The MARECA (national study of management of breast cancer locoregional recurrence and oncological outcomes) study: protocol for a prospective, multicentre cohort study.

Background: Despite a UK 5-year breast cancer survival rate of 86.6%, patients may develop breast cancer recurrence within the same breast after breast conserving surgery, as well as in the remaining skin or chest wall after mastectomy or in the ipsilateral lymph glands. These recurrences, collectively termed locoregional recurrence (LRR), occur in around 8% of patients within 10 years of their original diagnosis. Currently, there is a lack of robust information on the presentation and prevalence of LRR with no UK-specific clinical guidelines available for the optimal management of this patient group. Additionally, there is a need to identify patterns of LRR presentation and their progression, which will enable prognostic factors to be determined. This will subsequently enable the tailoring of treatment and improve patient outcome. Methods: The MARECA study is a prospective, multicentre cohort study recruiting patients diagnosed with breast cancer LRR +/- associated distant metastases. Over 50 UK breast units are participating in the study with the aim of recruiting at least 500 patients over a recruitment period of 24 months. The data collected will detail the tumour pathology, imaging results, surgical treatment, radiotherapy and systemic therapy of the primary and recurrent breast cancer. Study follow-up will be for up to 5 years following LRR diagnosis to determine subsequent oncological outcomes and evaluate potential prognostic factors. Discussion: This study will address the current knowledge gap and identify subgroups of patients who have less successful treatment outcomes. The results will determine the current management of LRR and the prognosis of patients diagnosed with breast cancer LRR +/- distant metastases in the UK, with the aim of establishing best practice and informing future national guidelines. The results will direct future research and inform the design of additional interventional trials and translational studies.

Reevaluating Axillary Lymph Node Dissection in Total Mastectomy for Low Axillary Burden Breast Cancer: Insights from a Meta-Analysis including the SINODAR-ONE Trial.

Complete axillary lymph node dissection (cALND) was previously the standard of care for breast cancer (BC) patients with axillary node disease or macro-metastases found via sentinel lymph node biopsy (SLNB). However, due to significant morbidity, contemporary management now considers a more selective approach, influenced by studies like ACOSOG Z0011. This trial showed that cALND could be omitted without compromising local control or survival in patients with low axillary nodal disease burden undergoing breast-conserving therapy, radiotherapy, and systemic therapy. The relevance of this approach for women with low axillary nodal burden undergoing total mastectomy (TM) remained unclear. A PubMed search up to September 2023 identified 147 relevant studies, with 6 meeting the inclusion criteria, involving 4184 patients with BC and low-volume axillary disease (1-3 positive lymph nodes) undergoing TM. Postmastectomy radiotherapy receipt was similar in both groups. After a mean 7.2-year follow-up, both the pooled results and the meta-analysis revealed no significant differences in overall survival. The combined analysis of the published studies, including the subgroup analysis of the SINODAR-One trial, indicates no survival advantage for cALND over SLNB in T1-T2 breast cancer patients with 1-3 positive sentinel lymph nodes (pN1) undergoing mastectomy. This suggests that, following a multidisciplinary evaluation, cALND can be safely omitted. However, the impact of other patient, tumor, and treatment factors on survival requires consideration and therefore further prospective trials are needed for conclusive validation.

Mastitis and Mammary Abscess Management Audit (MAMMA) in the UK and Ireland.

BACKGROUND: The aim of this multicentre prospective audit was to describe the current practice in the management of mastitis and breast abscesses in the UK and Ireland, with a specific focus on rates of surgical intervention. METHODS: This audit was conducted in two phases from August 2020 to August 2021; a phase 1 practice survey and a phase 2 prospective audit. Primary outcome measurements for phase 2 included patient management pathway characteristics and treatment type (medical/radiological/surgical). RESULTS: A total of 69 hospitals participated in phase 2 (1312 patients). The key findings were a high overall rate of incision and drainage (21.0 per cent) and a lower than anticipated proportion of ultrasound-guided aspiration of breast abscesses (61.0 per cent). Significant variations were observed regarding the rate of incision and drainage (range 0-100 per cent; P < 0.001) and the rate of needle aspiration (range 12.5-100 per cent; P < 0.001) between individual units. Overall, 22.5 per cent of patients were admitted for inpatient treatment, out of whom which 72.9 per cent were commenced on intravenous antibiotics. The odds of undergoing incision and drainage for a breast abscess or being admitted for inpatient treatment were significantly higher if patients presented at the weekend compared with a weekday (P ≤ 0.023). Breast specialists reviewed 40.9 per cent of all patients directly, despite the majority of patients (74.2 per cent) presenting within working hours on weekdays. CONCLUSIONS: Variation in practice exists in the management of mastitis and breast abscesses, with high rates of incision and drainage in certain regions of the UK. There is an urgent need for a national best-practice toolbox to minimize practice variation and standardize patient care.

Mastitis and breast abscess is a painful infection of the breast. It is an extremely common breast problem. One in three women can get this condition at some stage in their life. To treat a breast abscess, the pus inside should be drained out of the body. This can be done either by cutting into the breast using surgery or by inserting a fine needle using an ultrasonography scan (which uses ultrasound). Fine-needle drainage has the benefit that it does not require admission to hospital. Surgery can cause the breast to look misshapen. It is unknown which method is used more often in the UK and Ireland. The aim of this study was to describe how mastitis and breast abscesses are treated in the UK and Ireland. This study involved a survey of practice (phase 1) and collection of data, which are routinely recorded for these patients (phase 2). This study involved 69 hospitals and 1312 patient records. One in five women had an operation for a breast abscess. This was higher than expected. Six in 10 women had a pus drainage using a fine needle. The chance of having an operation depended on the hospital. Women that came to hospital at the weekend were almost twice as likely to have an operation. One in five women were admitted to hospital. The chances of that more than doubled if a woman came to hospital at the weekend. There are differences in treatment of mastitis and breast abscesses across the UK and Ireland. Changes need to be put in place to make access to treatment more equal.

Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.

Omitting Sentinel Lymph Node Biopsy after Neoadjuvant Systemic Therapy for Clinically Node Negative HER2 Positive and Triple Negative Breast Cancer: A Pooled Analysis.

Recent advances in systemic treatment for breast cancer have been underpinned by recognising and exploiting subtype-specific vulnerabilities to achieve higher rates of pathologic complete response (pCR) after neo-adjuvant systemic therapy (NAST). This down-staging of disease has permitted safe surgical de-escalation in patients who respond well. Triple-negative (TNBC) or HER2-positive breast cancer is most likely to achieve complete radiological response (rCR) and pCR after NAST. Hence, for selected patients, particularly those who are clinically node-negative (cN0) at diagnosis, the probability of disease in the sentinel node after NAST could be low enough to justify omitting axillary surgery. The aim of this pooled analysis was to determine the rate of sentinel node positivity (ypN+) in patients with TNBC or HER2-positive breast cancer who were initially cN0, achieving rCR and/or pCR in the breast after NAST. MedLine was searched using appropriate search terms. Five studies (N = 3834) were included in the pooled analysis, yielding a pooled ypN+ rate of 2.16% (95% CI: 1.70-2.63). This is significantly lower than the acceptable false negative rate of sentinel lymph node biopsy (SLNB) and supports consideration of omission of SLNB in this subset of patients.

The Impact of COVID-19 on Clinical Nurse Specialists and Patients With Cancer: A Pan-Specialty Cross-sectional Survey.

PURPOSE/AIMS: Uptake and delivery of cancer services across the United Kingdom have been significantly impacted by the COVID-19 pandemic. This study aimed to understand the impact of the pandemic on the working practices of clinical nurse specialists and their patient interactions across different cancer specialties. DESIGN: We performed a cross-sectional survey exploring nurses' experiences of delivering care during the pandemic, as well as their perceptions of the concerns that cancer patients were experiencing. METHODS: Clinical nurse specialists working in London cancer services were invited to complete an online questionnaire. Nurses' experiences and their perceptions of patients' concerns were analyzed descriptively. RESULTS: Fifty-four nurses participated. Almost half had been redeployed to other clinical areas during the pandemic (n = 19). COVID-19 discussions added 5 to 10 minutes on average to most consultations, with nurses either working longer/unpaid hours (34%) or spending less time talking to patients about cancer (39%) to deal with this. Approximately 50% of nurses would have liked additional information and support from their hospital. CONCLUSIONS: Clinical nurse specialist time and resources have been stretched during the COVID-19 pandemic. Hospitals need to work with nursing staff to ensure the specific information needs of cancer patients are being met.

Primary radiotherapy and deep inferior epigastric perforator flap reconstruction for patients with breast cancer (PRADA): a multicentre, prospective, non-randomised, feasibility study.

BACKGROUND: Radiotherapy before mastectomy and autologous free-flap breast reconstruction can avoid adverse radiation effects on healthy donor tissues and delays to adjuvant radiotherapy. However, evidence for this treatment sequence is sparse. We aimed to explore the feasibility of preoperative radiotherapy followed by skin-sparing mastectomy and deep inferior epigastric perforator (DIEP) flap reconstruction in patients with breast cancer requiring mastectomy. METHODS: We conducted a prospective, non-randomised, feasibility study at two National Health Service trusts in the UK. Eligible patients were women aged older than 18 years with a laboratory diagnosis of primary breast cancer requiring mastectomy and post-mastectomy radiotherapy, who were suitable for DIEP flap reconstruction. Preoperative radiotherapy started 3-4 weeks after neoadjuvant chemotherapy and was delivered to the breast, plus regional nodes as required, at 40 Gy in 15 fractions (over 3 weeks) or 42·72 Gy in 16 fractions (over 3·2 weeks). Adverse skin radiation toxicity was assessed preoperatively using the Radiation Therapy Oncology Group toxicity grading system. Skin-sparing mastectomy and DIEP flap reconstruction were planned for 2-6 weeks after completion of preoperative radiotherapy. The primary endpoint was the proportion of open breast wounds greater than 1 cm width requiring a dressing at 4 weeks after surgery, assessed in all participants. This study is registered with ClinicalTrials.gov, NCT02771938, and is closed to recruitment. FINDINGS: Between Jan 25, 2016, and Dec 11, 2017, 33 patients were enrolled. At 4 weeks after surgery, four (12·1%, 95% CI 3·4-28·2) of 33 patients had an open breast wound greater than 1 cm. One (3%) patient had confluent moist desquamation (grade 3). There were no serious treatment-related adverse events and no treatment-related deaths. INTERPRETATION: Preoperative radiotherapy followed by skin-sparing mastectomy and immediate DIEP flap reconstruction is feasible and technically safe, with rates of breast open wounds similar to those reported with post-mastectomy radiotherapy. A randomised trial comparing preoperative radiotherapy with post-mastectomy radiotherapy is required to precisely determine and compare surgical, oncological, and breast reconstruction outcomes, including quality of life. FUNDING: Cancer Research UK, National Institute for Health Research.

The MARECA (national study of management of breast cancer locoregional recurrence and oncological outcomes) study: National practice questionnaire of United Kingdom multi-disciplinary decision making.

INTRODUCTION: Evidence based guidelines for the optimal management of breast cancer locoregional recurrence (LRR) are limited, with potential for variation in clinical practice. This national practice questionnaire (NPQ) was designed to establish the current practice of UK breast multidisciplinary teams (MDTs) regarding LRR management. METHODS: UK breast units were invited to take part in the MARECA study MDT NPQ. Scenario-based questions were used to elicit preference in pre-operative staging investigations, surgical management, and adjuvant therapy. RESULTS: 822 MDT members across 42 breast units (out of 144; 29%) participated in the NPQ (February-August 2021). Most units (95%) routinely performed staging CT scan, but bone scan was selectively performed (31%). For patients previously treated with breast conserving surgery (BCS) and radiotherapy, few units (7%) always/usually offered repeat BCS. However, in the absence of radiotherapy, most units (90%) always/usually offered repeat BCS. For patients presenting with isolated local recurrence following previous BCS and SLNB (sentinel lymph node biopsy), most units (95%) advocated repeat SLNB. Where SLNs could not be identified, 86% proceeded to a four-node axillary sampling procedure. For ER positive, HER2 negative, node negative local recurrence, 10% of units always/usually offered chemotherapy. For ER positive, HER2 negative, node positive local recurrence, this recommendation increased to 64%. For triple negative breast cancer local recurrence, 90% of units always/usually offered chemotherapy. CONCLUSION: This survey has highlighted where consistencies and variations exist in the multidisciplinary management of breast cancer LRR. However, further research is required to determine how these management patterns influence patient outcomes, which will further refine optimal treatment pathways.

Pre-pectoral Immediate Breast Reconstruction Following Conservative Mastectomy Using Acellular Dermal Matrix and Semi-smooth Implants.

BACKGROUND/AIM: Improvements in acellular dermal matrix (ADM) and surgical techniques have facilitated pre-pectoral immediate breast reconstruction (IBR). Outer shell texturing is a key risk factor for anaplastic large cell lymphoma, prompting this evaluation of reconstruction with nano-textured rounded implants. PATIENTS AND METHODS: Fifty-one consecutive patients underwent 72 pre-pectoral ADM-assisted (fenestrated SurgiMend™) IBRs using nano-textured implants (Sebbin™). Patients were invited to complete a satisfaction questionnaire, including aesthetic outcome (linear scale 0-10) during follow-up. RESULTS: Average mastectomy weight was 300 g (range=83-1,018 g). After a mean follow-up of 18.3 month, 2 patients (2.8%) had minor wound complications. One patient suffered nipple necrosis. Capsular contracture occurred in 5 cases (6.9%) and significant rippling in one case. No implants were lost. Patient-reported aesthetic outcomes had a mean score of 9.3 (range=3-10; N=71). CONCLUSION: Pre-pectoral ADM-assisted IBR using semi-smooth implants following NSM is reliable and safe, with a low incidence of complications and high patient satisfaction.

Pathologic Response of Associated Ductal Carcinoma In Situ to Neoadjuvant Systemic Therapy: A Systematic Review.

Contrary to traditional assumptions, recent evidence suggests that neoadjuvant systemic therapy (NST) given for invasive breast cancer may eradicate co-existent ductal carcinoma in-situ (DCIS), which may facilitate de-escalation of breast resections. The aim of this systematic review was to assess the eradication rate of DCIS by NST given for invasive breast cancer. Searches were performed in MEDLINE using appropriate search terms. Six studies (N = 659) in which pathological data were available regarding the presence of DCIS prior to neoadjuvant chemotherapy (NACT) were identified. Only one study investigating the impact of neoadjuvant endocrine therapy (NET) met the search criteria. After pooled analysis, post-NACT pathology showed no residual DCIS in 40.5% of patients (267/659; 95% CI: 36.8-44.3). There was no significant difference in DCIS eradication rate between triple negative breast cancer (TNBC) and HER2-positive disease (45% vs. 46% respectively). NET achieved eradication of DCIS in 15% of patients (9/59). Importantly, residual widespread micro-calcifications after NST did not necessarily indicate residual disease. In view of the results of the pooled analysis, the presence of extensive DCIS prior to NST should not mandate mastectomy and de-escalation to breast conserving surgery (BCS) should be considered in patients identified by contrast enhanced magnetic resonance imaging (CE-MRI).

Epstein-Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship.

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein-Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

Intraoperative [18F]FDG flexible autoradiography for tumour margin assessment in breast-conserving surgery: a first-in-human multicentre feasibility study.

INTRODUCTION: In women undergoing breast-conserving surgery (BCS), 20-25% require a re-operation as a result of incomplete tumour resection. An intra-operative technique to assess tumour margins accurately would be a major advantage. A novel method for intraoperative margin assessment was developed by applying a thin flexible scintillating film to specimens-flexible autoradiography (FAR) imaging. A single-arm, multi-centre study was conducted to evaluate the feasibility of intraoperative [18F]FDG FAR for the assessment of tumour margins in BCS. METHODS: Eighty-eight patients with invasive breast cancer undergoing BCS received ≤ 300 MBq of [18F]FDG 60-180 min pre-operatively. Following surgical excision, intraoperative FAR imaging was performed using the LightPath® Imaging System. The first 16 patients were familiarisation patients; the remaining 72 patients were entered into the main study. FAR images were analysed post-operatively by three independent readers. Areas of increased signal intensity were marked, mean normalised radiances and tumour-to-tissue background (TBR) determined, agreement between histopathological margin status and FAR assessed and radiation dose to operating theatre staff measured. Subgroup analyses were performed for various covariates, with thresholds set based on ROC curves. RESULTS: Data analysis was performed on 66 patients. Intraoperative margin assessment using FAR was completed on 385 margins with 46.2% sensitivity, 81.7% specificity, 8.1% PPV, 97.7% NPV and an overall accuracy of 80.5%, detecting both invasive carcinoma and DCIS. A subgroup analysis based on [18F]FDG activity present at time of imaging revealed an increased sensitivity (71.4%), PPV (9.3%) and NPV (98.4%) in the high-activity cohort with mean tumour radiance and TBR of 126.7 ± 45.7 photons/s/cm2/sr/MBq and 2.1 ± 0.5, respectively. Staff radiation exposure was low (38.2 ± 38.1 µSv). CONCLUSION: [18F]FDG FAR is a feasible and safe technique for intraoperative tumour margin assessment. Further improvements in diagnostic performance require optimising the method for scintillator positioning and/or the use of targeted radiopharmaceuticals. TRIAL REGISTRATION: Identifier: NCT02666079. Date of registration: 28 January 2016. URL: https://clinicaltrials.gov/ct2/show/NCT02666079 . ISRCTN registry: Reference: ISRCTN17778965. Date of registration: 11 February 2016. URL: http://www.isrctn.com/ISRCTN17778965 .

Defining a metabolic landscape of tumours: genome meets metabolism.

Cancer is a complex disease of multiple alterations occuring at the epigenomic, genomic, transcriptomic, proteomic and/or metabolic levels. The contribution of genetic mutations in cancer initiation, progression and evolution is well understood. However, although metabolic changes in cancer have long been acknowledged and considered a plausible therapeutic target, the crosstalk between genetic and metabolic alterations throughout cancer types is not clearly defined. In this review, we summarise the present understanding of the interactions between genetic drivers of cellular transformation and cancer-associated metabolic changes, and how these interactions contribute to metabolic heterogeneity of tumours. We discuss the essential question of whether changes in metabolism are a cause or a consequence in the formation of cancer. We highlight two modes of how metabolism contributes to tumour formation. One is when metabolic reprogramming occurs downstream of oncogenic mutations in signalling pathways and supports tumorigenesis. The other is where metabolic reprogramming initiates transformation being either downstream of mutations in oncometabolite genes or induced by chronic wounding, inflammation, oxygen stress or metabolic diseases. Finally, we focus on the factors that can contribute to metabolic heterogeneity in tumours, including genetic heterogeneity, immunomodulatory factors and tissue architecture. We believe that an in-depth understanding of cancer metabolic reprogramming, and the role of metabolic dysregulation in tumour initiation and progression, can help identify cellular vulnerabilities that can be exploited for therapeutic use.

Hyperpolarised 13C MRI: a new horizon for non-invasive diagnosis of aggressive breast cancer.

Hyperpolarised 13C MRI (HP-MRI) is a novel imaging technique that allows real-time analysis of metabolic pathways in vivo.1 The technology to conduct HP-MRI in humans has recently become available and is starting to be clinically applied. As knowledge of molecular biology advances, it is increasingly apparent that cancer cell metabolism is related to disease outcomes, with lactate attracting specific attention. 2 Recent reviews of breast cancer screening programs have raised concerns and increased public awareness of over treatment. The scientific community needs to shift focus from improving cancer detection alone to pursuing novel methods of distinguishing aggressive breast cancers from those which will remain indolent. HP-MRI offers the opportunity to identify aggressive tumour phenotypes and help monitor/predict therapeutic response. Here we report one of the first cases of breast cancer imaged using HP-MRI alongside correlative conventional imaging, including breast MRI.

Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.

Resistance to endocrine therapy remains a major clinical problem in breast cancer. Genetic studies highlight the potential role of estrogen receptor-α (ESR1) mutations, which show increased prevalence in the metastatic, endocrine-resistant setting. No naturally occurring ESR1 mutations have been reported in in vitro models of BC either before or after the acquisition of endocrine resistance making functional consequences difficult to study. We report the first discovery of naturally occurring ESR1 Y537C and ESR1 Y537S mutations in MCF7 and SUM44 ESR1-positive cell lines after acquisition of resistance to long-term-estrogen-deprivation (LTED) and subsequent resistance to fulvestrant (ICIR). Mutations were enriched with time, impacted on ESR1 binding to the genome and altered the ESR1 interactome. The results highlight the importance and functional consequence of these mutations and provide an important resource for studying endocrine resistance.

Differences in the transcriptional response to fulvestrant and estrogen deprivation in ER-positive breast cancer.

PURPOSE: Endocrine therapies include aromatase inhibitors and the selective estrogen receptor (ER) downregulator fulvestrant. This study aimed to determine whether the reported efficacy of fulvestrant over anastrozole, and high- over low-dose fulvestrant, reflect distinct transcriptional responses. EXPERIMENTAL DESIGN: Global gene expression profiles from ERα-positive breast carcinomas before and during presurgical treatment with fulvestrant (n = 22) or anastrozole (n = 81), and corresponding in vitro models, were compared. Transcripts responding differently to fulvestrant and estrogen deprivation were identified and integrated using Gene Ontology, pathway and network analyses to evaluate their potential significance. RESULTS: The overall transcriptional response to fulvestrant and estrogen deprivation was correlated (r = 0.61 in presurgical studies, r = 0.87 in vitro), involving downregulation of estrogen-regulated and proliferation-associated genes. The transcriptional response to fulvestrant was of greater magnitude than estrogen deprivation (slope = 0.62 in presurgical studies, slope = 0.63 in vitro). Comparative analyses identified 28 genes and 40 Gene Ontology categories affected differentially by fulvestrant. Seventeen fulvestrant-specific genes, including CAV1/2, SNAI2, and NRP1, associated with ERα, androgen receptor (AR), and TP53, in a network regulating cell cycle, death, survival, and tumor morphology. Eighteen genes responding differently to fulvestrant specifically predicted antiproliferative response to fulvestrant, but not anastrozole. Transcriptional effects of low-dose fulvestrant correlated with high-dose treatment, but were of lower magnitude (ratio = 0.29). CONCLUSIONS: The transcriptional response to fulvestrant has much in common with estrogen deprivation, but is stronger with distinctions potentially attributable to arrest of estrogen-independent ERα activity and involvement of AR signaling. Genes responding differently to fulvestrant may have predictive utility. These data are consistent with the clinical efficacy of fulvestrant versus anastrozole and higher dosing regimens.

Effect of aromatase inhibition on functional gene modules in estrogen receptor-positive breast cancer and their relationship with antiproliferative response.

PURPOSE: To investigate potential associations between gene modules representing key biologic processes and response to aromatase inhibitors (AI) in estrogen receptor-positive (ER(+)) breast cancer. PATIENTS AND METHODS: Paired gene expression and Ki67 protein expression were available from 69 postmenopausal women with ER(+) early breast cancer, at baseline and 2 weeks post-anastrozole treatment, in the presurgical setting. Functional gene modules (n = 26) were retrieved from published studies and their module scores were computed before and after elimination of proliferation-associated genes (PAG). Ki67 and module scores were assessed at baseline and 2 weeks post-anastrozole. Unsupervised clustering was used to assess associations between modules and Ki67. RESULTS: Proliferation-based modules were highly correlated with Ki67 expression both pretreatment and on-treatment. At baseline with and without PAGs, Ki67 expression was significantly inversely correlated with ERG, ESR1.2, SET, and PIK3CA modules. Modules measuring estrogen signaling strongly predicted antiproliferative response to therapy with and without PAGs. Baseline expression of insulin-like growth factor-1 (IGF-I) module predicted a poor change in Ki67-implicating genes within the module as involved in de novo resistance to AIs. High expression of Immune.2.STAT1 module pretreatment predicted poor antiproliferative response to therapy. A significant association between estrogen-regulated genes modules (ESR1, ESR1-2, SET, and ERG) was evident post AI. CONCLUSIONS: Multiple processes and pathways are affected by AI treatment in ER(+) breast cancer. Modules closely associated with ESR1 expression were predictive of good antiproliferative response to AIs, but modules representing immune activity and IGF-I/MAPK were predictive of poor Ki67 response, supporting their therapeutic targeting in combination with AIs.

Biomarkers for the clinical management of breast cancer: international perspective.

The higher incidence of breast cancer in developed countries has been tempered by reductions in mortality, largely attributable to mammographic screening programmes and advances in adjuvant therapy. Optimal systemic management requires consideration of clinical, pathological and biological parameters. Oestrogen receptor alpha (ERα), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER2) are established biomarkers evaluated at diagnosis, which identify cardinal subtypes of breast cancer. Their prognostic and predictive utility effectively guides systemic treatment with endocrine, anti-HER2 and chemotherapy. Hence, accurate and reliable determination remains of paramount importance. However, the goals of personalized medicine and targeted therapies demand further information regarding residual risk and potential benefit of additional treatments in specific circumstances. The need for biomarkers which are fit for purpose, and the demands placed upon them, is therefore expected to increase. Technological advances, in particular high-throughput global gene expression profiling, have generated multi-gene signatures providing further prognostic and predictive information. The rational integration of routinely evaluated clinico-pathological parameters with key indicators of biological activity, such as proliferation markers, also provides a ready opportunity to improve the information available to guide systemic therapy decisions. The additional value of such information and its proper place in patient management is currently under evaluation in prospective clinical trials. Expanding the utility of biomarkers to lower resource settings requires an emphasis on cost effectiveness, quality assurance and possible international variations in tumor biology; the potential for improved clinical outcomes should be justified against logistical and economic considerations.

Ductal carcinoma in situ: recent advances and future prospects.

Introduction. This article reviews current management strategies for DCIS in the context of recent randomised trials, including the role of sentinel lymph node biopsy (SLNB), adjuvant radiotherapy (RT) and endocrine treatment. Methods. Literature review facilitated by Medline, PubMed, Embase and Cochrane databases. Results. DCIS should be managed in the context of a multidisciplinary team. Local control depends upon clear surgical margins (at least 2 mm is generally acceptable). SLNB is not routine, but can be considered in patients undergoing mastectomy (Mx) with risk factors for occult invasion. RT following BCS significantly reduces local recurrence (LR), particularly in those at high-risk. There remains a lack of level-1 evidence supporting omission of adjuvant RT in selected low-risk cases. Large, multi-centric or recurrent lesions should be treated by Mx and immediate reconstruction should be discussed. Adjuvant hormonal treatment may reduce the risk of LR in selected cases with hormone sensitive disease. Conclusion. Further research is required to determine the role of new RT regimes and endocrine therapies. Biological profiling and molecular analysis represent an opportunity to improve our understanding of tumour biology in DCIS to rationalise treatment. Reliable identification of low-risk lesions could allow treatment to be less radical.