Laia Domingo

Cost-effectiveness and harm-benefit analyses of risk-based screening strategies for breast cancer

The one-size-fits-all paradigm in organized screening of breast cancer is shifting towards a personalized approach. The present study has two objectives: 1) To perform an economic evaluation and to assess the harm-benefit ratios of screening strategies that vary in their intensity and interval ages based on breast cancer risk; and 2) To estimate the gain in terms of cost and harm reductions using risk-based screening with respect to the usual practice. We used a probabilistic model and input data from Spanish population registries and screening programs, as well as from clinical studies, to estimate the benefit, harm, and costs over time of 2,624 screening strategies, uniform or risk-based. We defined four risk groups, low, moderate-low, moderate-high and high, based on breast density, family history of breast cancer and personal history of breast biopsy. The risk-based strategies were obtained combining the exam periodicity (annual, biennial, triennial and quinquennial), the starting ages (40, 45 and 50 years) and the ending ages (69 and 74 years) in the four risk groups. Incremental cost-effectiveness and harm-benefit ratios were used to select the optimal strategies. Compared to risk-based strategies, the uniform ones result in a much lower benefit for a specific cost. Reductions close to 10% in costs and higher than 20% in false-positive results and overdiagnosed cases were obtained for risk-based strategies. Optimal screening is characterized by quinquennial or triennial periodicities for the low or moderate risk-groups and annual periodicity for the high-risk group. Risk-based strategies can reduce harm and costs. It is necessary to develop accurate measures of individual risk and to work on how to implement risk-based screening strategies.

Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screening in Spain

IntroductionInterval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories.MethodsWe included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd’s scale and was conflated into: <25%; 25 to 50%; 50 to 75%; >75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided.ResultsForty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (<25%) than in denser breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; <0.001). False-negatives and occult tumors had similar phenotypic characteristics to screening-detected cancers, extreme breast density being strongly associated with occult tumors (OR = 6.23 (95% CI:2.65-14.66)). Minimal-sign cancers were biologically close to true interval cancers but showed no association with breast density.ConclusionsOur findings revealed that both the distribution of tumor phenotype and breast density play specific and independent roles in each category of interval cancer. Further research is needed to understand the biological basis of the overrepresentation of triple-negative phenotype among predominantly fatty breasts in true interval cancers.

Aggressiveness features and outcomes of true interval cancers: comparison between screen-detected and symptom-detected cancers.

The question of whether screen detection confers an additional survival benefit in breast cancer is unclear and subject to several biases. Our aim was to examine the role of the diagnostic method (screen-detected, symptom-detected, and true interval cancers) and the clinical–pathological features in relapse-free survival and overall survival in breast cancer patients. We included 228 invasive breast cancers diagnosed in Barcelona from 1996 to 2008 among women aged 50–69 years. Ninety-seven patients were screen detected within the screening, 34 truly arose between 2-year screening mammograms (true interval cancers), and 97 were symptom detected outside the screening. The clinical–pathological features at diagnosis were compared. The overall and disease-free survival probabilities were computed using the Kaplan–Meier method. Cox proportional hazard models were applied, with adjustment by clinical–pathological variables. At diagnosis, symptom-detected and true interval cancers were in more advanced stages and were less differentiated. The highest proportion of triple-negative cancers was detected among true interval cancers (P=0.002). At 5 years of follow-up, the disease-free survival rates for screen-detected, true interval, and symptom-detected cancers were 87.5% (95% confidence interval, 80.5–95.2%), 64.1% (46.4–88.5%), and 79.4% (71.0–88.8%), respectively, and the overall survival rates were 94.5% (89.3–99.9%), 65.5% (47.1–91.2%), and 85.6% (78.3–93.6%), respectively. True interval cancers had the highest hazard ratio for relapse prediction (1.89; 0.67–5.31) and a hazard ratio of death of 5.55 (1.61–19.15) after adjustment for tumor–node–metastasis stage and phenotype. Clinically detected tumors, especially true interval cancers, more frequently showed biological features related to worse prognosis and were associated with poorer survival even after adjustment for clinical–pathological characteristics.

Mammographic and clinical characteristics of different phenotypes of screen-detected and interval breast cancers in a nationwide screening program

In the context of a population-based screening program, we aimed to evaluate the major mammographic features and clinicopathological characteristics of breast tumors at diagnosis and the associations between them, focusing on tumors with the worst prognosis. We analyzed cancers diagnosed in a cohort of 645,764 women aged 45–69 years participating in seven population-based screening programs in Spain, between January 1, 2000 and December 31, 2006 and followed up until June 2009. We included all interval cancers and a sample of screen-detected cancers, whether invasive or in situ. We compared tumor-related information and breast density for different phenotypes (Triple-negative (TN), HER2+, Luminal B and Luminal A) in screen-detected and interval cancers. We used Chi-square or Fisher’s exact test to compare major mammographic features of invasive versus in situ tumors, of screen-detected versus interval cancers, and of different types of interval cancers. We included 2582 tumors (1570 screen-detected and 1012 interval cancers). There were significant differences in the distribution of most clinicopathological variables between screen-detected and interval cancers. Invasive TN interval tumors were more common than other phenotypes in breasts with low mammographic density; three-quarters of these tumors presented as masses without associated calcifications. HER2+ tumors were more common in denser breasts and were associated with calcifications and multifocality. Architectural distortion was more common in Luminal A and Luminal B tumors. Certain radiologic findings are associated with pre-invasive lesions; these differ among invasive tumor phenotypes. We corroborate that TN and HER2+ cancers have distinctive appearances also in the context of population-based screening programs. This information can be useful for establishing protocols for diagnostic strategies in screening units.

Impact of Risk Factors on Different Interval Cancer Subtypes in a Population-Based Breast Cancer Screening Programme

Background Interval cancers are primary breast cancers diagnosed in women after a negative screening test and before the next screening invitation. Our aim was to evaluate risk factors for interval cancer and their subtypes and to compare the risk factors identified with those associated with incident screen-detected cancers. Methods We analyzed data from 645,764 women participating in the Spanish breast cancer screening program from 2000–2006 and followed-up until 2009. A total of 5,309 screen-detected and 1,653 interval cancers were diagnosed. Among the latter, 1,012 could be classified on the basis of findings in screening and diagnostic mammograms, consisting of 489 true interval cancers (48.2%), 235 false-negatives (23.2%), 172 minimal-signs (17.2%) and 114 occult tumors (11.3%). Information on the screening protocol and womens characteristics were obtained from the screening program registry. Cause-specific Cox regression models were used to estimate the hazard ratios (HR) of risks factors for interval cancer and incident screen-detected cancer. A multinomial regression model, using screen-detected tumors as a reference group, was used to assess the effect of breast density and other factors on the occurrence of interval cancer subtypes. Results A previous false-positive was the main risk factor for interval cancer (HR = 2.71, 95%CI: 2.28–3.23); this risk was higher for false-negatives (HR = 8.79, 95%CI: 6.24–12.40) than for true interval cancer (HR = 2.26, 95%CI: 1.59–3.21). A family history of breast cancer was associated with true intervals (HR = 2.11, 95%CI: 1.60–2.78), previous benign biopsy with a false-negatives (HR = 1.83, 95%CI: 1.23–2.71). High breast density was mainly associated with occult tumors (RRR = 4.92, 95%CI: 2.58–9.38), followed by true intervals (RRR = 1.67, 95%CI: 1.18–2.36) and false-negatives (RRR = 1.58, 95%CI: 1.00–2.49). Conclusion The role of womens characteristics differs among interval cancer subtypes. This information could be useful to improve effectiveness of breast cancer screening programmes and to better classify subgroups of women with different risks of developing cancer.

Risk of Breast Cancer in Women with False-Positive Results according to Mammographic Features

Purpose To assess the risk of breast cancer in women with false-positive screening results according to radiologic classification of mammographic features. Materials and Methods Review board approval was obtained, with waiver of informed consent. This retrospective cohort study included 521 200 women aged 50-69 years who underwent screening as part of the Spanish Breast Cancer Screening Program between 1994 and 2010 and who were observed until December 2012. Cox proportional hazards regression analysis was used to estimate the age-adjusted hazard ratio (HR) of breast cancer and the 95% confidence interval (CI) in women with false-positive mammograms as compared with women with negative mammograms. Separate models were adjusted for screen-detected and interval cancers and for screen-film and digital mammography. Time without a breast cancer diagnosis was plotted by using Kaplan-Meier curves. Results When compared with women with negative mammograms, the age-adjusted HR of cancer in women with false-positive results was 1.84 (95% CI: 1.73, 1.95; P < .001). The risk was higher in women who had calcifications, whether they were (HR, 2.73; 95% CI: 2.28, 3.28; P < .001) or were not (HR, 2.24; 95% CI: 2.02, 2.48; P < .001) associated with masses. Women in whom mammographic features showed changes in subsequent false-positive results were those who had the highest risk (HR, 9.13; 95% CI: 8.28, 10.07; P < .001). Conclusion Women with false-positive results had an increased risk of breast cancer, particularly women who had calcifications at mammography. Women who had more than one examination with false-positive findings and in whom the mammographic features changed over time had a highly increased risk of breast cancer. Previous mammographic features might yield useful information for further risk-prediction models and personalized follow-up screening protocols. (©) RSNA, 2016 Online supplemental material is available for this article.

Gene Expression Profiling in True Interval Breast Cancer Reveals Overactivation of the mTOR Signaling Pathway

Background: The development and progression of true interval breast cancers (tumors that truly appear after a negative screening mammogram) is known to be different from screen-detected cancers. However, the worse clinical behavior of true interval cancers is not fully understood from a biologic basis. We described the differential patterns of gene expression through microarray analysis in true interval and screen-detected cancers. Methods: An unsupervised exploratory gene expression profile analysis was performed on 10 samples (true interval cancers = 5; screen-detected cancers = 5) using Affymetrix Human Gene 1.0ST arrays and interpreted by Ingenuity Pathway Analysis. Differential expression of selected genes was confirmed in a validation series of 91 tumors (n = 12; n = 79) by immunohistochemistry and in 24 tumors (n = 8; n = 16) by reverse transcription quantitative PCR (RT-qPCR), in true interval and screen-detected cancers, respectively. Results: Exploratory gene expression analysis identified 1,060 differentially expressed genes (unadjusted P < 0.05) between study groups. On the basis of biologic implications, four genes were further validated: ceruloplasmin (CP) and ribosomal protein S6 kinase, 70 kDa, polypeptide 2 (RPS6KB2), both upregulated in true interval cancers; and phosphatase and tensin homolog (PTEN) and transforming growth factor beta receptor III (TGFBR3), downregulated in true interval cancers. Their differential expression was confirmed by RT-qPCR and immunohistochemistry, consistent with mTOR pathway overexpression in true interval cancers. Conclusions: True interval and screen-detected cancers show differential expression profile both at gene and protein levels. The mTOR signaling is significantly upregulated in true interval cancers, suggesting this pathway may mediate their aggressiveness. Impact: Linking epidemiologic factors and mTOR activation may be the basis for future personalized screening strategies in women at risk of true interval cancers. Cancer Epidemiol Biomarkers Prev; 23(2); 288–99. ©2013 AACR.

Clinical and radiological features of breast tumors according to history of false-positive results in mammography screening.

BACKGROUND Women with a false-positive result after a screening mammogram have an increased risk of cancer detection in subsequent participations, especially after assessments involving cytology or biopsy. We aimed to compare womens personal characteristics, tumoral features and the radiological appearance of cancers with and without a previous false-positive result generated by additional imaging or invasive procedures. METHODS From 1996 to 2007, 111,098 women aged 45-69 years participated in four population-based breast cancer screening programs in Spain, and 1281 cancers were detected. We included all cancers detected in subsequent screenings (n=703) and explored the occurrence of previous false-positive results. We identified false-positives requiring additional imaging or invasive procedures. Differences on tumoral features (invasiveness, tumor size, and lymph node status) and radiological appearance were assessed by Chi-square test, and agreement between the location of cancer and prior suspicious by Cohens kappa coefficient. A multivariate analysis was preformed to evaluate the effect of previous screening results and age on the odds of presenting an in situ carcinoma. RESULTS Among the 703 cancers detected in subsequent screenings, 148 women (21.1%) had a previous false-positive result. Of these, 105 were by additional imaging and 43 by invasive procedures. Women with prior false-positive result requiring invasive assessment, compared to women with negative tests, and women with prior false-positive requiring additional imaging, had a higher proportion of in situ carcinomas (31.7%, 15.3%, 12.9%, respectively; p=0.014) and microcalcifications (37.2%, 20.2%, 9.5%, respectively; p=0.003). The proportion of in situ carcinomas was even higher in women over 60 years (39.2%, 12.5%, 13.0%, respectively; p=0.001). Ipsilateral cancer was observed in 65.7% of cases with prior cytology or biopsy (k=0.479; 95%CI: 0.330-0.794). CONCLUSION A large number of in situ malignancies and calcification patterns were found among women with prior false-positive result in mammography screening requiring cytology or biopsies, suggesting progression from a previously benign lesion.

Biomarkers expression in benign breast diseases and risk of subsequent breast cancer: a case–control study

Women with benign breast diseases (BBD) have a high risk of breast cancer. However, no biomarkers have been clearly established to predict cancer in these women. Our aim was to explore whether estrogen receptor (ER), progesterone receptor (PR), and Ki67 expression stratify risk of breast cancer in screened women with BBD. We conducted a nested case–control study. Women with breast cancer and prior BBDs (86 cases) were matched to women with prior BBDs who were free from breast cancer (172 controls). The matching factors were age at BBD diagnosis, type of BBD, and follow‐up time since BBD diagnosis. ER, PR, and Ki67 expression were obtained from BBDs’ specimens. Conditional logistic regression was used to estimate odds ratios (ORs), and 95% confidence intervals (CIs) of breast cancer risk according to ER, PR, and Ki67 expression. Women with >90% of ER expression had a higher risk of breast cancer (OR = 2.63; 95% CI: 1.26–5.51) than women with ≤70% of ER expression. Similarly, women with >80% of PR expression had a higher risk of breast cancer (OR = 2.22; 95% CI: 1.15–4.27) than women with ≤40% of PR expression. Women with proliferative disease and ≥1% of Ki67 expression had a nonsignificantly increased risk of breast cancer (OR = 1.16; 95% CI: 0.46–2.90) than women with <1% of Ki67 expression. A high expression of ER and PR in BBD is associated with an increased risk of subsequent breast cancer. In proliferative disease, high Ki67 expression may also have an increased risk. This information is helpful to better characterize BBD and is one more step toward personalizing the clinical management of these women.

Survival and disease-free survival by breast density and phenotype in interval breast cancers

Background: We aimed to evaluate survival and disease-free survival in different subtypes of interval cancers by breast density, taking into account clinical and biological characteristics. Methods: We included 374 invasive breast tumors (195 screen-detected cancers; 179 interval cancers, classified into true interval, false-negatives, occult tumors and minimal-sign cancers) diagnosed in women ages 50–69 years undergoing biennial screening from 2000–2009, followed up to 2014. Breast density was categorized into non-dense (<25% dense tissue) and mixed dense breasts (≥25%). Survival curves were generated by the Kaplan–Meier method and compared by the log-rank test. Cox proportional hazard regression models were computed to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for death and recurrences by comparing women with interval and true interval cancers versus women with screen-detected cancers, controlling for tumor and patient characteristics. All analyses were stratified by breast density. Results: Interval cancers were detected in younger women, at more advanced stages, in denser breasts and showed a higher proportion of triple-negative cancers, especially among true interval cancers. Women with interval cancer and non-dense breasts had an aHR for death of 3.40 (95% CI, 0.92–12.62). Women with true interval cancers detected in non-dense breasts had the highest adjusted risk of death (aHR, 6.55; 95% CI, 1.37–31.39). Conclusions: Women with true interval cancer in non-dense breasts had a higher risk of death than women with screen-detected cancers. Impact: These results support the advisability of routinely collecting information on breast density, both for further tailoring of screening strategies and as a prognostic factor for diagnosed breast cancers. Cancer Epidemiol Biomarkers Prev; 27(8); 908–16. ©2018 AACR.