Promising techniques for breast cancer detection,diagnosis, and staging using non-ionizing radiation imaging techniques

Traditional imaging for the diagnosis and staging of breast cancer has relied on the tissue morphology of cancers in the background of normal patterns of fibroglandular breast tissue. X-ray mammography and ultrasound have been the primary modalities for the diagnosis and the work-up of breast cancer. New modalities have been validated including magnetic resonance imaging (MRI) and positron emission tomography (PET). New pulse sequences in MRI combined with contrast enhancement kinetic perfusion curves have greatly enhanced detection of mammographically occult cancers. New modalities on the horizon include optical imaging, exploiting again the differential perfusion properties of cancers in a background of normal glandular tissue. Even more specificity can be ach eved with the addition of ductal or intravenous introduction of optical probes specific to tumor associated antigens such as the HER-2/neu receptor in aggressive breast cancers. Quantum dots and other fluorescent dyes coupled to peptides or other probes will greatly enhance our ability to detect cancers earlier and without ionizing radiation.     

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.     

Approaches to improving breast cancer diagnosis using a high resolution,breast specific gamma camera

Mammography remains the gold standard in breast cancer detection, although there remains a challenge for improvement in sensitivity of breast cancer detection and diagnosis. Although mammography is the most frequently utilized examination to screen for breast cancer, which has resulted in a reduction of breast cancer mortality, still some cancers are unable to be visualized on mammographic images. Mammography films are interpreted using an anatomic approach. A new approach to breast cancer diagnosis utilizes a breast specific gamma camera to measure radiotracer uptake of abnormal tissue in the breast in patients with an abnormal mammogram or palpble mass using technetium sestamibi. Images are taken using the same positioning techniques as mammography for comparison of both types of images. Multi-Institutional trials using a traditional gamma camera demonstrated potential for this approach. However, the inability of traditional gamma camera intrinsic resolution and non-optinuized breast imaging limited scintimammography. Therefore, a breast specific, high resolution gamma camera was developed to overcome these limitations.Results of clinical studies evaluating BSGI are promising and are increasingly being used. Additionally, means for minimally invasive imaging-guided acquisition of tissue are being developed so that biopsies will be avaibles for areas of interest based on radiotracer uptake.Breast specific gamma camera nuclear imaging of the breast is a developing and increasingly utilized approach to improving breast cancer detection and diagnosis.     

Detection-ability evaluation of the PEImager for positron emission mammography applications

This work is a pilot study of using a dual-head scanner in positron emission mammograph (PEM). A positron emission imager (PEImager) developed at our laboratory was used as a PEM prototype to obtain data. Dual-head projection imaging mode was used in the PEM study. An iterative algebraic reconstruction was employed to reconstruct projection data to obtain tomograms. A cylindrizal phantom filled with water was applied to simulate a breast and five hollow spheres (2 mm–10 mm diameters) filled with F-18 fluoride simulated tumors in the breast phantom. Preliminary data revealed that the locations and sizes of the hot spots in the breast phantom were determined from the reconstructed images. The ability to detect the tumor embedded in the radioactive water was evaluated. At a tumor-to-normal tissue ratio 20:1, a 3 mm tumor was detected; 5 mm and 10 mm tumors could be detected at the ratios of 10:1 and 5:1, respectively.     

Supervised two-dimensional functional principal component analysis with time-to-event outcomes and mammogram imaging data

Screening mammography aims to identify breast cancer early and secondarily measures breast density to classify women at higher or lower than average risk for future breast cancer in the general population. Despite the strong association of individual mammography features to breast cancer risk, the statistical literature on mammogram imaging data is limited. While functional principal component analysis (FPCA) has been studied in the literature for extracting image-based features, it is conducted independently of the time-to-event response variable. With the consideration of building a prognostic model for precision prevention, we present a set of flexible methods, supervised FPCA (sFPCA) and functional partial least squares (FPLS), to extract image-based features associated with the failure time while accommodating the added complication from right censoring. Throughout the article, we hope to demonstrate that one method is favored over the other under different clinical setups. The proposed methods are applied to the motivating data set from the Joanne Knight Breast Health cohort at Siteman Cancer Center. Our approaches not only obtain the best prediction performance compared to the benchmark model, but also reveal different risk patterns within the mammograms.     

The role of various modalities in breast imaging

Background: Breast cancer is the most common type of cancer in women worldwide. Mammography is considered the "gold standard" in the evaluation of the breast from an imaging perspective. Apart from mammography, ultrasound examination and magnetic resonance imaging are being offered as adjuncts to the preoperative workup. Recently, other new modalities like positron emission tomography, 99mTc-sestamibi scintimammography, and electrical impedance tomography (EIT) are also being offered. However, there is still controversy over the most appropriate use of these new modalities. Based on the literature, this review evaluates the role of various modalities used in the screening and diagnosis of breast cancer. Methods and Results: Based on relevant literatures this article gives an overview of the old and new modalities used in the field of breast imaging. A narrative literature review of all the relevant papers known to the authors was conducted. The search of literatures was done using pubmed and ovid search engines. Additional references were found through bibliography reviews of relevant articles. It was clear that though various new technics and methods have emerged, none have substituted mammography and it is still the only proven screening method for the breast as of date. Conclusion: From the literature it is clear that apropos modern radiology's impact on diagnosis, staging and patient follow-up, only one imaging technique has had a significant impact on screening asymptomatic individuals for cancer i.e.; low-dose mammography. Mammography is the only screening test proven in breast imaging. Positron emission tomography (PET) also plays an important role in staging breast cancer and monitoring treatment response. As imaging techniques improve, the role of imaging will continue to evolve with the goal remaining a decrease in breast cancer morbidity and mortality. Progress in the development and commercialisation of EIT breast imaging system will definitely help to promote other systems and applications based on the EIT and similar visualization methods. Breast ultrasound and breast magnetic resonance imaging (MRI) are frequently used adjuncts to mammography in today's clinical practice and these techniques enhance the radiologist's ability to detect cancer and assess disease extent, which is crucial in treatment planning and staging.     

磁共振成像对乳腺肿瘤的诊断价值

乳腺癌是危及女性健康的常见恶性肿瘤之一,病死率较高,且发病年龄呈年轻化趋势。目前临床对乳腺疾病的检查方法很多,既往检查主要包括钼靶、超声等,因价格便宜、操作方便,已成为常规的乳腺疾病检查方法,但两者的敏感性和特异性较低并有自身的局限性。CT软组织分辨率较高,但检查过程中的X线剂量较大,并且动态增强时间较长,故作为乳腺钼靶的补充检查手段。这些检查方法对乳腺疾病均有不同的诊断意义,在当前众多诊断乳腺疾病方法中,具有无辐射,较高软组织分辨力及可多方位多层面成像的乳腺磁共振(MRI)成像有其独到的优势,某些方面能弥补超声和钼靶检查的局限性,乳腺磁共振可提供病灶形态学和增强血流动力学表现,可用于常规检查方法不能确诊病灶的鉴别诊断。乳腺肿瘤MRI成像对临床诊断、鉴别诊断及手术方案的选择有着极其重要的作用。本文就乳腺MRI影像技术、MRI影像学表现及其临床应用予以综述,探讨MRI在乳腺肿瘤中的应用。     

Balancing sensitivity and specificity: sixteen year's of experience from the mammography screening programme in Copenhagen, Denmark

Aim: To report on sensitivity and specificity from 7 invitation rounds of the organised, population-based mammography screening programme started in Copenhagen, Denmark, in 1991, and offered biennially to women aged 50–69. Changes over time were related to organisation and technology. Methods: Individualized data were retrieved on outcome of screening mammography, assessment, surgery, and interval cancers. European Guideline performance indicators were calculated, supplemented with false positive and interval cancer rates per 1000 screens. False positive tests were divided into those sorted out at assessment (Type 1) and at surgery (Type 2). Results: In total, 1392 invasive breast cancers/ductal carcinoma in situ cases (DCIS) were diagnosed, giving an overall detection rate of 7.6 per 1000 screens. Of 5178 false positive tests, 4666 were Type 1 and 512 Type 2. The 468 interval cancers constituted 25% of all breast cancers (=screen detected + interval cancer). Almost all outcome measures were well within the desirable level of the European Guidelines. Risk of Type 2 false positive tests was positively associated with detection rate especially at initial screen, and interval cancer rate was negatively associated with detection rate. This association was decoupled after introduction of high resolution ultrasound and stereotactic breast biopsies, resulting in a Benign-to-Malignant-Ratio (BMR) of 1:11.40. Conclusion: Mammography screening is a delicate balance between benefits and risks. Increase in detection rate came at cost of increase in risk of benign biopsies. Introduction of new technologies broke this pattern and a slight increase in detection rate coincided with an unprecedentedly low BMR.     

High-resolution gamma-camera for molecular breast imaging: First clinical results

Scintimair mography is a molecular breast imaging technique using tumour-seeking radiopharmaceuticals; with standard gamma-cameras, is proved of value especially when mammography is indeterminate and in women with dense breasts; nevertheless, this technique shows a high sensitivity only for cancers >1 cm. The issue of detecting small cancers is critical for the future development and clinical usefulness of breast imaging with radiopharmaceuticals, because other modalities are increasingly employed for early identification of small abnormalities. The use of high-resolution dedicated cameras for breast imaging is the best option to improve small cancers' detection: they allow greater flexibility in patient positioning, and the availability of projections similar to those of mammography. Moreover, the detector can be placed directly against the breast, and a mild compression is possible, with the results of reducing breast thickness, increasing the target-to-background ratio and the sensitivity. Our first clinical findings using the dedicased camera Lumagem 3200S (Gamma Medica, Inc., Northridge, USA) are very satisfactory. Till now, 29 patients with BI-RADS category III and IV lesions ≤1 cm were prospectively evaluated using a conventional gamma-camera and the dedicated device. Four out nine (44%) of the malignant lesions were detected with the standard gamma-camera, whereas the high-resolution camera visualized all the breast cancers. The standard gamma-camera and the dedicated one showed the same specificity: 19 out of 20 (95%) benign lesions were negative. Our results indicate that molecular breast imaging with this dedicated camera is able to detect small cancers in patients with probably benign or low-suspicion to indeterminate mammographic findings.     

Mammography: a surgeon's experience.

Most reports advocating mammography have been written by radiologists rather than by clinicians who are frequently confronted by women with breast complaints. The value of mammography in managing patients with breast problems was studied by reviewing its role in 1026 breast consultations; there were 129 patients with cancer. Mammography was performed in 95 patients. The procedure hastened the diagnosis of one comedocarcinoma, and in another patient was suspicious 3 years before she presented with a locally advanced lesion. It missed six cancers. In seven patients it recognized clinically obvious cancers, though in one of these it had given negative results 10 months before the patient presented with a lesion 15 cm in diameter. It also falsely suggested the possibility of cancer in 28 women. In the other 52 patients the clinical diagnosis of a benign condition was usually fairly evident. The morbidity caused by mammography does not seem to have been widely appreciated, no doubt because of the hope that clinically unrecognized cancers would be found by it. Most breast problems can be diagnosed without mammography.     

ClearPEM,un TEP dédié au sein

Conventional breast imaging (mammography, ultrasound, MRI) relies on the analysis of anatomical characteristics. Whole-body positron emission tomography (PET) allows for the acquisition of a metabolic image, yet is limited by its poor spatial resolution. The Crystal Clear Collaboration developed a PET dedicated for breast imaging, the ClearPEM, in order to offer a high-resolution nuclear imaging technique. The patient is installed in the prone position on the exam bed, with two detector plates rotating around to breast to acquire a 3-dimensional image. Two prototypes were built and installed in hospitals. We summarize the technical solutions necessary for the development of this system and present a summary of its performances as well as an outlook on preclinical and clinical tests.     

Crucial considerations for pipelines to validate circulating biomarkers for breast cancer

Despite decades of progress in breast imaging, breast cancer remains the second most common cause of cancer mortality in women. The rapidly proliferative breast cancers that are associated with high relapse rates and mortality frequently present in younger women, in unscreened individuals, or in the intervals between screening mammography. Biomarkers exist for monitoring metastatic disease, such as CEA, CA27.29 and CA15-3, but there are no circulating biomarkers clinically available for early detection, prognosis, or monitoring for clinical relapse. There has been significant progress in the discovery of potential circulating biomarkers, including proteins, autoantibodies, nucleic acids, exosomes, and circulating tumor cells, but the vast majority of these biomarkers have not progressed beyond initial research discovery, and none have yet been approved for clinical use in early stage disease. Here, the authors review the crucial considerations of developing pipelines for the rapid evaluation of circulating biomarkers for breast cancer.     

Clinical experience with positron emission tomography with 2-fluorine, 18F-2-deoxy-d-glucose used for the diagnosis of malignant breast neoplasms

The aim of the study was to evaluate sensitivity and specificity of positron emission tomography (PET) and 18F-fluorodesoxyglucose (18F-FDG) in breast cancer diagnosis and to assess tumor dissemination. Sixty two patients were examined: 10 without mammary disease, 10 with fibrous cystic mastopathy, and 42 with breast cancer, which was hystologically verified. PET scanning was recorded in the "Whole body" mode 70-90 min later administration of 370-420 MBq 18F-FDG. It was shown that PET has a high diagnostic accuracy in breast cancer detection. There were no False-positive cases in our investigations. PET scanning in the "Whole body" mode was allowed to assess dissemination of tumor process with high accuracy. Metastatic involvement of local lymph nodes was detected in 82.8% cases and bone metastases--86% in cases.     

Mutations in the BRCA1 gene: implications of inter-population differences for predicting the risk of radiation-induced breast cancers

The effects of cancer predisposition and increased tumorigenic radiosensitivity of the predisposed genotypes on radiation cancer risks (in the general population and in sisters and first cousins of affected probands) are studied using an autosomal dominant model of cancer predisposition and radiosensitivity. The model assumes that the predisposing alleles, which confer enhanced tumorigenic radiosensitivity, are incompletely penetrant. In addition, the model also allows for sporadic cancers, unrelated to the predisposing locus. The predictions of the model are illustrated using current estimates of BRCA1 mutant gene frequencies; the estimates of the strength of predisposition and radiosensitivity differentials used are based on animal and human studies. It is shown that, unless both the strength of predisposition and radiosensitivity differential are large (say, > 100-fold in comparison with normal homozygotes), (i) the effect of risk heterogeneity on cancer risk is marginal; (ii) dose-dependent radiation effect remains virtually the same as in a homogeneous irradiated population that has no predisposed subgroups; (iii) for the same radiation dose, relatives of affected probands show an enhancement of cancer risks; and (iv) most extra cancers in relatives can be attributed to radiosensitivity differentials. This simple model can give an upper bound of the effect of risk heterogeneity on radiation-induced breast cancer risks even when the cumulative breast cancer risk is age-dependent. Further, our model predicts that the benefits of mammography outweigh the risks.     

Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1980

Ascertainment of breast cancer incidence among the cohort of the RERF Life Span Study extended sample identified 574 breast cancers among 564 cases diagnosed during 1950-1980 of which 412 cancers were reviewed microscopically. There were no dose-dependent differences with respect to diagnostic certainty or histological type. As in previous studies, the dose response appeared to be roughly linear and did not differ between the two cities. The most remarkable new finding was the emergence of a radiation-related excess among women under 10 years of age at exposure. The risk of radiogenic breast cancer appears to decrease with increasing age at exposure, whether expressed in relative or absolute terms. These results suggest that exposure of female breast tissue to ionizing radiation at any time during the first four decades of life, even during the premature stage, can cause breast cancer later in life, and that the length of time that tumor promoters such as endogenous hormones operate following exposure has an important influence on the development of radiation-induced breast cancer. An unresolved question is whether breast cancer risk is increased by radiation exposure at ages older than 40.     

Therapy of Primary Breast Cancer

Most breast cancers are multicentric in origin. They drain into two primary lymphatic depots—the axilla and internal mammary chain of nodes. The incidence of metastasis to the internal mammary nodes rises as the location of the primary tumor approaches to the sternal margin of the breast.One hundred and thirty-seven patients primarily with in situ and non-infiltrating intraductal carcinoma were treated adequately by simple mastectomy and axillary dissection with preservation of the pectoral muscles.All have remained free of disease. Infiltrating cancers arising in the lateral portion of the breast are best treated by radical mastectomy since they spread mainly to the axillary nodes. Medial and central infiltrating cancers have been treated by radical mastectomy with internal mammary resection, since they show a higher incidence of internal mammary metastasis. Seventy-two percent of 500 patients treated in this fashion survived at five years and 65 percent were clinically free of disease. A five-year salvage rate of 60 percent and a ten-year salvage rate of 50 percent were obtained in patients with only internal mammary node metastasis or in those with only axillary involvement. When both nodal areas were involved 43 percent remained free of disease at five years and 20 percent at ten years.Mammography and biopsy of the contralateral breast at the time of radical mastectomy contributed to the detection of early localized breast cancer.     

Is mammography indicated for women with defective BRCA genes? Implications of recent scientific advances for the diagnosis, treatment, and prevention of hereditary breast cancer

About 5% of breast cancer patients have inherited their disease because of a mutation in genes encoding either the BRCA-1 or BRCA-2 proteins. Inheriting one of these mutations confers a 50% to 87% risk of breast cancer. Many physicians faced with such a patient would, at a minimum, suggest increased and earlier screening for breast cancer by routine mammography.[1] Normally, regular mammographic screening combined with appropriate and prompt treatment can reduce mortality from breast cancer by 30% in women aged 50-59 years and by about 14%-18% in women aged 40-49. There are no controlled clinical trials for screening young women who have multiple first-degree relatives developing breast cancer before age 45, or those known to carry BRCA-1 or BRCA-2 mutations. In fact, recent advances point out that BRCA-1 and BRCA-2 gene products are needed to repair radiation damage to DNA.[4,5] Based on this finding, I propose that women with defective BRCA genes are likely to have an inordinate sensitivity to radiation, and this raises a question about the advisability of routinely screening these women by frequent mammography.     

Accuracy and completeness of the New Zealand Cancer Registry for staging of invasive breast cancer

PurposePopulation based cancer registries are an invaluable resource for monitoring incidence and mortality for many types of cancer. Research and healthcare decisions based on cancer registry data rely on the case completeness and accuracy of recorded data. This study was aimed at assessing completeness and accuracy of breast cancer staging data in the New Zealand Cancer Registry (NZCR) against a regional breast cancer register.MethodologyData from 2562 women diagnosed with invasive primary breast cancer between 1999 and 2011 included in the Waikato Breast Cancer Register (WBCR) were used to audit data held on the same individuals by the NZCR. WBCR data were treated as the benchmark.ResultsOf 2562 cancers, 315(12.3%) were unstaged in the NZCR. For cancers with a known stage in the NZCR, staging accuracy was 94.4%. Lower staging accuracies of 74% and 84% were noted for metastatic and locally invasive (involving skin or chest wall) cancers, respectively, compared with localized (97%) and lymph node positive (94%) cancers. Older age (>80 years), not undergoing therapeutic surgery and higher comorbidity score were significantly (p < 0.01) associated with unstaged cancer. The high proportion of unstaged cancer in the NZCR was noted to have led to an underestimation of the true incidence of metastatic breast cancer by 21%. Underestimation of metastatic cancer was greater for Māori (29.5%) than for NZ European (20.6%) women. Overall 5-year survival rate for unstaged cancer (NZCR) was 55.9%, which was worse than the 5-year survival rate for regional (77.3%), but better than metastatic (12.9%) disease.ConclusionsUnstaged cancer and accuracy of cancer staging in the NZCR are major sources of bias for the NZCR based research. Improving completeness and accuracy of staging data and increasing the rate of TNM cancer stage recording are identified as priorities for strengthening the usefulness of the NZCR.     

Distinguishing metastatic triple‐negative breast cancer from nonmetastatic breast cancer using second harmonic generation imaging and resonance Raman spectroscopy

Triple‐negative breast cancer (TNBC) is an aggressive subset of breast cancer that is more common in African‐American and Hispanic women. Early detection followed by intensive treatment is critical to improving poor survival rates. The current standard to diagnose TNBC from histopathology of biopsy samples is invasive and time‐consuming. Imaging methods such as mammography and magnetic resonance (MR) imaging, while covering the entire breast, lack the spatial resolution and specificity to capture the molecular features that identify TNBC. Two nonlinear optical modalities of second harmonic generation (SHG) imaging of collagen, and resonance Raman spectroscopy (RRS) potentially offer novel rapid, label‐free detection of molecular and morphological features that characterize cancerous breast tissue at subcellular resolution. In this study, we first applied MR methods to measure the whole‐tumor characteristics of metastatic TNBC (4T1) and nonmetastatic estrogen receptor positive breast cancer (67NR) models, including tumor lactate concentration and vascularity. Subsequently, we employed for the first time in vivo SHG imaging of collagen and ex vivo RRS of biomolecules to detect different microenvironmental features of these two tumor models. We achieved high sensitivity and accuracy for discrimination between these two cancer types by quantitative morphometric analysis and nonnegative matrix factorization along with support vector machine. Our study proposes a new method to combine SHG and RRS together as a promising novel photonic and optical method for early detection of TNBC.     

Bilateral breast cancer in northern Alberta: risk factors and survival patterns.

Of 2231 women with stage I, II or III breast cancer who were registered and seen between 1971 and 1979 and followed to the end of 1981, 48 (2.2%) had synchronous and 58 (2.6%) asynchronous bilateral breast cancer. The unadjusted incidence rate for a second breast cancer was 6.4/1000 breast-years at risk, compared with a rate of 0.70 for the risk of a first breast cancer in women. When calculated from the date of diagnosis of the first breast cancer the survival rate was better for the group with asynchronous disease than for the group with synchronous disease or for a group with unilateral disease, but when calculated from the date of diagnosis of the second cancer the rate was the same in all three groups. Comparison of known risk factors showed a significant association between the development of bilateral cancer and a later age at the birth of the first child and a longer interval between menarche and that birth. There was a trend towards greater age and more stage III cancer in the group with synchronous disease. There was no correlation between receiving radiotherapy for the first breast cancer and development of the second cancer. Annual mammography and clinical examination of asymptomatic women at a cancer centre resulted in the detection of a significantly higher proportion of minimal breast cancers in the second breast compared with the first. Such screening practices should be even more valuable in the earlier detection of unilateral breast cancer in asymptomatic women who have not had breast cancer.