Breast Cancer
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Breast Cancer

Breast cancer is the most common type of cancer among women, the risk of breast cancer increases with age, it is most common after the age of 50. Each breast has 15- 20 sections (lobes), each of which has many smaller sections (lobules). The lobes and lobules are connected by thin tubes (ducts). The most frequent type of breast cancer is that starting in the ducts (ductal cancer), other types include cancer beginning in the lobes or lobules (lobular carcinoma), less common is Inflammatory breast cancer which causes the breast to be red, and swollen. The incidence of breast cancer has been increasing in Western countries, the rate of increase has been faster in younger women, however, the cause of most breast cancers remains unknown.

In the UK about 50,000 women and 400 men are diagnosed with breast cancer each year. (Source: Cancer Research UK)

This page shows only UK resources. For a more extensive list of resources from around the world see CancerIndex: Breast Cancer Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications

Information Patients and the Public (8 links)

Information for Health Professionals / Researchers (4 links)

  • PubMed search for publications about Breast Cancer - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Breast Cancer
    MeSH term: Breast Neoplasms
    International US National Library of Medicine
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Latest Research Publications

Showing publications with corresponding authors from the UK (Source: PubMed).

Saha S, Jacklin R, Siddika A, et al.
Safety of radioactive sentinel node biopsy for breast cancer and the pregnant surgeon - A review.
Int J Surg. 2016; 36(Pt A):298-304 [PubMed] Related Publications
INTRODUCTION: Sentinel node biopsy is an established key element in the surgical management of breast cancer and melanoma. Several studies have assessed radiation exposure during sentinel node biopsy and confirmed it to be safe for health workers. Recent demographic changes amongst surgeons has resulted in increasing numbers of women of childbearing age performing sentinel node procedures as a regular part of their surgical practice. We aimed to assess the radiation risk posed by sentinel node biopsy in breast cancer surgery to pregnant surgeons.
METHODS: A search of indexed citations from PUBMED and Cochrane databases for studies assessing the radiation exposure to the primary surgeon during sentinel node biopsy was undertaken. Due to the variability of melanoma location in relation to nodal basins, we have focused on sentinel node biopsy for breast cancer where surgeon positioning, radiopharmaceutical injection and nodal dissection sites are consistent.
RESULTS: From the eleven studies totalling 344 procedures, exposure doses to the abdomens and fingers of surgeons undertaking sentinel node biopsy were within the guideline maximum recommended exposure limit of 1 mSv as set out by the International Committee on Radiation Protection (ICRP) 107 recommendations as long as fewer than one hundred procedures are performed throughout the duration of the pregnancy. Of note the radiation doses in the newer studies were much lower and used more sensitive instruments to detect radiation exposure.
CONCLUSIONS: Providing the numbers of procedures are within defined limits, the radiation risks posed to pregnant surgeons undertaking sentinel node procedures are limited and within the regulatory guidelines for pregnancy.

Monk BJ, Lorusso D, Italiano A, et al.
Trabectedin as a chemotherapy option for patients with BRCA deficiency.
Cancer Treat Rev. 2016; 50:175-182 [PubMed] Related Publications
Trabectedin is a marine-derived product that was originally isolated from the Caribbean sea squirt Ecteinascidia turbinata and the first anticancer marine drug to be approved by the European Union. It is currently used as a single agent for the treatment of patients with soft tissue sarcoma after failure of anthracyclines and ifosfamide, or for those patients who are unsuited to receive these agents, and in patients with relapsed, platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin. Trabectedin has a unique multi-faceted mechanism of action that involves transcription regulation and DNA repair systems, including transcription-coupled nucleotide excision repair and homologous recombination repair (HRR) as the main hallmarks of its antiproliferative activity. In addition, trabectedin has shown the ability to modulate the tumor microenvironment. Indeed, the activity of trabectedin is related to altered function and expression of DNA repair genes, such as BRCA1 (BReast-CAncer susceptibility gene 1) and BRCA2. The particular sensitivity of sarcoma, ovarian and breast cancer cells deficient in HRR, previously observed in preclinical models, now has been confirmed in the clinical setting as well, suggesting that BRCA mutations are associated with improved clinical responses to trabectedin. Current efforts are focused on the evaluation of these unique features of trabectedin and on the identification of predictive factors for patients with an objective to determine whether a deficiency of HRR DNA repair pathway could impact the clinical benefit achieved from trabectedin.

Kulshrestha RK, Vinjamuri S, England A, et al.
The Role of 18F-Sodium Fluoride PET/CT Bone Scans in the Diagnosis of Metastatic Bone Disease from Breast and Prostate Cancer.
J Nucl Med Technol. 2016; 44(4):217-222 [PubMed] Related Publications
We describe the role of (18)F-sodium fluoride ((18)F-NaF) PET/CT bone scanning in the staging of breast and prostate cancer. (18)F-NaF PET was initially utilized as a bone scanning agent in the 1960s and early 1970s, however, its use was restricted by the then-available γ-cameras. The advent of hybrid PET/CT cameras in the late 1990s has shown a resurgence of interest in its use and role. After a brief introduction, this paper describes the radiopharmaceutical properties, dosimetry, pharmacokinetics, and mechanism of uptake of (18)F-NaF. The performance of (18)F-NaF PET/CT is then compared with that of conventional bone scintigraphy using current evidence from the literature. Strengths and weaknesses of (18)F-NaF PET/CT imaging are highlighted. Clinical examples of improved accuracy of diagnosis and impact on patient management are illustrated. Limitations of (18)F-NaF PET/CT imaging are outlined.

Metodieva G, Adoki S, Lausen B, Metodiev MV
Decreased Usage of Specific Scrib Exons Defines a More Malignant Phenotype of Breast Cancer With Worsened Survival.
EBioMedicine. 2016; 8:150-8 [PubMed] Free Access to Full Article Related Publications
SCRIB is a polarity regulator known to be abnormally expressed in cancer at the protein level. Here we report that, in breast cancer, an additional and hidden dimension of deregulations exists: an unexpected SCRIB exon usage pattern appears to mark a more malignant tumor phenotype and significantly correlates with survival. Conserved exons encoding the leucine-rich repeats tend to be overexpressed while others are underused. Mechanistic studies revealed that the underused exons encode part of the protein necessary for interaction with Vimentin and Numa1, a protein which is required for proper positioning of the mitotic spindle. Thus, the inclusion/exclusion of specific SCRIB exons is a mechanistic hallmark of breast cancer, which could potentially be exploited to develop more efficient diagnostics and therapies.

Ban HY, Schweiger M, Kavuri VC, et al.
Heterodyne frequency-domain multispectral diffuse optical tomography of breast cancer in the parallel-plane transmission geometry.
Med Phys. 2016; 43(7):4383 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
PURPOSE: The authors introduce a state-of-the-art all-optical clinical diffuse optical tomography (DOT) imaging instrument which collects spatially dense, multispectral, frequency-domain breast data in the parallel-plate geometry.
METHODS: The instrument utilizes a CCD-based heterodyne detection scheme that permits massively parallel detection of diffuse photon density wave amplitude and phase for a large number of source-detector pairs (10(6)). The stand-alone clinical DOT instrument thus offers high spatial resolution with reduced crosstalk between absorption and scattering. Other novel features include a fringe profilometry system for breast boundary segmentation, real-time data normalization, and a patient bed design which permits both axial and sagittal breast measurements.
RESULTS: The authors validated the instrument using tissue simulating phantoms with two different chromophore-containing targets and one scattering target. The authors also demonstrated the instrument in a case study breast cancer patient; the reconstructed 3D image of endogenous chromophores and scattering gave tumor localization in agreement with MRI.
CONCLUSIONS: Imaging with a novel parallel-plate DOT breast imager that employs highly parallel, high-resolution CCD detection in the frequency-domain was demonstrated.

Kurian AW, Antoniou AC, Domchek SM
Refining Breast Cancer Risk Stratification: Additional Genes, Additional Information.
Am Soc Clin Oncol Educ Book. 2016; 35:44-56 [PubMed] Related Publications
Recent advances in genomic technology have enabled far more rapid, less expensive sequencing of multiple genes than was possible only a few years ago. Advances in bioinformatics also facilitate the interpretation of large amounts of genomic data. New strategies for cancer genetic risk assessment include multiplex sequencing panels of 5 to more than 100 genes (in which rare mutations are often associated with at least two times the average risk of developing breast cancer) and panels of common single-nucleotide polymorphisms (SNPs), combinations of which are generally associated with more modest cancer risks (more than twofold). Although these new multiple-gene panel tests are used in oncology practice, questions remain about the clinical validity and the clinical utility of their results. To translate this increasingly complex genetic information for clinical use, cancer risk prediction tools are under development that consider the joint effects of all susceptibility genes, together with other established breast cancer risk factors. Risk-adapted screening and prevention protocols are underway, with ongoing refinement as genetic knowledge grows. Priority areas for future research include the clinical validity and clinical utility of emerging genetic tests; the accuracy of developing cancer risk prediction models; and the long-term outcomes of risk-adapted screening and prevention protocols, in terms of patients' experiences and survival.

O'Rorke MA, Murray LJ, Brand JS, Bhoo-Pathy N
The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: A systematic review and meta-analysis of 5507 patients.
Cancer Treat Rev. 2016; 47:12-21 [PubMed] Related Publications
BACKGROUND: The value of adjuvant radiotherapy in triple negative breast cancer (TNBC) remains unclear. A systematic review and meta-analysis was conducted in TNBC patients to assess survival and recurrence outcomes associated with radiotherapy following either breast conserving therapy (BCT) or post-mastectomy radiotherapy (PMRT).
METHODS: Four electronic databases were searched from January 2000 to November 2015 (PubMed, MEDLINE, EMBASE and Web of Science). Studies investigating overall survival and/or recurrence in TNBC patients according to radiotherapy administration were included. A random effects meta-analysis was conducted using mastectomy only patients as the reference.
RESULTS: Twelve studies were included. The pooled hazard ratio (HR) for locoregional recurrence comparing BCT and PMRT to mastectomy only was 0.61 (95% confidence interval [CI] 0.41-0.90) and 0.62 (95% CI 0.44-0.86), respectively. Adjuvant radiotherapy was not significantly associated with distant recurrence. The pooled HR for overall survival comparing BCT and PMRT to mastectomy only was 0.57 (95% CI 0.36-0.88) and HR 1.12 (95% CI 0.75, 1.69). Comparing PMRT to mastectomy only, tests for interaction were not significant for stage (p=0.98) or age at diagnosis (p=0.85). However, overall survival was improved in patients with late-stage disease (T3-4, N2-3) pooled HR 0.53 (95% CI 0.32-0.86), and women <40years, pooled HR 0.30 (95% CI 0.11-0.82).
CONCLUSIONS: Adjuvant radiotherapy was associated with a significantly lower risk of locoregional recurrence in TNBC patients, irrespective of the type of surgery. While radiotherapy was not consistently associated with an overall survival gain, benefits may be obtained in women with late-stage disease and younger patients.

Taylor-Phillips S, Wallis MG, Jenkinson D, et al.
Effect of Using the Same vs Different Order for Second Readings of Screening Mammograms on Rates of Breast Cancer Detection: A Randomized Clinical Trial.
JAMA. 2016; 315(18):1956-65 [PubMed] Related Publications
IMPORTANCE: Interpreting screening mammograms is a difficult repetitive task that can result in missed cancers and false-positive recalls. In the United Kingdom, 2 film readers independently evaluate each mammogram to search for signs of cancer and examine digital mammograms in batches. However, a vigilance decrement (reduced detection rate with time on task) has been observed in similar settings.
OBJECTIVE: To determine the effect of changing the order for the second film reader of batches of screening mammograms on rates of breast cancer detection.
DESIGN, SETTING, AND PARTICIPANTS: A multicenter, double-blind, cluster randomized clinical trial conducted at 46 specialized breast screening centers from the National Health Service Breast Screening Program in England for 1 year (all between December 20, 2012, and November 3, 2014). Three hundred sixty readers participated (mean, 7.8 readers per center)-186 radiologists, 143 radiography advanced practitioners, and 31 breast clinicians, all fully qualified to report mammograms in the NHS breast screening program.
INTERVENTIONS: The 2 readers examined each batch of digital mammograms in the same order in the control group and in the opposite order to one another in the intervention group.
MAIN OUTCOMES AND MEASURES: The primary outcome was cancer detection rate; secondary outcomes were rates of recall and disagreements between readers.
RESULTS: Among 1,194,147 women (mean age, 59.3; SD, 7.49) who had screening mammograms (596,642 in the intervention group; 597,505 in the control group), the images were interpreted in 37,688 batches (median batch size, 35; interquartile range [IQR]; 16-46), with each reader interpreting a median of 176 batches (IQR, 96-278). After completion of all subsequent diagnostic tests, a total of 10,484 cases (0.88%) of breast cancer were detected. There was no significant difference in cancer detection rate with 5272 cancers (0.88%) detected in the intervention group vs 5212 cancers (0.87%) detected in the control group (difference, 0.01% points; 95% CI, -0.02% to 0.04% points; recall rate, 24,681 [4.14%] vs 24,894 [4.17%]; difference, -0.03% points; 95% CI, -0.10% to 0.04% points; or rate of reader disagreements, 20,471 [3.43%] vs 20,793 [3.48%]; difference, -0.05% points; 95% CI, -0.11% to 0.02% points).
CONCLUSIONS AND RELEVANCE: Interpretation of batches of mammograms by qualified screening mammography readers using a different order vs the same order for the second reading resulted in no significant difference in rates of detection of breast cancer.

O'Connell RL, Rusby JE, Stamp GF, et al.
Long term results of treatment of breast cancer without axillary surgery - Predicting a SOUND approach?
Eur J Surg Oncol. 2016; 42(7):942-8 [PubMed] Related Publications
BACKGROUND: Traditionally axillary surgery has been used to provide staging information and until recently was thought to improve loco-regional control. However, a more minimal approach to the axilla is now being adopted. The aim of this study was to assess long term outcomes of patients with 'low-risk' breast cancers who did not undergo any axillary surgery. 'Low-risk' criteria were: postmenopausal, <20 mm grade 1 or <15 mm grade 2, LVI-ve, ER +ve.
METHODS: Women with invasive breast cancer that did not undergo any axillary surgery were identified. Patients were censored when an event or death occurred or at last follow-up at breast clinic or with their General Practitioner.
RESULTS: Between 05/01/1995-20/11/2006, 194 patients (199 tumours) were operated upon without axillary surgery. Median follow-up was 10.4 years. 128 patients met low-risk criteria and 71 did not (patient choice = 42, medical fitness = 29). In the 'low risk' cohort there were two axillary recurrences, with a cumulative incidence of 0.8% and 1.9% at 5 and 10 years respectively. DDFS was 99.2% (94.1-99.9%), and 97% (90.0-99%) at 5 and 10 years respectively and DFS was 96.6% (91.1-98.7%) and 91.2% (82.6-95.6%). OS was 90.3% (95% CI: 83.6-94.4) and 75.5% (95% CI: 65.9-82.8) at 5 and 10 years respectively.
CONCLUSION: Axillary recurrence and DDFS in this low-risk cohort is favourable. In the modern era of breast cancer management it is possible to define a group of women in whom axillary surgery can be omitted.

Sánchez JL, Henry OY, Joda H, et al.
Multiplex PCB-based electrochemical detection of cancer biomarkers using MLPA-barcode approach.
Biosens Bioelectron. 2016; 82:224-32 [PubMed] Related Publications
Asymmetric multiplex ligation-dependent probe amplification (MLPA) was developed for the amplification of seven breast cancer related mRNA markers and the MLPA products were electrochemically detected via hybridization. Seven breast cancer genetic markers were amplified by means of the MLPA reaction, which allows for multiplex amplification of multiple targets with a single primer pair. Novel synthetic MLPA probes were designed to include a unique barcode sequence in each amplified gene. Capture probes complementary to each of the barcode sequences were immobilized on each electrode of a low-cost electrode microarray manufactured on standard printed circuit board (PCB) substrates. The functionalised electrodes were exposed to the single-stranded MLPA products and following hybridization, a horseradish peroxidase (HRP)-labelled DNA secondary probe complementary to the amplified strand completed the genocomplex, which was electrochemically detected following substrate addition. The electrode arrays fabricated using PCB technology exhibited an excellent electrochemical performance, equivalent to planar photolithographically-fabricated gold electrodes, but at a vastly reduced cost (>50 times lower per array). The optimised system was demonstrated to be highly specific with negligible cross-reactivity allowing the simultaneous detection of the seven mRNA markers, with limits of detections as low as 25pM. This approach provides a novel strategy for the genetic profiling of tumour cells via integrated "amplification-to-detection".

Ordóñez-Mena JM, Schöttker B, Mons U, et al.
Quantification of the smoking-associated cancer risk with rate advancement periods: meta-analysis of individual participant data from cohorts of the CHANCES consortium.
BMC Med. 2016; 14:62 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: Smoking is the most important individual risk factor for many cancer sites but its association with breast and prostate cancer is not entirely clear. Rate advancement periods (RAPs) may enhance communication of smoking related risk to the general population. Thus, we estimated RAPs for the association of smoking exposure (smoking status, time since smoking cessation, smoking intensity, and duration) with total and site-specific (lung, breast, colorectal, prostate, gastric, head and neck, and pancreatic) cancer incidence and mortality.
METHODS: This is a meta-analysis of 19 population-based prospective cohort studies with individual participant data for 897,021 European and American adults. For each cohort we calculated hazard ratios (HRs) for the association of smoking exposure with cancer outcomes using Cox regression adjusted for a common set of the most important potential confounding variables. RAPs (in years) were calculated as the ratio of the logarithms of the HRs for a given smoking exposure variable and age. Meta-analyses were employed to summarize cohort-specific HRs and RAPs.
RESULTS: Overall, 140,205 subjects had a first incident cancer, and 53,164 died from cancer, during an average follow-up of 12 years. Current smoking advanced the overall risk of developing and dying from cancer by eight and ten years, respectively, compared with never smokers. The greatest advancements in cancer risk and mortality were seen for lung cancer and the least for breast cancer. Smoking cessation was statistically significantly associated with delays in the risk of cancer development and mortality compared with continued smoking.
CONCLUSIONS: This investigation shows that smoking, even among older adults, considerably advances, and cessation delays, the risk of developing and dying from cancer. These findings may be helpful in more effectively communicating the harmful effects of smoking and the beneficial effect of smoking cessation.

Herrera-Abreu MT, Palafox M, Asghar U, et al.
Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer.
Cancer Res. 2016; 76(8):2301-13 [PubMed] Related Publications
Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1-S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301-13. ©2016 AACR.

Seidenstuecker K, van Waes C, Munder BI, et al.
DIEAP flap for safe definitive autologous breast reconstruction.
Breast. 2016; 26:59-66 [PubMed] Related Publications
BACKGROUND: Breast cancer is the commonest form of cancer in women affecting almost a quarter of a million patients in the US annually. 30 percent of these patients and patients with genetic mutations undergo removal of the breast, as highlighted in a high profile celebrity patient. Although breast reconstruction with free microvascular transfer of a DIEAP flap from the abdomen is an ideal form of reconstruction, there have been misgivings about the complexity and potential complications. This study was aimed at clearing these misunderstandings and establishing the value of this form of breast reconstruction.
METHODS: 1036 DIEAP flap breast reconstructions carried out at the University Hospital, Gent (five year period) and at the Sana Kliniken, Düsseldorf (three year period) were included prospectively. Comorbid factors like chemotherapy, radiotherapy, patient age >65 years, BMI >30 and smoking were recorded. Outcomes were evaluated over a mean follow up of 2 years.
RESULTS: Overall complication rate related to the reconstructed breast and donor abdominal area was 6.8 percent. Total flap loss was seen in only 0.8 percent. The mean operating time was less than five hours. Older age, higher BMI, chemotherapy and radiotherapy did not have a significant influence on complication rates, however smoking resulted in significant delay in wound healing in the breast (p = 0.025) and abdominal wounds (p = 0.019).
CONCLUSION: The DIEAP flap is an excellent option for breast reconstruction, with a low level of donor site morbidity and complications. It is an autologous reconstruction that provides a stable long term result.

Ledger AE, Scurr ED, Hughes J, et al.
Comparison of Dixon Sequences for Estimation of Percent Breast Fibroglandular Tissue.
PLoS One. 2016; 11(3):e0152152 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
OBJECTIVES: To evaluate sources of error in the Magnetic Resonance Imaging (MRI) measurement of percent fibroglandular tissue (%FGT) using two-point Dixon sequences for fat-water separation.
METHODS: Ten female volunteers (median age: 31 yrs, range: 23-50 yrs) gave informed consent following Research Ethics Committee approval. Each volunteer was scanned twice following repositioning to enable an estimation of measurement repeatability from high-resolution gradient-echo (GRE) proton-density (PD)-weighted Dixon sequences. Differences in measures of %FGT attributable to resolution, T1 weighting and sequence type were assessed by comparison of this Dixon sequence with low-resolution GRE PD-weighted Dixon data, and against gradient-echo (GRE) or spin-echo (SE) based T1-weighted Dixon datasets, respectively.
RESULTS: %FGT measurement from high-resolution PD-weighted Dixon sequences had a coefficient of repeatability of ±4.3%. There was no significant difference in %FGT between high-resolution and low-resolution PD-weighted data. Values of %FGT from GRE and SE T1-weighted data were strongly correlated with that derived from PD-weighted data (r = 0.995 and 0.96, respectively). However, both sequences exhibited higher mean %FGT by 2.9% (p < 0.0001) and 12.6% (p < 0.0001), respectively, in comparison with PD-weighted data; the increase in %FGT from the SE T1-weighted sequence was significantly larger at lower breast densities.
CONCLUSION: Although measurement of %FGT at low resolution is feasible, T1 weighting and sequence type impact on the accuracy of Dixon-based %FGT measurements; Dixon MRI protocols for %FGT measurement should be carefully considered, particularly for longitudinal or multi-centre studies.

Ghanouni A, Meisel SF, Hersch J, et al.
Information on 'Overdiagnosis' in Breast Cancer Screening on Prominent United Kingdom- and Australia-Oriented Health Websites.
PLoS One. 2016; 11(3):e0152279 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
OBJECTIVES: Health-related websites are an important source of information for the public. Increasing public awareness of overdiagnosis and ductal carcinoma in situ (DCIS) in breast cancer screening may facilitate more informed decision-making. This study assessed the extent to which such information was included on prominent health websites oriented towards the general public, and evaluated how it was explained.
DESIGN: Cross-sectional study.
SETTING: Websites identified through Google searches in England (United Kingdom) and New South Wales (Australia) for "breast cancer screening" and further websites included based on our prior knowledge of relevant organisations.
MAIN OUTCOMES: Content analysis was used to determine whether information on overdiagnosis or DCIS existed on each site, how the concepts were described, and what statistics were used to quantify overdiagnosis.
RESULTS: After exclusions, ten UK websites and eight Australian websites were considered relevant and evaluated. They originated from charities, health service providers, government agencies, and an independent health organisation. Most contained some information on overdiagnosis (and/or DCIS). Descriptive information was similar across websites. Among UK websites, statistical information was often based on estimates from the Independent UK Panel on Breast Cancer Screening; the most commonly provided statistic was the ratio of breast cancer deaths prevented to overdiagnosed cases (1:3). A range of other statistics was included, such as the yearly number of overdiagnosed cases and the proportion of women screened who would be overdiagnosed. Information on DCIS and statistical information was less common on the Australian websites.
CONCLUSIONS: Online information about overdiagnosis has become more widely available in 2015-16 compared with the limited accessibility indicated by older research. However, there may be scope to offer more information on DCIS and overdiagnosis statistics on Australian websites. Moreover, the variability in how estimates are presented across UK websites may be confusing for the general public.

Bodilsen A, Bjerre K, Offersen BV, et al.
Importance of margin width in breast-conserving treatment of early breast cancer.
J Surg Oncol. 2016; 113(6):609-15 [PubMed] Related Publications
BACKGROUND AND METHOD: The association between margin width and ipsilateral breast tumour recurrence (IBTR, defined as invasive recurrence) was investigated in a population-based nationwide cohort of 11,900 patients undergoing breast-conserving therapy for invasive cancer.
RESULTS: The median follow-up was 4.9 years. The cumulative incidence of IBTR at 5 and 9 years was 2.4% and 5.9%, respectively. A final positive margin increased the risk of IBTR (HR 2.51; 95% CI 1.02-6.23). No decrease in IBTR with a wider negative margin compared to a narrow but negative margin was observed in the adjusted analysis of margin width (>0 to <2 mm vs. ≥2 to <5 mm vs. ≥5 mm (reference): HR 1.54 (CI 95% 0.81-2.93) vs. 0.95 (CI 95% 0.56-1.62) vs. 1). However, few patients had narrow margins. The factors associated with increased IBTR were young age (P < 0.001), >4 positive lymph nodes (P = 0.008) and re-excision (P = 0.003). A reduced risk of IBTR was observed with chemotherapy (P < 0.001), boost radiation (P = 0.023) and ER positivity (P < 0.001).
CONCLUSION: An overall low rate of IBTR was observed. A final positive margin was associated with a more than twofold risk of IBTR. There was no evidence for better local control with wider margins, but the data were insufficient to show whether narrow margins were as good as wider negative margins in terms of local control. J. Surg. Oncol. 2016;113:609-615. © 2016 Wiley Periodicals, Inc.

Fentiman IS
Male breast cancer is not congruent with the female disease.
Crit Rev Oncol Hematol. 2016; 101:119-24 [PubMed] Related Publications
It has become customary to extrapolate from the results of treatment trials for female breastcancer and apply them to males with the disease. In the absence of results from national and international randomised trials for male breast cancer (MBC) this appears superficially to be an appropriate response. Closer examination of available data reveals that aspects of the aetiology and treatment of MBC do not fit the simplistic model that men usually have endocrine sensitive tumours which behave like those in postmenopausal women. Most females and males with breast cancer have none of the recognised risk factors, indicating the gaps in our knowledge of the epidemiology of this disease. Several studies have compared epidemiological risk factors for MBC and female breast cancer (FBC) but many have been blighted by small numbers. In comparison with FBC there is a larger proportion of BRCA2 tumours, (occurring in 10% of MBC), and underrepresentation of BRCA1 tumours (found in only 1%), suggesting significant differences in the genetic aetiology of MBC and FBC. Genome-wide association studies in FBC reported single nucleotide polymorphisms (SNPs) in 12 novel independent loci were consistently associated with disease but for MBC 2 SNPs had a significantly increased risk. Molecular profiles of matched cancers in males and females showed a gender-associated modulation of major processes including energy metabolism, regulation of translation, matrix remodelling and immune recruitment. Immunohistochemistry for kinase inhibitor proteins (KIPs) p27Kip1 and p21Waf1 indicate a significant difference in the immunostaining of tumours from male patients compared with females. MBC is almost always estrogen receptor positive (ER+ve) and so systemic treatment is usually endocrine. With evidence in FBC that aromatase inhibitors are more effective than tamoxifen in the postmenopausal it was seemingly logical that the same would be true for MBC. Results however suggest less efficacy with AIs and an increase in risk of mortality compared to tamoxifen. The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. These important biological differences point the way to the development of new therapies for MBC based on differences rather than similarities with FBC.

Banerjee SM, Williams NR, Davidson TI, et al.
The use of onestep nucleic acid amplification (OSNA) and tumour related factors in the treatment of axillary breast cancer: A predictive model.
Eur J Surg Oncol. 2016; 42(5):641-9 [PubMed] Related Publications
AIMS: We aimed to determine the effectiveness of CK19 mRNA copy number and tumour related factors in predicting non-sentinel axillary nodal involvement, in order to facilitate the formulation of local treatment guidelines for axillary clearance (ANC) following intra-operative analysis of the sentinel node biopsy (SNB) using one-step nucleic acid amplification (OSNA).
METHODS: Patients due to have (SNB) at our institution for breast cancer as well as patients with high grade ductal carcinoma in situ with pre-operative negative assessment of the axilla were included. Alternate slices of each node were sent for assessment by either OSNA or histopathology. Immediate ANC was performed if OSNA was positive. The CK19 mRNA nodal copy number, the total tumour load (TTL) measured by summation of mRNA copy numbers of all positive nodes, the nodal status at ANC and tumour characteristics for each patient were recorded. A model of risk probability was constructed using TTL and tumour related factors.
RESULTS: 664 nodes were analysed from 425 patients who had SNB performed between 2011 and 2014. ANC was performed on 105 of these patients. The concordance between OSNA and histology was 91.4% and negative predictive value (NPV) was 97%. TTL (p = 0.003) and LVI (p = 0.04) were identified as risk factors for non-sentinel nodal involvement. The risk probability model identified all patients with pN2 disease for ANC.
CONCLUSION: In the future a decision to perform ANC will be based on a risk stratification model based on TTL and tumour related factors.

O'Flynn EA, Collins D, D'Arcy J, et al.
Multi-parametric MRI in the early prediction of response to neo-adjuvant chemotherapy in breast cancer: Value of non-modelled parameters.
Eur J Radiol. 2016; 85(4):837-42 [PubMed] Related Publications
OBJECTIVE: To prospectively evaluate individual functional MRI metrics for the early prediction of pathological complete response (pCR) to neo-adjuvant chemotherapy (NAC) in breast cancer.
MATERIALS AND METHODS: Thirty-two women (median age 52 years; range 32-71 years) with biopsy proven breast cancer due to receive neo-adjuvant anthracycline and/or taxane-based chemotherapy were prospectively recruited following local research ethics committee approval and written informed consent. Breast MRI was performed prior to and after two cycles of NAC and pCR was assessed after surgery. The enhancement fraction (EF), tumour volume, initial area under the gadolinium curve (IAUGC), pharmacokinetic parameters (K(trans), kep and ve), the apparent diffusion coefficient (ADC) and R2* values, along with the percentage change in these parameters after two cycles were evaluated according to pCR status using an independent samples t-test. The area under the receiver operating characteristics curve (AUC) was calculated for each parameter. Linear discriminant analysis (LDA) determined the most important parameter in predicting pCR.
RESULTS: A reduction in the EF (-41% ± 38%) and tumour volume (-80% ± 25%) after 2 cycles of NAC were significantly greater in those achieving pCR (p=0.025, p=0.011 respectively). A reduction in the EF of 7% after 2 cycles of NAC identified those more likely to achieve pCR (AUC 0.76). AUC changes in other parameters were tumour volume (0.77), IAUGC (0.64), K(trans) (0.60), kep (0.68), ve (0.58), ADC (0.69) and R2* (0.41).
CONCLUSION: In a multi-parametric MRI model, the decrease in a non-model based vascular parameter the enhancement fraction as well as the tumour volume are the most important early predictors of pCR in breast cancer.

Kandil S, Westwell AD, McGuigan C
7-Substituted umbelliferone derivatives as androgen receptor antagonists for the potential treatment of prostate and breast cancer.
Bioorg Med Chem Lett. 2016; 26(8):2000-4 [PubMed] Related Publications
The clinically used androgen receptor (AR) antagonists (bicalutamide, flutamide and nilutamide) bind with low affinity to AR and can induce escape mechanisms. Furthermore, under AR gene amplification or mutation conditions they demonstrate agonist activity and fail to inhibit AR, causing relapse into castration resistant prostate cancer (CRPC). Discovery of new scaffolds distinct from the 4-cyano/nitro-3-(trifluoromethyl)phenyl group common to currently used antiandrogens is urgently needed to avoid cross-resistance with these compounds. In this study, a series of twenty-nine 7-substituted umbelliferone derivatives was prepared and their antiproliferative activities were evaluated. The most active compound 7a demonstrated submicromolar inhibitory activity in the human prostate cancer cell line (22Rv1); IC50=0.93 μM which represents a 50 fold improvement over the clinical antiandrogen bicalutamide (IC50=46 μM) and a more than 30 fold improvement over enzalutamide (IC50=32 μM). Interestingly, this compound showed even better activity against the human breast cancer cell line (MCF-7); IC50=0.47 μM. Molecular modelling studies provided a plausible theoretical explanation for our findings.

Johnson N, De Ieso P, Migliorini G, et al.
Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.
Cancer Res. 2016; 76(6):1485-93 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.

Smith TA, Phyu SM
Metformin Decouples Phospholipid Metabolism in Breast Cancer Cells.
PLoS One. 2016; 11(3):e0151179 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
INTRODUCTION: The antidiabetic drug metformin, currently undergoing trials for cancer treatment, modulates lipid and glucose metabolism both crucial in phospholipid synthesis. Here the effect of treatment of breast tumour cells with metformin on phosphatidylcholine (PtdCho) metabolism which plays a key role in membrane synthesis and intracellular signalling has been examined.
METHODS: MDA-MB-468, BT474 and SKBr3 breast cancer cell lines were treated with metformin and [3H-methyl]choline and [14C(U)]glucose incorporation and lipid accumulation determined in the presence and absence of lipase inhibitors. Activities of choline kinase (CK), CTP:phosphocholine cytidylyl transferase (CCT) and PtdCho-phospholipase C (PLC) were also measured. [3H] Radiolabelled metabolites were determined using thin layer chromatography.
RESULTS: Metformin-treated cells exhibited decreased formation of [3H]phosphocholine but increased accumulation of [3H]choline by PtdCho. CK and PLC activities were decreased and CCT activity increased by metformin-treatment. [14C] incorporation into fatty acids was decreased and into glycerol was increased in breast cancer cells treated with metformin incubated with [14C(U)]glucose.
CONCLUSION: This is the first study to show that treatment of breast cancer cells with metformin induces profound changes in phospholipid metabolism.

Drolez A, Vandenhaute E, Julien S, et al.
Selection of a Relevant In Vitro Blood-Brain Barrier Model to Investigate Pro-Metastatic Features of Human Breast Cancer Cell Lines.
PLoS One. 2016; 11(3):e0151155 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Around 7-17% of metastatic breast cancer patients will develop brain metastases, associated with a poor prognosis. To reach the brain parenchyma, cancer cells need to cross the highly restrictive endothelium of the Blood-Brain Barrier (BBB). As treatments for brain metastases are mostly inefficient, preventing cancer cells to reach the brain could provide a relevant and important strategy. For that purpose an in vitro approach is required to identify cellular and molecular interaction mechanisms between breast cancer cells and BBB endothelium, notably at the early steps of the interaction. However, while numerous studies are performed with in vitro models, the heterogeneity and the quality of BBB models used is a limitation to the extrapolation of the obtained results to in vivo context, showing that the choice of a model that fulfills the biological BBB characteristics is essential. Therefore, we compared pre-established and currently used in vitro models from different origins (bovine, mice, human) in order to define the most appropriate tool to study interactions between breast cancer cells and the BBB. On each model, the BBB properties and the adhesion capacities of breast cancer cell lines were evaluated. As endothelial cells represent the physical restriction site of the BBB, all the models consisted of endothelial cells from animal or human origins. Among these models, only the in vitro BBB model derived from human stem cells both displayed BBB properties and allowed measurement of meaningful different interaction capacities of the cancer cell lines. Importantly, the measured adhesion and transmigration were found to be in accordance with the cancer cell lines molecular subtypes. In addition, at a molecular level, the inhibition of ganglioside biosynthesis highlights the potential role of glycosylation in breast cancer cells adhesion capacities.

Papadakis E, Robson N, Yeomans A, et al.
A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells.
Oncotarget. 2016; 7(14):18851-64 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial.

Lorenzen EL, Brink C, Taylor CW, et al.
Uncertainties in estimating heart doses from 2D-tangential breast cancer radiotherapy.
Radiother Oncol. 2016; 119(1):71-6 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND AND PURPOSE: We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002.
MATERIAL AND METHODS: Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left-sided patients, mean heart dose was related to maximum heart distance in the medial field.
RESULTS: For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from <1Gy to >8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always <1Gy and maximum dose always <5Gy for all three regimens.
CONCLUSIONS: The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT-scans.

Sutton L, McGlone E, Lambert K
Do postoperative NSAIDs improve breast cancer outcomes? A Best Evidence Topic.
Int J Surg. 2016; 28:173-8 [PubMed] Related Publications
A Best Evidence Topic was undertaken to systematically review the evidence regarding the use of NSAIDS in breast cancer patients. The search strategy generated 149 titles, of which six were best placed to answer the clinical question. These included three prospective cohort studies, two retrospective cohort studies and one case control study, examining a total of 18,415 breast cancer patients. The study methodologies were highly variable and all relied on approximate measures of NSAID consumption. There is limited evidence that use of aspirin and non-aspirin NSAIDs may be associated with decreased breast cancer mortality and all-cause mortality in patients diagnosed with breast cancer. Optimum type and dosage of NSAID for this purpose remains unclear. There is a need for large-scale randomised controlled trials to further clarify.

Raimondi S, Botteri E, Munzone E, et al.
Use of beta-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers and breast cancer survival: Systematic review and meta-analysis.
Int J Cancer. 2016; 139(1):212-9 [PubMed] Related Publications
Breast cancer (BC) is the second leading cause of cancer death among women in Western Countries. Beta-blocker (BB) drugs, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) were suggested to have a favorable role in the development and progression of BC. We have performed a meta-analysis to clarify the potential benefits of these drugs on BC survival. A total number of 46 265 BC patients from eleven papers were included, ten independent studies on BB use and seven on ACEi/ARB use. The summary hazard ratio (SHR) was estimated by pooling the study-specific estimates with random effects models and maximum likelihood estimation. We assessed the homogeneity of the effects across studies and evaluated between-study heterogeneity by meta-regression and sensitivity analyses. We found a significant improvement in BC specific survival for patients treated with BB drugs at the time of BC diagnosis (SHR: 0.44; 95%CI: 0.26-0.73 with I(2) = 78%). We also observed a borderline significant improvement in disease free survival for subjects treated with BB (SHR: 0.71, 95%CI: 0.19-1.03). No association of ACEi/ARB use with disease free and overall survival was found. In conclusion, we report epidemiological evidence that BB improve BC-specific survival. Clinical trials addressing this hypothesis are warranted.

Laimighofer M, Krumsiek J, Buettner F, Theis FJ
Unbiased Prediction and Feature Selection in High-Dimensional Survival Regression.
J Comput Biol. 2016; 23(4):279-90 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
With widespread availability of omics profiling techniques, the analysis and interpretation of high-dimensional omics data, for example, for biomarkers, is becoming an increasingly important part of clinical medicine because such datasets constitute a promising resource for predicting survival outcomes. However, early experience has shown that biomarkers often generalize poorly. Thus, it is crucial that models are not overfitted and give accurate results with new data. In addition, reliable detection of multivariate biomarkers with high predictive power (feature selection) is of particular interest in clinical settings. We present an approach that addresses both aspects in high-dimensional survival models. Within a nested cross-validation (CV), we fit a survival model, evaluate a dataset in an unbiased fashion, and select features with the best predictive power by applying a weighted combination of CV runs. We evaluate our approach using simulated toy data, as well as three breast cancer datasets, to predict the survival of breast cancer patients after treatment. In all datasets, we achieve more reliable estimation of predictive power for unseen cases and better predictive performance compared to the standard CoxLasso model. Taken together, we present a comprehensive and flexible framework for survival models, including performance estimation, final feature selection, and final model construction. The proposed algorithm is implemented in an open source R package (SurvRank) available on CRAN.

Mascini NE, Cheng M, Jiang L, et al.
Mass Spectrometry Imaging of the Hypoxia Marker Pimonidazole in a Breast Tumor Model.
Anal Chem. 2016; 88(6):3107-14 [PubMed] Related Publications
Although tumor hypoxia is associated with tumor aggressiveness and resistance to cancer treatment, many details of hypoxia-induced changes in tumors remain to be elucidated. Mass spectrometry imaging (MSI) is a technique that is well suited to study the biomolecular composition of specific tissue regions, such as hypoxic tumor regions. Here, we investigate the use of pimonidazole as an exogenous hypoxia marker for matrix-assisted laser desorption/ionization (MALDI) MSI. In hypoxic cells, pimonidazole is reduced and forms reactive products that bind to thiol groups in proteins, peptides, and amino acids. We show that a reductively activated pimonidazole metabolite can be imaged by MALDI-MSI in a breast tumor xenograft model. Immunohistochemical detection of pimonidazole adducts on adjacent tissue sections confirmed that this metabolite is localized to hypoxic tissue regions. We used this metabolite to image hypoxic tissue regions and their associated lipid and small molecule distributions with MALDI-MSI. We identified a heterogeneous distribution of 1-methylnicotinamide and acetylcarnitine, which mostly colocalized with hypoxic tumor regions. As pimonidazole is a widely used immunohistochemical marker of tissue hypoxia, it is likely that the presented direct MALDI-MSI approach is also applicable to other tissues from pimonidazole-injected animals or humans.

Natrajan R, Sailem H, Mardakheh FK, et al.
Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology-Genomic Integration Analysis.
PLoS Med. 2016; 13(2):e1001961 [PubMed] Article available free on PMC after 01/07/2017 Related Publications
BACKGROUND: The intra-tumor diversity of cancer cells is under intense investigation; however, little is known about the heterogeneity of the tumor microenvironment that is key to cancer progression and evolution. We aimed to assess the degree of microenvironmental heterogeneity in breast cancer and correlate this with genomic and clinical parameters.
METHODS AND FINDINGS: We developed a quantitative measure of microenvironmental heterogeneity along three spatial dimensions (3-D) in solid tumors, termed the tumor ecosystem diversity index (EDI), using fully automated histology image analysis coupled with statistical measures commonly used in ecology. This measure was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set. In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or any other data types. However, this association was not observed in low-grade (grade 1 and 2) breast cancers. The prognostic value of EDI was superior to known prognostic factors and was enhanced with the addition of TP53 mutation status (multivariate analysis test set, p = 9 × 10-4, hazard ratio = 1.47, 95% CI 1.17-1.84; validation set, p = 0.0011, hazard ratio = 1.78, 95% CI 1.26-2.52). Integration with genome-wide profiling data identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors with high microenvironmental diversity that also substratified patients into poor prognostic groups. Limitations of this study include the number of cell types included in the model, that EDI has prognostic value only in grade 3 tumors, and that our spatial heterogeneity measure was dependent on spatial scale and tumor size.
CONCLUSIONS: To our knowledge, this is the first study to couple unbiased measures of microenvironmental heterogeneity with genomic alterations to predict breast cancer clinical outcome. We propose a clinically relevant role of microenvironmental heterogeneity for advanced breast tumors, and highlight that ecological statistics can be translated into medical advances for identifying a new type of biomarker and, furthermore, for understanding the synergistic interplay of microenvironmental heterogeneity with genomic alterations in cancer cells.

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