Cystic soft tissue tumours of the dorsal aspect of the wrist have two distinct histological subtypes.

In total, 38 patients with cystic dorsal wrist tumours managed with surgical excision were prospectively followed up for 2 years. Tissue was examined histologically after primary surgery and at recurrence. Two distinct tissue types were found: ganglion cyst and synovial cyst.

Pitfalls in machine learning-based assessment of tumor-infiltrating lymphocytes in breast cancer: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state-of-the-art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false-positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in-depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple-negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The impact of metabolic supply lines - and the patterns between them - on the development of distant metastases in 64 women with breast cancer.

Cancer cells upregulate their metabolism to underlie the increased malignant activity. This requires an increased amount of 'metabolic building materials', for example glucose, amino acids etc., which have the blood circulation as their principal supply lines. Targeting these metabolic supply lines, and thus the availability of metabolic building materials in the blood, therefore carries treatment potential. A central observation is that the malignant alterations comprise great complexity and that compensatory mechanisms exist. Therefore, targeted supply lines should presumably constitute specific patterns to achieve therapeutic effect. The aim of the present study was to investigate if such patterns could be seen to correlate with the development of distant metastases. The study was conducted using a case-cohort design. In total, 64 women diagnosed with breast cancer between January 2011 and December 2015 were included. Among these, 32 had developed distant metastases and 32 had not. From a blood sample drawn at the time of diagnosis, the levels of glucose (HbA1c), glutamine, arginine and cystathionine were measured. Cox regression was applied to investigate the impact of the supply lines of these 'building materials' and specifically the patterns between them on the development of distant metastases. The results demonstrate a significant impact of the investigated metabolic supply lines, centrally in relation to interaction between them and in relation to the impact of the increased cumulated utilization of multiple supply lines simultaneously. In conclusion, the results indicated that the metabolic supply lines may impact clinical outcome, and, in this regard, the results placed a substantial emphasis on the effect of the patterns between these supply lines.

[Ganglion cysts on wrists and hands].

The ganglion cyst is the most common soft-tissue tumour of the hand and wrist. 60-70% are found dorsally on the wrist. Ultrasound and MRI-imaging can distinguish whether the tumour is cystic or solid and may be helpful in making a diagnosis. This article reviews the different treatment techniques and rates of recurrence. Arthroscopic excision has shown promising results, but open excision remains the gold standard. The aetiology and pathogenesis of the condition is still unknown and further research is needed especially in reducing the risk of recurrence.

Prognostic and Clinicopathologic Associations of LAG-3 Expression in Triple-negative Breast Cancer.

The immune checkpoint molecule lymphocyte activation gene 3 (LAG-3) is currently being investigated as a possible target for immunotherapy in triple-negative breast cancer (TNBC), frequently as an addition to treatment with programmed cell death protein 1/programmed death ligand 1 (PD-L1) inhibition. However, expression of LAG-3, the frequency of coexpression with PD-L1, and the prognostic significance of this marker have not been studied extensively in TNBC. For this study, tissue microarrays (TMAs) were constructed from surgical specimens of 514 patients with TNBC. TMAs were stained immunohistochemically for LAG-3 and PD-L1 expression. Tumor-infiltrating lymphocytes (TILs) were evaluated on full glass slides. LAG-3 expression was significantly associated with improved overall survival and relapse-free survival. When adjusted for clinicopathologic factors, each increment of 10 LAG-3-positive intratumoral lymphocytes per TMA core was associated with improved overall survival (hazard ratio=0.93, 95% confidence interval: 0.89-0.97, P=0.002), and recurrence-free survival (hazard ratio=0.91, 95% confidence interval: 0.85-0.97, P=0.002). PD-L1 expression on immune cells and PD-L1 expression evaluated with the combined positive score and TILs were also associated with improved survival in both univariate and multivariate analyses. PD-L1 expression on tumor cells was only associated with improved survival in univariate analysis. LAG-3 expression was associated with both TILs and PD-L1 expression. Coexpression of LAG-3 and PD-L1 did not confer additional survival benefits. In conclusion, LAG-3 expression is associated with improved survival in TNBC. LAG-3 is often coexpressed with PD-L1, confirming that TNBC is likely a suitable candidate for cotreatment with LAG-3 and programmed cell death protein 1/PD-L1 inhibitors. However, coexpression does not confer additional survival benefits.

Automated Quantification of sTIL Density with H&E-Based Digital Image Analysis Has Prognostic Potential in Triple-Negative Breast Cancers.

Triple-negative breast cancer (TNBC) is an aggressive and difficult-to-treat cancer type that represents approximately 15% of all breast cancers. Recently, stromal tumor-infiltrating lymphocytes (sTIL) resurfaced as a strong prognostic biomarker for overall survival (OS) for TNBC patients. Manual assessment has innate limitations that hinder clinical adoption, and the International Immuno-Oncology Biomarker Working Group (TIL-WG) has therefore envisioned that computational assessment of sTIL could overcome these limitations and recommended that any algorithm should follow the manual guidelines where appropriate. However, no existing studies capture all the concepts of the guideline or have shown the same prognostic evidence as manual assessment. In this study, we present a fully automated digital image analysis pipeline and demonstrate that our hematoxylin and eosin (H&E)-based pipeline can provide a quantitative and interpretable score that correlates with the manual pathologist-derived sTIL status, and importantly, can stratify a retrospective cohort into two significant distinct prognostic groups. We found our score to be prognostic for OS (HR: 0.81 CI: 0.72-0.92 p = 0.001) independent of age, tumor size, nodal status, and tumor type in statistical modeling. While prior studies have followed fragments of the TIL-WG guideline, our approach is the first to follow all complex aspects, where appropriate, supporting the TIL-WG vision of computational assessment of sTIL in the future clinical setting.

Targeting the Supply Lines of Cancer - A Possible Strategy for Combating the Disease?

Cancer cells alter and up-regulate their metabolic activity in order to facilitate the increased demands of malignancy. This leads to an increased need for metabolic "building materials", for example glucose and amino acids. The blood circulation represents the principal supply lines delivering these materials. It, therefore, becomes relevant to investigate if these supply lines - in terms of the concentrations of building materials in the blood - may exhibit a therapeutic window and could be intervened, as they deliver the most basal components required to exert malignant functioning. A key aspect in this strategy is that it targets - in theory - the thermodynamic foundation enabling the activities that, essentially, "make a cancer a cancer". As an initial step, this review examines if the metabolic supply lines carry clinical implications; specifically, if they impact survival and the development of metastases in patients with cancer. Furthermore, it presents and discusses perspectives on potentially targeting these supply lines.

The immune microenvironment and relation to outcome in patients with advanced breast cancer treated with docetaxel with or without gemcitabine.

Preclinical studies suggest that some effects of conventional chemotherapy, and in particular, gemcitabine, are mediated through enhanced antitumor immune responses. The objective of this study was to use material from a randomized clinical trial to evaluate whether patients with preexisting immune infiltrates responded better to treatment with gemcitabine + docetaxel (GD) compared to docetaxel alone. Formalin fixed, paraffin-embedded breast cancer tissues from SBG0102 phase 3 trial patients randomly assigned to treatment with GD or docetaxel were used. Immunohistochemical staining for CD8, FOXP3, LAG3, PD-1, PD-L1 and CD163 was performed. Tumor infiltrating lymphocytes (TILs) and tumor associated macrophages were evaluated. Prespecified statistical analyses were performed in a formal prospective-retrospective design. Time to progression was primary endpoint and overall survival secondary endpoint. Correlations between biomarker status and endpoints were evaluated using the Kaplan-Meier method and Cox proportional hazards models. Biomarker data was obtained for 237 patients. There was no difference in treatment effect according to biomarker status for the whole cohort. In planned subgroup analysis by PAM50 subtype, in non-luminal (basal-like and HER2E) breast cancers FOXP3 was a significant predictor of treatment effect with GD compared to docetaxel, with a HR of 0.22 (0.09-0.52) for tumors with low FOXP3 compared to HR 0.92 (0.47-1.80) for high FOXP3 TILs (Pinteraction = 0.01). Immune biomarkers were not predictive of added benefit of gemcitabine in a cohort of mixed breast cancer subtypes. However, in non-luminal breast cancers, patients with low FOXP3+ TILs may have significant benefit from added gemcitabine.

Prediction of Pathologic Complete Response in Breast Cancer Patients Comparing Magnetic Resonance Imaging with Ultrasound in Neoadjuvant Setting.

BACKGROUND: Some subgroups of breast cancer patients receiving neoadjuvant chemotherapy (NACT) show high rates of pathologic complete response (pCR) in the breast, proposing the possibility of omitting surgery. Prediction of pCR is dependent on accurate imaging methods. This study investigated whether magnetic resonance imaging (MRI) is better than ultrasound (US) in predicting pCR in breast cancer patients receiving NACT. METHODS: This institutional, retrospective study enrolled breast cancer patients receiving NACT who were examined by either MRI or combined US and mammography before surgery from 2016 to 2019. Imaging findings were compared with pathologic response evaluation of the tumor. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for prediction of pCR were calculated and compared between MRI and US. RESULTS: Among 307 patients, 151 were examined by MRI and 156 by US. In the MRI group, 37 patients (24.5 %) had a pCR compared with 51 patients (32.7 %) in the US group. Radiologic complete response (rCR) was found in 35 patients (23.2 %) in the MRI group and 26 patients (16.7 %) in the US group. In the MRI and US groups, estimates were calculated respectively for sensitivity (87.7 % vs 91.4 %), specificity (56.8 % vs 33.3 %), PPV (86.2 % vs 73.8 %), NPV (60.0 % vs 65.4 %), and accuracy (80.1 % vs 72.4 %). CONCLUSIONS: In predicting pCR, MRI was more specific than US, but not sufficiently specific enough to be a valid predictor of pCR for omission of surgery. As an imaging method, MRI should be preferred when future studies investigating prediction of pCR in NACT patients are planned.

Expression of Secretory Phospholipase A2 Group IIa in Breast Cancer and Correlation to Prognosis in a Cohort of Advanced Breast Cancer Patients.

Secreted phospholipase A2 group IIa (sPLA2-IIa) has been shown to promote tumor genesis and cell proliferation. The properties of this group of enzymes are utilized in liposomal drug delivery of chemotherapy. sPLA2-IIa is also under investigation as a possible treatment target in itself, and as a prognostic marker. The expression of sPLA2-IIa in breast cancer has not been examined extensively, and never using immunohistochemistry. We sought to investigate the expression of sPLA2-IIa in a cohort of advanced breast cancer patients with correlation to known clinicopathologic risk factors and survival. Material from 525 breast cancer patients (426 primary tumors and 99 metastases or local recurrences) was examined for sPLA2-IIa expression using immunohistochemistry. Out of these, 262 showed expression of sPLA2-IIa. We found that there was no correlation to clinicopathologic characteristics, and no impact of sPLA2-IIa expression on prognosis. However, we found that a large proportion of patients in our study had high levels of sPLA2-IIa expression, and that sPLA2-IIa was equally expressed in primary tumors and metastases. These findings may be significant in the future development of liposomal drug delivery or targeted sPLA2-IIa treatment.

Evaluation of analytical accuracy of HER2 status in patients with breast cancer: Comparison of HER2 GPA with HER2 IHC and HER2 FISH.

Human epidermal growth factor receptor 2 (HER2) gene status and overexpression, occurring in ~ 13.6% of primary breast cancers, is essential for identifying patients likely to benefit from biological treatment. In this method of evaluation study, we tested and compared the HER2 gene-protein assay (GPA) with routine HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The GPA was evaluated using 67 formalin-fixed paraffin-embedded (FFPE) HER2 equivoval IHC (2+) breast cancer tissue samples. Overall, agreement between GPA silver in situ hybridization (SISH) and FISH was 91.9% (57/62). Regression analysis revealed slightly higher, but non-significant difference in HER2/chromosome enumeration probe 17 (CEP17) ratio for GPA as compared to FISH (p = 0.074). Intraclass correlation coefficients (ICCs) of 0.94 and Spearman´s rank correlation coefficients of 0.93 (p < 0.0001) for FISH and GPA SISH suggested strong inter-observer association for methods with one observer counting on average 0.23 significant higher for GPA SISH (p = 0.014). Intra-observer IHC method reproducibility was 52.6% (κ = 0.3122, p = 0.004) and 79.7% (κ = 0.6428, p = 0.9197), suggesting fair significant and substantial non-significant difference between tests for reviewers. Inter-observer reproducibility for IHC methods was 53%. While inter-observer reproducibility for experienced IHC interpretation suggested significant differences (κ = 0.3636, p = 0.0332), unexperienced interpretation of IHC GPA suggested fair non-significant difference between reviewers (κ = 0.3101, p = 0.0747). Using FISH as reference, the diagnostic indices for GPA SISH were as follows: sensitivity 100%, specificity 95% and accuracy 92%. Inaccuracy between tests was in 80% of cases due to ISH categorization as equivocal by one of the methods. IHC results highlight that it may be beneficial with a method for simultaneously visualization of HER2 gene and protein status.

Prognostic value of histopathological DCIS features in a large-scale international interrater reliability study.

PURPOSE: For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. METHODS: Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS ± RT) using Krippendorff's alpha (KA) and Gwet's AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. RESULTS: Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05-6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35-5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34-10.23) were independently associated with a higher iIBC risk. CONCLUSIONS: Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features.

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

Synchronous bilateral breast cancer: a nationwide study on histopathology and etiology.

PURPOSE: The aim of the present study was to describe histopathologic characteristics of synchronous bilateral breast cancer (SBBC), and by comparing SBBC to unilateral breast cancer (UBC), identify possible etiological mechanisms of SBBC. METHODS: Patients with primary SBBC (diagnosed within 4 months) and UBC diagnosed in Denmark between 1999 and 2015 were included. Detailed data on histopathology were retrieved from the Danish Breast Cancer Group database and the Danish Pathology Register. Associations between bilateral disease and the different histopathologic characteristics were evaluated by odds ratios and estimated by multinomial regression models. RESULTS: 1214 patients with SBBC and 59,221 with UBC were included. Patients with SBBC more often had invasive lobular carcinomas (OR 1.29; 95% CI 1.13-1.47), a clinically distinct subtype of breast cancer, than UBC patients. Further, they were older than UBC patients, more often had multifocal cancer (OR 1.13; 95% CI 1.01-1.26), and a less aggressive subtype than UBC patients. Invasive lobular carcinoma was associated with having multiple tumors in breast tissue-both in the form of bilateral disease and multifocal disease, and this association was independent of laterality. No similar pattern was observed for other tumor characteristics. CONCLUSION: We identified two etiological mechanisms that could explain some of the occurrence of SBBC. The high proportion of less aggressive carcinomas and higher age of SBBC compared to UBC patients suggests that many are diagnosed at a subclinical stage as slow-growing tumors have a higher probability of simultaneous diagnosis. The high proportion of invasive lobular carcinoma observed in bilateral and multifocal disease, being independent of laterality, suggests that these patients have an increased propensity to malignant tumor formation in breast tissue.

The Prosigna 50-gene profile and responsiveness to adjuvant anthracycline-based chemotherapy in high-risk breast cancer patients.

The DBCG89D trial randomized high-risk early breast cancer patients to adjuvant CMF (cyclophosphamide, methotrexate and fluorouracil) or CEF (cyclophosphamide, epirubicin and fluorouracil). Prosigna assays were performed by researchers with no access to clinical data. Time to distant recurrence (DR) was the primary endpoint, time to recurrence (TR) and overall survival (OS) secondary. Among the 980 Danish patients enrolled, Prosigna results were obtained in 686. Continuous ROR score was associated with DR for CMF (adjusted hazard ratio (HR) 1.20, 95% CI 1.09-1.33), and for CEF (HR 1.04, 95% CI 0.92-1.18), P interaction = 0.06. DR was significantly longer in CEF compared to CMF treated patients with Her2-enriched tumors (HR 0.58, 95% CI 0.38-0.86), but not in patients with luminal tumors. Heterogeneity of treatment effect was significant for TR and OS. In this prospective-retrospective analysis, patients with Her2-enriched breast cancer derived substantial benefit from anthracycline chemotherapy whereas anthracyclines are not an essential component of chemotherapy for patients with luminal subtypes. The benefit of CEF vs. CMF correlated with increasing ROR Score.

Prediction of fulvestrant efficacy in patients with advanced breast cancer: retrospective-prospective evaluation of the predictive potential of a multigene expression assay.

BACKGROUND: Fulvestrant is a selective oestrogen receptor (ER) degrader used as monotherapy and combination therapy for ER positive HER2 negative advanced breast cancer (ABC) in postmenopausal women. The drug response predictor (DRP), is a mathematical algorithm based on the expression of multiple genes in the tumour. The fulvestrant DRP algorithm has previously shown effect in BC. In this study, we investigated the DRP's potential in predicting fulvestrant benefit. METHOD: Among 695 patients with ABC prospectively included in a Danish Breast Cancer Cooperative Group (DBCG) cohort we retrospectively included 226 patients who received fulvestrant as monotherapy. The DRP result was based on mRNA extracted from tumour biopsies and analysed using Affymetrix array. Primary endpoint was time to progression (TTP). RESULTS: For patients who received fulvestrant in line one to four and were previously unexposed to adjuvant endocrine therapy, we identified a hazard ratio (HR) of 0.44 (90% confidence interval (90% CI) upper limit of 1.08, one sided p = 0.066) for a predicted positive vs negative outcome. A weaker association was seen when including patients exposed to adjuvant endocrine treatment or received fulvestrant in fifth or later lines. Exploratory analyses showed that the DRP was efficient when using recent biopsies for DRP estimate and among recently treated patients. CONCLUSION: The DRP showed a potential in predicting fulvestrant treatment but was not significant in the overall analysis. Use of older biopsies, long-term endocrine treatment and multiple therapies between biopsy used for analysis and fulvestrant treatment, probably affect the predictive accuracy.

Two open-label, single arm, non-randomized phase II studies of irinotecan for the treatment of metastatic breast cancer in patients with increased copy number of the topoisomerase I gene.

BACKGROUND: Treatment options in metastatic breast cancer are limited. New therapies preferable with predictive biomarkers are needed. The aim of these trials was to investigate if gene copy number of the topoisomerase 1 gene was predictive of response to the topoisomerase inhibitor irinotecan. METHODS: Two open-label, single-arm phase II studies including HER2 positive and negative patients were conducted. Patients were eligible for inclusion if the primary tumor or a metastatic lesion had increased expression of the topoisomerase 1 gene defined as a TOP1 gene copy number of ≥4 or a TOP1/CEN20 ratio of ≥2. Patients were treated with irinotecan +/- trastuzumab weekly for 4 weeks following 2 weeks break, until progression or unacceptable toxicities. Evaluation scans were performed every 6 weeks. Primary endpoint was clinical benefit rate defined as the fraction of patients with stable disease for ≥4 months. RESULTS: The pre-planned number of 18 patients in each trial was not reached, thus no formal statistical analysis could be performed. Nine patients with HER2 negative disease and three patients with HER2 positive disease were included. Three patients obtained a partial remission and two patients had SD. CONCLUSIONS: The trials did not include the planned number of patients. No association between gene copy number of the topoisomerase 1 gene and response to irinotecan could be proved, however a clinical benefit was found in 5/12 patients and in 2/3 patients with HER2 positive disease. This could call for further investigation of the drug in the metastatic setting, especially in HER2 positive BC. TRIAL REGISTRATION: Eudract registration numbers 2012-002348-26 and 2012-002347-23 . Registration date August 20th 2012.

Sentinel and non-sentinel lymph node metastases in patients with microinvasive breast cancer: a nationwide study.

PURPOSE: To determine the incidence and risk factors of sentinel lymph node (SN) and non-SN metastases in patients with microinvasive breast cancer (MIBC, T1mic). This to identify MIBC patients in whom axillary staging can be safely omitted. METHODS: The Danish Breast Cancer Group database was used to identify a total of 409 women with breast cancer ≤ 1 mm who underwent sentinel lymph node biopsy (SLNB) between 2002 and 2015. After validation, 233 patients were eligible for the analysis. The incidence rates of SN and non-SN metastases were determined. The associations between clinicopathological variables and a positive SN [pN1, pN1mi, or pN0(i+)] were analyzed using univariate and multivariate designs. RESULTS: Of 233 patients with MIBC, only 9 (3.9%) had SN macrometastases. An additional 18 (7.7%) and 23 (9.9%) had SN micrometastases and isolated tumor cells (ITCs), respectively. Of patients with SN macrometastases, two (22.2%) had non-SN macrometastases. In the adjusted analysis, a positive SN was associated with younger age (P = 0.0001) and a positive human epidermal growth factor 2 receptor (HER2) status (P = 0.03). CONCLUSIONS: The low incidence of SN macrometastases < 4% suggests omission of axillary staging in MIBC patients without staging at primary surgery, especially in older (≥ 50 years) HER2- patients. Still, the relatively high proportion of patients with non-SN macrometastases indicates that axillary treatment might be considered in SN positive patients, especially in younger HER2+ MIBC patients.

Breast cancer mortality in synchronous bilateral breast cancer patients.

BACKGROUND: Evidence suggests that patients with synchronous bilateral breast cancer (SBBC), diagnosed within 4 months, have an inferior prognosis compared to unilateral breast cancer (UBC) patients. Using data from nationwide Danish clinical databases, this cohort study investigated whether the inferior prognosis could be explained by SBBC patients having a more aggressive disease, or whether the prognosis could be explained by the fact that they have two simultaneous cancers. METHODS: Patients were diagnosed from 1999-2015. The main outcome was excess mortality, subtracting background population mortality from observed mortality. Differences between SBBC and UBC patients were evaluated by rate ratios (RR) and estimated by Poisson regression. RESULTS: In total, 1214 SBBC and 59 177 UBC patients were included. SBBC patients had a significantly higher excess mortality than UBC patients after adjustment for age and period (RR = 1.73; 95% CI:1.44-2.08; p < 0.01) and after adjusting for characteristics of the worst tumour as traditionally done (RR = 1.31; 95% CI:1.08-1.57; p = 0.01). However, adjusting for characteristics of both tumours, using a more advanced competing risks model, no difference was observed (RR = 1.01; 95% CI:0.83-1.22; p = 0.93). CONCLUSIONS: Our study does not support that the inferior prognosis in SBBC patients is due to having more aggressive tumours per se, but rather the combined effect of having two simultaneous cancers.

PD-L1 expression in breast cancer: expression in subtypes and prognostic significance: a systematic review.

PURPOSE: To systematically review the literature on the expression of PD-L1 in primary BC, variation of expression between subtypes and effect on overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS). Additionally, for studies in the neoadjuvant setting, we have reviewed the ability of PD-L1 to predict pathological complete response (pCR). METHODS: Articles included in this review were retrieved by searching PubMed (1966-2018) and EMBASE (1980-2018). The following search terms were used: "PD-L1 expression" and "breast cancer" (PubMed234; EMBASE 161). RESULTS: Thirty-seven articles were found relevant to this study. We summarize important findings from these works, and show that the observed PD-L1 expression in the studies varies greatly, with expression rates ranging from 0 to 83% across subtypes. PD-L1 expression in relation to prognosis both in the adjuvant and neoadjuvant chemotherapy setting remains controversial, with studies finding better, worse, or no effect on prognosis. We also show that a wide variety of strategies are used when evaluating PD-L1 immunohistochemically, e.g., different cut-off points, different cell types evaluated, and different perceptions of when a cell is positive for PD-L1 (cytoplasmic vs membrane staining). CONCLUSION: Further investigation of PD-L1 expression in breast cancer and its effect on prognosis is required. There is little consensus on the methods used to evaluate PD-L1 expression immunohistochemically, and this may contribute to the diverging results found in this study.