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.).

Impact of type 2 diabetes on complications after primary breast cancer surgery: Danish population-based cohort study.

BACKGROUND: Knowledge is sparse on the impact of type 2 diabetes (T2D) on surgical outcomes after breast cancer surgery. This study investigated the association between T2D and risk of complications after primary breast cancer surgery, and evaluated the biological interaction between T2D and co-morbidities. METHODS: Using the Danish Breast Cancer Group clinical database, a cohort of all Danish women diagnosed with early-stage breast cancer during 1996-2022 was created. All patients underwent mastectomy or breast-conserving surgery. Information on prevalent T2D was collected from Danish medical and prescription registries. Surgical complications were defined as hospital diagnoses for medical or surgical complications developing within 30 days after primary breast cancer surgery. The 30-day cumulative incidence proportion of complications was calculated, and Cox regression was used to estimate HRs. Interaction contrasts were computed to determine the additive interaction between T2D and co-morbidities on the incidence rate of complications. RESULTS: Among 98 589 women with breast cancer, 6332 (6.4%) had T2D at breast cancer surgery. Overall, 1038 (16.4%) and 9861 (10.7%) women with and without T2D developed surgical complications, yielding cumulative incidence proportions of 16 (95% c.i. 15 to 17) and 11 (10 to 11)% respectively, and a HR of 1.43 (95% c.i. 1.34 to 1.53). The incidence rate of surgical complications explained by the interaction of T2D with moderate and severe co-morbidity was 21 and 42%, respectively. CONCLUSION: Women with breast cancer and T2D had a higher risk of complications after primary breast cancer surgery than those without T2D. A synergistic effect of T2D and co-morbidity on surgical complications can explain this association.

Late effects following breast cancer treatment.

Improved survival after breast cancer treatment comes at a cost in the form of increased risk of late effects. A number of these are summarised in this review. The late effects can be divided in 1) late effects after locoregional treatment, e.g., lymphoedema, impaired shoulder movement, and pain; 2) consequences of systemic treatment, e.g. polyneuropathy, problems related to premature menopause, and increased risk of cardio-vascular disease; and 3) general late effects, commonly seen across all cancer types, including fatigue, insomnia, and cognitive impairment. There is a need for more knowledge about risk factors, prognoses, and the most effective treatments.

Surgical treatment of breast cancer.

Surgical treatment of breast cancer has changed towards less invasive procedures as summarised in this review. Breast conserving surgery (BCS) and radiotherapy (RT) are now recommended as standard of care. Several flexible marking methods for removal of non-palpable tumours have gradually replaced wire-guided localisation. Neoadjuvant systemic treatment increases tumour shrinkage and BCS and may lead to omission of axillary clearance (AC). The prognostic significance of AC in patients with metastases to 1-2 sentinel nodes at primary surgery is questioned. Results from the SENOMAC trial are expected to change guidelines from AC to axillary RT.

Antibodies toward Na+,HCO3--cotransporter NBCn1/SLC4A7 block net acid extrusion and cause pH-dependent growth inhibition and apoptosis in breast cancer.

BACKGROUND: Na+,HCO3--cotransporter NBCn1/Slc4a7 accelerates murine breast carcinogenesis. Lack of specific pharmacological tools previously restricted therapeutic targeting of NBCn1 and identification of NBCn1-dependent functions in human breast cancer. METHODS: We develop extracellularly-targeted anti-NBCn1 antibodies, screen for functional activity on cells, and evaluate (a) mechanisms of intracellular pH regulation in human primary breast carcinomas, (b) proliferation, cell death, and tumor growth consequences of NBCn1 in triple-negative breast cancer, and (c) association of NBCn1-mediated Na+,HCO3--cotransport with human breast cancer metastasis. RESULTS: We identify high-affinity (KD ≈ 0.14 nM) anti-NBCn1 antibodies that block human NBCn1-mediated Na+,HCO3--cotransport in cells, without cross-reactivity towards human NBCe1 or murine NBCn1. These anti-NBCn1 antibodies abolish Na+,HCO3--cotransport activity in freshly isolated primary organoids from human breast carcinomas and lower net acid extrusion effectively in primary breast cancer tissue from patients with macrometastases in axillary lymph nodes. Inhibitory anti-NBCn1 antibodies decelerate tumor growth in vivo by ~50% in a patient-derived xenograft model of triple-negative breast cancer and pH-dependently reduce colony formation, cause G2/M-phase cell cycle accumulation, and increase apoptosis of metastatic triple-negative breast cancer cells in vitro. CONCLUSIONS: Inhibitory anti-NBCn1 antibodies block net acid extrusion in human breast cancer tissue, particularly from patients with disseminated disease, and pH-dependently limit triple-negative breast cancer growth.

Digital breast tomosynthesis versus X-ray of the breast specimen for intraoperative margin assessment: A randomized trial.

BACKGROUND: Involved resection margins after breast conserving surgery (BCS) often require a re-operation with increased patient anxiety and risk of impaired cosmesis. We investigated the number of re-operations due to involved resection margins after BCS comparing digital breast tomosynthesis(DBT) with X-ray for intraoperative margin evaluation. Furthermore, we assessed the diagnostic accuracy of these methods to predict histopathological margin status. Finally, we evaluated risk factors for re-operation. METHODS: In this randomized, non-blinded study, 250 invasive breast cancer patients were randomized (1:1), whereof 241 were analyzed intraoperatively with either DBT (intervention, n = 119) or X-ray (standard, n = 122). Pearson's chi-squared test, Fisher's exact test, t-test, logistic and ordinal regression analysis was used as appropriate. RESULTS: No difference was found in the number of re-operations between the DBT and X-ray group (16.8 % vs 19.7 %, p = 0.57), or in diagnostic accuracy to predict histopathological margin status (77.5 %, CI: 68.6-84.9 %) and (67.3 %, CI: 57.7-75.9 %), respectively. We evaluated 5 potential risk factors for re-operation: Ductal carcinoma in situ (DCIS) outside tumor, OR = 9.4 (CI: 4.3-20.6, p < 0.001); high mammographic breast density, OR = 6.1 (CI: 1.0-38.1, p = 0.047); non-evaluable margins on imaging, OR = 3.8 (CI: 1.3-10.8, p = 0.016); neoadjuvant chemotherapy, OR = 3.0 (CI: 1.0-8.8, p = 0.048); and T2 tumor-size, OR = 2.6 (CI: 1.0-6.4, p = 0.045). CONCLUSIONS: No difference was found in the number of re-operations or in diagnostic accuracy to predict histopathological margin status between DBT and X-ray groups. DCIS outside the tumor showed the highest risk of re-operation. Intraoperative methods with improved visualization of DCIS are needed to obtain tumor free margins in BCS.

Examining the efficacy of treatments for arm lymphedema in breast cancer survivors: an overview of systematic reviews with meta-analyses.

Background: Lymphedema affects one in six breast cancer survivors making it a global healthcare challenge. There is considerable debate about the efficacy of different treatments for lymphedema. We aimed to summarize the current evidence for treatments for lymphedema in breast cancer survivors. Methods: In this overview of systematic reviews with meta-analyses (SRMAs), five databases were searched for SRMAs of randomised controlled trials (RCTs) reporting effects of medications, surgery, exercise, laser therapy, acupuncture, kinesio taping, or complex decongestive physiotherapy (CDP) for breast cancer-related lymphedema published from database inception up to March 7, 2023. Data extraction was performed for the SRMAs and RCTs, and SRMAs were appraised with AMSTAR2. Random effects meta-analyses of the RCTs provided estimates of the pooled effects sizes (Hedges' g) for each treatment modality. This study is registered with PROSPERO, CRD42020184813. Findings: 1569 studies were identified by the search and eighteen SRMAs with 51 RCTs were included, investigating manual lymphatic drainage (MLD), compression pump, exercise, kinesio taping, laser, and acupuncture. Overall, the methodological quality of the SRMAs was low. SRMAs reached different conclusions for all treatment modalities, except for kinesio taping where the two SRMAs found no effect. The analysis of 40 RCTs with 1970 participants revealed a small effect across all interventions compared to any control (g = 0.20, p = 0.047, I2 = 0.79), corresponding to volume reductions of 119.7 ml (95% CI 135-104) and 88.0 ml (95% CI 99-77) in the intervention and control groups, respectively, and a small effect of exercise (g = 0.26, p = 0.022, I2 = 0.44). The between-group differences in volume reduction were small and did not reach statistical significance for any one treatment modality. Interpretation: Based on the available data, there is no evidence of superiority of any one treatment on volume reduction nor any solid research refuting these treatments. Thus, definitive conclusions to inform clinical practice about the efficacy of these treatments cannot be drawn. Due to poor-quality evidence, more research is needed to untangle the efficacy of each treatment component for different stages of lymphedema. Funding: Danish Cancer Society.

The King is in the altogether: Radiation therapy after oncoplastic breast surgery.

Breast cancer is the most common malignancy, and the majority of the patients are diagnosed at an early disease stage. Breast conservation is the preferred locoregional approach, and oncoplastic breast conservation surgery is becoming more popular. This narrative review aims to discuss the challenges and uncertainties in target volume definition for postoperative radiation after these procedures, to improve radiation therapy decisions and encourage multidisciplinary.

Diagnosis and treatment of breast cancer in Denmark during the COVID-19 pandemic: a nationwide population-based study.

BACKGROUND: The COVID-19 pandemic was a global health crisis with population-wide behavioural restrictions imposed worldwide to reduce transmission of infection and to limit the potential burden on the healthcare systems. We examined whether there was any change in the diagnosis or treatment of breast cancer during the pandemic as compared to previous years. MATERIAL AND METHODS: The study population comprised all women aged ≥18 years diagnosed with breast cancer in 2015-2021 with data obtained from the clinical quality registry of the Danish Breast Cancer Cooperative Group (DBCG). Data on socioeconomic factors were retrieved from Statistics Denmark. Prevalence ratios (PR) with 95% confidence intervals (CI) were estimated from a generalised linear model (GLM) with a log link for the Poisson family with robust standard errors (SE) of each outcome, using the COVID-19 pandemic period in Denmark as the exposure of interest. RESULTS: In total, 30,598 breast cancers were diagnosed during the study period. There was a small decrease (4.5%) in the total number of breast cancer cases in 2020 compared with previous years. During the pandemic, a lower proportion of the patients diagnosed with breast cancer had a short educational level (28.5 vs. 26.9%; PR = 0.91; 95% CI: 0.88-0.95), a low income (20.5 vs. 19.0%; PR = 0.90; 0.85-0.95) and fewer than expected in the age group 60-69 years (27.8 vs. 25.3; PR = 0.90; 0.86-0.94) were diagnosed, as compared with the pre-pandemic period. No difference in type of surgery or tumour size was observed. A higher proportion of patients received neo-adjuvant chemotherapy (49.0 vs 55.0%; PR = 1.15; 1.06-1.24), whereas a lower proportion received adjuvant chemotherapy (93.5 vs 85.6%; PR = 0.92; 0.90-0.93) during the pandemic, compared with the pre-pandemic period. CONCLUSIONS: During the pandemic, a small decrease in the number of breast cancer diagnoses was observed particularly among socially disadvantaged groups. Overall, the quality of breast cancer treatment was maintained.

Social inequality in cancer survivorship: Educational differences in health-related quality of life among 27,857 cancer survivors in Denmark.

BACKGROUND: With a growing population of cancer survivors in Denmark, the evaluation of health-related quality of life (HRQoL) has become increasingly important. We describe variations in HRQoL between educational groups in a national population of cancer survivors. METHODS: We conducted a cross-sectional questionnaire study among breast, prostate, lung, and colon cancer survivors diagnosed in 2010-2019 in Denmark. We used the EORTC QLQ-C30 to assess HRQoL including physical, role, emotional, cognitive, social functioning, and symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Information on educational level and clinical data were extracted from national registers and clinical databases. Levels of impaired functioning and severe symptoms were identified using newly established thresholds for clinical importance. Multivariate logistic regression was used to examine associations between education and HRQoL. All statistical tests were 2-sided. RESULTS: In total, 27,857 (42%) participated in the study. Up to 72% and 75% of cancer survivors with short education (≤9 years) reported impaired functioning and severe symptoms, respectively. Cancer survivors with short compared to long education (>12 years) were more likely to report impaired functioning and severe symptoms, with for example significantly higher odds ratios (ORs) for impaired physical function (breast OR = 2.41, 99% CI = 2.01-2.89; prostate OR = 1.81, 99% CI = 1.48-2.21; lung OR = 2.97, 99% CI = 1.95-4.57; and colon cancer OR = 1.69, 99% CI = 1.28-2.24). CONCLUSIONS: Cancer survivors with short education are at greater risk of impaired HRQoL than survivors with long education 2-12 years after diagnosis. This underscores the need for systematic screening and symptom management in cancer aftercare, in order to reach all cancer survivors, also cancer survivors with short education.

Educational differences in healthcare use among survivors after breast, prostate, lung, and colon cancer - a SEQUEL cohort study.

BACKGROUND: Many cancer survivors experience late effects after cancer. Comorbidity, health literacy, late effects, and help-seeking behavior may affect healthcare use and may differ among socioeconomic groups. We examined healthcare use among cancer survivors, compared with cancer-free individuals, and investigated educational differences in healthcare use among cancer survivors. METHODS: A Danish cohort of 127,472 breast, prostate, lung, and colon cancer survivors from the national cancer databases, and 637,258 age- and sex-matched cancer-free individuals was established. Date of entry was 12 months after diagnosis/index date (for cancer-free individuals). Follow-up ended at death, emigration, new primary cancer, December 31st, 2018, or up to 10 years. Information about education and healthcare use, defined as the number of consultations with general practitioner (GP), private practicing specialists (PPS), hospital, and acute healthcare contacts 1-9 years after diagnosis/index date, was extracted from national registers. We used Poisson regression models to compare healthcare use between cancer survivors and cancer-free individuals, and to investigate the association between education and healthcare use among cancer survivors. RESULTS: Cancer survivors had more GP, hospital, and acute healthcare contacts than cancer-free individuals, while the use of PPS were alike. One-to-four-year survivors with short compared to long education had more GP consultations (breast, rate ratios (RR) = 1.28, 95% CI = 1.25-1.30; prostate, RR = 1.14, 95% CI = 1.10-1.18; lung, RR = 1.18, 95% CI = 1.13-1.23; and colon cancer, RR = 1.17, 95% CI = 1.13-1.22) and acute contacts (breast, RR = 1.35, 95% CI = 1.26-1.45; prostate, RR = 1.26, 95% CI = 1.15-1.38; lung, RR = 1.24, 95% CI = 1.16-1.33; and colon cancer, RR = 1.35, 95% CI = 1.14-1.60), even after adjusting for comorbidity. One-to-four-year survivors with short compared to long education had less consultations with PPS, while no association was observed for hospital contacts. CONCLUSION: Cancer survivors used more healthcare than cancer-free individuals. Cancer survivors with short education had more GP and acute healthcare contacts than survivors with long education. To optimize healthcare use after cancer, we need to better understand survivors' healthcare-seeking behaviors and their specific needs, especially among survivors with short education.

Carbonic anhydrases reduce the acidity of the tumor microenvironment, promote immune infiltration, decelerate tumor growth, and improve survival in ErbB2/HER2-enriched breast cancer.

BACKGROUND: Carbonic anhydrases catalyze CO2/HCO3- buffer reactions with implications for effective H+ mobility, pH dynamics, and cellular acid-base sensing. Yet, the integrated consequences of carbonic anhydrases for cancer and stromal cell functions, their interactions, and patient prognosis are not yet clear. METHODS: We combine (a) bioinformatic analyses of human proteomic data and bulk and single-cell transcriptomic data coupled to clinicopathologic and prognostic information; (b) ex vivo experimental studies of gene expression in breast tissue based on quantitative reverse transcription and polymerase chain reactions, intracellular and extracellular pH recordings based on fluorescence confocal microscopy, and immunohistochemical protein identification in human and murine breast cancer biopsies; and (c) in vivo tumor size measurements, pH-sensitive microelectrode recordings, and microdialysis-based metabolite analyses in mice with experimentally induced breast carcinomas. RESULTS: Carbonic anhydrases-particularly the extracellular isoforms CA4, CA6, CA9, CA12, and CA14-undergo potent expression changes during human and murine breast carcinogenesis. In patients with basal-like/triple-negative breast cancer, elevated expression of the extracellular carbonic anhydrases negatively predicts survival, whereas, surprisingly, the extracellular carbonic anhydrases positively predict patient survival in HER2/ErbB2-enriched breast cancer. Carbonic anhydrase inhibition attenuates cellular net acid extrusion and extracellular H+ elimination from diffusion-restricted to peripheral and well-perfused regions of human and murine breast cancer tissue. Supplied in vivo, the carbonic anhydrase inhibitor acetazolamide acidifies the microenvironment of ErbB2-induced murine breast carcinomas, limits tumor immune infiltration (CD3+ T cells, CD19+ B cells, F4/80+ macrophages), lowers inflammatory cytokine (Il1a, Il1b, Il6) and transcription factor (Nfkb1) expression, and accelerates tumor growth. Supporting the immunomodulatory influences of carbonic anhydrases, patient survival benefits associated with high extracellular carbonic anhydrase expression in HER2-enriched breast carcinomas depend on the tumor inflammatory profile. Acetazolamide lowers lactate levels in breast tissue and blood without influencing breast tumor perfusion, suggesting that carbonic anhydrase inhibition lowers fermentative glycolysis. CONCLUSIONS: We conclude that carbonic anhydrases (a) elevate pH in breast carcinomas by accelerating net H+ elimination from cancer cells and across the interstitial space and (b) raise immune infiltration and inflammation in ErbB2/HER2-driven breast carcinomas, restricting tumor growth and improving patient survival.

Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study.

BACKGROUND: Women treated for breast cancer (BC) often suffer genitourinary syndrome of menopause. These symptoms may be alleviated by vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT). However, there are concerns of risks of recurrence of BC and death following treatment. METHODS: Our study included longitudinal data from a national cohort of postmenopausal women, diagnosed 1997-2004 with early-stage invasive estrogen receptor-positive nonmetastatic BC, who received no treatment or 5 years of adjuvant endocrine therapy. We ascertained prescription data on hormone therapy, VET or MHT, from a national prescription registry. We evaluated mortality and risk of recurrence associated with use of VET and MHT vs non-use using multivariable models adjusted for potential confounders. RESULTS: Among 8461 women who had not received VET or MHT before BC diagnosis, 1957 and 133 used VET and MHT, respectively, after diagnosis. Median follow-up was 9.8 years for recurrence and 15.2 years for mortality. The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for VET (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for VET and MHT, respectively. CONCLUSIONS: In postmenopausal women treated for early-stage estrogen receptor-positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.

Amplified Ca2+ dynamics and accelerated cell proliferation in breast cancer tissue during purinergic stimulation.

Intracellular Ca2+ dynamics shape malignant behaviors of cancer cells. Whereas previous studies focused on cultured cancer cells, we here used breast organoids and colonic crypts freshly isolated from human and murine surgical biopsies. We performed fluorescence microscopy to evaluate intracellular Ca2+ concentrations in breast and colon cancer tissue with preferential focus on intracellular Ca2+ release in response to purinergic and cholinergic stimuli. Inhibition of the sarco-/endoplasmic reticulum Ca2+ ATPase with cyclopiazonic acid elicited larger Ca2+ responses in breast cancer tissue, but not in colon cancer tissue, relative to respective normal tissue. The resting intracellular Ca2+ concentration was elevated, and ATP, UTP and acetylcholine induced strongly augmented intracellular Ca2+ responses in breast cancer tissue compared with normal breast tissue. In contrast, resting intracellular Ca2+ levels and acetylcholine-induced increases in intracellular Ca2+ concentrations were unaffected and ATP- and UTP-induced Ca2+ responses were smaller in colon cancer tissue compared with normal colon tissue. In accordance with the amplified Ca2+ responses, ATP and UTP substantially increased proliferative activity-evaluated by bromodeoxyuridine incorporation-in breast cancer tissue, whereas the effect was minimal in normal breast tissue. ATP caused cell death-identified with ethidium homodimer-1 staining-in breast cancer tissue only at concentrations above the expected pathophysiological range. We conclude that intracellular Ca2+ responses are amplified in breast cancer tissue, but not in colon cancer tissue, and that nucleotide signaling stimulates breast cancer cell proliferation within the extracellular concentration range typical for solid cancer tissue.

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).

Diagnostic accuracy of radiography, digital breast tomosynthesis, micro-CT and ultrasound for margin assessment during breast surgery: A systematic review and meta-analysis.

RATIONALE AND OBJECTIVES: Achieving adequate resection margins in breast conserving surgery is challenging and often demands more than one surgical procedure. We evaluated pooled diagnostic sensitivity, and specificity of radiological methods for intraoperative margin assessment and their impact on repeat surgery rate. MATERIALS AND METHODS: We included studies using radiography, digital breast tomosynthesis (DBT), micro-CT, and ultrasound for intraoperative margin assessment with the histological assessment as the reference method. A systematic search was performed in PubMed, Embase, Cochrane Library, Scopus, and Web of Science. Two investigators screened the studies for eligibility criteria and extracted data of the included studies independently. The quality assessment on diagnostic accuracy studies (QUADAS)-2 tool was used. A bivariate random effect model was used to obtained pooled sensitivity and specificity of the index tests in the meta-analysis. RESULTS: The systematic search resulted in screening of 798 unique records. Twenty-two articles with 29 radiological imaging methods were selected for meta-analysis. Pooled sensitivity and specificity and area under the curve were calculated for each of the 4 subgroups in the meta-analysis respectively: Radiography; 52%, 77%, 60%, DBT; 67%, 76%, 76%, micro-CT; 68%, 69%, 72%, and ultrasound; 72%, 78%, 80%. The repeat surgery rate was poorly reported in the included studies. CONCLUSION: Ultrasound showed the highest and radiography the lowest diagnostic performance for intraoperative margin assessment. However, the heterogeneity between studies was high and the subgroups small. The radiological methods for margin assessment need further improvement to provide reliable guidance in the clinical workflow and to prevent repeat surgeries.