Showing papers on "Breast cancer published in 2013"

Breast Cancer Statistics

Abstract: Among U.S. women, breast cancer is the most commonly diagnosed cancer (excluding skin cancers) and the second leading cause of cancer death, following lung cancer. In 2012, an estimated 226,870 new cases of invasive breast cancer and 39,510 breast cancer deaths are expected to occur among U.S. women. Breast cancer rates vary largely by race/ethnicity and socioeconomic status (SES), and geographic region. Death rates are higher in African American women than in whites, despite their lower incidence rates. Historically, breast cancer was recognized as a disease of western countries. However, over the past 20 years, breast cancer incidence and mortality rates have been increasing rapidly in economically less developed regions. According to 2008 GLOBOCAN estimates, half of the new worldwide breast cancer cases (1.38 million) and 60 % of the breast cancer deaths (458,000) occurred in developing countries. This chapter reviews breast cancer incidence and mortality patterns among women in the U.S. and worldwide, and the possible explanations for these patterns.

Risk of Ischemic Heart Disease in Women After Radiotherapy for Breast Cancer

Abstract: Background Radiotherapy for breast cancer often involves some incidental exposure of the heart to ionizing radiation. The effect of this exposure on the subsequent risk of ischemic heart disease is uncertain. Methods We conducted a population-based case-control study of major coronary events (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease) in 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001 in Sweden and Denmark; the study included 963 women with major coronary events and 1205 controls. Individual patient information was obtained from hospital records. For each woman, the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from her radiotherapy chart. Results The overall average of the mean doses to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with the mean dose to the heart by 7.4% per gray (95% confidence interval, 2.9 to 14.5; P Conclusions Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease. The increase is proportional to the mean dose to the heart, begins within a few years after exposure, and continues for at least 20 years. Women with preexisting cardiac risk factors have greater absolute increases in risk from radiotherapy than other women. (Funded by Cancer Research UK and others.).

Evaluation of Factors Related to Late Recurrence - Later than 10 Years after the Initial Treatment - in Primary Breast Cancer

Abstract: Background: Breast cancer is associated with a relatively good prognosis. Prognostic factors examined to date are related to early recurrence while those related

Analysis of Circulating Tumor DNA to Monitor Metastatic Breast Cancer

Abstract: Background The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer. Methods We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points. Results Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%). Conclusions This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.)

Global estimates of cancer prevalence for 27 sites in the adult population in 2008

Abstract: Recent estimates of global cancer incidence and survival were used to update previous figures of limited duration prevalence to the year 2008. The number of patients with cancer diagnosed between 2004 and 2008 who were still alive at the end of 2008 in the adult population is described by world region, country and the human development index. The 5-year global cancer prevalence is estimated to be 28.8 million in 2008. Close to half of the prevalence burden is in areas of very high human development that comprise only one-sixth of the world's population. Breast cancer continues to be the most prevalent cancer in the vast majority of countries globally; cervix cancer is the most prevalent cancer in much of Sub-Saharan Africa and Southern Asia and prostate cancer dominates in North America, Oceania and Northern and Western Europe. Stomach cancer is the most prevalent cancer in Eastern Asia (including China); oral cancer ranks as the most prevalent cancer in Indian men and Kaposi sarcoma has the highest 5-year prevalence among men in 11 countries in Sub-Saharan Africa. The methods used to estimate point prevalence appears to give reasonable results at the global level. The figures highlight the need for long-term care targeted at managing patients with certain very frequently diagnosed cancer forms. To be of greater relevance to cancer planning, the estimation of other time-based measures of global prevalence is warranted.

Screening for breast cancer with mammography.

Abstract: Screening with mammography uses X-ray imaging to find breast cancer before a lump can be felt. The goal is to treat cancer earlier, when a cure is more likely. The review includes seven trials that involved 600,000 women in the age range 39 to 74 years who were randomly assigned to receive screening mammograms or not. The studies which provided the most reliable information showed that screening did not reduce breast cancer mortality. Studies that were potentially more biased (less carefully done) found that screening reduced breast cancer mortality. However, screening will result in some women getting a cancer diagnosis even though their cancer would not have led to death or sickness. Currently, it is not possible to tell which women these are, and they are therefore likely to have breasts or lumps removed and to receive radiotherapy unnecessarily. If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that overdiagnosis and overtreatment is at 30%, it means that for every 2000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings. Women invited to screening should be fully informed of both the benefits and harms. To help ensure that the requirements for informed choice for women contemplating whether or not to attend a screening programme can be met, we have written an evidence-based leaflet for lay people that is available in several languages on www.cochrane.dk. Because of substantial advances in treatment and greater breast cancer awareness since the trials were carried out, it is likely that the absolute effect of screening today is smaller than in the trials. Recent observational studies show more overdiagnosis than in the trials and very little or no reduction in the incidence of advanced cancers with screening.

Mitosis detection in breast cancer histology images with deep neural networks.

Abstract: We use deep max-pooling convolutional neural networks to detect mitosis in breast histology images. The networks are trained to classify each pixel in the images, using as context a patch centered on the pixel. Simple postprocessing is then applied to the network output. Our approach won the ICPR 2012 mitosis detection competition, outperforming other contestants by a significant margin.

Prognostic and Predictive Value of Tumor-Infiltrating Lymphocytes in a Phase III Randomized Adjuvant Breast Cancer Trial in Node-Positive Breast Cancer Comparing the Addition of Docetaxel to Doxorubicin With Doxorubicin-Based Chemotherapy: BIG 02-98

Abstract: Purpose Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT—in this case, anthracycline-only CT—in selected BC subtypes. Patients and Methods We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years.

Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis

Abstract: Summary Background The body of evidence related to breast-cancer-related lymphoedema incidence and risk factors has substantially grown and improved in quality over the past decade. We assessed the incidence of unilateral arm lymphoedema after breast cancer and explored the evidence available for lymphoedema risk factors. Methods We searched Academic Search Elite, Cumulative Index to Nursing and Allied Health, Cochrane Central Register of Controlled Trials (clinical trials), and Medline for research articles that assessed the incidence or prevalence of, or risk factors for, arm lymphoedema after breast cancer, published between Jan 1, 2000, and June 30, 2012. We extracted incidence data and calculated corresponding exact binomial 95% CIs. We used random effects models to calculate a pooled overall estimate of lymphoedema incidence, with subgroup analyses to assess the effect of different study designs, countries of study origin, diagnostic methods, time since diagnosis, and extent of axillary surgery. We assessed risk factors and collated them into four levels of evidence, depending on consistency of findings and quality and quantity of studies contributing to findings. Findings 72 studies met the inclusion criteria for the assessment of lymphoedema incidence, giving a pooled estimate of 16·6% (95% CI 13·6–20·2). Our estimate was 21·4% (14·9–29·8) when restricted to data from prospective cohort studies (30 studies). The incidence of arm lymphoedema seemed to increase up to 2 years after diagnosis or surgery of breast cancer (24 studies with time since diagnosis or surgery of 12 to Interpretation Our findings suggest that more than one in five women who survive breast cancer will develop arm lymphoedema. A clear need exists for improved understanding of contributing risk factors, as well as of prevention and management strategies to reduce the individual and public health burden of this disabling and distressing disorder. Funding The National Breast Cancer Foundation, Australia.

Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials

Abstract: RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.781.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer: The ACOSOG Z1071 (Alliance) Clinical Trial

Abstract: IMPORTANCE Sentinel lymph node (SLN) surgery provides reliable nodal staging information with less morbidity than axillary lymph node dissection (ALND) for patients with clinically node-negative (cN0) breast cancer. The application of SLN surgery for staging the axilla following chemotherapy for women who initially had node-positive cN1 breast cancer is unclear because of high false-negative results reported in previous studies.

Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value

Abstract: Background Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses.

Large-scale genotyping identifies 41 new loci associated with breast cancer risk

Abstract: Breast cancer is the most common cancer among women Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC) The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)) Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility

The UK Standardisation of Breast Radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials

Abstract: Summary Background 5-year results of the UK Standardisation of Breast Radiotherapy (START) trials suggested that lower total doses of radiotherapy delivered in fewer, larger doses (fractions) are at least as safe and effective as the historical standard regimen (50 Gy in 25 fractions) for women after primary surgery for early breast cancer. In this prespecified analysis, we report the 10-year follow-up of the START trials testing 13 fraction and 15 fraction regimens. Methods From 1999 to 2002, women with completely excised invasive breast cancer (pT1–3a, pN0–1, M0) were enrolled from 35 UK radiotherapy centres. Patients were randomly assigned to a treatment regimen after primary surgery followed by chemotherapy and endocrine treatment (where prescribed). Randomisation was computer-generated and stratified by centre, type of primary surgery (breast-conservation surgery or mastectomy), and tumour bed boost radiotherapy. In START-A, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 41·6 Gy or 39 Gy in 13 fractions over 5 weeks. In START-B, a regimen of 50 Gy in 25 fractions over 5 weeks was compared with 40 Gy in 15 fractions over 3 weeks. Eligibility criteria included age older than 18 years and no immediate surgical reconstruction. Primary endpoints were local-regional tumour relapse and late normal tissue effects. Analysis was by intention to treat. Follow-up data are still being collected. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. Findings START-A enrolled 2236 women. Median follow-up was 9·3 years (IQR 8·0–10·0), after which 139 local-regional relapses had occurred. 10-year rates of local-regional relapse did not differ significantly between the 41·6 Gy and 50 Gy regimen groups (6·3%, 95% CI 4·7–8·5 vs 7·4%, 5·5–10·0; hazard ratio [HR] 0·91, 95% CI 0·59–1·38; p=0·65) or the 39 Gy (8·8%, 95% CI 6·7–11·4) and 50 Gy regimen groups (HR 1·18, 95% CI 0·79–1·76; p=0·41). In START-A, moderate or marked breast induration, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 39 Gy group than in the 50 Gy group. Normal tissue effects did not differ significantly between 41·6 Gy and 50 Gy groups. START-B enrolled 2215 women. Median follow-up was 9·9 years (IQR 7·5–10·1), after which 95 local-regional relapses had occurred. The proportion of patients with local-regional relapse at 10 years did not differ significantly between the 40 Gy group (4·3%, 95% CI 3·2–5·9) and the 50 Gy group (5·5%, 95% CI 4·2–7·2; HR 0·77, 95% CI 0·51–1·16; p=0·21). In START-B, breast shrinkage, telangiectasia, and breast oedema were significantly less common normal tissue effects in the 40 Gy group than in the 50 Gy group. Interpretation Long-term follow-up confirms that appropriately dosed hypofractionated radiotherapy is safe and effective for patients with early breast cancer. The results support the continued use of 40 Gy in 15 fractions, which has already been adopted by most UK centres as the standard of care for women requiring adjuvant radiotherapy for invasive early breast cancer. Funding Cancer Research UK, UK Medical Research Council, UK Department of Health.

Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study

Abstract: Summary Background The optimum timing of sentinel-lymph-node biopsy for breast cancer patients treated with neoadjuvant chemotherapy is uncertain. The SENTINA (SENTinel NeoAdjuvant) study was designed to evaluate a specific algorithm for timing of a standardised sentinel-lymph-node biopsy procedure in patients who undergo neoadjuvant chemotherapy. Methods SENTINA is a four-arm, prospective, multicentre cohort study undertaken at 103 institutions in Germany and Austria. Women with breast cancer who were scheduled for neoadjuvant chemotherapy were enrolled into the study. Patients with clinically node-negative disease (cN0) underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arm A). If the sentinel node was positive (pN1), a second sentinel-lymph-node biopsy procedure was done after neoadjuvant chemotherapy (arm B). Women with clinically node-positive disease (cN+) received neoadjuvant chemotherapy. Those who converted to clinically node-negative disease after chemotherapy (ycN0; arm C) were treated with sentinel-lymph-node biopsy and axillary dissection. Only patients whose clinical nodal status remained positive (ycN1) underwent axillary dissection without sentinel-lymph-node biopsy (arm D). The primary endpoint was accuracy (false-negative rate) of sentinel-lymph-node biopsy after neoadjuvant chemotherapy for patients who converted from cN1 to ycN0 disease during neoadjuvant chemotherapy (arm C). Secondary endpoints included comparison of the detection rate of sentinel-lymph-node biopsy before and after neoadjuvant chemotherapy, and also the false-negative rate and detection rate of sentinel-lymph-node biopsy after removal of the sentinel lymph node. Analyses were done according to treatment received (per protocol). Findings Of 1737 patients who received treatment, 1022 women underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arms A and B), with a detection rate of 99·1% (95% CI 98·3–99·6; 1013 of 1022). In patients who converted after neoadjuvant chemotherapy from cN+ to ycN0 (arm C), the detection rate was 80·1% (95% CI 76·6–83·2; 474 of 592) and false-negative rate was 14·2% (95% CI 9·9–19·4; 32 of 226). The false-negative rate was 24·3% (17 of 70) for women who had one node removed and 18·5% (10 of 54) for those who had two sentinel nodes removed (arm C). In patients who had a second sentinel-lymph-node biopsy procedure after neoadjuvant chemotherapy (arm B), the detection rate was 60·8% (95% CI 55·6–65·9; 219 of 360) and the false-negative rate was 51·6% (95% CI 38·7–64·2; 33 of 64). Interpretation Sentinel-lymph-node biopsy is a reliable diagnostic method before neoadjuvant chemotherapy. After systemic treatment or early sentinel-lymph-node biopsy, the procedure has a lower detection rate and a higher false-negative rate compared with sentinel-lymph-node biopsy done before neoadjuvant chemotherapy. These limitations should be considered if biopsy is planned after neoadjuvant chemotherapy. Funding Brustkrebs Deutschland, German Society for Senology, German Breast Group.

Clinical Ascertainment of Health Outcomes Among Adults Treated for Childhood Cancer

Abstract: Importance Adult survivors of childhood cancer are known to be at risk for treatment-related adverse health outcomes. A large population of survivors has not been evaluated using a comprehensive systematic clinical assessment to determine the prevalence of chronic health conditions. Objective To determine the prevalence of adverse health outcomes and the proportion associated with treatment-related exposures in a large cohort of adult survivors of childhood cancer. Design, Setting, and Participants Presence of health outcomes was ascertained using systematic exposure–based medical assessments among 1713 adult (median age, 32 [range, 18-60] years) survivors of childhood cancer (median time from diagnosis, 25 [range, 10-47] years) enrolled in the St Jude Lifetime Cohort Study since October 1, 2007, and undergoing follow-up through October 31, 2012. Main Outcomes and Measures Age-specific cumulative prevalence of adverse outcomes by organ system. Results Using clinical criteria, the crude prevalence of adverse health outcomes was highest for pulmonary (abnormal pulmonary function, 65.2% [95% CI, 60.4%-69.8%]), auditory (hearing loss, 62.1% [95% CI, 55.8%-68.2%]), endocrine or reproductive (any endocrine condition, such as hypothalamic-pituitary axis disorders and male germ cell dysfunction, 62.0% [95% CI, 59.5%-64.6%]), cardiac (any cardiac condition, such as heart valve disorders, 56.4% [95% CI, 53.5%-59.2%]), and neurocognitive (neurocognitive impairment, 48.0% [95% CI, 44.9%-51.0%]) function, whereas abnormalities involving hepatic (liver dysfunction, 13.0% [95% CI, 10.8%-15.3%]), skeletal (osteoporosis, 9.6% [95% CI, 8.0%-11.5%]), renal (kidney dysfunction, 5.0% [95% CI, 4.0%-6.3%]), and hematopoietic (abnormal blood cell counts, 3.0% [95% CI, 2.1%-3.9%]) function were less common. Among survivors at risk for adverse outcomes following specific cancer treatment modalities, the estimated cumulative prevalence at age 50 years was 21.6% (95% CI, 19.3%-23.9%) for cardiomyopathy, 83.5% (95% CI, 80.2%-86.8%) for heart valve disorder, 81.3% (95% CI, 77.6%-85.0%) for pulmonary dysfunction, 76.8% (95% CI, 73.6%-80.0%) for pituitary dysfunction, 86.5% (95% CI, 82.3%-90.7%) for hearing loss, 31.9% (95% CI, 28.0%-35.8%) for primary ovarian failure, 31.1% (95% CI, 27.3%-34.9%) for Leydig cell failure, and 40.9% (95% CI, 32.0%-49.8%) for breast cancer. At age 45 years, the estimated cumulative prevalence of any chronic health condition was 95.5% (95% CI, 94.8%-98.6%) and 80.5% (95% CI, 73.0%-86.6%) for a serious/disabling or life-threatening chronic condition. Conclusions and Relevance Among adult survivors of childhood cancer, the prevalence of adverse health outcomes was high, and a systematic risk-based medical assessment identified a substantial number of previously undiagnosed problems that are more prevalent in an older population. These findings underscore the importance of ongoing health monitoring for adults who survive childhood cancer.

ESR1 ligand-binding domain mutations in hormone-resistant breast cancer

Abstract: Sarat Chandarlapaty and colleagues report the identification of mutations in the ESR1 gene affecting the ligand-binding domain of the encoded estrogen receptor in 20% of metastatic hormone-resistant breast cancers. They determine that the mutant receptor has a hormone-independent active state that likely promotes resistance to estrogen-depriving therapies. Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit.

Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-Term Follow-Up of CALGB 9343

Abstract: Purpose To determine whether there is a benefit to adjuvant radiation therapy after breast-conserving surgery and tamoxifen in women age 70 years with early-stage breast cancer. Patients and Methods Between July 1994 and February 1999, 636 women (age 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) –positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women). Primary end points were time to local or regional recurrence, frequency of mastectomy, breast cancer–specific survival, time to distant metastasis, and overall survival (OS). Results Median follow-up for treated patients is now 12.6 years. At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences. There were no significant differences in time to mastectomy, time to distant metastasis, breast cancer–specific survival, or OS between the two groups. Ten-year OS was 67% (95% CI, 62% to 72%) and 66% (95% CI, 61% to 71%) in the TamRT and Tam groups, respectively. Conclusion With long-term follow-up, the previously observed small improvement in locoregional recurrence with the addition of radiation therapy remains. However, this does not translate into an advantage in OS, distant disease-free survival, or breast preservation. Depending on the value placed on local recurrence, Tam remains a reasonable option for women age 70 years with ER-positive early-stage breast cancer.

Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay

Abstract: It has been hypothesized that carcinoma metastasis is initiated by a subpopulation of circulating tumor cells (CTCs) found in the blood of patients. However, although the presence of CTCs is an indicator of poor prognosis in several carcinoma entities, the existence and phenotype of metastasis-initiating cells (MICs) among CTCs has not been experimentally demonstrated. Here we developed a xenograft assay and used it to show that primary human luminal breast cancer CTCs contain MICs that give rise to bone, lung and liver metastases in mice. These MIC-containing CTC populations expressed EPCAM, CD44, CD47 and MET. In a small cohort of patients with metastases, the number of EPCAM(+)CD44(+)CD47(+)MET(+) CTCs, but not of bulk EPCAM(+) CTCs, correlated with lower overall survival and increased number of metastasic sites. These data describe functional circulating MICs and associated markers, which may aid the design of better tools to diagnose and treat metastatic breast cancer.

Activating ESR1 mutations in hormone-resistant metastatic breast cancer

Abstract: Arul Chinnaiyan and colleagues report the results of prospective clinical sequencing of 11 estrogen receptor–positive metastatic breast cancers. They identify ESR1 mutations affecting the ligand-binding domain in six hormone-resistant metastatic breast cancers and show that the mutant estrogen receptors are constitutively active and continue to be responsive to anti-estrogen therapies in vitro. Breast cancer is the most prevalent cancer in women, and over two-thirds of cases express estrogen receptor-α (ER-α, encoded by ESR1). Through a prospective clinical sequencing program for advanced cancers, we enrolled 11 patients with ER-positive metastatic breast cancer. Whole-exome and transcriptome analysis showed that six cases harbored mutations of ESR1 affecting its ligand-binding domain (LBD), all of whom had been treated with anti-estrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas (TCGA) identified four endometrial cancers with similar mutations of ESR1. The five new LBD-localized ESR1 mutations identified here (encoding p.Leu536Gln, p.Tyr537Ser, p.Tyr537Cys, p.Tyr537Asn and p.Asp538Gly) were shown to result in constitutive activity and continued responsiveness to anti-estrogen therapies in vitro. Taken together, these studies suggest that activating mutations in ESR1 are a key mechanism in acquired endocrine resistance in breast cancer therapy.

Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

Abstract: Background: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. Methods: Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan–Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. Results: The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P = .02). Conclusions: Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.

APOBEC3B is an enzymatic source of mutation in breast cancer

Abstract: Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours and breast cancer cell lines. Tumours that express high levels of APOBEC3B have twice as many mutations as those that express low levels and are more likely to have mutations in TP53. Endogenous APOBEC3B protein is predominantly nuclear and the only detectable source of DNA C-to-U editing activity in breast cancer cell-line extracts. Knockdown experiments show that endogenous APOBEC3B correlates with increased levels of genomic uracil, increased mutation frequencies, and C-to-T transitions. Furthermore, induced APOBEC3B overexpression causes cell cycle deviations, cell death, DNA fragmentation, γ-H2AX accumulation and C-to-T mutations. Our data suggest a model in which APOBEC3B-catalysed deamination provides a chronic source of DNA damage in breast cancers that could select TP53 inactivation and explain how some tumours evolve rapidly and manifest heterogeneity.

Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study.

Abstract: Summary Background Digital breast tomosynthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer. We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening. Methods Screening with Tomosynthesis OR standard Mammography (STORM) was a prospective comparative study. We recruited asymptomatic women aged 48 years or older who attended population-based breast-cancer screening through the Trento and Verona screening services (Italy) from August, 2011, to June, 2012. We did screen-reading in two sequential phases—2D only and integrated 2D and 3D mammography—yielding paired data for each screen. Standard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read. Outcomes were measured from final assessment or excision histology. Primary outcome measures were the number of detected cancers, the number of detected cancers per 1000 screens, the number and proportion of false positive recalls, and incremental cancer detection attributable to integrated 2D and 3D mammography. We compared paired binary data with McNemar's test. Findings 7292 women were screened (median age 58 years [IQR 54–63]). We detected 59 breast cancers (including 52 invasive cancers) in 57 women. Both 2D and integrated 2D and 3D screening detected 39 cancers. We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only (p Interpretation Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls. Randomised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening. Funding National Breast Cancer Foundation, Australia; National Health and Medical Research Council, Australia; Hologic, USA; Technologic, Italy.

Activating HER2 Mutations in HER2 Gene Amplification Negative Breast Cancer

Abstract: Data from 8 breast cancer genome-sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized 13 HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755–759, which is homologous to EGF receptor (EGFR) exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings show that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment. SIGNIFICANCE: We show that the majority of HER2 somatic mutations in breast cancer patients are activating mutations that likely drive tumorigenesis. Several patients had mutations that are resistant to the reversible HER2 inhibitor lapatinib, but are sensitive to the irreversible HER2 inhibitor, neratinib. Our results suggest that patients with HER2 mutation–positive breast cancers could benefit from existing HER2-targeted drugs. Cancer Discov; 3(2); 1–14. ©2013 AACR.

The benefits and harms of breast cancer screening: an independent review

Abstract: © 2013 Cancer Research UK. All rights reserved. 1.1 Introduction: The breast cancer screening programmes in the United Kingdom currently invite women aged 50-70 years for screening mammography every 3 years. Since the time the screening programmes were established, there has been debate, at times sharply polarised, over the magnitude of their benefit and harm, and the balance between them. The expected major benefit is reduction in mortality from breast cancer. The major harm is overdiagnosis and its consequences; overdiagnosis refers to the detection of cancers on screening, which would not have become clinically apparent in the woman's lifetime in the absence of screening. Professor Sir Mike Richards, National Cancer Director, England, and Dr Harpal Kumar, Chief Executive Officer of Cancer Research UK, asked Professor Sir Michael Marmot to convene and chair an independent panel to review the evidence on benefits and harms of breast screening in the context of the UK breast screening programmes. The panel, authors of this report, reviewed the extensive literature and heard testimony from experts in the field who were the main contributors to the debate. The nature of information communicated to the public, which too has sparked debate, was not part of the terms of reference of the panel, which are listed in Appendix 1. 1.2 Relative mortality benefit: The purpose of screening is to advance the time of diagnosis so that prognosis can be improved by earlier intervention. A consequence of earlier diagnosis is that it increases the apparent incidence of breast cancer in a screened population and extends the average time from diagnosis to death, even if screening were to confer no benefit. The appropriate measure of benefit, therefore, is reduction in mortality from breast cancer in women offered screening compared with women not offered screening. In the panel's judgement, the best evidence for the relative benefit of screening on mortality reduction comes from 11 randomised controlled trials (RCTs) of breast screening. Meta-analysis of these trials with 13 years of follow-up estimated a 20% reduction in breast cancer mortality in women invited for screening. The relative reduction in mortality will be higher for women actually attending screening, but by how much is difficult to say because women who do not attend are likely to have a different background risk. Three types of uncertainties surround this estimate of 20% reduction in breast cancer mortality. The first is statistical: the 95% confidence interval (CI) around the relative risk (RR) reduction of 20% was 11-27%. The second is bias: there are a number of potential sources of distortion in the trials that have been widely discussed in the literature ranging from suboptimal randomisation to problems in adjudicating cause of death. The third is the relevance of these old trials to the current screening programmes. The panel acknowledged these uncertainties, but concluded that a 20% reduction is still the most reasonable estimate of the effect of the current UK screening programmes on breast cancer mortality. Most other reviews of the RCTs have yielded similar estimates of relative benefit. The RCTs were all conducted at least 20-30 years ago. More contemporary estimates of the benefit of breast cancer screening come from observational studies. The panel reviewed three types of observational studies. The first were ecological studies comparing areas, or time periods, when screening programmes were and were not in place. These have generated diverse findings, partly because of the major advances in treatment of breast cancer, which have a demonstrably larger influence on mortality trends than does screening, and partly because of the difficulty of excluding imbalances in other factors that could affect breast cancer mortality. The panel did not consider these studies helpful in estimating the effect of screening on mortality. The other two types of studies, case-control studies and incidence-based mortality studies, showed breast screening to confer a greater benefit than did the trials. Although these studies, in general, attempted to control for non-comparability of screened and unscreened women, the panel was concerned that residual bias could inflate the estimate of benefit. However, the panel notes that these studies' findings are in the same direction as the trials. 1.3 Absolute mortality benefit: Estimates of absolute benefit of screening have varied from one breast cancer death avoided for 2000 women invited to screening to 1 avoided for about 100 women screened, about a 20-fold difference. Major determinants of that large variation are the age of women screened, and the durations of screening and follow-up. The age of the women invited is important, as mortality from breast cancer increases markedly with age. The panel therefore applied the relative mortality reduction of 20% to achieve the observed cumulative absolute risk of breast cancer mortality over the ages 55-79 years for women in the United Kingdom, assuming that women who began screening at 50 years would gain no benefit in the first 5 years, but that the mortality reduction would continue for 10 years after screening ended. This yielded the estimate that for every 235 women invited to screening, one breast cancer death would be prevented; correspondingly 180 women would need to be screened to prevent one breast cancer death. Uncertainties in the figure of a 20% RR reduction would carry through to these estimates of absolute mortality benefit. Nonetheless, the panel's estimate of benefit is in the range of one breast cancer death prevented for B250 women invited, rather than the range of 1 in 2000. 1.4 Overdiagnosis: The major harm of screening considered by the panel was that of overdiagnosis. Given the definition of an overdiagnosed cancer, either invasive or non-invasive, as one diagnosed by screening, which would not otherwise have come to attention in the woman's lifetime, there is need for a long follow-up to assess the frequency of overdiagnosis. In the view of the panel, some cancers detected by screening will be overdiagnosed, but the uncertainty surrounding the extent of overdiagnosis is greater than that for the estimate of mortality benefit because there are few sources of reliable data. The issue for the UK screening programmes is the magnitude of overdiagnosis in women who have been in a screening programme from age 50 to 70, then followed for the rest of their lives. There are no data to answer this question directly. Any estimate will therefore be, at best, provisional. Although the definition of an overdiagnosed case, and thus the numerator in a ratio, is clear, the choice of denominator has been the source of further variability in published estimates. Different studies have used: only the cancers found by screening; cancers found during the whole screening period, both screen-detected and interval; cancers diagnosed during the screening period and for the remainder of the women's lifetime. The panel focused on two estimates: the first from a population perspective using as the denominator the number of breast cancers, both invasive and ductal carcinoma in situ (DCIS), diagnosed throughout the rest of a woman's lifetime after the age that screening begins, and the second from the perspective of a woman invited to screening using the total number of breast cancers diagnosed during the screening period as the denominator. The panel thought that the best evidence came from three RCTs that did not systematically screen the control group at the end of the screening period and followed these women for several more years. The frequency of overdiagnosis was of the order of 11% from a population perspective, and about 19% from the perspective of a woman invited to screening. Trials that included systematic screening of the control group at the end of the active part of the trial were not considered to provide informative estimates of the frequency of overdiagnosis. Information from observational studies was also considered. One method that has been used is investigation of time trends in incidence rates of breast cancer for different age groups over the period that population screening was introduced. The published results of these studies varied greatly and have been interpreted as providing either reassurance or cause for alarm. So great was the variation in results that the panel conducted an exercise by varying the assumptions and statistical methods underlying these studies, using the same data sets; estimates of overdiagnosis rates were found to vary across the range of 0-36% of invasive breast cancers diagnosed during the screening period. The panel had no reason to favour one set of estimates over another, and concluded that this method could give no reliable estimate of the extent of overdiagnosis. Were it possible to distinguish at screening those cancers that would not otherwise have come to attention from those that, untreated, would lead to death, the overdiagnosis problem could be much reduced, at least in terms of unnecessary worry and treatment. Currently this is not possible, so neither the woman nor her doctor can know whether a screen-detected cancer is an 'overdiagnosed' case or not. In particular, DCIS, most often diagnosed at screening, does not inevitably equate to overdiagnosis - screen-detected DCIS, after wide local excision (WLE) only, is associated with subsequent development of invasive breast cancer in 10% of women within 10 years. The consequences of overdiagnosis matter, women are turned into patients unnecessarily, surgery and other forms of cancer treatment are undertaken, and quality of life and psychological well being are adversely affected.