Patient-reported outcome after oncoplastic breast surgery compared with conventional breast-conserving surgery in breast cancer.

INTRODUCTION: Oncoplastic breast surgery (OBS) has developed as an extension of breast-conserving surgery (BCS) in an effort to improve esthetic and functional outcome following surgery for breast cancer. The aim of the present study was to evaluate the possible benefits of OBS, as compared with BCS, with regard to health-related quality of life (HRQoL), using patient-reported outcome measures (PROMs). PATIENTS AND METHODS: Patients treated with OBS (n = 200) and BCS (n = 1304) in the period 1 January 2008 to 31 December 2013 were identified in a research database and in the Danish Breast Cancer Cooperative Group (DBCG) registry. Data on patient, tumor, and treatment characteristics were retrieved from the DBCG registry. Patients were sent a survey including the Breast-Q™ BCT postoperative module and a study-specific questionnaire (SSQ) in 2016. A good outcome in the Breast-Q module was defined as above the median. OBS was compared to BCS using a logistic regression analysis, and then adjusted for potential confounders, yielding odds ratios (OR) with 95% confidence intervals. RESULTS: There was a statistically significant better outcome considering the HRQoL domain "Psychosocial Well-being " for patients treated with OBS as compared with BCS (OR 2.15: 1.25-3.69). No statistically significant differences were found for the domains "Physical Well-being" (0.83: 0.50-1.39), "Satisfaction with Breast" (0.95: 0.57-1.59), or "Sexual Well-being" (1.42: 0.78-2.58). CONCLUSION: The present study indicates better outcomes of HRQoL for breast cancer patients treated with OBS as compared to patients treated with BCS. There was no increase in physical discomfort among OBS patients despite more extensive surgery.

Oncoplastic Breast Surgery Compared to Conventional Breast-Conserving Surgery With Regard to Oncologic Outcome.

INTRODUCTION: Oncoplastic breast surgery (OBS) has been implemented with increasing frequency in the treatment of breast cancer. The aim of this study was to compare the oncologic outcome after OBS to the outcome after conventional breast-conserving surgery (BCS) in patients with invasive breast cancer. PATIENTS AND METHODS: In all, 197 patients treated with OBS were compared to 1399 patients treated with conventional BCS from 2008 to 2013. We evaluated nonradical primary tumor excision, time to initiation of adjuvant therapy, disease-free survival (risk of recurrent disease), and survival (cause specific and overall). Identification of patients and follow-up were made using the Danish Breast Cancer Cooperative Group registry and the Danish Cause of Death registry. Multivariate logistic regression and the Cox proportional hazard analysis were used to obtain odds ratios and hazard ratios with 95% confidence intervals (CI). RESULTS: There was a lower risk for nonradical primary tumor excision for patients undergoing OBS versus conventional BCS (adjusted odds ratio:95% CI, 0.50:0.29-0.84). No significant differences were found with regard to a delay in initiation of adjuvant chemotherapy (adjusted hazard ratio:95% CI, 1.14:0.89-1.45) or radiotherapy (0.91:0.71-1.16), disease-free survival (1.23:0.61-2.47), breast cancer as cause of death (1.46:0.52-4.09), breast cancer as underlying or multiple cause of death (0.90:0.34-2.37), or overall survival (0.90:0.51-1.60). CONCLUSION: We found no significant differences in oncologic outcome comparing OBS to conventional BCS. However, a lower risk of nonradical primary tumor excision was found for patients treated with OBS. These results indicate that OBS is a safe procedure.

Aesthetic result after breast-conserving therapy is associated with quality of life several years after treatment. Swedish women evaluated with BCCT.core and BREAST-Q™.

PURPOSE: A gold standard for evaluation of aesthetic outcome after breast-conserving therapy (BCT) is still lacking. The BCCT.core software has been developed to assess aesthetic result in a standardised way. We aimed to study how the result of BCCT.core after BCT is associated with quality of life, measured with the BREAST-Q™, a validated questionnaire. METHODS: Women eligible for BCT were consecutively recruited between February 1st 2008 and January 31st 2012 (n = 653). Photographs of 310 women, taken one year after BCT, were evaluated using the BCCT.core software. The postoperative BCT module of the BREAST-Q™ questionnaire was administered by mail and 348 questionnaires were returned (median 5.5 years after BCT). In all, 216 women had both BCCT.core results and completed BREAST-Q™ questionnaires available. RESULTS: The results from the BCCT.core evaluation were: excellent n = 49 (15.8%); good n = 178 (57.4%); fair n = 73 (23.5%); poor n = 10 (3.2%). The median BREAST-Q™ score for satisfaction with breasts was 66 [interquartile range (IQR) 57-80] and for psychosocial well-being 82 (IQR 61-100). Poor/fair results on BCCT.core were associated with Q-scores below median for both satisfaction with breasts [odds ratio (OR) 3.4 (confidence interval (CI) 1.7-6.8)] as well as for psychosocial well-being [OR 2.2 (CI 1.1-4.2)]. CONCLUSIONS: A statistically significant association between BCCT.core results one year after BCT and quality of life ratings using BREAST-Q™ several years later is shown in this study. This implies that the BCCT.core may be valuable in BCT follow-up and used as a standardised instrument in the evaluation of aesthetic results.

Patients Undergoing Breast-Conserving Surgery Can Benefit from the Opportunity to Participate in Choosing Their Surgical Technique.

BACKGROUND: Shared decision-making is increasingly advocated in many countries. The aims of this study were to investigate whether patients receiving breast-conserving surgery at Skåne University Hospital Malmö, Sweden, perceived an offered possibility to join in the decision-making process regarding the surgical method; to identify potential determinants for not having perceived such an offer; and to study how this perception of being offered an opportunity to take part in the decision-making process affected satisfaction with the aesthetic outcome. METHODS: Women offered breast-conserving surgery were consecutively recruited over a period of 4 years. In all, 324 women completed a study-specific questionnaire. RESULTS: A majority of the women (53 %) perceived that they had not, or had only partly, been offered a possibility to take part in the decision-making process. Patients who reported that they had received enough preoperative information regarding the expected aesthetic result were more likely to have perceived such an offer (odds ratio (OR) 5.44; confidence interval (CI) 2.83-10.43). Women who had perceived an opportunity to be involved were more satisfied with the aesthetic result (OR 2.71; CI 1.18-6.25) and more likely to have had their expectations met regarding the aesthetic result (OR 5.91; CI 2.01-17.38). CONCLUSION: When deciding on a suitable surgical approach for women with early breast cancer, physicians could try to more clearly communicate to the women that they can choose whether or not to participate in the decision-making regarding surgical technique. This might improve satisfaction. An important part of patient involvement is sufficient preoperative information.

Determinants for patient satisfaction regarding aesthetic outcome and skin sensitivity after breast-conserving surgery.

BACKGROUND: With the development of new surgical techniques in breast cancer, such as oncoplastic breast surgery, increased knowledge of risk factors for poor satisfaction with conventional breast-conserving surgery (BCS) is needed in order to determine which patients to offer these techniques to. The aim of this study was to investigate patient satisfaction regarding aesthetic result and skin sensitivity in relation to patient, tumour, and treatment factors, in a consecutive sample of patients undergoing conventional BCS. METHODS: Women eligible for BCS were recruited between February 1, 2008 and January 31, 2012 in a prospective setup. In all, 297 women completed a study-specific questionnaire 1 year after conventional BCS and radiotherapy. Potential risk factors for poor satisfaction were investigated using logistic regression analysis. RESULTS: The great majority of the women, 84%, were satisfied or very satisfied with the overall aesthetic result. The rate of satisfaction regarding symmetry between the breasts was 68% and for skin sensitivity in the operated breast it was 67%. Excision of more than 20% of the preoperative breast volume was associated with poor satisfaction regarding overall aesthetic outcome, as was axillary clearance. A high BMI (≥30 kg/m2) seemed to affect satisfaction with symmetry negatively. Factors associated with less satisfied patients regarding skin sensitivity in the operated breast were an excision of ≥20% of preoperative breast volume, a BMI of 25-30 kg/m2, axillary clearance, and radiotherapy. Re-excision and postoperative infection were associated with lower rates of satisfaction regarding both overall aesthetic outcome and symmetry, as well as with skin sensitivity. CONCLUSIONS: Several factors affect patient satisfaction after BCS. A major determinant of poor satisfaction in this study was a large excision of breast volume. If the percentage of breast volume excised is estimated to exceed 20%, other techniques, such as oncoplastic breast surgery, with or without contralateral surgery, or mastectomy with reconstruction, may be considered.

Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 years follow-up in the randomized SweDCIS Trial.

PURPOSE: Four randomized studies show that adjuvant radiotherapy (RT) lowers the risk of subsequent ipsilateral breast events (IBEs) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) by approximately 50% after 10 to 15 years. We present 20 years of follow-up data for the SweDCIS trial. PATIENTS AND METHODS: Between 1987 and 1999 1,046 women were randomly assigned to RT or not after BCS for primary DCIS. Results up to 2005 have been published, and we now add another 7 years of follow-up. All breast cancer events and causes of death were registered. RESULTS: There were 129 in situ and 129 invasive IBEs. Absolute risk reduction in the RT arm was 12.0% at 20 years (95% CI, 6.5 to 17.7), with a relative risk reduction of 37.5%. Absolute reduction was 10.0% (95% CI, 6.0 to 14.0) for in situ and 2.0% (95% CI, -3.0 to 7.0) for invasive IBEs. There was a nonstatistically significantly increased number of contralateral events in the RT arm (67 v 48 events; hazard ratio, 1.38; 95% CI, 0.95 to 2.00). Breast cancer-specific death and overall survival were not influenced. Younger women experienced a relatively higher risk of invasive IBE and lower effect of RT. The hazard over time looked different for in situ and invasive IBEs. CONCLUSION: Use of adjuvant RT is supported by 20-year follow-up. Modest protection against invasive recurrences and a possible increase in contralateral cancers still call for a need to find groups of patients for whom RT could be avoided or mastectomy with breast reconstruction is indicated.

Epithelial and stromal microRNA signatures of columnar cell hyperplasia linking Let-7c to precancerous and cancerous breast cancer cell proliferation.

Columnar cell hyperplasia (CCH) is the earliest histologically identifiable breast lesion linked to cancer progression and is characterized by increased proliferation, decreased apoptosis and elevated oestrogen receptor α (ERα) expression. The mechanisms underlying the initiation of these lesions have not been clarified but might involve early and fundamental changes in cancer progression. MiRNAs are key regulators of several biological processes, acting by influencing the post-transcriptional regulation of numerous targets, thus making miRNAs potential candidates in cancer initiation. Here we have defined novel epithelial as well as stromal miRNA signatures from columnar cell hyperplasia lesions compared to normal terminal duct lobular units by using microdissection and miRNA microarrays. Let-7c were among the identified downregulated epithelial miRNAs and its functions were delineated in unique CCH derived cells and breast cancer cell line MCF-7 suggesting anti-proliferative traits potentially due to effects on Myb and ERα. MiR-132 was upregulated in the stroma surrounding CCH compared to stoma surrounding normal terminal duct lobular units (TDLUs), and overexpression of miR-132 in immortalized fibroblasts and in fibroblasts co-cultured with epithelial CCH cells caused substantial expression changes of genes involved in metabolism, DNA damage and cell motility. The miRNA signatures identified in CCH indicate early changes in the epithelial and stromal compartment of CCH and could represent early key alterations in breast cancer progression that potentially could be targeted in novel prevention or treatment schedules.

Inter-observer reliability of clinical measurement of suprasternal notch-nipple distance and breast ptosis.

CONTEXT: Suprasternal notch-nipple distance and breast ptosis are two measurements that are often used in everyday plastic surgical clinical practice. Nonetheless, the reliability of standard breast measurements has never been tested. AIM: The aim of the present study was to test the inter-observer reliability of clinical measurement of ptosis and suprasternal notch-nipple distance. SETTINGS AND DESIGN: Six raters measured ptosis and suprasternal notch-nipple distance in 12 breasts on the same day. STATISTICAL ANALYSIS USED: Intra-class correlation (ICC) coefficients, the coefficient of variation (CV) and Bland-Altman plots. RESULTS AND CONCLUSIONS: The results show that there is certain variation between different raters. The ICC of average measures between raters is 0.92 for the ptosis and 0.94 for the suprasternal notch-nipple distance, that is, the agreement between different raters is high. According to the Bland - Altman plots, the overall assessment of the comparisons of measurements between the different raters shows that the direction of the mean differences is close to zero. This study shows that there is a good reliability for measurements of suprasternal notch-nipple distance and ptosis. Nonetheless, there is a slight inter-rater variability in the measurements. Even though standardised, measurement of breasts is not an exact science and care has to be taken when the measurements are performed. The surgeon should have this in mind when measurements are used in clinical practice to evaluate breasts and to choose the right surgical method, as well as when guidelines for indications for surgery are set up.

A feasible computer-based evaluation tool for reduction mammaplasty patients: indications for operation and monitoring of guidelines.

In Sweden, evidence-based national guidelines for the indication for reduction mammaplasty in the public health-care system have been developed by a group of experts. They were defined as breast volume≥800 ml at normal weight. Furthermore, a volume asymmetry of 25% or at least 200 ml or an extreme ptosis may be an indication in some cases. The aim of the present paper was to describe an easy-to-use computer-based tool that has been developed to assure that patients with mammary hyperplasia are evaluated and offered care in a standardized fashion and that the adherence to the guidelines is monitored. Included variables were based on a model for priority grouping originally presented by Strömbeck and Malm in 1986 and comprise body mass index (BMI), BMI-corrected breast volume, ptosis, asymmetry, and general breast-related factors preoperatively and 1 year postoperatively and complications postoperatively. Between June 2007 and January 2013, 377 patients were evaluated. Of which, 275 qualified for operation. With the help of the computer-based tool, compliance to the indications for operation can be easily followed, and hence the intended patients offered a reduction mammaplasty in the public health-care system.

Surgical strategy, methods of reconstruction, surgical margins and postoperative complications in oncoplastic breast surgery.

BACKGROUND: Oncoplastic breast surgery is an evolving discipline in the surgical treatment of breast cancer aimed to improve the outcome. METHODS: Oncoplastic breast surgery was performed between January 2008 and December 2010 on 72 women with 74 breast cancers selected from a population of 1,018 primary breast cancer patients. Careful preoperative planning revealed the possibility of partial breast reconstruction with volume reduction, volume displacement or volume replacement depending on breast size as well as tumour size and location. Data were registered consecutively. RESULTS: The surgical plan was successful in all but one case, where a mastectomy had to be performed during the primary surgery. In 53 cases, a contralateral mammoplasty was performed during the operation to achieve symmetry. During the follow-up period until November 2011, only one patient needed corrective surgery. Final histopathological examination indicated that seven cases required extended resection and three cases required a mastectomy. Five patients experienced delayed wound healing, although complications requiring further surgery occurred for the reconstructed breast in four cases, the contralateral breast in three cases and the axilla after exaeresis in two cases because of haematoma. Such complications led to slight delay in adjuvant therapy for four patients. CONCLUSIONS: This study demonstrates that it is feasible to implement oncoplastic breast surgery into daily clinical practice as a supplement to conventional breast cancer surgery. As such, oncoplastic breast surgery may provide a markedly better outcome than breast-conserving surgery in terms of shape and symmetry without compromising the surgical margins. Level of Evidence: Level IV, prognostic/risk study.

Measurement of breast volume is a useful supplement to select candidates for surgical breast reduction.

INTRODUCTION: The indication for breast reduction in a public welfare or an insurance paid setting depends on the severity of the subjective symptoms and the clinical evaluation. The purpose of this study was to evaluate the use of breast volume as an objective criterion to establish the indication for breast reduction surgery, thus establishing a standard decision basis that can be shared by surgeons and departments to secure patients fair and equal treatment opportunities. MATERIAL AND METHODS: A total of 427 patients who were referred to three Danish public hospitals with breast hypertrophy in the period from January 2007 to March 2011 were included prospectively in the study. The patients' subjective complaints, height, weight and standard breast measurements were registered as well as the decision for or against surgery. Breast volume was measured using transparent plastic cups. RESULTS: Cut-off values for breast volume were calculated based on whether or not the patients were offered reduction surgery. Most patients (93%) with a breast volume below 800 cc were not offered surgery, while most with a volume exceeding 900 cc were offered surgery (94%). In the grey zone between 800 and 900 cc, the indication seemed to be less clear-cut, and additional parameters need to be included. CONCLUSION: Breast volume can be used as an objective criterion in addition to the presently used criteria. Breast volume can easily be measured and has become appreciated by plastic surgeons dealing with patients with breast hypertrophy as a tool which facilitates their decision-making and patients' acceptance of the decisions made. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

When is the deep inferior epigastric artery flap indicated for breast reconstruction in patients not treated with radiotherapy?

BACKGROUND: It is controversial whether breast reconstruction with a microvascular free flap should be done without restrictions in patients who have not had radiotherapy. Many regard it as too expensive, but some consider it better and more economically advantageous than an implant reconstruction. METHODS: Databases of publications were searched to find out under what conditions is it suitable to offer a deep inferior epigastric perforator (DIEP) or a transverse rectus abdominis myocutaneous flap to normalize the body's appearance in a woman whose breast(s) had been removed for cancer or to prevent the development of breast cancer. The effect of breast reconstruction with DIEP flaps was analyzed, taking account of the following factors: general satisfaction (quality of life), aesthetic satisfaction (cosmesis), and morbidity. To find out which factors were of potential importance, we recorded age, hypertension, whether scars from previous abdominal surgery were present, microcirculation, whether the patient was overweight or obese, and costs of the procedure. RESULTS: Patients planning to have DIEP flaps should be willing to stop smoking at least 4 weeks before and after the procedure and have a body mass index of less than 30 kg/m to avoid a higher risk of complications. Because of the paucity of papers, it is difficult to recommend one approach over the other when considering general satisfaction, aesthetic satisfaction, and health economics. However, economical long-term outcome is highly dependent on the initial costs of each procedure and the cumulative costs of complications for each reconstruction method. CONCLUSIONS: The scientific foundation of assessment of methods of techniques of breast reconstruction is weak. Therefore, it is important that future studies should present more comparable series, highlight the long-term effects in high-quality studies, to provide the patients with optimal results without undue risks and to avoid financial burdens on society.

Reliability of plastic cups to measure breast volume.

Breast volume measurement is valuable in clinical practice, and various methods have been used. Nonetheless, no commonly accepted standard technique exists for clinical everyday use and there is no optimal method that is quick, cheap, minimally invasive, and acceptable for the patient and for the surgeon. Previously, a study has shown that the volume measured with plastic cups differed little from that measured from mastectomy specimens. The aim of the present study was to test the reliability of breast volume measurements with plastic cups as a tool to measure breast volume in everyday clinical practice. The plastic cups were designed by the senior author (AR) and comprise 14 cups from 125 millilitres (ml) to 2000 ml. Six raters measured 12 breasts on the same day. The results show that there is a certain variation between different raters, and that a certain rater seems to consistently measure slightly lower or higher volumes than the other raters. The Intra Class Correlation (ICC) coefficient of average measures between raters is 0.89, that is, the agreement between different raters is high. According to the Bland-Altman plot, the overall assessment of the comparisons of measurements between the different raters shows that the direction of the mean differences is close to zero. The limits of agreements of the differences were within ±56 ml. The coefficient of variation (CV) between different raters was 14%. Breast volume measurement with plastic cups is an easily usable quick and cheap way to measure breast volume in everyday clinical practice. The measurements have an acceptable reliability.

A Comparison of Tumor Biology in Primary Ductal Carcinoma In Situ Recurring as Invasive Carcinoma versus a New In Situ.

Introduction. About half of all new ipsilateral events after a primary ductal carcinoma in situ (DCIS) are invasive carcinoma. We studied tumor markers in the primary DCIS in relation to type of event (invasive versus in situ). Methods. Two hundred and sixty-six women with a primary DCIS from two source populations, all with a known ipsilateral event, were included. All new events were regarded as recurrences. Patient and primary tumor characteristics (estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, and Ki67) were evaluated. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses. Results. One hundred and thirty-six of the recurrences were invasive carcinoma and 130 were in situ. The recurrence was more often invasive if the primary DCIS was ER+ (OR 2.5, 95% CI 1.2-5.1). Primary DCIS being HER2+ (OR 0.5, 95% CI 0.3-0.9), EGFR+ (OR 0.4, 95% CI 0.2-0.9), and ER95-/HER2+ (OR 0.2, 95% CI 0.1-0.6) had a lower risk of a recurrence being invasive. Conclusions. In this study, comparing type of recurrence after a DCIS showed that the ER-/HER2+ tumors were related to a recurrence being a new DCIS. And surprisingly, tumors being ER+, HER2-, and EGFR- were related to a recurrence being invasive cancer.

Given breast cancer, does breast size matter? Data from a prospective breast cancer cohort.

PURPOSE: Body mass index (BMI), waist-to-hip ratio (WHR), and tumor characteristics affect disease-free survival. Larger breast size may increase breast cancer risk, but its influence on disease-free survival is unclear. The purpose of this study was to elucidate whether breast size independently influenced disease-free survival in breast cancer patients. METHODS: Body measurements were obtained preoperatively from 772 breast cancer patients in a population-based ongoing cohort from southern Sweden. The research nurse measured breast volumes with plastic cups used by plastic surgeons doing breast reductions. Clinical data were obtained from patient charts and pathology reports. RESULTS: Patients with a BMI ≥ 25 kg/m(2) had larger tumors (p < 0.001) and more axillary nodal involvement (p = 0.030). Patients with a WHR > 0.85 had larger tumors (p = 0.013), more advanced histological grade (p = 0.0016), and more axillary nodal involvement (p = 0.012). Patients with right + left breast volume ≥ 850 mL were more likely to have larger tumor sizes (p = 0.018), more advanced histological grade (p = 0.031), and more axillary nodal involvement (p = 0.025). There were 62 breast cancer events during the 7-year follow-up. Breast volume ≥ 850 mL was associated with shorter disease-free survival (p = 0.004) and distant metastasis-free survival (p = 0.001) in patients with estrogen receptor (ER)-positive tumors independent of other anthropometric measurements and age. In patients with ER-positive tumors, breast size was an independent predictor of shorter disease-free (HR 3.64; 95 % CI 1.42-9.35) and distant metastasis-free survival (HR 6.33; 95 %CI 1.36-29.43), adjusted for tumor characteristics, BMI, age, and treatment. CONCLUSION: A simple and cheap anthropometric measurement with standardized tools may help identify a subgroup of patients in need of tailored breast cancer therapy.

Bilateral prophylactic mastectomy in Swedish women at high risk of breast cancer: a national survey.

BACKGROUND/OBJECTIVE: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. METHODS: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. RESULTS: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low (3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1unanticipated secondary operation. CONCLUSIONS: Bilateral prophylactic mastectomy is safe and efficacious in reducing future breast cancer in asymptomatic women at high risk. Unanticipated reoperations are common. Given the small number of patients centralization seems justified.

Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiency.

Multiple biopsies of normal breast tissue from 10 BRCA1 mutation carriers have been analyzed using array-based comparative genomic hybridization. Normal breast tissue from five age-matched control subjects without a family history of breast cancer was included for reference purposes. We repeatedly found multiple low copy number aberrations at a significantly higher frequency in histopathologically normal tissue from BRCA1 mutation carriers than in normal control tissue. Some of these aberrations were similar across samples from different patients and linked to biological functions such as transcriptional regulation and DNA binding. We also observed a high degree of genomic heterogeneity between samples from the same patient, suggestive of tissue heterogeneity and etiological clonality in the breast epithelium. We show that neither loss of heterozygosity nor promoter methylation of the wild-type BRCA1 allele is the predominant mechanistic origin of the observed genomic instability. Instead, we propose that haploinsufficiency of BRCA1 might be the underlying cause responsible for initiation of breast cancer in these predisposed women, making cells vulnerable to mitotic recombination. We also propose that loss of ERalpha expression is preceded by genetic instability in the initiation of BRCA1-dependent tumorigenesis, indicating that the breast epithelium of BRCA1 mutation carriers may initially be estrogen-responsive. Our results imply that genomic instability instigated by BRCA1 haploinsufficiency may be required for breast cancer initiation in BRCA1 mutation carriers. Finding molecular markers of tumor initiation and progression, for the potential use in early disease detection, may be of great clinical importance for the improved management of at-risk women.

Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast.

PURPOSE: Evaluate the effects of radiotherapy after sector resection for ductal carcinoma in situ of the breast (DCIS) in patient groups as defined by age, size of the lesion, focality, completeness of excision and mode of detection. PATIENTS AND METHODS: A total of 1,067 women in Sweden were randomly assigned to either postoperative radiotherapy (RT) or control from 1987 to 1999, and 1,046 were followed for a mean of 8 years. The main outcome was new ipsilateral breast cancer events and distant metastasis-free survival analyzed according to intention to treat. RESULTS: There were 64 ipsilateral events in the RT arm and 141 in the control group corresponding to a risk reduction of 16.0 percentage points at 10 years (95% CI, 10.3% to 21.6%) and a relative risk of 0.40 (95% CI, 0.30 to 0.54). There was no statistically significant difference in distant metastasis-free survival. There was an effect modification by age, yielding a low effect of RT in women younger than 50, but substantial protection in women older than 60 years. The age effect was not confounded by focality, lesion size, completeness of excision, or detection mode. There was no group as defined by our stratification variables that had a low risk without radiotherapy. CONCLUSION: Our results indicate that younger women have a low protective effect of conventional RT after sector resection. Older women benefit substantially. We caution that the age effect was seen in a subgroup analysis. Further search with conventional clinical variables for a low risk group that does not need RT does not seem fruitful.

SweDCIS: Radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening.

We studied the effect of postoperative radiotherapy (RT) after breast sector resection for ductal carcinoma in situ (DCIS). The study protocol stipulated radical surgery but microscopically clear margins were not mandatory. We randomised 1,046 operated women to postoperative RT or control between 1987 and 1999. The primary endpoint was ipsilateral local recurrence. Secondary endpoints were contralateral breast cancer, distant metastasis and death. After a median follow-up of 5.2 years (range 0.1-13.8) there were 44 recurrences in the RT group corresponding to a cumulative incidence of 0.07 (95% confidence interval (CI) 0.05-0.10). In the control group there were 117 recurrences giving a cumulative incidence of 0.22 (95% CI 0.18-0.26) giving an overall hazard ratio of 0.33 (95% CI 0.24-0.47, p < 0.0001). Twenty two percent of the patients had microscopically unknown or involved margins. We found no evidence for different effects of RT on the relative risk of invasive or in situ recurrence. Secondary endpoints did not differ. Women undergoing sector resection for DCIS under conditions of population based screening mammography benefit from postoperative RT to the breast. Seven patients needed RT-treatment to prevent one recurrence.