Sherry Yueh Hsia Chiu

Swedish Two-County Trial: Impact of Mammographic Screening on Breast Cancer Mortality during 3 Decades

PURPOSE To estimate the long-term (29-year) effect of mammographic screening on breast cancer mortality in terms of both relative and absolute effects. MATERIALS AND METHODS This study was carried out under the auspices of the Swedish National Board of Health and Welfare. The board determined that, because randomization was at a community level and was to invitation to screening, informed verbal consent could be given by the participants when they attended the screening examination. A total of 133 065 women aged 40-74 years residing in two Swedish counties were randomized into a group invited to mammographic screening and a control group receiving usual care. Case status and cause of death were determined by the local trial end point committees and, independently, by an external committee. Mortality analysis was performed by using negative binomial regression. RESULTS There was a highly significant reduction in breast cancer mortality in women invited to screening according to both local end point committee data (relative risk [RR] = 0.69; 95% confidence interval: 0.56, 0.84; P < .0001) and consensus data (RR = 0.73; 95% confidence interval: 0.59, 0.89; P = .002). At 29 years of follow-up, the number of women needed to undergo screening for 7 years to prevent one breast cancer death was 414 according to local data and 519 according to consensus data. Most prevented breast cancer deaths would have occurred (in the absence of screening) after the first 10 years of follow-up. CONCLUSION Invitation to mammographic screening results in a highly significant decrease in breast cancer-specific mortality. Evaluation of the full impact of screening, in particular estimates of absolute benefit and number needed to screen, requires follow-up times exceeding 20 years because the observed number of breast cancer deaths prevented increases with increasing time of follow-up.

Effect of Baseline Breast Density on Breast Cancer Incidence, Stage, Mortality, and Screening Parameters: 25-Year Follow-up of a Swedish Mammographic Screening

Background: We aimed to quantitatively assess the effect of baseline breast density on the incidence, stage, and mortality, and also the natural course of the disease, considering the sensitivity of mammography to clarify its causal or masking effect. Methods: In total, 15,658 women ages 45 to 59 years from the Kopparberg randomized controlled trial in Sweden were prospectively followed from 1977 until 2004 to ascertain breast cancer incidence and death. Dense breast tissue collected at the beginning of the study was defined as pattern IV or V by the Tabár classification. Conventional risk factors were also collected at baseline. The three-state Markov model was used to estimate the preclinical incidence rate and the mean sojourn time given the fixed sensitivity. Results: Dense breast tissue was significantly associated with breast cancer incidence [relative risk (RR) = 1.57 (1.18-1.67)] and with breast cancer mortality [RR = 1.91 (1.26-2.91)] after adjusting for other risk factors. Cumulative incidence rates irrespective of nonadvanced and advanced breast cancer were higher in dense breast tissue compared with nondense tissue but no difference in survival was detected between dense and nondense breast tissue. Dense breast tissue had a higher preclinical incidence rate (causal effect) and shorter mean sojourn time (masking effect) compared with nondense breast tissue by controlling the sensitivity of mammography. Conclusion: We corroborated the effect of baseline breast density with a higher incidence and mortality and also showed its contribution to a masking effect with long-term follow-up data. Impact: Results suggest that the screening policy with a predominantly shorter screening interval and with alternative imaging techniques might be indicated in women with dense breast tissue. Cancer Epidemiol Biomarkers Prev; 19(5); 1219–28. ©2010 AACR.

Breast cancer multifocality, disease extent, and survival

The prognostic information implied in subgross morphologic parameters such as lesion distribution (unifocal, multifocal, or diffuse) and disease extent in breast cancer has remained largely unexplored in the literature. We aimed to test whether these parameters influence survival in breast carcinoma. The parameters were assessed in a series of 574 cases, all documented in large-format histology sections. We used Cox proportional hazards regression accompanied by Kaplan-Meyer survival curves, with P < .05 regarded as significant. The invasive component was unifocal in 62% (311/499), multifocal in 24% (122/499), and diffuse in 5% (26/499) of the cases. Combining the in situ and invasive tumor components resulted in 48% (274/574) unifocal, 25% (141/574) multifocal, and 20% (117/574) diffuse tumors. Sixty percent (347/574) of the tumors were categorized as having limited extent (occupying an area <40 mm in largest dimension) and 29% (164/574) as extensive. Highly significant (P < .0001) differences were observed in 10-year disease-specific cumulative survival among the cases with unifocal, multifocal, and diffuse invasive (89.6%, 76.0%, and 63.6%, respectively) and combined (92.3%, 82.3%, and 75.7%, respectively) lesion distribution. Patients with extensive tumors exhibited a significantly lower cumulative survival (P < .0001) compared with those with limited extent (91.6% and 75.5%) and a statistically significantly 1.89-fold (95% confidence interval, 1.07-3.37; P = .03) risk for breast cancer death after controlling for tumor attributes, type of surgery, and adjuvant therapy. The hazard ratio for breast cancer death for mutifocal and/or diffuse tumors versus unifocal ones was 1.96 (95%; 1.11-3.48; P = .02) after controlling for the same factors. Lesion distribution and disease extent represent important independent survival-related prognostic parameters in breast carcinoma.

Difference in Performance of Fecal Immunochemical Tests With the Same Hemoglobin Cutoff Concentration in a Nationwide Colorectal Cancer Screening Program

BACKGROUND & AIMS We investigated whether 2 quantitative fecal immunochemical tests (FITs) with the same cutoff concentration of fecal hemoglobin perform equivalently in identifying patients with colorectal cancer (CRC). METHODS A total of 956,005 Taiwanese subjects, 50 to 69 years old, participated in a nationwide CRC screening program to compare results from 2 FITs; 78% were tested using the OC-Sensor (n = 747,076; Eiken Chemical Co, Tokyo, Japan) and 22% were tested using the HM-Jack (n = 208,929; Kyowa Medex Co Ltd, Tokyo, Japan), from 2004 through 2009. The cutoff concentration for a positive finding was 20 μg hemoglobin/g feces, based on a standardized reporting unit system. The tests were compared using short-term and long-term indicators of performance. RESULTS The OC-Sensor test detected CRC in 0.21% of patients, with a positive predictive value of 6.8%. The HM-Jack test detected CRC in 0.17% of patients, with a positive predictive value of 5.2%. The rate of interval cancer rate was 30.7/100,000 person-years among subjects receiving the OC-Sensor test and 40.6/100,000 person-years among those receiving the HM-Jack test; there was significant difference in test sensitivity (80% vs 68%, P = .005) that was related to the detectability of proximal CRC. After adjusting for differences in city/county, age, sex, ambient temperature, and colonoscopy quality, significant differences were observed between the tests in the positive predictive value for cancer detection (adjusted relative risk = 1.29; 95% confidence interval, 1.14-1.46) and the rates of interval cancer (0.75; 95% confidence interval, 0.62-0.92). Although each test was estimated to reduce CRC mortality by approximately 10%, no significant difference in mortality was observed when the 2 groups were compared. CONCLUSIONS Different brands of quantitative FITs, even with the same cutoff hemoglobin concentration, perform differently in mass screening. Population-level data should be gathered to verify the credibility of quantitative laboratory findings.

Effectiveness of fecal immunochemical testing in reducing colorectal cancer mortality from the One Million Taiwanese Screening Program

The effectiveness of fecal immunochemical testing (FIT) in reducing colorectal cancer (CRC) mortality has not yet been fully assessed in a large, population‐based service screening program.

Baseline faecal occult blood concentration as a predictor of incident colorectal neoplasia: longitudinal follow-up of a Taiwanese population-based colorectal cancer screening cohort

BACKGROUND Despite widespread use of the immunochemical faecal occult blood test (iFOBT), little is known about the subsequent risk of developing colorectal neoplasia for participants with negative iFOBT results. We investigated whether the concentration of faecal haemoglobin at the first screen is predictive of the subsequent incidence of colorectal neoplasia in those with a negative screening result. METHODS Between 2001 and 2007, we did a prospective cohort study within the Keelung community-based iFOBT screening programme for residents aged 40-69 years, using a cutoff faecal haemoglobin concentration of 100 ng/mL to classify attendees as negative and positive groups for further clinical investigations. 44,324 participants with negative findings and 1668 with a positive result at the first screen (854 non-referrals who refused colonoscopy and 814 with a false-positive result as assessed by colonoscopy) were followed up to ascertain cases of colorectal neoplasia. We investigated the association between baseline faecal haemoglobin concentration and risk of incident colorectal neoplasia, after adjusting for possible confounders. FINDINGS Median follow-up was 4·39 years (IQR 2·53-6·12) for all 45 992 participants, during which the incidence of colorectal neoplasia increased from 1·74 per 1000 person-years for those with baseline faecal haemoglobin concentration 1-19 ng/mL, to 7·08 per 1000 person-years for those with a baseline concentration of 80-99 ng/mL. The adjusted hazard ratios (HRs) increased from 1·43 (95% CI 1·08-1·88) for baseline faecal haemoglobin concentration of 20-39 ng/mL, to 3·41 (2·02-5·75) for a baseline concentration of 80-99 ng/mL (trend test p<0·0001), relative to 1-19 ng/mL. These results did not change when we included repeated iFOBT measurements. Non-referrals had the highest risk of incident colorectal neoplasia (adjusted HR 8·46 [6·08-11·76]). INTERPRETATION Quantitative faecal haemoglobin concentration at first screening predicts subsequent risk of incident colorectal neoplasia. During follow-up, risk stratification based on faecal haemoglobin could help clinicians, with particular attention being paid to those with higher initial faecal haemoglobin concentrations, especially those just under the threshold taken to indicate presence of colorectal neoplasia. FUNDING None.

Insights from the Breast Cancer Screening Trials: How Screening Affects the Natural History of Breast Cancer and Implications for Evaluating Service Screening Programs

It is desirable to have a strategy for evaluation of breast cancer service screening programs years before the long‐term breast cancer mortality data are available. Since successful mammography screening has a significant impact on two components of the TNM (tumor size, node status, presence or absence of distant metastases) classification system, tumor size and node status, we investigated the effect of the randomized breast screening trials on incidence of advanced stage disease and on the subsequent breast cancer death rate. In the trials that achieved a 20% or greater reduction in advanced stage disease, there was an average breast cancer mortality reduction of 28% among women invited to screening (attenders and nonattenders combined). In the trials that achieved a reduction in advanced stage disease of less than 10%, there was no reduction in breast cancer mortality among women invited to screening. This study provides evidence that the average mortality reduction in all the trials underestimates the true mortality reduction, and that substantially greater breast cancer mortality reductions can be expected in screening programs that are effective in reducing advanced stage breast cancer. In addition, monitoring the incidence of advanced stage breast cancer in an ongoing screening program can provide a sensitive and early indicator of the subsequent mortality from the disease.

Evaluation of abdominal ultrasonography mass screening for hepatocellular carcinoma in Taiwan

Mass screening with abdominal ultrasonography (AUS) has been suggested as a tool to control adult hepatocellular carcinoma (HCC) in individuals, but its efficacy in reducing HCC mortality has never been demonstrated. This study aimed to assess the effectiveness of reducing HCC mortality by mass AUS screening for HCC based on a program designed and implemented in the Changhua Community‐based Integrated Screening (CHCIS) program with an efficient invitation scheme guided by the risk score. We invited 11,114 (27.0%) of 41,219 eligible Taiwanese subjects between 45 and 69 years of age who resided in an HCC high‐incidence area to attend a risk score‐guided mass AUS screening between 2008 and 2010. The efficacy of reducing HCC mortality was estimated. Of the 8,962 AUS screening attendees (with an 80.6% attendance rate), a total of 16 confirmed HCC cases were identified through community‐based ultrasonography screening. Among the 16 screen‐detected HCC cases, only two died from HCC, indicating a favorable survival. The cumulative mortality due to HCC (per 100,000) was considerably lower in the invited AUS group (17.26) compared with the uninvited AUS group (42.87) and the historical control group (47.51), yielding age‐ and gender‐adjusted relative mortality rates of 0.69 (95% confidence interval [CI]: 0.56‐0.84) and 0.63 (95% CI: 0.52‐0.77), respectively. Conclusion: The residents invited to community‐based AUS screening for HCC, compared with those who were not invited, showed a reduction in HCC mortality by ∼31% among subjects aged 45‐69 years who had not been included in the nationwide vaccination program against hepatitis B virus infection. (Hepatology 2014;59:1840–1849)

Long‐term incidence of breast cancer by trial arm in one county of the Swedish Two‐County Trial of mammographic screening

This study estimated the excess incidence (overdiagnosis) of breast cancer associated with starting mammographic screening at an earlier age, by using data from the Dalarna County component of the Swedish Two‐County Trial of breast cancer screening.

Impact of faecal haemoglobin concentration on colorectal cancer mortality and all-cause death

Objective To assess the effect of an incremental increase in faecal haemoglobin (f-Hb) concentration on colorectal cancer (CRC) mortality and all-cause death. Design We conducted an observational study of cohorts over time based on two population-based CRC screening programmes. Setting Two cities of Taiwan. Participants 1233 individuals with CRC (217 prevalent cases and 1016 incident cases) and 2640 with colorectal adenoma (1246 prevalent cases and 1394 incident cases) found in the two cohorts of 59 767 and 125 976 apparently healthy individuals, aged 40 years and above, who had been invited to participate in screening since 2001 and 2003, respectively. Main outcome measures Death from CRC and all-cause death ascertained by following up from the entire two cohorts over time until 2009. Results The effect of an incremental increase in f-Hb on the risk for CRC mortality was noted, increasing from a slightly increased risk for the category of f-Hb of 20–49 ng Hb/mL (adjusted HR (aHR)=1.09; 95% CI 0.68 to 1.75) to 11.67 (95% CI 7.71 to 17.66) for the group with f-Hb≥450 ng Hb/mL as compared with the group considered baseline with f-Hb of 1–19 ng Hb/mL (p<0.001). A similar but less marked increasing trend was found for all-cause mortality, aHR increasing from 1.15 (95% CI 1.07 to 1.24) for the group with f-Hb of 20–49 ng Hb/mL to 1.67 (95% CI 1.54 to 2.07) for the group with f-Hb≥450 ng Hb/mL. Conclusions We substantiated the impacts of an incremental increase in f-Hb on the risk for death from CRC and all-cause death, consistently showing a significant gradient relationship. Both discoveries suggest that f-Hb may not only make contribution to facilitating individually tailored screening for CRC but also can be used as a significant predictor for life expectancy.