Breast conserving surgery versus mastectomy: overall and relative survival-a population based study by the Danish Breast Cancer Cooperative Group (DBCG).

BACKGROUND: Observational studies have pointed at a better survival after breast conserving surgery (BCS) compared with mastectomy. The aim of the present study was to evaluate whether this remains true when more extensive tumor characteristics and treatment data were included. METHODS: The cohort included patients registered after primary surgery for early invasive breast cancer in the database of the Danish Breast Cancer Cooperative Group, in the period 1995-2012. The cohort was divided into three groups: (i) patients who primarily had a mastectomy, (ii) patients treated by BCS, and (iii) patients who primarily had BCS and then mastectomy [intention to treat (ITT) by BCS]. The association between overall mortality and standard mortality ratio (SMR) and risk factors was analyzed in univariate and multivariate Poisson regression models. RESULTS: A total of 58,331 patients were included: 27,143 in the mastectomy group, 26,958 in the BCS group, and 4230 in the BCS-ITT group. After adjusting for patient and treatment characteristics, the relative risk (RR) was 1.20 (95% CI: 1.15-1.25) after mastectomy and 1.08 (95% CI: 1.01-1.15) after BCS first and then mastectomy, as compared to BCS. Statistically significant interactions were not observed for age, period of treatment, and nodal status, but patients with Charlson's Comorbidity Index (CCI) score 2+ had no increased mortality after mastectomy, as opposed to patients with CCI 0-1. Loco-regional radiation therapy (RT) in node positive patients did not reduce the increased risk associated with mastectomy [RR = 1.28 (95% CI 1.19-1.38)]. CONCLUSION: Patients assigned to BCS have a better survival than patients assigned to mastectomy. Residual confounding after adjustment for registered characteristics presumably explained the different outcomes, thus consistent with selection bias. Diversities in RT did not appear to explain the observed difference in survival after BCS and mastectomy.

Importance of margin width in breast-conserving treatment of early breast cancer.

BACKGROUND AND METHOD: The association between margin width and ipsilateral breast tumour recurrence (IBTR, defined as invasive recurrence) was investigated in a population-based nationwide cohort of 11,900 patients undergoing breast-conserving therapy for invasive cancer. RESULTS: The median follow-up was 4.9 years. The cumulative incidence of IBTR at 5 and 9 years was 2.4% and 5.9%, respectively. A final positive margin increased the risk of IBTR (HR 2.51; 95% CI 1.02-6.23). No decrease in IBTR with a wider negative margin compared to a narrow but negative margin was observed in the adjusted analysis of margin width (>0 to <2 mm vs. ≥2 to <5 mm vs. ≥5 mm (reference): HR 1.54 (CI 95% 0.81-2.93) vs. 0.95 (CI 95% 0.56-1.62) vs. 1). However, few patients had narrow margins. The factors associated with increased IBTR were young age (P < 0.001), >4 positive lymph nodes (P = 0.008) and re-excision (P = 0.003). A reduced risk of IBTR was observed with chemotherapy (P < 0.001), boost radiation (P = 0.023) and ER positivity (P < 0.001). CONCLUSION: An overall low rate of IBTR was observed. A final positive margin was associated with a more than twofold risk of IBTR. There was no evidence for better local control with wider margins, but the data were insufficient to show whether narrow margins were as good as wider negative margins in terms of local control. J. Surg. Oncol. 2016;113:609-615. © 2016 Wiley Periodicals, Inc.

Pattern of relapse after breast conserving therapy, a study of 1519 early breast cancer patients treated in the Central Region of Denmark 2000-2009.

BACKGROUND: The continuous improvements in diagnosing and treatment of breast cancer are reflected in the ever changing pattern of recurrence. The aim of the study was to investigating recurrence pattern and prognostic factors of recurrence in a population-based cohort. MATERIAL AND METHOD: In total 1519 consecutive patients treated with breast conserving therapy (BCT) for invasive carcinoma between 2000 and 2009 in the Central Region of Denmark was included. Patients received adjuvant irradiation and systemic treatment according to the guidelines of the Danish Breast Cancer Cooperative Group, including boost for young women and those with a narrow margin. RESULTS: Median follow-up was 5.3 years (range 0.3-14.4). In total 183 women experienced breast cancer recurrence, 44 ipsilateral breast cancer recurrence, 13 regional recurrences, and 126 distant metastasis (DM). This corresponds to a cumulative risk of DM as first event at five and nine years of 6.5% and 12.6%, respectively. Further 42 women developed breast cancer in the contralateral breast. Disease-free survival (DFS) at five and nine years was 88% and 76%, respectively. Large tumor size (>20 mm), lymph node involvement, and vascular invasion were significantly associated with increased risk of DM. Margin width and age were not associated with risk of DM. CONCLUSION: Acceptable recurrence rates and DFS were observed. Patients with large tumors, lymph node involvement, and vascular invasion had an increased risk of DM.

The Influence of Repeat Surgery and Residual Disease on Recurrence After Breast-Conserving Surgery: A Danish Breast Cancer Cooperative Group Study.

BACKGROUND: A significant proportion of women who have breast-conserving surgery (BCS) subsequently undergo re-excision or proceed to mastectomy. This study aimed to identify factors associated with residual disease after repeat surgery and to determine their effect on ipsilateral breast tumor recurrence (IBTR) and survival. METHODS: The study cohort was identified within the national population-based registry of the Danish Breast Cancer Cooperative Group, including women who underwent BCS for unilateral invasive breast cancer between 2000 and 2009. RESULTS: The study investigated 12,656 women. Within 2 months after initial BCS, 1342 (11 %) of these women had a re-excision, and 756 (6 %) of the women had a mastectomy. Residual disease was found in 20 % of re-excisions and 59 % of mastectomies. In adjusted analysis, ductal carcinoma in situ (DCIS) outside the invasive tumor, positive initial margin, and age younger than 50 years were associated with increased risk of residual disease. In the adjusted analysis, patients with residual disease after re-excision had an increased risk of IBTR regardless whether residual findings were invasive carcinoma [hazard ratio (HR), 2.97; 95 % confidence interval (CI) 1.57-5.62] or DCIS (HR, 2.58; 95 % CI 1.50-4.45). However, no difference was seen in overall survival comparing patients receiving one excision with those having repeat surgery with or without residual disease (p = 0.96). CONCLUSION: A higher risk of IBTR seen after re-excision was associated with residual disease. Overall survival was similar regardless of repeat surgery and residual findings.

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.

Challenges presented by complete response to immune checkpoint blockade in patients with dMMR colorectal cancer: A case report.

INTRODUCTION: Early clinical trials have demonstrated remarkable responses to immune checkpoint blockade (ICB) in patients with colorectal cancers with deficient mismatch repair (dMMR) mechanisms. The precise role immunotherapy will play in the treatment of these patients is undefined, with these agents likely to produce new challenges as well as opportunities. PRESENTATION OF CASE: A 74-year-old patient was diagnosed with a locally advanced dMMR adenocarcinoma in the transverse colon with clinical suspicion of peritoneal metastases (cT4N2M1). The burden of disease was assessed as incurable, and a referral was made for palliative oncological treatment. After 5 months of treatment with pembrolizumab, a complete radiological response in the primary tumour was seen although there was still radiological suspicion of peritoneal and lymph node metastases. The patient underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy but unfortunately died 6 weeks later due to complications. Final histology of the surgical specimen showed no evidence of residual disease (ypT0N0M0). DISCUSSION: This case highlights the opportunities and challenges presented by the efficacy of ICB in dMMR colorectal cancer. These agents were able to cure a patient who had disseminated disease presumed to be incurable at the time of diagnosis. However, due to current limitations in determining the degree of response to ICB, this result could only be confirmed after major surgery, which ultimately led to the patient's death. CONCLUSION: ICB can lead to dramatic responses in patients with dMMR colorectal cancers. Major challenges remain in differentiating complete and partial responders and determining the indications for conventional surgery.

Breast-Conserving Surgery or Mastectomy?: Impact on Survival.

The early randomized controlled trials revealed no differences in survival between breast-conserving surgery (BCS) and mastectomy. However, breast cancer treatment has undergone changes, and the results of recent population-based registry studies suggest superior long-term survival after BCS. To explore the current evidence, a systematic review and meta-ana lysis of population-based observational studies from 2010 and onward was conducted. Methods: A literature search was conducted in the PubMed, Embase, and Cochrane databases to identify relevant literature. Keywords included "mastectomy," "breast conserving surgery," and "survival." The identified studies were narratively reviewed and effect sizes (hazard ratios [HRs]) for overall (OS) and breast cancer-specific survival (BCSS) were combined with random-effects models. Results: A total of 30 reports were included in the review, and results from 25 studies were included in the meta-analyses. Compared with mastectomy, BCS was associated with better OS (HR = 1.34 [1.20-1.51]; N = 1,311,600) and BCSS (HR = 1.38 [1.29-1.47]; N = 494,267). Selected subgroups of patients, based on lymph node status, age (<50 years/≥50 years), and radiation therapy after mastectomy (±), all showed better overall survival after BCS. The number (range 4-12) and type of prognostic variables adjusted for in the survival analyses of the studies did not statistically significantly moderate the differences in survival between BCS and mastectomy. Conclusions: The combined findings from large population-based studies indicate that BCS is associated with survival benefit compared with mastectomy, suggesting that BCS be the recommended treatment of early breast cancer (T1-2N0-1M0) if a radical lumpectomy can be performed.

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.

Inflammatory breast cancer: A review from our experience.

INTRODUCTION: Inflammatory Breast Cancer (IBC) is a distinct and rare type of breast cancer accounting for up to 6% of all breast cancer cases in Europe. The aim of this study was to investigate diagnostic methods, treatments, and outcome after IBC in patients treated at a single institution in Denmark. METHOD: All patients treated for IBC at Aarhus University Hospital between 2000 and 2014 were identified and included in the cohort. Survival was assessed using Kaplan-Meier curves and log-rank statistics. RESULTS: A total of 89 patients were identified with a median follow up of 3.6 years. The overall survival at 5 and 10 years were 41% and 18%, respectively. The disease free survival at 5 and 10 years were 47% and 27%, respectively. Thirty-four percent had distant metastasis at time of diagnosis. Patients with ER positive tumors had a significantly better overall survival than patients with ER negative tumors (p = 0.01). CONCLUSION: Despite a more aggressive systemic and loco-regional treatment today, IBC is still a very serious disease with a high mortality.

Socio-demographic, clinical, and health-related factors associated with breast reconstruction - A nationwide cohort study.

We collected registry- and questionnaire-based data on socio-economic and health status, tumor- and treatment-related variables, and explored associations with receipt of reconstruction and information about treatment options in a nationwide cohort of Danish women, treated for primary breast cancer. A total of 594 women were available for analysis, 240 (40%) of these received reconstruction. Multivariate analyses showed that receipt of reconstruction was associated with 1) younger age at time of primary surgery (<36 years: OR = 10.04, [3.80-26.50], p < 0.001 and 36-49 years: OR = 2.48, [1.73-3.56], p < 0.001, compared to 50-60 year olds), 2) having received radiotherapy (OR = 0.57, [0.40-0.81], p = 0.002), 3) high income (Second quartile: OR = 1.74, [1.05-2.90], p = 0.033 and fourth quartile: OR = 2.18, [1.31-3.62], p = 0.003, compared with the lowest income quartile), and 4) ethnicity other than Danish (OR = 6.32, [1.58-25.36], p = 0.009). Health-related factors at the time of primary surgery (physical functioning, body mass index, smoking, use of alcohol, and comorbidity) were not associated with reconstruction. Odds of having received information about the option of reconstruction decreased by 8% per year of age in the multivariate analysis (OR = 0.92, [0.87-0.97], p = 0.003). In conclusion, younger age and not having been treated with radiotherapy was independently associated with reconstruction. In addition, higher income was also found to be associated with reconstruction despite free and equal access to reconstruction and healthcare in Denmark. Healthrelated factors were not associated with the use of reconstruction following mastectomy. Our findings underscore the need for physicians to ensure optimal level of information and accessibility to reconstruction for all women regardless of age, treatment, and socio-economic status.