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.

Complex cross-talk between EZH2 and miRNAs confers hallmark characteristics and shapes the tumor microenvironment.

Cancer epigenetic mechanisms support the acquisition of hallmark characteristics during oncogenesis. EZH2 - an important histone methyltransferase that writes histone H3 lysine 27 trimethylation marks - is known to be dysregulated in cancer cells. However, the interactions between EZH2 and miRNAs that form a complex network of cross-talk and reciprocal regulation that enable cancer cells to acquire hallmark characteristics have been relatively poorly appreciated. The specific functions of EZH2 appear to be regulated by a vast array of miRNAs, which direct EZH2 toward regulation over the development of specific hallmark characteristics. This review discusses recent advances in the understanding of EZH2, focusing on its collaboration with miRNAs to orchestrate oncogenesis. These epigenetic processes promote the evasion of apoptosis/cell cycle arrest, cellular dedifferentiation and the establishment of a tumor microenvironment that facilitates local cancer cell invasion, anti-cancer drug resistance and evasion of the immune response.

Cancer epigenetics involves cellular processes that ensure that gene expression changes that enable cancer cells to outcompete their neighboring normal tissues are passed on from one cancer cell to the next. One key epigenetic player is called EZH2, which is an enzyme that transfers methyl (CH₃) groups from donor molecules to the histone proteins around which DNA is coiled. The transfer of methyl groups to histones ­ a process called histone methylation ­ silences the production of proteins from the genes coded in DNA. To achieve this goal, EZH2 is directed to affect specific genes through interactions with other molecules consisting of short sequences of RNA (a molecule similar in structure to DNA). The specific RNA molecules in question are called miRNAs or non-coding RNAs. These EZH2/miRNA interactions form a complex web of circuits that enables cancer cells to gain characteristics that give them a competitive advantage over their normal tissue neighbors. This review discusses recent advances in the understanding of the role of EZH2 in cancer formation, focusing on the interactions it has with miRNAs (and other non-coding RNAs) to organize many different processes linked with cancer formation. These processes include the avoidance of cell death or cell growth arrest, the development of stem cell properties and the formation of an environment around tumor cells that allows them to invade adjacent normal tissue (i.e., metastasize) and avoid being killed by anti-cancer drugs and the immune system.

Priority setting in breast reconstructive surgery: A DELPHI consensus.

OBJECTIVES: Breast reconstructive surgery is often performed following breast cancer treatment to restore the natural appearance of the breast. Despite various research performed in this field, there is a discrepancy between the research question that is considered crucial jointly by patients, carers and healthcare professionals and the research performed. The Breast Reconstruction Priority Setting Partnership was formed to determine the top research priorities in all aspects of breast reconstructive surgery. METHODS: The Priority Setting Partnership (PSP) was conducted in line with James Lind Alliance (JLA) principles involving patients and clinicians. An online survey was conducted to gather uncertainties related to breast reconstruction by involving patients, carers and clinicians. Following this, a modified Delphi consensus process was performed to identify the top 10 research priorities. RESULT: A total of 239 unique research uncertainties were identified via the online survey, which involved 100 participants. A review of literature established that 58 of these uncertainties did not have a high-quality systematic review, prompting the need for more in-depth research. A further 28 research uncertainties were obtained by performing a literature search. Of the final 86 unique questions, the Delphi panel achieved consensus on the top ten research priorities. Recommendations to address these research priorities have been put forward based on current evidence. CONCLUSION: This study involved patients, carers and healthcare professionals to establish the top 10 priority areas for research in breast reconstructive surgery. Recommendations have been put forward on the necessary future research that is required to address these uncertainties.

Breast Density Notification: Current UK National Practice.

Increased breast density is a risk factor for breast cancer and can mask cancer on mammography. This survey attempts to understand clinician views regarding breast density notification in the United Kingdom. Two separate breast density surveys were distributed to radiologists and breast surgeons between May 2019 and May 2020. Invited participants were members of the British Society of Breast Radiology and the Association of Breast Surgeons. We received 232 completed questionnaires from 109 surgeons (71%) and 123 radiologists (41%). Fourteen percent of the surgeons reported discussing the increased risk of developing cancer with their patients, and 20% of the surgeons recommended further imaging compared with 50% of the radiologists. Fifty-two percent of surgeons and 28% of radiologists felt women should not be informed of their breast density scores considering the lack of National Health Service-funded supplementary imaging. Almost all respondents of this survey called for guidelines regarding the reporting and management of UK patients with increased breast density (90%). Density notification is becoming increasingly central to breast screening, and our results highlight an urgent need for a national consensus.

A systematic review and meta-analysis on the effect of neoadjuvant chemotherapy on complications following immediate breast reconstruction.

BACKGROUND: The impact of neoadjuvant chemotherapy (NACT) on surgical outcomes following immediate breast reconstruction (IBR) remains unclear. While it is generally considered safe practice to perform an IBR post NACT, reported complication rates in published data are highly variable with the majority of studies including fewer than 50 patients in the NACT and IBR arm. To evaluate this further, we conducted a systematic review and meta-analysis on the effect of NACT on autologous and implant based immediate breast reconstructions. We aimed to assess for differences in the post-operative course following IBR between patients who received NACT with those who did not. METHODS: PubMed, EMBASE, and Cochrane Library were searched from 1995 to Sept 2, 2020 to identify articles that assessed the impact of NACT on IBR. All included studies assessed outcomes following IBR. Only studies comparing reconstructed patients receiving NACT to a control group of women who did not receive NACT were included. Unadjusted relative risk of outcomes between patients who received or did not receive NACT were synthesized using a fixed-effect meta-analysis. The evidence was assessed using the Newcastle Ottawa Scale scores and GRADE. Primary effect measures were risk ratios (RRs) with 95% confidence intervals. RESULTS: A total 17 studies comprising 3249 patients were included in the meta-analyses. Overall, NACT did not increase the risk of complications after immediate breast reconstructions (risk ratio [RR]: 0.91, 95% CI 0.74 to 1.11, p = 0.34). There was a moderate, but not significant, increase in flap loss following NACT compared with controls (RR: 1.23, 95% CI 0.70 to 2.18, p = 0.47; I2 = 0%). Most notably, there was a statistically significant increase in implant/expander loss after NACT (RR: 1.54, 95% CI 1.04 to 2.29, p = 0.03; I2 = 34%). NACT was not shown to significantly increase the incidence of hematomas, seromas or wound complications, or result in a significant delay to commencing adjuvant therapy (RR: 1.59, 95% CI 0.66 to 3.87, p = 0.30). CONCLUSION: Immediate breast reconstruction after NACT is a safe procedure with an acceptable post-operative complication profile. It may result in a slight increase in implant loss rates, but it does not delay commencing adjuvant therapy.

Oro-facial fibrosis in systemic sclerosis: a reconstructive journey.

Oro-facial fibrosis presents a significant disease burden in patients with systemic sclerosis, but there remains no established treatment modality. Autologous fat grafting is a minimally invasive surgical procedure that is now increasingly recognised for its regenerative capacity, propagating an expansion of heterogeneous indications beyond volume restoration, including fibrotic diseases such as systemic sclerosis. We present a 42-year-old woman with oro-facial involvement of systemic sclerosis leading to severe limitation in mouth opening and closure, with marked retraction of the lower lip and gingival display. We describe the reconstructive journey over a 12-year period, where the antifibrotic effect of autologous fat grafting served as the basis on which a series of surgical procedures were performed to achieve functional and aesthetic improvement. Autologous fat grafting provides a novel treatment modality for oro-facial skin fibrosis, previously considered a non-treatable disease manifestation of systemic sclerosis.

Measuring Differential Volume Using the Subtraction Tool for Three-Dimensional Breast Volumetry: A Proof of Concept Study.

Background. Three-dimensional (3D) photography provides a promising means of breast volumetry. Sources of error using a single-captured surface to calculate breast volume include inaccurate designation of breast boundaries and prediction of the invisible chest wall generated by computer software. An alternative approach is to measure differential volume using subtraction of 2 captured surfaces. Objectives. To explore 3D breast volumetry using the subtraction of superimposed images to calculate differential volume. To assess optimal patient positioning for accurate volumetric assessment. Methods. Known volumes of breast enhancers simulated volumetric changes to the breast (n = 12). 3D photographs were taken (3dMDtorso) with the subject positioned upright at 90° and posteriorly inclined at 30°. Patient position, breathing, distance and camera calibration were standardised. Volumetric analysis was performed using 3dMDvultus software. Results. A statistically significant difference was found between actual volume and measured volumes with subjects positioned at 90° (P < .05). No statistical difference was found at 30° (P = .078), but subsequent Bland-Altman analysis showed evidence of proportional bias (P < .05). There was good correlation between measured and actual volumes in both positions (r = .77 and r = .85, respectively). Univariate analyses showed breast enhancer volumes of 195 mL and 295 mL to incur bias. The coefficient of variation was 5.76% for single observer analysis. Conclusion. Positioning the subject at a 30° posterior incline provides more accurate results from better exposure of the inferior breast. The subtraction tool is a novel method of measuring differential volume. Future studies should explore methodology for application into the clinical setting.

Advances in Epigenetic Cancer Therapeutics.

Cancer has traditionally been hailed a genetic disease, dictated by successive genetic aberrations which alter gene expression. Yet, recent advances in molecular sequencing technologies, enabling the characterisation of cancer patient phenotypes on a large scale, have highlighted epigenetic changes as a hallmark of cancer. Epigenetic modifications, including DNA methylation and demethylation and histone modifications, have been found to play a key role in the pathogenesis of a wide variety of cancers through the regulation of chromatin state, gene expression and other nuclear events. Targeting epigenetic aberrations offers remarkable promise as a potential anti-cancer therapy given the reversible nature of epigenetic changes. Hence, epigenetic therapy has emerged as a rapidly advancing field of cancer research. A plethora of epigenetic therapies which inhibit enzymes of post-translational histone modifications, so-called 'writers', 'erasers' and 'readers', have been developed, with several epigenetic inhibitor agents approved for use in routine clinical practice. Epigenetic therapeutics inhibit the methylation or demethylation and acetylation or deacetylation of DNA and histone proteins. Their targets include writers (DNA methyltransferases [DNMT], histone acetyltransferases [HAT] and histone deacetylases [HDAC]) and erasers (histone demethylases [HDM] and histone methylases [HMT]). With new epigenetic mechanisms increasingly being elucidated, a vast array of targets and therapeutics have been brought to the fore. This review discusses recent advances in cancer epigenetics with a focus on molecular targets and mechanisms of action of epigenetic cancer therapeutics.

Fat Hypertrophy as a Complication of Fat Transfer for Hemifacial Atrophy.

Fat hypertrophy is a less commonly known complication of autologous fat transfer. We present a 32-year-old female with left hemifacial atrophy associated with systemic sclerosis, who was treated with 7 fat transfer procedures to correct the facial asymmetry. A total of 236.5 mL of fat was injected to the hemiface over a 4-year period to achieve good symmetry. A progressively enlarging, painless, soft mass over the left parotid region was noted at 3 months after the final fat transfer procedure. Magnetic resonance imaging showed a markedly enlarged bulk of subcutaneous fat over the left cheek with no evidence of necrosis, edema, or pathologic enhancement. Concurrent weight gain was noted secondary to additional nutritional input. The patient's aesthetic, symptomatic, and functional concerns led to the subsequent removal of 115 mL fat by liposuction.

Historical Overview of Stem Cell Biology and Fat Grafting.

The last two decades have seen significant advances within the field of adipose stromal cell transfers, with novel clinical applications being published every few months. This article gives a brief historical overview of the development of stem cell biology and fat grafting.

Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy.

BACKGROUND: The applications for fat grafting have increased recently, within both regenerative and reconstructive surgery. Although fat harvesting, processing and injection techniques have been extensively studied and standardised, this has not had a big impact on the variability of outcome following fat grafting. This suggests a possible larger role of patient characteristics on adipocyte and adipose-derived stem cell (ADSC) viability and function. This systematic review aims to collate current evidence on the effect of patient factors on adipocyte and ADSC behaviour. METHODS: A systematic literature review was performed using MEDLINE, Cochrane Library and EMBASE. It includes outcomes observed in in vitro analyses, in vivo animal studies and clinical studies. Data from basic science work have been included in the discussion to enhance our understanding of the mechanism behind ADSC behaviour. RESULTS: A total of 41 papers were included in this review. Accumulating evidence indicates decreased proliferation and differentiation potential of ADSCs with increasing age, body mass index, diabetes mellitus and exposure to radiotherapy and Tamoxifen, although this was not uniformly seen across all studies. Gender, donor site preference, HIV status and chemotherapy did not show a significant influence on fat retention. Circulating oestrogen levels have been shown to support both adipocyte function and graft viability. Evidence so far suggests no significant impact of total cholesterol, hypertension, renal disease, physical exercise and peripheral vascular disease on ADSC yield. CONCLUSIONS: A more uniform comparison of all factors highlighted in this review, with the application of a combination of tests for each outcome measure, is essential to fully understand factors that affect adipocyte and ADSC viability, as well as functionality. As these patient factors interact, future studies looking at adipocyte viability need to take them into consideration for conclusions to be meaningful. This would provide crucial information for surgeons when deciding appropriate volumes of lipoaspirate to inject, improve patient selection, and counsel patient expectations with regards to outcomes and likelihood for repeat procedures. An improved understanding will also assist in identification of patient groups that would benefit from graft enrichment and cryopreservation techniques.

Large-scale genotyping identifies a new locus at 22q13.2 associated with female breast size.

BACKGROUND: Individual differences in breast size are a conspicuous feature of variation in human females and have been associated with fecundity and advantage in selection of mates. To identify common variants that are associated with breast size, we conducted a large-scale genotyping association meta-analysis in 7169 women of European descent across three independent sample collections with digital or screen film mammograms. METHODS: The samples consisted of the Swedish KARMA, LIBRO-1 and SASBAC studies genotyped on iCOGS, a custom illumina iSelect genotyping array comprising of 211 155 single nucleotide polymorphisms (SNPs) designed for replication and fine mapping of common and rare variants with relevance to breast, ovary and prostate cancer. Breast size of each subject was ascertained by measuring total breast area (mm(2)) on a mammogram. RESULTS: We confirm genome-wide significant associations at 8p11.23 (rs10086016, p=1.3×10(-14)) and report a new locus at 22q13 (rs5995871, p=3.2×10(-8)). The latter region contains the MKL1 gene, which has been shown to impact endogenous oestrogen receptor α transcriptional activity and is recruited on oestradiol sensitive genes. We also replicated previous genome-wide association study findings for breast size at four other loci. CONCLUSIONS: A new locus at 22q13 may be associated with female breast size.

The heritability of mammographic breast density and circulating sex-hormone levels: two independent breast cancer risk factors.

BACKGROUND: Mammographic breast density and endogenous sex-hormone levels are both strong risk factors for breast cancer. This study investigated whether there is evidence for a shared genetic basis between these risk factors. METHODS: Using data on 1,286 women from 617 families, we estimated the heritabilities of serum estradiol, testosterone, and sex-hormone binding globulin (SHBG) levels and of three measures of breast density (dense area, nondense area, and percentage density). We tested for associations between hormone levels and density measures and estimated the genetic and environmental correlations between pairs of traits using variance and covariance components models and pedigree-based maximum likelihood methods. RESULTS: We found no significant associations between estradiol, testosterone, or SHBG levels and any of the three density measures, after adjusting for body mass index (BMI). The estimated heritabilities were 63%, 66%, and 65% for square root-transformed adjusted percentage density, dense area, and nondense area, respectively, and 40%, 25%, and 58% for log-transformed-adjusted estradiol, testosterone, and SHBG. We found no evidence of a shared genetic basis between any hormone levels and any measure of density, after adjusting for BMI. The negative genetic correlation between dense and nondense areas remained significant even after adjustment for BMI and other covariates (ρ = -0.34; SE = 0.08; P = 0.0005). CONCLUSIONS: Breast density and sex hormones can be considered as independent sets of traits. IMPACT: Breast density and sex hormones can be used as intermediate phenotypes in the search for breast cancer susceptibility loci.

Identification of a novel percent mammographic density locus at 12q24.

Percent mammographic density adjusted for age and body mass index (BMI) is one of the strongest risk factors for breast cancer and has a heritable component that remains largely unidentified. We performed a three-stage genome-wide association study (GWAS) of percent mammographic density to identify novel genetic loci associated with this trait. In stage 1, we combined three GWASs of percent density comprised of 1241 women from studies at the Mayo Clinic and identified the top 48 loci (99 single nucleotide polymorphisms). We attempted replication of these loci in 7018 women from seven additional studies (stage 2). The meta-analysis of stage 1 and 2 data identified a novel locus, rs1265507 on 12q24, associated with percent density, adjusting for age and BMI (P = 4.43 × 10(-8)). We refined the 12q24 locus with 459 additional variants (stage 3) in a combined analysis of all three stages (n = 10 377) and confirmed that rs1265507 has the strongest association in the 12q24 region (P = 1.03 × 10(-8)). Rs1265507 is located between the genes TBX5 and TBX3, which are members of the phylogenetically conserved T-box gene family and encode transcription factors involved in developmental regulation. Understanding the mechanism underlying this association will provide insight into the genetics of breast tissue composition.

Common breast cancer susceptibility variants in LSP1 and RAD51L1 are associated with mammographic density measures that predict breast cancer risk.

BACKGROUND: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures. METHODS: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status. RESULTS: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07). CONCLUSION: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland. IMPACT: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.

Mammographic breast density and breast cancer: evidence of a shared genetic basis.

Percent mammographic breast density (PMD) is a strong heritable risk factor for breast cancer. However, the pathways through which this risk is mediated are still unclear. To explore whether PMD and breast cancer have a shared genetic basis, we identified genetic variants most strongly associated with PMD in a published meta-analysis of five genome-wide association studies (GWAS) and used these to construct risk scores for 3,628 breast cancer cases and 5,190 controls from the UK2 GWAS of breast cancer. The signed per-allele effect estimates of single-nucleotide polymorphisms (SNP) were multiplied with the respective allele counts in the individual and summed over all SNPs to derive the risk score for an individual. These scores were included as the exposure variable in a logistic regression model with breast cancer case-control status as the outcome. This analysis was repeated using 10 different cutoff points for the most significant density SNPs (1%-10% representing 5,222-50,899 SNPs). Permutation analysis was also conducted across all 10 cutoff points. The association between risk score and breast cancer was significant for all cutoff points from 3% to 10% of top density SNPs, being most significant for the 6% (2-sided P = 0.002) to 10% (P = 0.001) cutoff points (overall permutation P = 0.003). Women in the top 10% of the risk score distribution had a 31% increased risk of breast cancer [OR = 1.31; 95% confidence interval (CI), 1.08-1.59] compared with women in the bottom 10%. Together, our results show that PMD and breast cancer have a shared genetic basis that is mediated through a large number of common variants.

Common variants in ZNF365 are associated with both mammographic density and breast cancer risk.

High-percent mammographic density adjusted for age and body mass index is one of the strongest risk factors for breast cancer. We conducted a meta analysis of five genome-wide association studies of percent mammographic density and report an association with rs10995190 in ZNF365 (combined P = 9.6 × 10(-10)). Common variants in ZNF365 have also recently been associated with susceptibility to breast cancer.