Mammographic breast density as a mediator and surrogate marker for breast cancer risk

Women with the highest mammographic density have a four to six-fold increased risk of breast cancer when compared to the ones with the least dense breasts. Mammographic breast density has also been associated with a wide array of factors related to the risk of breast cancer including age, menopausal status, age at first live birth, parity, body mass index, physical activity, alcohol consumption, hormone replacement therapy, endogenous levels of IGF-I and prolactin, family history of breast cancer, tamoxifen use and others. A question of interest is whether mammographic density is in the pathway by which these factors are related to breast cancer. To address this question, we conducted causal mediation analyses on two datasets using a newly developed statistical approach based on the counterfactual framework to examine the extent to which mammographic density acts as a mediator. The first dataset is pooled from four case-control studies performed in the western Washington state, contains 547 breast cancer cases (ascertained from a local Surveillance, Epidemiology, and End Results Program registry) and 472 controls (ascertained by random digit dialing) who had screening mammograms under age 50. The second dataset is from the Mayo Mammography Health Study (MMHS), which is a prospective cohort, comprised of 19,924 women (51.2% adjusted response rate) ages 35 and over, residing in the tri-state region (Minnesota, Iowa, and Wisconsin) surrounding the Mayo Clinic in Rochester, MN, without a history of breast cancer, who were scheduled for a screening mammogram at the Mayo Clinic between October 2003 and September 2006. Previous analyses from these two datasets have shown associations between some breast cancer risk factors and mammographic density. Results showed that mammographic density partially mediated the associations for some breast cancer risk factors such as breast calcifications, being parous, history of breast biopsy/aspiration/lumpectomy, and current use of hormone replacement therapy (HRT), but not factors such as a first-degree family history of breast cancer and age at first live birth, history of smoking, age at menopause. These results help us better understand the pathways and mechanisms whereby a risk factor may cause breast cancer. It also helps inform and refine clinical and public health interventions for breast cancer by assessing the relative importance of different pathways

Mammography

In this volume, the topics are constructed from a variety of contents: the bases of mammography systems, optimization of screening mammography with reference to evidence-based research, new technologies of image acquisition and its surrounding systems, and case reports with reference to up-to-date multimodality images of breast cancer. Mammography has been lagged in the transition to digital imaging systems because of the necessity of high resolution for diagnosis. However, in the past ten years, technical improvement has resolved the difficulties and boosted new diagnostic systems. We hope that the reader will learn the essentials of mammography and will be forward-looking for the new technologies. We want to express our sincere gratitude and appreciation?to all the co-authors who have contributed their work to this volume

Characterising the tumour morphological response to therapeutic intervention:an ex vivo model

In cancer, morphological assessment of histological tissue samples is a fundamental part of both diagnosis and prognosis. Image analysis offers opportunities to support that assessment through quantitative metrics of morphology. Generally, morphometric analysis is carried out on two dimensional tissue section data and so only represents a small fraction of any tumour. We present a novel application of three-dimensional (3D) morphometrics for 3D imaging data obtained from tumours grown in a culture model. Minkowski functionals, a set of measures that characterise geometry and topology in n-dimensional space, are used to quantify tumour topology in the absence of and in response to therapeutic intervention. These measures are used to stratify the morphological response of tumours to therapeutic intervention. Breast tumours are characterised by estrogen receptor (ER) status, human epidermal growth factor receptor (HER)2 status and tumour grade. Previously, we have shown that ER status is associated with tumour volume in response to tamoxifen treatment ex vivo. Here, HER2 status is found to predict the changes in morphology other than volume as a result of tamoxifen treatment ex vivo. Finally, we show the extent to which Minkowski functionals might be used to predict tumour grade.Minkowski functionals are generalisable to any 3D data set, including in vivo and cellular systems. This quantitative topological analysis can provide a valuable link among biomarkers, drug intervention and tumour morphology that is complementary to existing, non-morphological measures of tumour response to intervention and could ultimately inform patient treatment

Analyzing the breast tissue in mammograms using deep learning

La densitat mamogràfica de la mama (MBD) reflecteix la quantitat d'àrea fibroglandular del teixit mamari que apareix blanca i brillant a les mamografies, comunament coneguda com a densitat percentual de la mama (PD%). El MBD és un factor de risc per al càncer de mama i un factor de risc per emmascarar tumors. Tot i això, l'estimació precisa de la DMO amb avaluació visual continua sent un repte a causa del contrast feble i de les variacions significatives en els teixits grassos de fons en les mamografies. A més, la interpretació correcta de les imatges de mamografia requereix experts mèdics altament capacitats: És difícil, laboriós, car i propens a errors. No obstant això, el teixit mamari dens pot dificultar la identificació del càncer de mama i associar-se amb un risc més gran de càncer de mama. Per exemple, s'ha informat que les dones amb una alta densitat mamària en comparació amb les dones amb una densitat mamària baixa tenen un risc de quatre a sis vegades més gran de desenvolupar la malaltia. La clau principal de la computació de densitat de mama i la classificació de densitat de mama és detectar correctament els teixits densos a les imatges mamogràfiques. S'han proposat molts mètodes per estimar la densitat mamària; no obstant això, la majoria no estan automatitzats. A més, s'han vist greument afectats per la baixa relació senyal-soroll i la variabilitat de la densitat en aparença i textura. Seria més útil tenir un sistema de diagnòstic assistit per ordinador (CAD) per ajudar el metge a analitzar-lo i diagnosticar-lo automàticament. El desenvolupament actual de mètodes daprenentatge profund ens motiva a millorar els sistemes actuals danàlisi de densitat mamària. L'enfocament principal de la present tesi és desenvolupar un sistema per automatitzar l'anàlisi de densitat de la mama ( tal com; Segmentació de densitat de mama (BDS), percentatge de densitat de mama (BDP) i classificació de densitat de mama (BDC) ), utilitzant tècniques d'aprenentatge profund i aplicant-la a les mamografies temporals després del tractament per analitzar els canvis de densitat de mama per trobar un pacient perillós i sospitós.La densidad mamográfica de la mama (MBD) refleja la cantidad de área fibroglandular del tejido mamario que aparece blanca y brillante en las mamografías, comúnmente conocida como densidad porcentual de la mama (PD%). El MBD es un factor de riesgo para el cáncer de mama y un factor de riesgo para enmascarar tumores. Sin embargo, la estimación precisa de la DMO con evaluación visual sigue siendo un reto debido al contraste débil y a las variaciones significativas en los tejidos grasos de fondo en las mamografías. Además, la interpretación correcta de las imágenes de mamografía requiere de expertos médicos altamente capacitados: Es difícil, laborioso, caro y propenso a errores. Sin embargo, el tejido mamario denso puede dificultar la identificación del cáncer de mama y asociarse con un mayor riesgo de cáncer de mama. Por ejemplo, se ha informado que las mujeres con una alta densidad mamaria en comparación con las mujeres con una densidad mamaria baja tienen un riesgo de cuatro a seis veces mayor de desarrollar la enfermedad. La clave principal de la computación de densidad de mama y la clasificación de densidad de mama es detectar correctamente los tejidos densos en las imágenes mamográficas. Se han propuesto muchos métodos para la estimación de la densidad mamaria; sin embargo, la mayoría de ellos no están automatizados. Además, se han visto gravemente afectados por la baja relación señal-ruido y la variabilidad de la densidad en apariencia y textura. Sería más útil disponer de un sistema de diagnóstico asistido por ordenador (CAD) para ayudar al médico a analizarlo y diagnosticarlo automáticamente. El desarrollo actual de métodos de aprendizaje profundo nos motiva a mejorar los sistemas actuales de análisis de densidad mamaria. El enfoque principal de la presente tesis es desarrollar un sistema para automatizar el análisis de densidad de la mama ( tal como; Segmentación de densidad de mama (BDS), porcentaje de densidad de mama (BDP) y clasificación de densidad de mama (BDC)), utilizando técnicas de aprendizaje profundo y aplicándola en las mamografías temporales después del tratamiento para analizar los cambios de densidad de mama para encontrar un paciente peligroso y sospechoso.Mammographic breast density (MBD) reflects the amount of fibroglandular breast tissue area that appears white and bright on mammograms, commonly referred to as breast percent density (PD%). MBD is a risk factor for breast cancer and a risk factor for masking tumors. However, accurate MBD estimation with visual assessment is still a challenge due to faint contrast and significant variations in background fatty tissues in mammograms. In addition, correctly interpreting mammogram images requires highly trained medical experts: it is difficult, time-consuming, expensive, and error-prone. Nevertheless, dense breast tissue can make it harder to identify breast cancer and be associated with an increased risk of breast cancer. For example, it has been reported that women with a high breast density compared to women with a low breast density have a four- to six-fold increased risk of developing the disease. The primary key of breast density computing and breast density classification is to detect the dense tissues in the mammographic images correctly. Many methods have been proposed for breast density estimation; however, most are not automated. Besides, they have been badly affected by low signal-to-noise ratio and variability of density in appearance and texture. It would be more helpful to have a computer-aided diagnosis (CAD) system to assist the doctor analyze and diagnosing it automatically. Current development in deep learning methods motivates us to improve current breast density analysis systems. The main focus of the present thesis is to develop a system for automating the breast density analysis ( such as; breast density segmentation(BDS), breast density percentage (BDP), and breast density classification ( BDC)), using deep learning techniques and applying it on the temporal mammograms after treatment for analyzing the breast density changes to find a risky and suspicious patient

Determinants of interval cancer and tumor size among breast cancer screening participants

Breast cancer is the most common cancer of women in Sweden and globally. In the more affluent countries, mammography screening has been in place for a few decades and has successfully reduced mortality. However, there is increasing interest in enhancing the impact of screening by going from the current age-based screening system to a risk-based system. There are two risk components that must be taken into account – the underlying breast cancer risk and the risk of delayed detection. Mammographic density, the amount of dense tissue in the breast, has been shown to be a risk factor for both. In this thesis, my aim was to identify novel determinants of delayed breast cancer detection by studying observed cases of interval cancer or large cancer at diagnosis. The potential risk factors for delayed detection were based on negative mammograms and other data that can be determined before diagnosis. Study I to III, were based on a retrospective case-only population, while Study IV was based on a prospective cohort. In Study I, we developed an estimate of the longitudinal fluctuation in mammographic percent density between screenings. Based on our results, we concluded that women that were subsequently diagnosed with interval cancer had higher density fluctuations than women with screen-detected cancer. In Study II, we went beyond density and examined 32 other image features which were computer-extracted from digitized mammograms. We identified two novel features that were associated with an increased risk of interval cancer compared to screen-detected cancer. One feature seemed to be related to the shape of the entire dense area, being flat rather than round increased the risk of interval cancer, possibly due to making clinical detection easier. The other feature seemed to be related to whether the density was more concentrated or instead was interspersed with fatty streaks. When density was more concentrated, the risk of interval cancer increased, possibly by making mammographic detection more difficult. In Study III, we determined risk factors for the cancer diagnosis being delayed until the cancer had reached a size larger than 2 cm. High density and high body mass index (BMI) were already known risk factors in general. Our aim was to understand if different factors were involved depending on the detection mode, screen-detection or interval cancer detection. We found that high BMI increased the risk of large cancer markedly among interval cancers and somewhat among screen-detected cancers. High density was associated with large cancer only among screen-detected cases. In survival analysis, we showed that high BMI increased the risk of disease progression, but only among women with interval cancer. In Study IV, we found that the localized density category at the site of the subsequent cancer was often different compared to the overall density. We examined the effect of high localized density, independent of overall density, and found that it was strongly associated with large cancer at diagnosis. In addition, it was associated with interval cancer among the less aggressive node-negative cases. It remains to be elucidated whether this effect is purely due to visual masking or also due to an association with biological characteristics of the tumor microenvironment. In conclusion, we have identified several novel determinants of delayed breast cancer detection, which could be further validated in trials of risk-stratified screening

Integrated Multiparametric Radiomics and Informatics System for Characterizing Breast Tumor Characteristics with the OncotypeDX Gene Assay

Optimal use of multiparametric magnetic resonance imaging (mpMRI) can identify key MRI parameters and provide unique tissue signatures defining phenotypes of breast cancer. We have developed and implemented a new machine-learning informatic system, termed Informatics Radiomics Integration System (IRIS) that integrates clinical variables, derived from imaging and electronic medical health records (EHR) with multiparametric radiomics (mpRad) for identifying potential risk of local or systemic recurrence in breast cancer patients. We tested the model in patients (n = 80) who had Estrogen Receptor positive disease and underwent OncotypeDX gene testing, radiomic analysis, and breast mpMRI. The IRIS method was trained using the mpMRI, clinical, pathologic, and radiomic descriptors for prediction of the OncotypeDX risk score. The trained mpRad IRIS model had a 95% and specificity was 83% with an Area Under the Curve (AUC) of 0.89 for classifying low risk patients from the intermediate and high-risk groups. The lesion size was larger for the high-risk group (2.9 ± 1.7 mm) and lower for both low risk (1.9 ± 1.3 mm) and intermediate risk (1.7 ± 1.4 mm) groups. The lesion apparent diffusion coefficient (ADC) map values for high- and intermediate-risk groups were significantly (p \u3c 0.05) lower than the low-risk group (1.14 vs. 1.49 × 10−3 mm2/s). These initial studies provide deeper insight into the clinical, pathological, quantitative imaging, and radiomic features, and provide the foundation to relate these features to the assessment of treatment response for improved personalized medicine

Clinical and epidemiological issues and applications of mammographic density

The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the authorMammographic density, the amount of radiodense tissue on a mammogram, is a strong risk factor for breast cancer, with properties that could be an asset in screening and prevention programmes. Its use in risk prediction contexts is currently limited, however, mainly due to di culties in measuring and interpreting density. This research investigates rstly, the properties of density as an independent marker of breast cancer risk and secondly, how density should be measured. The rst question was addressed by analysing data from a chemoprevention trial, a trial of hormonal treatment, and a cohort study of women with a family history of breast cancer . Tamoxifen-induced density reduction was observed to be a good predictor of breast cancer risk reduction in high-risk una ected subjects. Density and its changes did not predict risk or treatment outcome in subjects with a primary invasive breast tumour. Finally absolute density predicted risk better than percent density and showed a potential to improve existing risk-prediction models, even in a population at enhanced familial risk of breast cancer. The second part of thesis focuses on density measurement and in particular evaluates two fully-automated volumetric methods, Quantra and Volpara. These two methods are highly correlated and in both cases absolute density (cm3) discriminated cases from controls better than percent density. Finally, we evaluated and compared di erent measurement methods. Our ndings suggested good reliability of the Cumulus and visual assessments. Quantra volumetric estimates appeared negligibly a ected by measurement error, but were less variable than visual bi-dimensional ones, a ecting their ability to discriminate cases from controls. Overall, visual assessments showed the strongest association with breast cancer risk in comparison to computerised methods. Our research supports the hypothesis that density should have a role in personalising screening programs and risk management. Volumetric density measuring methods, though promising, could be improved.Cancer Research U

Radiomics in photon-counting dedicated breast CT: potential of texture analysis for breast density classification

BACKGROUND We investigated whether features derived from texture analysis (TA) can distinguish breast density (BD) in spiral photon-counting breast computed tomography (PC-BCT). METHODS In this retrospective single-centre study, we analysed 10,000 images from 400 PC-BCT examinations of 200 patients. Images were categorised into four-level density scale (a-d) using Breast Imaging Reporting and Data System (BI-RADS)-like criteria. After manual definition of representative regions of interest, 19 texture features (TFs) were calculated to analyse the voxel grey-level distribution in the included image area. ANOVA, cluster analysis, and multinomial logistic regression statistics were used. A human readout then was performed on a subset of 60 images to evaluate the reliability of the proposed feature set. RESULTS Of the 19 TFs, 4 first-order features and 7 second-order features showed significant correlation with BD and were selected for further analysis. Multinomial logistic regression revealed an overall accuracy of 80% for BD assessment. The majority of TFs systematically increased or decreased with BD. Skewness (rho -0.81), as a first-order feature, and grey-level nonuniformity (GLN, -0.59), as a second-order feature, showed the strongest correlation with BD, independently of other TFs. Mean skewness and GLN decreased linearly from density a to d. Run-length nonuniformity (RLN), as a second-order feature, showed moderate correlation with BD, but resulted in redundant being correlated with GLN. All other TFs showed only weak correlation with BD (range -0.49 to 0.49, p < 0.001) and were neglected. CONCLUSION TA of PC-BCT images might be a useful approach to assess BD and may serve as an observer-independent tool

Imaging Biomarkers for Precision Medicine in Locally Advanced Breast Cancer

Guidelines from the American National Comprehensive Cancer Network (NCCN)recommend neoadjuvant chemotherapy (NAC) to patients with locally advanced breast cancer (LABC) to downstage tumors before surgery. However, only a small fraction (15-17%) of LABC patients achieve complete pathologic response (pCR), i.e. no residual tumor in the breast, after treatment. Measuring tumor response during 53 neoadjuvant chemotherapy can potentially help physicians adapt treatment thus, potentially improving the pCR rate. Recently, imaging biomarkers that are used to measure the tumor’s functional and biological features have been studied as pre-treatment markers for pCR or as an indicator for intra-treatment tumor response. Also, imaging biomarkers have been the focus of intense research to characterize tumor heterogeneity as well as to advance our understanding of the principle mechanisms behind chemoresistance. Advances in investigational radiology are moving rapidly to high-resolution imaging, capturing metabolic data, performing tissue characterization and statistical modelling of imaging biomarkers, with an endpoint of personalized medicine in breast cancer treatment. In this commentary, we present studies within the framework of imaging biomarkers used to measure breast tumor response to chemotherapy. Current studies are showing that significant progress has been made in the accuracy of measuring tumor response either before or during chemotherapy, yet the challenges at the forefront of these works include translational gaps such as needing large-scale clinical trials for validation, and standardization of imaging methods. However, the ongoing research is showing that imaging biomarkers may play an important role in personalized treatments for LABC