonstrated in randomized controlled trials. However, the evaluation of organized screening outside of research settings (so-called "service screening") faces unique methodologic and conceptual challenges. The current study describes the evaluation of organized mammography screening in a clinical setting and demonstrates the benefit obtained from service screening in two Swedish counties. METHODS: In the group of subjects ages 20--69 years, there were 6807 women diagnosed with breast carcinoma over a 29-year period in 2 counties in Sweden and 1863 breast carcinoma deaths. All patients were classified from patient charts based on their screening status (i.e., whether they had been invited to undergo screening and whether they actually had undergone screening). The number of women who lived in the 2 counties during the 29-year study period was provided by the Central Bureau of Statistics. Breast carcinoma-specific mortality was compared across three time periods: 1) 1968--1977, when no screening was taking place because mammography had not been introduced; 2) 1978--1987, the approximate period of the Two-County randomized controlled trial of screening in women ages 40--74 years; and 3) 1988--1996, when all women in the 2 counties ages 40--69 years were invited to undergo screening (service screening). When comparing breast carcinoma mortality in screened women with that in women diagnosed before screening was introduced, a correction for self-selection bias was incorporated to prevent overestimation of the benefit of screening. RESULTS: The mortality from incident breast carcinoma diagnosed in women ages 40-69 years who actually were screened during the service screening period (1988--1996) declined significantly by 63% (relative risk [RR] = 0.37; 95% CI, 0.30--0.46) compared with breast carcinoma mortality during the time period when no screening was available (1968--1977). The mortality decline was 50% (RR = 0.50; 95% CI, 0.41--0.60) when breast carcinoma mortality among all women who were invited to undergo screening (nonattendees included) was compared with breast cancer mortality during the time period when no screening was available (1968--1977). The reduction in mortality observed during the service screening period, adjusted for selection bias, was 48% (RR = 0.52; 95% CI, 0.43--0.63). No significant change in breast carcinoma mortality was observed over the three time periods in women who did not undergo screening. This group included women ages 20--39 years because these individuals were never invited to undergo screening, and women ages 40--69 years who did not undergo screening (not invited during the randomized trial or invited during the second and third time periods but declined). CONCLUSIONS: Regular mammographic screening resulted in a 63% reduction in breast carcinoma death among women who actually underwent screening. The policy of invitation to organized screening with mammography appears to have reduced breast carcinoma mortality by 50% in these 2 counties.

The Swedish Two-County Trial twenty years later. Updated mortality results and new insights from long-term follow-up.

The benefit of invitation to mammographic screening observed in this trial is maintained as a highly significant 32% reduction in breast cancer mortality. Mammographic screening for breast cancer continues to save lives after up to 20 years. Screening derives this benefit by improving the distribution of tumors diagnosed with respect to prognostic categories based on node status, size, and histology of tumors. There is potential for modern screening programs with shorter interscreening intervals to achieve even greater improvements in prognostic category and greater reductions in breast cancer mortality. Mammography can discriminate a subpopulation of high-risk cases, those displaying casting-type calcifications on the mammogram, among very small tumors, with fundamental implications for diagnosis and treatment.

A novel method for prediction of long-term outcome of women with T1a, T1b, and 10-14 mm invasive breast cancers: a prospective study.

BACKGROUND: Women with small mammographically detected breast cancers generally have good long-term outcomes, but a few with T1a (1-5 mm) and T1b (6-10 mm) tumours will eventually die from breast cancer. We investigated whether women at high risk of breast-cancer death could be identified with mammographic criteria and differentiated from women with small cancers of the breast and good outcomes. METHODS: We prospectively applied mammographic classifications of tumour type to a consecutive series of 343 mammograms of invasive breast cancers of size 1-14 mm. Classifications were: stellate (spiculated) mass with no calcifications; circular or oval lesions with no calcifications; spiculated or circular lesions with non-casting-type calcifications; and casting-type calcifications. FINDINGS: 20-year survival for women with 1-14 mm invasive tumours with casting-type calcifications was 55%. 14% of 138 women with 1-9 mm tumours had casting-type calcifications on mammography, which accounted for 73% of all breast-cancer deaths (p<0.001). T1a, T1b, and 10-14 mm tumours with casting-type calcifications behaved as if they were larger lesions, since the rate of death was similar to that for women with advanced high-grade tumours. Most women who died were node-negative. The long-term survival of women who had tumours of 1-9 mm with no casting-type calcifications was about 95%. INTERPRETATION: Mammographic classification seemed to reliably predict good and bad long-term outcomes for survival in tumours of 14 mm or smaller, and especially for those smaller than 10 mm. The implications for therapy are substantial.

Estimation of sojourn time in chronic disease screening without data on interval cases.

Estimation of the sojourn time on the preclinical detectable period in disease screening or transition rates for the natural history of chronic disease usually rely on interval cases (diagnosed between screens). However, to ascertain such cases might be difficult in developing countries due to incomplete registration systems and difficulties in follow-up. To overcome this problem, we propose three Markov models to estimate parameters without using interval cases. A three-state Markov model, a five-state Markov model related to regional lymph node spread, and a five-state Markov model pertaining to tumor size are applied to data on breast cancer screening in female relatives of breast cancer cases in Taiwan. Results based on a three-state Markov model give mean sojourn time (MST) 1.90 (95% CI: 1.18-4.86) years for this high-risk group. Validation of these models on the basis of data on breast cancer screening in the age groups 50-59 and 60-69 years from the Swedish Two-County Trial shows the estimates from a three-state Markov model that does not use interval cases are very close to those from previous Markov models taking interval cancers into account. For the five-state Markov model, a reparameterized procedure using auxiliary information on clinically detected cancers is performed to estimate relevant parameters. A good fit of internal and external validation demonstrates the feasibility of using these models to estimate parameters that have previously required interval cancers. This method can be applied to other screening data in which there are no data on interval cases.

Evaluation of a selective screening for colorectal carcinoma: the Taiwan Multicenter Cancer Screening (TAMCAS) project.

BACKGROUND: Although the efficacy of mass screening for colorectal carcinoma (CRC) with a fecal occult blood test has been demonstrated in several randomized trials, a mass screening approach used in countries with intermediate or low incidence of CRC might be costly. Screening high risk people may be an alternative approach, to aid in the prevention of death from CRC. However, the efficacy of CRC screening for high risk people in such countries is uncertain. METHODS: For this study, a multicenter design was devised to identify high risk groups without clinical symptoms related to CRC; these subjects were identified through the study of index cases of CRC in Taiwan. Colonoscopy, in combination with a fecal occult blood test or double-contrast barium enema, was used to screen high risk groups. A total of 8909 subjects were invited to attend screening. Of 8909, 81 with asymptomatic CRC were detected in one-shot screening. Markov models, in conjunction with a simulated approach, were proposed to estimate relevant parameters in relation to disease progression and to assess the effect of the interval between screenings on the efficacy of CRC screening for these high risk groups. RESULTS: The estimated preclinical incidence rate was 0. 00396 (95% confidence interval [CI], 0.002944-0.004985), which was 21 times that reported from a cancer registry in 1994. The simultaneous estimations of mean sojourn time (the average duration between the preclinical screen-detectable phase and the clinical phase) and sensitivity were 2.8 years (95% CI, 2.15-4.30) and 95.0% (95% CI, 24.4-99.9%), respectively. Predictions of mortality reduction for people who received annual, biennial, and triennial screening regimes compared with controls were 26% (95% CI, 0-50%), 23% (95% CI, 0-48%), and 21% (95% CI, 0-47%), respectively. CONCLUSIONS: The efficacy of selective colorectal carcinoma screening has been demonstrated in this study. A high preclinical CRC incidence rate also suggests that such a screening strategy might be cost-effective for countries with intermediate or low incidence of CRC. Methods proposed in this study can be used to evaluate the efficacy of CRC screening in similar screening trials.

Efficacy of breast-cancer screening for female relatives of breast-cancer-index cases: Taiwan multicentre cancer screening (TAMCAS).

Although the efficacy of mass screening for breast cancer has been established in Western countries, this strategy may be too costly for other countries with low incidence rates of breast cancer. We propose an alternative approach to screen female relatives of breast-cancer-index cases from hospitals, as part of the Taiwan multicentre cancer screening (TAMCAS) project. In order to assess the efficacy of this programme, and to estimate how often this high-risk group should be screened, we firstly elucidated the disease natural history from the pre-clinical screen-detectable phase (PCDP) by estimating the relevant parameters based on Markov chain models. We further predicted the proportion of interval cancers, advanced breast tumours and deaths from breast cancers by different screening frequencies. Results showed that the estimate of mean sojourn time (MST) for this high-risk group (1.9 years; 95% CI.1.18-4.86) is shorter than that for females from the general population. Analysis of a surrogate endpoint based on regional lymph-node spread and tumour size shows that annual screening for this high-risk group is likely to confer a significant 33% reduction in breast-cancer mortality compared with a non-significant 25 and 20% reduction for 2 yearly and 3-yearly screening regimes respectively. The above results suggest that a 1-year interval might be appropriate for this high-risk group. A simple cost-effectiveness analysis indicates a cost per year of life saved for mass screening ($72,480) 15 times that for the high-risk group ($4,851 ).