Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases.

BACKGROUND: Trials evaluating the omission of completion axillary-lymph-node dissection in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases have been compromised by limited statistical power, uncertain nodal radiotherapy target volumes, and a scarcity of data on relevant clinical subgroups. METHODS: We conducted a noninferiority trial in which patients with clinically node-negative primary T1 to T3 breast cancer (tumor size, T1, ≤20 mm; T2, 21 to 50 mm; and T3, >50 mm in the largest dimension) with one or two sentinel-node macrometastases (metastasis size, >2 mm in the largest dimension) were randomly assigned in a 1:1 ratio to completion axillary-lymph-node dissection or its omission (sentinel-node biopsy only). Adjuvant treatment and radiation therapy were used in accordance with national guidelines. The primary end point was overall survival. We report here the per-protocol and modified intention-to-treat analyses of the prespecified secondary end point of recurrence-free survival. To show noninferiority of sentinel-node biopsy only, the upper boundary of the confidence interval for the hazard ratio for recurrence or death had to be below 1.44. RESULTS: Between January 2015 and December 2021, a total of 2766 patients were enrolled across five countries. The per-protocol population included 2540 patients, of whom 1335 were assigned to undergo sentinel-node biopsy only and 1205 to undergo completion axillary-lymph-node dissection (dissection group). Radiation therapy including nodal target volumes was administered to 1192 of 1326 patients (89.9%) in the sentinel-node biopsy-only group and to 1058 of 1197 (88.4%) in the dissection group. The median follow-up was 46.8 months (range, 1.5 to 94.5). Overall, 191 patients had recurrence or died. The estimated 5-year recurrence-free survival was 89.7% (95% confidence interval [CI], 87.5 to 91.9) in the sentinel-node biopsy-only group and 88.7% (95% CI, 86.3 to 91.1) in the dissection group, with a country-adjusted hazard ratio for recurrence or death of 0.89 (95% CI, 0.66 to 1.19), which was significantly (P<0.001) below the prespecified noninferiority margin. CONCLUSIONS: The omission of completion axillary-lymph-node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. (Funded by the Swedish Research Council and others; SENOMAC ClinicalTrials.gov number, NCT02240472.).

Current clinical practice in the management of phyllodes tumors of the breast: an international cross-sectional study among surgeons and oncologists.

PURPOSE: Phyllodes tumors of the breast are rare fibroepithelial lesions that are classified as benign, borderline or malignant. There is little consensus on best practice for the work-up, management, and follow-up of patients with phyllodes tumors of the breast, and evidence-based guidelines are lacking. METHODS: We conducted a cross-sectional survey of surgeons and oncologists with the aim to describe current clinical practice in the management of phyllodes tumors. The survey was constructed in REDCap and distributed between July 2021 and February 2022 through international collaborators in sixteen countries across four continents. RESULTS: A total of 419 responses were collected and analyzed. The majority of respondents were experienced and worked in a university hospital. Most agreed to recommend a tumor-free excision margin for benign tumors, increasing margins for borderline and malignant tumors. The multidisciplinary team meeting plays a major role in the treatment plan and follow-up. The vast majority did not consider axillary surgery. There were mixed opinions on adjuvant treatment, with a trend towards more liberal regiments in patients with locally advanced tumors. Most respondents preferred a five-year follow-up period for all phyllodes tumor types. CONCLUSIONS: This study shows considerable variation in clinical practice managing phyllodes tumors. This suggests the potential for overtreatment of many patients and the need for education and further research targeting appropriate surgical margins, follow-up time and a multidisciplinary approach. There is a need to develop guidelines that recognize the heterogeneity of phyllodes tumors.

False-negative rate in the extended prospective TATTOO trial evaluating targeted axillary dissection by carbon tattooing in clinically node-positive breast cancer patients receiving neoadjuvant systemic therapy.

PURPOSE: In clinically node-positive breast cancer patients receiving neoadjuvant systemic therapy (NST), nodal metastases can be initially marked and then removed during surgical axillary staging. Marking methods vary significantly in terms of feasibility and cost. The purpose of the extended TATTOO trial was to report on the false-negative rate (FNR) of the low-cost method carbon tattooing. METHODS: The international prospective single-arm TATTOO trial included clinically node-positive breast cancer patients planned for NST from November 2017 to January 2021. For the present analysis, patients who received both the targeted procedure with or without an additional sentinel lymph node (SLN) biopsy and a completion axillary lymph node dissection (ALND) were selected. Primary endpoint was the FNR. RESULTS: Out of 172 included patients, 149 had undergone a completion ALND. The detection rate for the tattooed node was 94.6% (141 out of 149). SLN biopsy was attempted in 132 out of 149 patients with a detection rate of 91.7% (121 out of 132). SLN and tattooed node were identical in 58 out of 121 individuals (47.9%). The combined procedure, i.e. targeted axillary dissection (TAD) was successful in 147 of 149 cases (98.7%). Four out of 65 patients with a clinically node-negative status after NST had a negative TAD but metastases on ALND, corresponding to a FNR of 6.2%. All false-negative TAD procedures were performed in the first 2 years of the trial (2018-2019, p = 0.022). CONCLUSION: Carbon tattooing is a feasible marking method for TAD with a high detection rate and an acceptably low FNR. The TATTOO trial was preregistered as prospective trial before initiation at the University of Rostock, Germany (DRKS00013169).

Effect of radiotherapy on expanders and permanent implants in immediate breast reconstruction: long-term surgical and patient-reported outcomes in a large multicentre cohort.

BACKGROUND: Current evidence for the effects of radiotherapy (RT) on implant-based immediate breast reconstruction (IBR) is limited by short follow-up and lack of patient-reported outcomes (PROs). It is central to integrate long-term comprehensive outcome data into the preoperative decision-making process. The aim of the present study was to determine long-term surgical outcomes and PROs in relation to RT after implant-based IBR. METHODS: This was a longitudinal cohort study of PRO data obtained in surveys conducted in 2012 and 2020 using the BREAST-Q questionnaire. All women undergoing therapeutic mastectomy and implant-based IBR between 1 January 2007 and 31 December 2011 at four breast centres in Stockholm, Sweden, were identified. The endpoint was implant removal owing to surgical complications or patient preference. RESULTS: Median follow-up was 120 (range 1-171) months. After 754 IBRs in 729 women, implant removal occurred in 128 (17 per cent): 34 of 386 (8.8 per cent) in the no-RT group, 20 of 64 (31.3 per cent) in the group with previous RT, and 74 of 304 (24.3 per cent) in the postoperative RT group (P < 0.001). Implant removal was because of surgical complications in 60 instances (7.9 per cent), and patient preference in 68 (9.0 per cent). The BREAST-Q response rate was 72.2 per cent. Women with previous RT scored lower than those without RT on all scales, apart from psychosocial well-being. Women with postoperative RT scored lower only on physical well-being. No scores in the two RT groups had deteriorated between the survey time points, whereas satisfaction with breasts and overall outcome had decreased in the no-RT group. CONCLUSION: Although RT was significantly associated with higher implant removal rates, PROs remained stable over 8 years despite irradiation.

Current evidence for the effects of radiotherapy (RT) on implant-based immediate breast reconstruction (IBR) is limited by short follow-up. The aim was to determine surgical outcomes and patient-reported outcomes (PROs) in relation to RT up to 13 years after implant-based IBR. After 754 implant-based breast reconstructions in 729 women in Stockholm, Sweden, implant removal was more common in irradiated than non-irradiated patients (P < 0.001). The response rate to the BREAST-Q questionnaire was 72.2 per cent. Women with previous RT scored lower than those without RT on all scales apart from psychosocial well-being. Women who had postoperative RT scored lower only on physical well-being. Although RT was significantly associated with higher implant removal rates, PROs remained stable despite irradiation.

The generalisability of randomised clinical trials: an interim external validity analysis of the ongoing SENOMAC trial in sentinel lymph node-positive breast cancer.

PURPOSE: None of the key randomised trials on the omission of axillary lymph node dissection (ALND) in sentinel lymph-positive breast cancer have reported external validity, even though results indicate selection bias. Our aim was to assess the external validity of the ongoing randomised SENOMAC trial by comparing characteristics of Swedish SENOMAC trial participants with non-included eligible patients registered in the Swedish National Breast Cancer Register (NKBC). METHODS: In the ongoing non-inferiority European SENOMAC trial, clinically node-negative cT1-T3 breast cancer patients with up to two sentinel lymph node macrometastases are randomised to undergo completion ALND or not. Both breast-conserving surgery and mastectomy are eligible interventions. Data from NKBC were extracted for the years 2016 and 2017, and patient and tumour characteristics compared with Swedish trial participants from the same years. RESULTS: Overall, 306 NKBC cases from non-participating and 847 NKBC cases from participating sites (excluding SENOMAC participants) were compared with 463 SENOMAC trial participants. Patients belonging to the middle age groups (p = 0.015), with smaller tumours (p = 0.013) treated by breast-conserving therapy (50.3 versus 47.1 versus 65.2%, p < 0.001) and less nodal tumour burden (only 1 macrometastasis in 78.8 versus 79.9 versus 87.3%, p = 0.001) were over-represented in the trial population. Time trends indicated, however, that differences may be mitigated over time. CONCLUSIONS: This interim external validity analysis specifically addresses selection mechanisms during an ongoing trial, potentially increasing generalisability by the time full accrual is reached. Similar validity checks should be an integral part of prospective clinical trials. TRIAL REGISTRATION: NCT02240472, retrospective registration date September 14, 2015 after trial initiation on January 31, 2015.

Implant Based Breast Reconstruction With Acellular Dermal Matrix: Safety Data From an Open-label, Multicenter, Randomized, Controlled Trial in the Setting of Breast Cancer Treatment.

OBJECTIVE: To evaluate clinical outcomes of using acellular dermal matrix (ADM) with implant based breast reconstructions (IBBRs) in a randomized controlled trial. SUMMARY BACKGROUND DATA: The use of ADMs in IBBRs is widespread, but link between ADM and complications remain a controversial topic. In view of reports concerning harm, we present 6-months safety data of ADM-assisted IBBR in the setting of breast cancer treatment. METHODS: An open-label, randomized, controlled trial recruiting patients from 4 centers in Sweden and 1 in UK. Eligible were women with breast cancer planned for mastectomy with immediate IBBR. Participants were randomly allocated to IBBR with or without ADM (Strattice, Branchburg, NJ), with stratification by center in blocks of 6. Main primary endpoint was number of unplanned reoperations at 24 months, and safety expressed as the incidence of adverse events with a 6-month follow-up time for all participants. Analysis were done per protocol using Fisher exact test for complications and reoperations. RESULTS: From start of enrolment on April 24, 2014, to close of trial on May 10, 2017, 135 women were enrolled, of whom 64 with ADM and 65 without ADM were included in the final analysis. Four patients (6%) in each group had reconstructive failure with implant loss, but IBBR with ADM exhibited a trend of more overall complications and reoperations (difference 0·16, 95% CI, -0·01 to 0·32, P = 0·070), and with higher risk of wound healing problems (P = 0·013). CONCLUSIONS: With 6-months follow-up for all participants, immediate IBBR with ADM carried a risk of implant loss equal to conventional IBBR without ADM, but was associated with more adverse outcomes requiring surgical intervention. Further investigation of risk factors and patient selection in a long-term follow-up is warranted.

Swedish prospective multicenter trial on the accuracy and clinical relevance of sentinel lymph node biopsy before neoadjuvant systemic therapy in breast cancer.

PURPOSE: The timing of sentinel lymph node biopsy (SLNB) in the context of neoadjuvant systemic therapy (NAST) in breast cancer is still controversial. SLNB before NAST has been evaluated in few single-institution studies in which axillary lymph node dissection (ALND), however, was commonly not performed in case of a negative SLNB. We investigated the potential clinical relevance of SLNB before NAST by performing ALND in all patients after NAST. METHODS: This national multicenter trial prospectively enrolled clinically node-negative breast cancer patients planned for NAST at 13 recruiting Swedish hospitals between October 2010 and December 2015. SLNB before NAST was followed by ALND after NAST in all individuals. Repeat SLNB after NAST was encouraged but not mandatory. RESULTS: SLNB before NAST was performed in 224 patients. The identification rate was 100% (224/224). The proportion of patients with a negative SLNB before NAST but positive axillary lymph nodes after NAST was 7.4% (nine of 121 patients, 95% CI 4.0-13.5). Among those with a positive SLNB before NAST, 23.2% (86/112) had further positive lymph nodes after NAST. CONCLUSIONS: In clinically node-negative patients, SLNB before NAST is highly reliable. With this sequence, ALND and regional radiotherapy can be safely omitted in patients with a negative SLNB provided good clinical response to NAST. Additionally, SLNB-positive patients upfront will receive correct nodal staging unaffected by NAST and be consequently offered adjuvant locoregional treatment according to current guidelines pending the results of ongoing randomized trials.

Swedish prospective multicenter trial evaluating sentinel lymph node biopsy after neoadjuvant systemic therapy in clinically node-positive breast cancer.

PURPOSE: Patients with clinically node-positive breast cancer planned for neoadjuvant systemic therapy (NAST) may draw advantages from the nodal downstaging effect and reduce the extent of axillary surgery with sentinel lymph node biopsy (SLNB) performed after NAST. Since there are concerns about lower sentinel lymph node (SLN) detection and higher false-negative rates (FNR) in this setting, our aim was to define the accuracy of SLNB after NAST. METHODS: This Swedish national multicenter trial prospectively recruited 195 breast cancer patients from ten hospitals with T1-T4d biopsy-proven node-positive disease planned for NAST between October 1, 2010 and December 31, 2015. Clinically node-negative axillary status after NAST was not mandatory. SLNB was always attempted and followed by a completion axillary lymph node dissection (ALND). RESULTS: The SLN identification rate was 77.9% (152/195) but improved to 80.7% (138/171) with dual mapping. The median number of SLNs was two (range 1-5). A positive SLNB was found in 52% (79/152), almost 66% (52/79) of whom had additional positive non-sentinel lymph nodes. The overall pathologic nodal response rate was 33.3% (66/195). The overall FNR was 14.1% (13/92) but decreased to 4% (2/50) when only patients with two or more sentinel nodes were analyzed. CONCLUSIONS: In biopsy-proven node-positive breast cancer, SLNB after NAST is feasible even though the identification rate is lower than in clinically node-negative patients. Since the overall FNR is unacceptably high, the omission of ALND should only be considered if two or more SLNs are identified.

Intra-tumor heterogeneity in breast cancer has limited impact on transcriptomic-based molecular profiling.

BACKGROUND: Transcriptomic profiling of breast tumors provides opportunity for subtyping and molecular-based patient stratification. In diagnostic applications the specimen profiled should be representative of the expression profile of the whole tumor and ideally capture properties of the most aggressive part of the tumor. However, breast cancers commonly exhibit intra-tumor heterogeneity at molecular, genomic and in phenotypic level, which can arise during tumor evolution. Currently it is not established to what extent a random sampling approach may influence molecular breast cancer diagnostics. METHODS: In this study we applied RNA-sequencing to quantify gene expression in 43 pieces (2-5 pieces per tumor) from 12 breast tumors (Cohort 1). We determined molecular subtype and transcriptomic grade for all tumor pieces and analysed to what extent pieces originating from the same tumors are concordant or discordant with each other. Additionally, we validated our finding in an independent cohort consisting of 19 pieces (2-6 pieces per tumor) from 6 breast tumors (Cohort 2) profiled using microarray technique. Exome sequencing was also performed on this cohort, to investigate the extent of intra-tumor genomic heterogeneity versus the intra-tumor molecular subtype classifications. RESULTS: Molecular subtyping was consistent in 11 out of 12 tumors and transcriptomic grade assignments were consistent in 11 out of 12 tumors as well. Molecular subtype predictions revealed consistent subtypes in four out of six patients in this cohort 2. Interestingly, we observed extensive intra-tumor genomic heterogeneity in these tumor pieces but not in their molecular subtype classifications. CONCLUSIONS: Our results suggest that macroscopic intra-tumoral transcriptomic heterogeneity is limited and unlikely to have an impact on molecular diagnostics for most patients.

Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled SENOMAC trial.

BACKGROUND: The role of axillary lymph node dissection (ALND) has increasingly been called into question among patients with positive sentinel lymph nodes. Two recent trials have failed to show a survival difference in sentinel node-positive breast cancer patients who were randomized either to undergo completion ALND or not. Neither of the trials, however, included breast cancer patients undergoing mastectomy or those with tumors larger than 5 cm, and power was debatable to show a small survival difference. METHODS: The prospective randomized SENOMAC trial includes clinically node-negative breast cancer patients with up to two macrometastases in their sentinel lymph node biopsy. Patients with T1-T3 tumors are eligible as well as patients prior to systemic neoadjuvant therapy. Both breast-conserving surgery and mastectomy, with or without breast reconstruction, are eligible interventions. Patients are randomized 1:1 to either undergo completion ALND or not by a web-based randomization tool. This trial is designed as a non-inferiority study with breast cancer-specific survival at 5 years as the primary endpoint. Target accrual is 3500 patients to achieve 80% power in being able to detect a potential 2.5% deterioration of the breast cancer-specific 5-year survival rate. Follow-up is by annual clinical examination and mammography during 5 years, and additional controls after 10 and 15 years. Secondary endpoints such as arm morbidity and health-related quality of life are measured by questionnaires at 1, 3 and 5 years. DISCUSSION: Several large subgroups of breast cancer patients, such as patients undergoing mastectomy or those with larger tumors, have not been included in key trials; however, the use of ALND is being questioned even in these groups without the support of high-quality evidence. Therefore, the SENOMAC Trial will investigate the need of completion ALND in case of limited spread to the sentinel lymph nodes not only in patients undergoing any breast surgery, but also in neoadjuvantly treated patients and patients with larger tumors. TRIAL REGISTRATION: NCT 02240472 , retrospective registration date September 14, 2015 after trial initiation on January 31, 2015.

The impact of in situ breast cancer and family history on risk of subsequent breast cancer events and mortality - a population-based study from Sweden.

BACKGROUND: The clinical behavior of in situ breast cancer is incompletely understood and several factors have been associated with invasive recurrence. The purpose of this study was to evaluate long-term risk of subsequent breast cancer and mortality among women diagnosed with in situ breast cancer, in relation to family history METHODS: Using the population-based Swedish Multi-Generation and Cancer Registers we identified 8111 women diagnosed with in situ breast cancer between 1980 and 2004. We used standardized incidence ratios (SIRs) to measure the relative risk of subsequent invasive or contralateral in situ breast cancer and standardized mortality ratios (SMRs) for relative risks of death. RESULTS: Among women diagnosed with in situ breast cancer, the cumulative 10-year and 20-year risk for subsequent contralateral or ipsilateral invasive cancer was approximately 10 % and 18 %, respectively. The risk of subsequent invasive breast cancer was increased more than 4-fold (SIR 4.6 (95 % CI 4.2 - 4.9)) among women with in situ breast cancer as compared to women in the general population and the risk of contralateral in situ breast cancer was increased almost 16-fold (SIR 16.0 (95 % CI 13.2-19.1)). Having a family history of breast cancer increased the risk of contralateral invasive breast cancer by almost 50 % (incidence rate ratio 1.5 (95 % CI 1.0-2.0)). Women under forty years old at diagnosis, without family history, had a 7-fold increased risk, and those with a family history had a 14-fold increased risk for subsequent invasive breast cancer with SIRs of 7.2 (95 % CI 4.8-10.5) and 14.3 (95 % CI 7.4-25.0), respectively. The overall risk of death in women with in situ breast cancer was significantly increased by 30 % compared to the general population but was highly dependent on the occurrence of a second invasive cancer event (SMR 1.3 (95 % CI 1.2-1.4)). CONCLUSIONS: Among women with in situ breast cancer, a positive family history increases the risk of contralateral invasive breast cancer by almost 50 %. The risk of subsequent invasive breast cancer and mortality is substantially higher in younger women, which should be taken into account when planning their treatment and follow up.

Long-term outcome in young women with breast cancer: a population-based study.

PURPOSE: Whether young age at diagnosis of breast cancer is an independent risk factor for death remains controversial, and the question whether young age should be considered in treatment decisions is still to be answered. METHODS: From a population-based cohort of 22,017 women with breast cancer, all women <35 years (n = 471) were compared to a random sample of 700 women aged 35-69 years from the same cohort. Information on patient and tumor characteristics, treatment, and follow-up was collected from the medical records. Tissue microarrays were produced for analysis of classical biomarkers. Breast cancer-specific survival (BCSS), distant disease-free survival (DDFS), and locoregional recurrence-free survival (LRFS) by age were compared using women 50-69 years as reference. RESULTS: At 10 years follow-up, women <35 years and 35-39 years had a worse BCSS [age <35 years 69 % (HR 2.75, 95 % CI 1.93-3.94), age 35-39 years 76 % (HR 2.33, 95 % CI 1.54-3.52), age 40-49 years 84 % (HR 1.53, 95 % CI 0.97-2.39), and age 50-69 years 89 % (reference)]. The worse BCSS was statistically significant in stages I-IIa and Luminal B tumors. At multivariate analysis age <35 years and 35-39 years confined a risk in LRFS (HR 2.13, 95 % CI 1.21-3.76 and HR 1.97, 95 % CI 1.06-3.68) but not in DDFS and BCSS. In the subgroup of women <40 years with luminal tumors stage I-IIa, low age remained an independent risk factor also in DDFS (HR 1.87, 95 % CI 1.03-3.44). CONCLUSION: Young women have a high risk of systemic disease even when diagnosed in an early stage. The excess risk of relapse is most pronounced in Luminal B tumors, where low age is an independent prognostic factor of DDFS and LRFS.

Time trends in axilla management among early breast cancer patients: Persisting major variation in clinical practice across European centers.

Background We examined time trends in axilla management among patients with early breast cancer in European clinical settings. Material and methods EUROCANPlatform partners, including population-based and cancer center-specific registries, provided routinely available clinical cancer registry data for a comparative study of axillary management trends among patients with first non-metastatic breast cancer who were not selected for neoadjuvant therapy during the last decade. We used an additional short questionnaire to compare clinical care patterns in 2014. Results Patients treated in cancer centers were younger than population-based registry populations. Tumor size and lymph node status distributions varied little between settings or over time. In 2003, sentinel lymph node biopsy (SLNB) use varied between 26% and 81% for pT1 tumors, and between 2% and 68% for pT2 tumors. By 2010, SLNB use increased to 79-96% and 49-92% for pT1 and pT2 tumors, respectively. Axillary lymph node dissection (ALND) use for pT1 tumors decreased from between 75% and 27% in 2003 to 47% and 12% in 2010, and from between 90% and 55% to 79% and 19% for pT2 tumors, respectively. In 2014, important differences in axillary management existed for patients with micrometastases only, and for patients fulfilling the ACOSOG Z0011 criteria for omitting ALND. Conclusion This study demonstrates persisting differences in important aspects of axillary management throughout the recent decade. The results highlight the need for international comparative patterns of care studies in oncology, which may help to identify areas where further studies and consensus building may be necessary.

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.

Quality assessment of radiotherapy in the prospective randomized SENOMAC trial.

BACKGROUND AND PURPOSE: Recommendations for regional radiotherapy (RT) of sentinel lymph node (SLN)-positive breast cancer are debated. We here report a RT quality assessment of the SENOMAC trial. MATERIALS AND METHODS: The SENOMAC trial randomized clinically node-negative breast cancer patients with 1-2 SLN macrometastases to completion axillary lymph node dissection (cALND) or SLN biopsy only between 2015-2021. Adjuvant RT followed national guidelines. RT plans for patients included in Sweden and Denmark until June 2019 were collected (N = 1176) and compared to case report forms (CRF). Dose to level I (N = 270) and the humeral head (N = 321) was analyzed in detail. RESULTS: CRF-data and RT plans agreed in 99.3 % (breast/chest wall) and in 96.6 % of patients (regional RT). Congruence for whether level I was an intended RT target was lower (78 %). In accordance with Danish national guidelines, level I was more often an intended target in the SLN biopsy only arm (N = 334/611, 55 %,) than in the cALND arm (N = 174/565, 31 %,). When an intended target, level I received prescribed dose to 100 % (IQR 98-100 %) of the volume. However, even when not an intended target, full dose was delivered to > 80 % of level I (IQR 75-90 %). The intentional inclusion of level I in the target volume more than doubled the dose received by ≥ 50 % of the humeral head. CONCLUSION: Congruence between CRF data and RT plans was excellent. Level I received a high dose coverage even when not intentionally included in the target. Including level I in target significantly increased dose to the humeral head.

Effectiveness of Single vs Multiple Doses of Prophylactic Intravenous Antibiotics in Implant-Based Breast Reconstruction: A Randomized Clinical Trial.

Importance: Multiple-dose antibiotic prophylaxis is widely used to prevent infection after implant-based breast reconstruction despite the lack of high-level evidence regarding its clinical benefit. Objective: To determine whether multiple-dose antibiotic prophylaxis is superior to single-dose antibiotic prophylaxis in preventing surgical site infection (SSI) after implant-based breast reconstruction. Design, Setting, and Participants: This prospective, multicenter, randomized clinical superiority trial was conducted at 7 hospitals (8 departments) in Sweden from April 25, 2013, to October 31, 2018. Eligible participants were women aged 18 years or older who were planned to undergo immediate or delayed implant-based breast reconstruction. Follow-up time was 12 months. Data analysis was performed from May to October 2021. Interventions: Multiple-dose intravenous antibiotic prophylaxis extending over 24 hours following surgery, compared with single-dose intravenous antibiotic. The first-choice drug was cloxacillin (2 g per dose). Clindamycin was used (600 mg per dose) for patients with penicillin allergy. Main Outcomes and Measures: The primary outcome was SSI leading to surgical removal of the implant within 6 months after surgery. Secondary outcomes were the rate of SSIs necessitating readmission and administration of intravenous antibiotics, and clinically suspected SSIs not necessitating readmission but oral antibiotics. Results: A total of 711 women were assessed for eligibility, and 698 were randomized (345 to single-dose and 353 to multiple-dose antibiotics). The median (range) age was 47 (19-78) years for those in the multiple-dose group and 46 (25-76) years for those in the single-dose group. The median (range) body mass index was 23 (18-38) for the single-dose group and 23 (17-37) for the multiple-dose group. Within 6 months of follow-up, 30 patients (4.3%) had their implant removed because of SSI. Readmission for intravenous antibiotics because of SSI occurred in 47 patients (7.0%), and 190 women (27.7%) received oral antibiotics because of clinically suspected SSI. There was no significant difference between the randomization groups for the primary outcome implant removal (odds ratio [OR], 1.26; 95% CI, 0.69-2.65; P = .53), or for the secondary outcomes readmission for intravenous antibiotics (OR, 1.18; 95% CI, 0.65-2.15; P = .58) and prescription of oral antibiotics (OR, 0.72; 95% CI, 0.51-1.02; P = .07). Adverse events associated with antibiotic treatment were more common in the multiple-dose group than in the single-dose group (16.4% [58 patients] vs 10.7% [37 patients]; OR, 1.64; 95% CI, 1.05-2.55; P = .03). Conclusions and Relevance: The findings of this randomized clinical trial suggest that multiple-dose antibiotic prophylaxis is not superior to a single-dose regimen in preventing SSI and implant removal after implant-based breast reconstruction but comes with a higher risk of adverse events associated with antibiotic treatment. Trial Registration: EudraCT 2012-004878-26.

Patient-reported outcomes one year after positive sentinel lymph node biopsy with or without axillary lymph node dissection in the randomized SENOMAC trial.

INTRODUCTION: This report evaluates whether health related quality of life (HRQoL) and patient-reported arm morbidity one year after axillary surgery are affected by the omission of axillary lymph node dissection (ALND). METHODS: The ongoing international non-inferiority SENOMAC trial randomizes clinically node-negative breast cancer patients (T1-T3) with 1-2 sentinel lymph node (SLN) macrometastases to completion ALND or no further axillary surgery. For this analysis, the first 1181 patients enrolled in Sweden and Denmark between March 2015, and June 2019, were eligible. Data extraction from the trial database was on November 2020. This report covers the secondary outcomes of the SENOMAC trial: HRQoL and patient-reported arm morbidity. The EORTC QLQ-C30, EORTC QLQ-BR23 and Lymph-ICF questionnaires were completed in the early postoperative phase and at one-year follow-up. Adjusted one-year mean scores and mean differences between the groups are presented corrected for multiple testing. RESULTS: Overall, 976 questionnaires (501 in the SLN biopsy only group and 475 in the completion ALND group) were analysed, corresponding to a response rate of 82.6%. No significant group differences in overall HRQoL were identified. Participants receiving SLN biopsy only, reported significantly lower symptom scores on the EORTC subscales of pain, arm symptoms and breast symptoms. The Lymph-ICF domain scores of physical function, mental function and mobility activities were significantly in favour of the SLN biopsy only group. CONCLUSION: One year after surgery, arm morbidity is significantly worse affected by ALND than by SLN biopsy only. The results underline the importance of ongoing attempts to safely de-escalate axillary surgery. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov prior to initiation (https://clinicaltrials.gov/ct2/show/NCT02240472).

Effect of Immediate Implant-Based Breast Reconstruction After Mastectomy With and Without Acellular Dermal Matrix Among Women With Breast Cancer: A Randomized Clinical Trial.

Importance: The use of acellular dermal matrix (ADM) in implant-based breast reconstructions (IBBRs) is established practice. Existing evidence validating ADMs proposed advantages, including improved cosmetics and more single-stage IBBRs, is lacking. Objective: To evaluate whether IBBR with ADM results in fewer reoperations and increased health-related quality of life (HRQoL) compared with conventional IBBR without ADM. Design, Setting, and Participants: This was an open-label, multicenter, randomized clinical trial of women with primary breast cancer who planned for mastectomy and immediate IBBR, with a 2-year follow-up for all participants. Participants were enrolled at 5 breast cancer units in Sweden and the United Kingdom between 2014 and May 2017. Exclusion criteria included previous radiotherapy and neo-adjuvant chemotherapy. Data were analyzed until August 2017. Interventions: Participants were allocated to immediate IBBR with or without ADM. Main Outcomes and Measures: The primary trial end point was number of reoperations at 2 years. HRQoL, a secondary end point, was measured as patient-reported outcome measures using 3 instruments from the European Organization for Research and Treatment of Cancer Quality of life Questionnaire. Results: From start of enrollment on April 24, 2014, to close of trial on May 10, 2017, a total of 135 women were enrolled (mean [SD] age, 50.4 [9.5] years); 64 were assigned to have an IBBR procedure with ADM and 65 to the control group who had IBBR without ADM. There was no statistically significant difference between groups for the primary outcome. Of 129 patients analyzed at 2-year follow-up, 44 of 64 (69%) had at least 1 surgical event in the ADM group vs 43 of 65 (66%) in the control group. In the ADM group, 31 patients (48%) had at least 1 reoperation on the ipsilateral side vs 35 (54%) in the control group. The overall number of reoperations on the ipsilateral side were 42 and 43 respectively. Within the follow-up time of 24 months, 9 patients (14%) in the ADM group had the implant removed compared with 7 (11%) in the control group. We found no significant mean differences in postoperative patient-reported HRQoL domains, including perception of body image (mean difference, 3; 99% CI, -11 to 17; P = .57) and satisfaction with cosmetic outcome (mean difference, 8; 99% CI, -6 to 20; P = .11). Conclusions and Relevance: Immediate IBBR with ADM did not yield fewer reoperations compared with conventional IBBR without ADM, nor was IBBR with ADM superior in terms of HRQoL or patient-reported cosmetic outcomes. Patients treated for breast cancer contemplating ADM-supported IBBR should be informed about the lack of evidence validating ADM's suggested benefits. Trial Registration: ClinicalTrials.gov Identifier: NCT02061527.

Reduced breast cancer mortality after 20+ years of follow-up in the Swedish randomized controlled mammography trials in Malmö, Stockholm, and Göteborg.

Objective To analyze the age- and trial-specific effects of the breast cancer screening trials with mammography in Malmö, Stockholm, and Göteborg. Methods The original trial files were linked to the Swedish Cancer and Cause of Death Registers to obtain date of breast cancer diagnosis and date and cause of death. Relative risks and 95% confidence intervals were calculated using the evaluation model (only breast cancers diagnosed between date of randomization and date when the first screening round of the control group was completed were included in the analysis). Results Women aged 40-70 at randomization in the Malmö I and II, Stockholm, and Göteborg trials were followed-up for an average of 30, 22, 25, and 24 years, respectively. The overview of all trials resulted in a significant decrease of 15% in breast cancer mortality. The variation by consecutive 10-year age group at randomization was small-from 21% in the age group 40-49 to 11% in the age group 50-59. After adjustment for age, there was a significant reduction in breast cancer mortality in the Göteborg trial (26%), and a non-significant reduction in the Malmö I and II and Stockholm trials (12%, 15%, and 5.8%, respectively). Conclusions The overview showed a 15% significant relative reduction in breast cancer mortality due to invitation to mammography screening. Heterogeneity in age, trial time, attendance rates, and length of screening intervals may have contributed to the variation in effect between the trials.