High-value breast cancer care within resource limitations.

Breast cancer care is a costly global health issue where effective management depends on early detection and treatment. A breast cancer diagnosis can result in financial catastrophe especially in low- and middle-income countries (LMIC). Large inequities in breast cancer care are observed and represent a global challenge to caregivers and patients. Strategies to improve early diagnosis include awareness and clinical breast examination in LMIC, and screening in high-income countries (HIC). The use of clinical guidelines for the management of breast cancer is needed. Adapted guidelines from HIC can address disparities in populations with limited resources. Locally developed strategies still provide effective guidance in improving survival. Integrated practice units (IPU) with timely multidisciplinary breast care conferences and patient navigators are required to achieve high-value, personalized breast cancer management in HIC as well as LMIC. Breast cancer patient care should include a quality of life evaluation using ideally patient-reported outcomes (PROM) and experience measurements (PREM). Evaluation of breast cancer outcomes must include the financial cost of delivered care. The resulting value perspective should guide resource allocation and program priorities. The value of care must be improved by translating the findings of social and economic research into practice and resolving systemic inequity in clinical breast cancer research. Cancer survivorship programs must be put in place everywhere. The treatment of patients with metastatic breast cancer must require more attention in the future, especially in LMIC.

Efficacy of intraoperative specimen radiography as margin assessment tool in breast conserving surgery.

PURPOSE: To explore the ability of intraoperative specimen radiography (SR) to correctly identify positive margins in patients receiving breast conserving surgery (BCS). To assess whether the reoperation rate can be reduced by using this method. METHODS: This retrospective study included 470 consecutive cases receiving BCS due to a primarily diagnosed breast cancer. SR was carried out in two planes, assessing the specimen regarding the presence of the lesion and its relation to all margins. If indicated, re-excision of selective orientations was advised. Under consideration of gross inspection and the SR-findings, it was up to the surgeon whether to perform re-resections. The recommendations for re-excision were, separately for each orientation, compared to the histopathological results, serving as gold standard. RESULTS: Intraoperative SR was performed in 470 cases, thus 2820 margins were assessed. Of those, 2510 (89.0%) were negative and 310 (11.0%) positive. SR identified 2179 (77.3%) margins correctly as negative, whereas 331 (11.7%) clear margins were misjudged as positive. Of 310 infiltrated margins, SR identified 114 (4.0%) correctly, whereas 196 (7.0%) infiltrated margins were missed. This resulted in a sensitivity/specificity of 36.8%/86.8% and PPV/NPV of 25.6%/91.8%. Through targeted re-resections positive margins could be reduced by 31.0% [310 to 214 (7.6%)]. On case level, the rate of secondary procedures could be reduced by 37.0% [from 162 to 102 (21.7%)]. CONCLUSIONS: SR is a helpful tool to identify infiltrated margins and to reduce the rate of secondary surgeries by recommending targeted re-excisions of according orientations in order to obtain a final negative margin status.

Evaluation of an automated breast 3D-ultrasound system by comparing it with hand-held ultrasound (HHUS) and mammography.

PURPOSE: Automated three-dimensional (3D) breast ultrasound (US) systems are meant to overcome the shortcomings of hand-held ultrasound (HHUS). The aim of this study is to analyze and compare clinical performance of an automated 3D-US system by comparing it with HHUS, mammography and the clinical gold standard (defined as the combination of HHUS, mammography and-if indicated-histology). METHODS: Nine hundred and eighty three patients (=1,966 breasts) were enrolled in this monocentric, explorative and prospective cohort study. All examinations were analyzed blinded to the patients´ history and to the results of the routine imaging. The agreement of automated 3D-US with HHUS, mammography and the gold standard was assessed with kappa statistics. Sensitivity, specificity and positive and negative predictive value were calculated to assess the test performance. RESULTS: Blinded to the results of the gold standard the agreement between automated 3D-US and HHUS or mammography was fair, given by a Kappa coefficient of 0.31 (95% CI [0.26;0.36], p < 0.0001) and 0.25 (95% CI [0.2;0.3], p < 0.0001), respectively. Our results showed a high negative predictive value (NPV) of 98%, a high specificity of 85% and a sensitivity of 74% based on the cases with US-guided biopsy. Including the cases where the lesion was seen in a second-look automated 3D-US the sensitivity improved to 84% (NPV = 99%, specificity = 85%). CONCLUSION: The results of this study let us suggest, that automated 3D-US might be a helpful new tool in breast imaging, especially in screening.

Circulating microRNAs in plasma as early detection markers for breast cancer.

In recent years, circulating miRNAs have attracted a great deal of attention as promising novel markers for various diseases. Here, we investigated their potential to serve as minimally invasive, early detection markers for breast cancer in blood plasma. We profiled miRNAs extracted from the plasma of early stage breast cancer patients (taken at the time-point of diagnosis) and healthy control individuals using TaqMan low-density arrays (TLDA). Selected candidates identified in the initial screen were further validated in an extended study cohort of 207 individuals including 127 sporadic breast cancer cases and 80 healthy controls via RT-qPCR. Four miRNAs (miR-148b, miR-376c, miR-409-3p and miR-801) were shown to be significantly upregulated in the plasma of breast cancer patients. ROC curve analysis showed that the combination of only three miRNAs (miR-148b, miR-409-3p and miR-801) had an equal discriminatory power between breast cancer cases and healthy controls as all four miRNAs together (AUC = 0.69). In conclusion, the identified miRNAs might be of potential use in the development of a multimarker blood-based test to complement and improve early detection of breast cancer. Such a multimarker blood test might for instance provide a prescreening tool, especially for younger women, to facilitate decisions about which individuals to recommend for further diagnostic tests.

Molecular and clinical characterization of an in frame deletion of uncertain clinical significance in the BRCA2 gene.

In this study, we analyzed a "variant of uncertain significance" (VUS) located in exon 23 of the BRCA2 gene exhibited by six members of five distinct families with hereditary breast cancer (BC). The variant was identified by DNA sequencing, and cDNA analysis revealed its co-expression with wild-type mRNA. We analyzed co-occurrence with other pathological mutations in BRCA1/2, performed a case-control study, looked for evolutionary data and used in-silico analyses to predict its potential clinical significance. Sequencing revealed an in frame deletion of 126 nucleotides in exon 23, leading to a deletion of 42 amino acids (c.9203_9328del126, p.Pro2992_Thr3033del). All of the VUS-carriers suffered from either BC or ovarian/pancreatic cancer. No other definite pathologic mutation of BRCA genes was found in the five families. The identified deletion could not be observed in a control cohort of 2,652 healthy individuals, but in 5 out of 916 (0.5%) tested BC families without a bona fide pathogenic BRCA1/2 mutation (P = 0.0011). According to these results, the in frame deletion c.9203_9328del126 is a rare mutation strongly associated with familial BC. In summary, our investigations indicate that this BRCA2 deletion is pathogenic.

Does a supplementary preoperative breast MRI in patients with invasive lobular breast cancer change primary and secondary surgical interventions?

BACKGROUND: We evaluated whether a supplementary preoperative breast MRI in patients with invasive lobular breast cancer (ILC) has changed number and methods of primary and number of secondary surgical interventions. MATERIALS AND METHODS: This was a retrospective controlled single-center analysis of 178 ILC patients. The 2 study groups consisted of 92 patients with breast MRI (MRI group) and of 86 patients without breast MRI (non-MRI group). We investigated the primary and final surgical procedures and factors that influenced the number of secondary surgical interventions. RESULTS: A total of 40 primary mastectomies (38%) have been performed in the MRI group, compared with 27 (30%) in the non-MRI group (P = .119).There have been more bilateral surgical interventions in the MRI group (14 vs 3 patients; P = .002). The 2 groups did not differ with respect to secondary surgery rates (P = .429). The MRI and non-MRI group were significantly different with respect to age and breast density (P = .003 and P = .002). Yet, both variables seemed not to influence secondary surgery rates (P = .516 and P = .788, respectively). CONCLUSIONS: The implementation of preoperative breast MRI tended to result in more primary mastectomies and bilateral surgeries and did not seem to decrease the secondary surgery rate.

Influence of different HRT regimens on mammographic density.

OBJECTIVES: A prospective, randomized, open-label study was conducted to evaluate effects on mammographic density in postmenopausal and late perimenopausal women receiving continuous combined or sequential combined hormone replacement therapy (HRT). METHODS: The subjects were randomized to treatment with low-dose continuous combined HRT containing 1 mg 17beta-estradiol plus 0.5 mg norethisterone acetate (Activelle) or a sequential combined HRT regimen consisting of 0.625 mg conjugated equine estrogens for 28 days plus 5 mg medrogestone for 14 days (Presomen). Mammograms were obtained at baseline and after 9 cycles (each 28 days) of treatment. RESULTS: The majority of women (approximately two-thirds in each treatment group) had no changes in mammographic breast density between baseline and the final study visit. There were no marked differences between treatment groups. Approximately 20% of women in both groups had a slight increase in mammographic density. Only 10-14% of women in both groups had a pronounced increase in mammographic density. The analyses of the degree of change showed no remarkable differences between treatments. CONCLUSION: These results indicate that the increase in mammographic density with a low-dose continuous combined HRT regimen is no greater than that with a sequential combined HRT regimen. The type of progestogen does not have an impact on the extent of mammographic density changes.

Prediction of underestimated invasiveness in patients with ductal carcinoma in situ of the breast on percutaneous biopsy as rationale for recommending concurrent sentinel lymph node biopsy.

AIM: To develop a model to predict invasion and improve the indication of concurrent sentinel lymph node biopsy (SLNB) for patients with ductal carcinoma in situ (DCIS) on minimally invasive biopsy. METHODS: We evaluated the data of 205 patients with DCIS in minimally invasive biopsy specimens. Clinical, radiological and histological variables were assessed in order to identify predictors of invasive carcinoma in final pathology using logistic regression analyses. We developed and retrospectively tested an algorithm to indicate concurrent SLNB. RESULTS: Invasiveness was underestimated in 18.0% (37 of 205). Univariate analysis revealed the following significant risk factors: lesion palpability, a mass lesion on ultrasound, the presence of a mammographically detectable mass, architectural distortion or density, a BI-RADS score of 5, a lesion diameter ≥50 mm, and ≥50% of histologically affected ducts. With a palpable mass, which remained the only independent predictor of invasion after multivariate adjustment, and the presence of at least three of the remaining five risk factors, the probability of invasion was 56.0%. If the prediction model had been used to indicate SLNB 9.8% (20 of 205) of patients could have been benefited (i.e. spared unnecessary or correctly recommended concurrent SLNB) compared to the factual performed SLNB procedures. Those patients with pure DCIS treated with breast conserving surgery (BCS) benefited most with a relative risk reduction of nearly 50% for unnecessary SLNB. CONCLUSION: The prediction model could rationally guide an informed discussion about risks and benefits of concurrent SLNB in patients with DCIS on minimally invasive biopsy.

Interobserver reliability of automated breast volume scanner (ABVS) interpretation and agreement of ABVS findings with hand held breast ultrasound (HHUS), mammography and pathology results.

OBJECTIVES: Handheld breast ultrasound (HHUS) lacks standardization and reproducibility. The automated breast volume scanner (ABVS) could overcome this limitation. To analyze the interobserver reliability of ABVS and the agreement with HHUS, mammography and pathology is the aim of this study. METHODS: All 42 study participants (=84 breasts) received an ABVS examination in addition to the conventional breast diagnostic work-up. 25 breasts (30%) showed at least one lesion. The scans were interpreted by six breast diagnostic specialists blinded to results of breast imaging and medical history. 32 lesions received histological work-up: 20 cancers were detected. We used kappa statistics to interpret agreement between examiners and diagnostic instruments. RESULTS: On the basis of the Breast Imaging Reporting and Data System (BI-RADS) classification of the 84 breasts an agreement (defined as ≥4 of 6 examiners) was achieved in 63 cases (75%) (mk=0.35) and even improved when dichotomizing the interpretation in benign (BI-RADS 1, 2) and suspicious (BI-RADS 4, 5) to 98% (mk=0.52). Agreement of ABVS examination to HHUS, mammography and pathology was fair to substantial depending on the specific analysis. CONCLUSIONS: The development of an ABVS seems to be a promising diagnostic method with a good interobserver reliability, as well as a comparable good test criteria as HHUS.

Normal breast tissue stiffness measured by a new ultrasound technique: virtual touch tissue imaging quantification (VTIQ).

OBJECTIVE: To evaluate normal breast tissue stiffness with virtual touch tissue imaging quantification (VTIQ) using prospectively collected data. MATERIALS AND METHODS: B-mode ultrasound and VTIQ were performed in 132 breasts in 97 women. Mean values of VTIQ for parenchyma and fatty tissue were compared between those measured in healthy breasts and in the surrounding of histologically proven benign and malignant breast lesions. Moreover we reviewed VTIQ values according to breast density measured by the American College of Radiology (ACR) categories. In addition we analyzed re-test reliability of VTIQ. RESULTS: In 132 breasts the mean VTIQ values in parenchyma were significantly higher than in fatty tissue (3.23 m/s ± 0.74 versus 2.5 m/s ± 0.61; p<0.0001). In healthy breasts as well as in the surrounding of a benign or malignant lesions the VTIQ values of parenchyma were similar (p=0.12). In fatty tissue, small differences between mean VTIQ values of 2.25 m/s ± 0.51, 2.52 m/s ± 0.48 and 2.65 m/s ± 0.71 (p=0.01) in the respective groups were observed. The comparison of mean VTIQ values of parenchyma and fatty tissue in more and less dense breasts (ACR 1+2 versus ACR 3+4 breasts) also yielded no statistically significant difference. The re-test reliability of VTIQ assessed with three independent measurements was moderate (interclass-correlation of 0.52 (p<0.0001)). CONCLUSION: VTIQ is a reliable method for measuring the stiffness of breast tissue. We propose standard values for healthy parenchyma and fatty tissues independent of the surrounding tissue or the ACR category.

Plasma microRNA panel for minimally invasive detection of breast cancer.

Over the last few years, circulating microRNAs (miRNAs) have emerged as promising novel and minimally invasive markers for various diseases, including cancer. We already showed that certain miRNAs are deregulated in the plasma of breast cancer patients when compared to healthy women. Herein we have further explored their potential to serve as breast cancer early detection markers in blood plasma. Circulating miR-127-3p, miR-376a and miR-652, selected as candidates from a miRNA array-based screening, were found to be associated with breast cancer for the first time (n = 417). Further we validated our previously reported circulating miRNAs (miR-148b, miR-376c, miR-409-3p and miR-801) in an independent cohort (n = 210) as elevated in the plasma of breast cancer patients compared to healthy women. We described, for the first time in breast cancer, an over-representation of deregulated miRNAs (miR-127-3p, miR-376a, miR-376c and miR-409-3p) originating from the chromosome 14q32 region. The inclusion of patients with benign breast tumors enabled the observation that miR-148b, miR-652 and miR-801 levels are even elevated in the plasma of women with benign tumors when compared to healthy controls. Furthermore, an analysis of samples stratified by cancer stage demonstrated that miR-127-3p, miR-148b, miR-409-3p, miR-652 and miR-801 can detect also stage I or stage II breast cancer thus making them attractive candidates for early detection. Finally, ROC curve analysis showed that a panel of these seven circulating miRNAs has substantial diagnostic potential with an AUC of 0.81 for the detection of benign and malignant breast tumors, which further increased to 0.86 in younger women (up to 50 years of age).

Detected, yet not Diagnosed - Breast Cancer Screening with MRI Mammography in High-Risk Women.

BACKGROUND: MRI has been demonstrated to be the most sensitive imaging method for detecting breast cancer in women at high risk, allowing depiction of cancers that are occult on mammography, ultrasound and clinical breast examination. This high sensitivity is tempered by imperfect specificity due to overlap in the features of benign and malignant lesions. CASE: We present the case of a young BRCA2 mutation carrier whose breast cancer could have been diagnosed 2 years earlier; this is a rare case of a false-negative finding in MRI. DISCUSSION: We discuss morphological, physiological and psychological reasons for underestimation of MRI sets, especially in young women. CONCLUSION: We conclude that double reading in MR screening for breast cancer in high-risk women, as conducted for mammography screening, could be considered.

Benefit and risk of mammography screening: considerations from an epidemiological viewpoint.

INTRODUCTION: An organized mammography screening program is being implemented in Germany since the end of 2005. Even before its inception, a heated debate surrounded the question of how to communicate its rationale appropriately. METHODS: Selective literature review identifying facts relevant to informing decision making about mammography attendance. RESULTS: Decision making about individual attendance for mammography screening is crucially dependent on the reduction of risk of death from breast cancer for a diseased woman. This can be communicated in the following way: out of 100 women with a diagnosis of breast cancer 31 will die within the following 10 years without screening and 20 with screening (35% fewer). DISCUSSION: The actuarial concept of risk is defined by the probability of the undesired event multiplied by the expected magnitude of loss. This approach appears more appropriate for the appraisal of risk in the context of mammography screening than a pure event probability. It could help understand why women attend screening even if they perceive the risk of getting breast cancer as low--namely, that they rank the consequences of getting the disease as highly significant for themselves and others in their social environment.

Retrospective quantification of background incidence and stage distribution of breast cancer for the mammography screening pilot project in Wiesbaden, Germany.

Several parameters for quality assurance of mammography screening require background incidence rates, i.e. the breast cancer incidence in the absence of screening. For new programmes, incidence rates for the years prior to the programme are usually taken as a substitute with the appropriate source being cancer registries. In Germany, the feasibility of quality-assured screening was examined in three pilot projects over the years 2001-2005, so that background incidence was needed for quality assurance. Since countrywide cancer registration was not yet well established and especially in the pilot area of Wiesbaden an active cancer registry did not exist, other ways to obtain accurate rates were needed. Thus, in this pilot a manual data collection of breast cancer cases from diagnosing pathologic institutes was conducted to quantify local breast cancer incidence and compare it with available regional registry data from a distant part of the country. Results showed large similarities of rates for the mid of the 1990s, but a stronger increase of incidence for the subsequent years specifically in the pilot area. This increase was likely related to particular efforts in favour of opportunistic screening in that area. They led to increased detection of small cancers, but were too unsystematic to initiate decline of advanced breast cancers on the population level. In view of getting appropriate figures for background incidence these results indicate that emphasis should be put on using rates which are less affected by opportunistic screening rather than obtaining geographically proximate data. We propose to use the 50-69 years incidence rate of breast cancer for the years 1996-2000 in the Saarland cancer registry as background incidence rate which is almost identical to the Wiesbaden data for 1996 and 1997 but increased less strongly during 1998-2000. This incidence rate is 2.5 per 1,000, while that found in the Wiesbaden area was 2.7 per 1,000.

Importance of comparison of current and prior mammograms in breast cancer screening.

PURPOSE: To retrospectively determine the influence of comparing current mammograms with prior mammograms on breast cancer detection in screening and to investigate a protocol in which prior mammograms are viewed only when necessary. MATERIALS AND METHODS: Institutional review board approval was not required. Participants gave written informed consent. Twelve experienced screening radiologists read 160 soft-copy screening mammograms twice, once with and once without prior mammograms. Eighty mammograms were obtained in women in whom breast cancer was diagnosed later; the other 80 mammograms had been reported as normal or benign. All cancers were visible in retrospect. Readers located potential abnormalities, estimated likelihood of malignancy for each finding, and indicated whether prior mammograms were considered necessary. The effect of prior mammograms on detection was determined by computing the mean lesion localized fraction in a range of low fractions of nonlesion locations corresponding to operating points in screening. Scores for both reading sessions were combined to assess the effect of making prior mammograms available only when requested. Data were analyzed by comparing the number of localized lesions between the two reading conditions with a paired two-tailed Student t test and applying a linear mixed model to test differences in average mean lesion localized fraction between reading conditions. P values less than .05 indicated statistical significance. RESULTS: Without prior mammograms, significantly more annotations were made. When only positive cases were considered, no difference was observed. Reading performance was significantly better when prior screening mammograms were available. At fixed lesion localized fraction, nonlesion localized fraction was reduced by 44% (P<.001) on average when prior mammograms were read. Performance was also increased for combined reading mode (ie, when prior mammograms were available on request only). However, this increase was smaller than that when prior mammograms were always available. Prior mammograms were requested in 24%-33% of all cases and were requested more often in positive cases. CONCLUSION: Comparison with prior mammograms significantly improves overall performance and can reduce referrals due to nonlesion locations. Limiting the availability of prior mammograms to cases selected by the reader reduces the beneficial effect of prior mammograms.