Effect of Breast Screening Regimen on Breast Cancer Outcomes: A Modeling Study.

Guidelines vary for the age at which to begin breast cancer screening and the interval between examinations. A validated computer model was used to compare estimated outcomes between various screening regimens. The OncoSim-Breast microsimulation model (Canadian Partnership Against Cancer) was used to simulate a cohort of 1.53 million Canadian women born in 1975. The effect of screening regimen on absolute breast cancer mortality rates, stage at diagnosis, number needed to be screened to avert a breast cancer death or save a life year, abnormal recall rates and negative biopsy rates was examined for unscreened women or those entering screening at age 40 or 50 and screened annually or biennially to age 74. Compared to no screening, absolute mortality reduction was 4.6 (biennial 50-74), 5.9 (biennial 40-74) and 7.9 (annual 40-74) fewer deaths per 1000 women. The absolute rate of diagnosis of advanced cancers (Stage 2, 3 and 4) falls in favor of earlier stages as the number of lifetime screens increases. Annual screening beginning at age 40 until age 74 would provide an additional reduction of 2 and 3.3 breast cancer deaths per 1000 women compared to biennial screening beginning at ages 40 and 50, respectively. There is a corresponding drop in the absolute number of Stage 2, 3 and 4 cancers diagnosed.

Audit of data from examination image headers collected for quality assurance in the ECOG-ACRIN EA1151 tomosynthesis mammographic imaging screening trial (TMIST).

PURPOSE: A comprehensive, centrally-monitored physics quality control (QC) program was developed for the Tomosynthesis Imaging Screening Trial (TMIST), a randomized controlled trial of digital breast tomosynthesis (TM) versus digital mammography (DM) for cancer screening. As part of the program, in addition to a set of phantom-based tests, de-identified data on image acquisition and processing parameters were captured from the DICOM headers of all individual patient images in the trial. These data were analyzed to assess the potential usefulness of header data from digital mammograms and tomosynthesis images of patients for quality assurance in breast imaging. METHODS: Data were automatically extracted from the headers of all de-identified patient mammograms and tomosynthesis images in the TMIST study. Image acquisition parameters and estimated radiation doses were tracked for individual sites, systems and across system types. These parameters included (among others) kV, target/filter use, number of acquired views per examination, AEC mode, compression thickness and force and detector temperature. Consistency of manually entered study data parameters (subject ID, screening time-point) from TMIST was evaluated. Preliminary observations from the program are presented. RESULTS: We report on data from 812 651 images from 135 525 examinations acquired between October, 2017 and December, 2022. Data came from 6 system models from 3 manufacturers. There was greater variability both in the number of views used and in the estimated (proxy) doses received in DM exams compared to TM. Mean proxy doses per examination varied among manufacturers from 2.76-4.54 mGy for DM and 3-4.84 mGy for the tomosynthesis component in the TM arm with maximum examination proxy doses of 20 and 26 mGy for DM and TM respectively. Mean proxy doses per examination for the combination examination in TM (tomosynthesis plus digital mammography) varied from 6.6 to 7.6 mGy among manufacturers with a maximum of 44.5 mGy. CONCLUSIONS: Overall, modern digital mammography and tomosynthesis systems used in TMIST have operated very reliably. Doses vary considerably due to variation in the number of views per examination, thickness and fibro-glandularity of the breast, and choices in the use of synthesized versus actual 2D mammography in the TM examination. These data may also be useful in predicting equipment problems. Header information is valuable not only for automated QC, but also for cross-checking accuracy and consistency of data in a clinical study.

Quality control for digital tomosynthesis in the ECOG-ACRIN EA1151 TMIST trial.

BACKGROUND: The Tomosynthesis Mammography Imaging Screening Trial (TMIST), EA1151 conducted by the Eastern Cooperative Oncology Group (ECOG)/American College of Radiology Imaging Network (ACRIN) is a randomized clinical trial designed to assess the effectiveness for breast cancer screening of digital breast tomosynthesis (TM) compared to digital mammography (DM). Equipment from multiple vendors is being used in the study. PURPOSE: For the findings of the study to be valid and capture the true capacities of the two technology types, it is important that all equipment is operated within appropriate parameters with regard to image quality and dose. A harmonized QC program was established by a core physics team. Since there are over 120 trial sites, a centralized, automated QC program was chosen as the most practical design. This report presents results of the weekly QC testing program. A companion paper will review quality monitoring based on data from the headers of the patient images. METHODS: Study images are collected centrally after de-identification using the "TRIAD" application developed by ACR. The core physics team devised and implemented a minimal set of quality control (QC) tests to evaluate the tomosynthesis and 2D mammography systems. Weekly, monthly and annual testing is performed by the site mammography technologists with images submitted directly to the physics core. The weekly physics QC tests are described: SDNR of a low-contrast mass object, artifact spread, spatial resolution, tracking of technical factors, and in-slice noise power spectra. RESULTS: As of December 31, 2022 (5 years), 145 sites with 411 machines had submitted QC data. A total of 136 742 TMIST participant screening imaging studies had been performed. The 5th and 95th percentile mean glandular doses for a single tomosynthesis exposure to a 4.0 cm thick PMMA phantom ("standard breast phantom") were 1.24 and 1.68 mGy respectively. The largest sources of QC non-conformance were: operator error, not following the QC protocol exactly, unreported software updates and preventive maintenance activities that affected QC setpoints. Noise power spectra were measured, however, standardization of performance targets across machine types and software revisions was difficult. Nevertheless, for each machine type, test measurement results were very consistent when the protocol was followed. Deviations in test results were mostly related to software and hardware changes. CONCLUSION: Most systems performed very consistently. Although this is a harmonized program using identical phantoms and testing protocols, it is not appropriate to apply universal threshold or target metrics across the machine types because the systems have different non-linear reconstruction algorithms and image display filters. It was found to be more useful to assess pass/fail criteria in terms of relative deviations from baseline values established when a system is first characterized and after equipment is changed. Generally, systems which needed repair failed suddenly, but in retrospect, for a few cases, drops in SDNR and increases in mAs were observed prior to tube failure. TMIST is registered as NCT03233191 by Clinicaltrials.gov.

Correction for Self-Selection in Breast Cancer Screening. Comment on Dibden et al. Worldwide Review and Meta-Analysis of Cohort Studies Measuring the Effect of Mammography Screening Programmes on Incidence-Based Breast Cancer Mortality. Cancers 2020, 12, 976.

Observational studies of cancer screening are subject to bias associated with the self-selection of screening participants for whom the underlying probability of cancer death may be different from those who do not participate. Dibden et al. reviewed data on mortality reduction from 27 observational studies of mammography screening expressed in terms of relative risk for women who were screened versus not screened. Results were given, both unadjusted and after application of a correction for self-selection. The correction was based on a constant (1.17)-the ratio of risks of death in screening non-attenders versus those not invited, derived from a Swedish study. For some of the studies this correction had a large effect in diminishing the measured mortality benefit associated with screening. In particular, application to The Pan-Canadian Study of Mammography Screening, a study whose authors had previously tested for and found no evidence of self-selection bias, caused the estimated benefit to decrease from 40% to 10%. The appropriateness of applying a correction based on a constant to a population whose healthcare environment and screening participation rates are very different from those from which it was derived is questionable.

Capturing the True Cost of Breast Cancer Treatment: Molecular Subtype and Stage-Specific per-Case Activity-Based Costing.

BACKGROUND: Breast cancer (BC) treatment is rapidly evolving with new and costly therapeutics. Existing costing models have a limited ability to capture current treatment costs. We used an Activity-Based Costing (ABC) method to determine a per-case cost for BC treatment by stage and molecular subtype. METHODS: ABC was used to proportionally integrate multidisciplinary evidence-based patient and provider treatment options for BC, yielding a per-case cost for the total duration of treatment by stage and molecular subtype. Diagnostic imaging, pathology, surgery, radiation therapy, systemic therapy, inpatient, emergency, home care and palliative care costs were included. RESULTS: BC treatment costs were higher than noted in previous studies and varied widely by molecular subtype. Cost increased exponentially with the stage of disease. The per-case cost for treatment (2023C$) for DCIS was C$ 14,505, and the mean costs for all subtypes were C$ 39,263, C$ 76,446, C$ 97,668 and C$ 370,398 for stage I, II, III and IV BC, respectively. Stage IV costs were as high as C$ 516,415 per case. When weighted by the proportion of molecular subtype in the population, case costs were C$ 31,749, C$ 66,758, C$ 111,368 and C$ 289,598 for stage I, II, III and IV BC, respectively. The magnitude of cost differential was up to 10.9 times for stage IV compared to stage I, 4.4 times for stage III compared to stage I and 35.6 times for stage IV compared to DCIS. CONCLUSION: The cost of BC treatment is rapidly escalating with novel therapies and increasing survival, resulting in an exponential increase in treatment costs for later-stage disease. We provide real-time, case-based costing for BC treatment which will allow for the assessment of health system economic impacts and an accurate understanding of the cost-effectiveness of screening.

Examination of fully automated mammographic density measures using LIBRA and breast cancer risk in a cohort of 21,000 non-Hispanic white women.

BACKGROUND: Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on associations with long-term breast cancer risk are limited. We examined LIBRA assessments and breast cancer risk and compared results to prior assessments using Cumulus, an established computer-assisted method requiring manual thresholding. METHODS: We conducted a cohort study among 21,150 non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were 40-74 years at enrollment, followed for up to 10 years, and had archived processed screening mammograms acquired on Hologic or General Electric full-field digital mammography (FFDM) machines and prior Cumulus density assessments available for analysis. Dense area (DA), non-dense area (NDA), and percent density (PD) were assessed using LIBRA software. Cox regression was used to estimate hazard ratios (HRs) for breast cancer associated with DA, NDA and PD modeled continuously in standard deviation (SD) increments, adjusting for age, mammogram year, body mass index, parity, first-degree family history of breast cancer, and menopausal hormone use. We also examined differences by machine type and breast view. RESULTS: The adjusted HRs for breast cancer associated with each SD increment of DA, NDA and PD were 1.36 (95% confidence interval, 1.18-1.57), 0.85 (0.77-0.93) and 1.44 (1.26-1.66) for LIBRA and 1.44 (1.33-1.55), 0.81 (0.74-0.89) and 1.54 (1.34-1.77) for Cumulus, respectively. LIBRA results were generally similar by machine type and breast view, although associations were strongest for Hologic machines and mediolateral oblique views. Results were also similar during the first 2 years, 2-5 years and 5-10 years after the baseline mammogram. CONCLUSION: Associations with breast cancer risk were generally similar for LIBRA and Cumulus density measures and were sustained for up to 10 years. These findings support the suitability of fully automated LIBRA assessments on processed FFDM images for large-scale research on breast density and cancer risk.

Targeting tumour-associated macrophages in hodgkin lymphoma using engineered extracellular matrix-mimicking cryogels.

Tumour-associated macrophages are linked with poor prognosis and resistance to therapy in Hodgkin lymphoma; however, there are no suitable preclinical models to identify macrophage-targeting therapeutics. We used primary human tumours to guide the development of a mimetic cryogel, wherein Hodgkin (but not Non-Hodgkin) lymphoma cells promoted primary human macrophage invasion. In an invasion inhibitor screen, we identified five drug hits that significantly reduced tumour-associated macrophage invasion: marimastat, batimastat, AS1517499, ruxolitinib, and PD-169316. Importantly, ruxolitinib has demonstrated recent success in Hodgkin lymphoma clinical trials. Both ruxolitinib and PD-169316 (a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor) decreased the percent of M2-like macrophages; however, only PD-169316 enhanced the percentage of M1-like macrophages. We validated p38 MAPK as an anti-invasion drug target with five additional drugs using a high-content imaging platform. With our biomimetic cryogel, we modeled macrophage invasion in Hodgkin lymphoma and then used it for target discovery and drug screening, ultimately identifying potential future therapeutics.

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop.

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.

Effects of ionizing radiation exposure during pregnancy.

PURPOSE: To review the effects of ionizing radiation to the conceptus and the relationship to the timing of the exposure during pregnancy. To consider strategies that would mitigate potential harms associated with exposure to ionizing radiation during pregnancy. METHODS: Data reported in the peer-reviewed literature on entrance KERMA received from specific radiological examinations were combined with published results from experiment or Monte Carlo modeling of tissue and organ doses per entrance KERMA to estimate total doses that could be received from specific procedures. Data reported in the peer-reviewed literature on dose mitigation strategies, best practices for shielding, consent, counseling and emerging technologies were reviewed. RESULTS: For procedures utilizing ionizing radiation for which the conceptus is not included in the primary radiation beam, typical doses are well below the threshold for causing tissue reactions and the risk of induction of childhood cancer is low. For procedures that include the conceptus in the primary radiation field, longer fluoroscopic interventional procedures or multiphase/multiple exposures potentially could approach or exceed thresholds for tissue reactions and the risk of cancer induction must be weighed against the expected risk/benefit of performing (or not) the imaging examination. Gonadal shielding is no longer considered best practice. Emerging technologies such as whole-body DWI/MRI, dual-energy CT and ultralow dose studies are gaining importance for overall dose reduction strategies. CONCLUSION: The ALARA principle, considering potential benefits and risks should be followed with respect to the use of ionizing radiation. Nevertheless, as Wieseler et al. (2010) state, "no examination should be withheld when an important clinical diagnosis is under consideration." Best practices require updates on current available technologies and guidelines.

Digital mammography: The excitement of creating a new imaging modality.

Beginning around 1972 with the introduction of CT, a steady transition from analog to digital imaging in radiology took place. Here, I offer a personal perspective of the exciting multi-institutional and multidisciplinary team effort of developing digital mammography. That effort required the collaboration of visionary individuals in academic research labs, industry, and the clinical arena, catalyzed by a focused commitment from government (NCI and The Office of Women's Health). This collaboration greatly accelerated the timeline from laboratory prototypes to clinical systems and evaluation, resulting in a new imaging modality and, later, several spinoff applications (CAD, contrast-enhanced mammography, tomosynthesis) that provide improved earlier detection of breast cancer.