Reporting on patient's body mass index (BMI) in recent clinical trials for patients with breast cancer: a systematic review.

BACKGROUND: The proportion of patients with breast cancer and obesity is increasing. While the therapeutic landscape of breast cancer has been expanding, we lack knowledge about the potential differential efficacy of most drugs according to the body mass index (BMI). Here, we conducted a systematic review on recent clinical drug trials to document the dosing regimen of recent drugs, the reporting of BMI and the possible exclusion of patients according to BMI, other adiposity measurements and/or diabetes (leading comorbidity of obesity). We further explored whether treatment efficacy was evaluated according to BMI. METHODS: A search of Pubmed and ClinicalTrials.gov was performed to identify phase I-IV trials investigating novel systemic breast cancer treatments. Dosing regimens and exclusion based on BMI, adiposity measurements or diabetes, documentation of BMI and subgroup analyses according to BMI were assessed. RESULTS: 495 trials evaluating 26 different drugs were included. Most of the drugs (21/26, 81%) were given in a fixed dose independent of patient weight. BMI was an exclusion criterion in 3 out of 495 trials. Patients with diabetes, the leading comorbidity of obesity, were excluded in 67/495 trials (13.5%). Distribution of patients according to BMI was mentioned in 8% of the manuscripts, subgroup analysis was performed in 2 trials. No other measures of adiposity/body composition were mentioned in any of the trials. Retrospective analyses on the impact of BMI were performed in 6 trials. CONCLUSIONS: Patient adiposity is hardly considered as most novel drug treatments are given in a fixed dose. BMI is generally not reported in recent trials and few secondary analyses are performed. Given the prevalence of patients with obesity and the impact obesity can have on pharmacokinetics and cancer biology, more attention should be given by investigators and study sponsors to reporting patient's BMI and evaluating its impact on treatment efficacy and toxicity.

Aging-accumulated methylmalonic acid serum levels at breast cancer diagnosis are not associated with distant metastases.

PURPOSE: Recent evidence suggests that age-accumulated methylmalonic acid (MMA) promotes breast cancer progression in mice. This study aims to investigate the association between baseline serum MMA concentrations in patients with breast cancer and the development of subsequent distant metastases. METHODS: We included 32 patients with early Luminal B-like breast cancer (LumB, median age 62.4y) and 52 patients with early triple-negative breast cancer (TNBC, median age 50.5y) who developed distant metastases within 5 years. They were matched to an equal number of early breast cancer patients (median age 62.2y for LumB and 50.5y for TNBC) who did not develop distant metastases with at least 5 years of follow-up. RESULTS: Baseline serum MMA levels at breast cancer diagnosis showed a positive correlation with age (P < 0.001) and a negative correlation with renal function and vitamin B12 (all P < 0.02), but no statistical association was found with BMI or tumor stage (P > 0.6). Between matched pairs, no significant difference was observed in MMA levels, after adjusting for kidney function and age (P = 0.19). Additionally, in a mouse model, a significant decline in MMA levels was observed in the tumor-bearing group compared to the group without tumors before and after tumor establishment or at identical times for the control group (P = 0.03). CONCLUSION: Baseline serum MMA levels in patients with breast cancer are not correlated with secondary distant metastasis. Evidence in the mouse model suggests that the presence of a tumor perturbates MMA levels.

Circulating biomarkers at diagnosis correlate with distant metastases of early luminal-like breast cancer.

There is an urgent need for new and better biomarker modalities to estimate the risk of recurrence within the luminal-like breast cancer (BC) population. Molecular diagnostic tests used in the clinic lack accuracy in identifying patients with early luminal BC who are likely to develop metastases. This study provides proof of concept that various liquid biopsy read-outs could serve as valuable candidates to build a multi-modal biomarker model distinguishing, already at diagnosis, between early metastasizing and non-metastasizing patients. All these blood biomarkers (chemokines, microRNAs, leukemia inhibitory factor, osteopontin, and serum-induced functional myeloid signaling responses) can be measured in baseline plasma/serum samples and could be added to the existing prognostic factors to improve risk stratification and more patient-tailored treatment in early luminal BC.

PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in ~ 200,000 patients.

BACKGROUND: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. METHODS: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. RESULTS: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56-0.74) versus 0.63 (95%PI 0.54-0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34-2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.

Concordance between results of inexpensive statistical models and multigene signatures in patients with ER+/HER2- early breast cancer.

Multigene signatures (MGS) are used to guide adjuvant chemotherapy (aCT) decisions in patients diagnosed with estrogen receptor (ER)-positive HER2-negative early breast cancer. We used results from three MGS (Oncotype DX® (ODX), MammaPrint® (MP) or Prosigna®) and assessed the concordance between high or low risk of recurrence and the predicted risk of recurrence based on statistical models. In addition, we looked at the impact of MGS results on final aCT administration during the multidisciplinary meeting (MDM). We retrospectively included 129 patients with ER-positive HER2-negative early breast cancer for which MGS testing was performed after MDM at University Hospitals Leuven between May 2013 and April 2019 in case there was doubt about aCT recommendation. Tumor tissue was analyzed either by ODX (N = 44), MP (N = 28), or Prosigna® (N = 57). Eight statistical models were computed: Magee equations (ME), Memorial Sloan Kettering simplified risk score (MSK-SRS), Breast Cancer Recurrence Score Estimator (BCRSE), OncotypeDXCalculator (ODXC), new Adjuvant! Online (nAOL), Mymammaprint.com (MyMP), PREDICT, and SiNK. Concordance, negative percent agreement, and positive percent agreement were calculated. Of 129 cases, 53% were MGS low and 47% MGS high risk. Concordances of 100.0% were observed between risk results obtained by ODX and ME. For MP, BCRSE demonstrated the best concordance, and for Prosigna® the average of ME. Concordances of <50.0% were observed between risk results obtained by ODX and nAOL, ODX and MyMP, ODX and SiNK, MP and MSK-SRS, MP and nAOL, MP and MyMP, MP and SiNK, and Prosigna® and ODXC. Integration of MGS results during MDM resulted in change of aCT recommendation in 47% of patients and a 15% relative and 9% absolute reduction. In conclusion, statistical models, especially ME and BCRSE, can be useful in selecting ER-positive HER2-negative early breast cancer patients who may need MGS testing resulting in enhanced cost-effectiveness and reduced delay in therapeutic decision-making.

Breast cancer-related lymphedema and its treatment: how big is the financial impact?

PURPOSE: Decongestive lymphatic treatment (DLT) is still the gold standard for treatment of breast cancer-related lymphedema (BCRL). With up to 17% of the patients treated for breast cancer developing BCRL, this morbidity imposes a tremendous financial burden for patients and society. Knowledge about this economic burden related to BCRL and its conservative treatment in a European setting is lacking. The aim of this prospective, longitudinal cohort study was to estimate the direct healthcare costs related to BCRL and its treatment in a European setting. METHODS: Patients with BCRL were treated with DLT consisting of an intensive treatment phase of 3 weeks, followed by a maintenance treatment phase of 6 months. Additionally, the follow-up period comprised 6 months. During these 3 weeks and 12 months, all direct costs associated with the treatment of BCRL and its sequelae were documented through billing prices and a self-developed questionnaire which was administered after the intensive treatment phase, and subsequently 3-monthly during the entire period. RESULTS: A total of 194 patients were enrolled in this study. Of these, 17% (n = 32) showed lymphedema stage I, 56% (n = 109) had lymphedema stage IIa, and 27% (n = 53) had lymphedema stage IIb. Total direct healthcare costs per patient were €2248.93 on average during the entire period of 3 weeks of intensive treatments and 12 months of maintenance decongestive therapy. Within these mean direct costs, €1803.35 (80%) was accounted for statutory health insurances, and €445.58 (20%) was out-of-pocket expenses for patients. CONCLUSION: This study is one of the first standardized high-quality health economic analyses of BRCL treatment in Europe. The present study indicates that the price tag of BCRL treatment in Belgium is high not only for the health insurance but also for the patients Clinical trial registration number The study makes part of a double-blind, multi-center, randomized controlled trial (EFforT-BCRL trial), which is registered in clinicaltrials.gov (NCT02609724). CME reference S58689, EudraCT Number 2015-004822-33.

Behavior of metastatic breast cancer according to subtype.

PURPOSE: To explore the impact of breast cancer subtype on metastatic behavior and long-term outcome defined as breast cancer specific survival (BCSS). METHODS: Retrospective single centre cross-sectional study of 5972 patients with newly diagnosed, unilateral first diagnosis of breast cancer, diagnosed 2000-2010. Patients had either early breast cancer (EBC) treated primarily by surgery (SURG n = 5072), neoadjuvant systemic therapy (NEO n = 592), or upfront metastatic disease (META n = 308). Surrogate breast cancer subtypes were defined according to classical pathological criteria. Analysis was performed using Kaplan-Meier method and logistic/Cox regression. RESULTS: After median follow-up time of 103.6 months (IQR 73.4-139.2 months), 817 patients with EBC at diagnosis (14.4%) developed distant metastases of which 621 (12.2%) SURG and 196 (33.1%) NEO. Metastasis rate after EBC was: LuminalA 8.1%, LuminalB1(HER2-) 20.4%, LuminalB2(HER2+) without (neo)adjuvant trastuzumab 21.7%, LuminalB2(HER2+) with trastuzumab 9.0%, HER2Positive(ER-) without trastuzumab 30.0%, HER2Positive(ER-) with trastuzumab 19.9% and TripleNegative 25.3%. There were major differences in site of first metastases according to subtype. For single site first metastases, median BCSS assessed from time of metastases was worst for brain localization (13.9 months) and best for bone (48.4 months). Multiple sites of first metastases had worse BCSS from date of metastases than single site first metastases (median BCSS for 1 site 40.0, 2 sites 27.1, ≥ 3 sites 20.5 months). Median BCSS from date of metastases is longer in upfront metastases compared to secondary metastases after EBC (43.4 vs. 27.9 months). CONCLUSIONS: Tumor subtype influences the metastatic behavior and survival after development of distant metastases.

Assessment of stromal tumor infiltrating lymphocytes and immunohistochemical features in invasive micropapillary breast carcinoma with long-term outcomes.

PURPOSE: We studied the long-term outcomes of invasive micropapillary carcinoma (IMPCs) of the breast in relation to stromal tumor infiltrating lymphocytes (sTILs), prognostic biomarkers and clinicopathological features. METHODS: Stage I-III IMPCs treated with upfront surgery at our institution (January 2000 and December 2016) were included. Central pathology review was performed and sTILs (including zonal distribution and hot spot analysis) and tumor-associated plasma cells (TAPC) were evaluated. Expression of P53, BCL2, FOXP3, and WT1, which are variably linked to breast cancer prognosis, was measured by immunohistochemistry using tissue microarrays. Time-to-event endpoints were distant recurrence free interval (DRFI) and breast cancer-specific survival (BCSS). RESULTS: We included 111 patients of whom 59% were pure IMPCs. Standard clinicopathological features were comparable between pure and non-pure IMPCs. Overall, the mean sTILs level was 20% with higher proportion of sTILs present at the invasive front. There were no significant differences between pure- and non-pure IMPCs in sTILs levels, nor in the spatial distribution of the hot spot regions or in the distribution of TAPC. Higher sTILs correlated with worse DRFI (HR = 1.55; p = 0.0172) and BCSS (HR = 2.10; p < 0.001). CONCLUSIONS: Clinicopathological features, geographical distribution of sTILs and TAPC are similar between pure and non-pure IMPCs. Despite a high proportion of grade 3 tumors and lymph node involvement, we observed a low rate of distant recurrences and breast cancer-related death in this cohort of stage I-III IMPCs treated with primary surgery. Caution in interpretation of the observed prognostic correlations is required given the very low number of events, warranting validation in other cohorts.

What are the economic burden and costs associated with the treatment of breast cancer-related lymphoedema? A systematic review.

OBJECTIVES: To provide an overview of costs associated with the treatment of breast cancer-related lymphoedema (BCRL) and its possible sequelae, borne by patients or by society. DATA SOURCES: According to the PRISMA guideline, a systematic literature search was carried out in four electronic databases: PubMed, Web of Science, Cochrane Clinical Trials and EMBASE. Searches were performed on October 1, 2018. STUDY SELECTION: Eligibility criteria: (1) expenses of adults (age > 18 years), (2) concerning patients with BCRL, (3) overview of (in)direct costs associated with BCRL, (4) expenses in which at least one type of conservative treatment modality for lymphoedema is included and/or costs for hospital admissions due to infections. Reviews and meta-analyses were excluded. DATA EXTRACTION: After assessing the risk of bias and level of evidence, quantitative data on (in)direct costs for BCRL treatment during a well-mentioned timeframe were extracted. DATA SYNTHESIS: Eight studies were included. Three studies reported on patient-borne costs related to BCRL. Mean direct costs per year borne by patients ranged between USD$2306 and USD$2574. Indirect costs borne by patients ranged between USD$3325 and USD$5545 per year. Five studies estimated society-borne costs related to BCRL from claims data, billing prices and providers' services during 12 to 24 months of follow-up. Mean direct treatment costs after 1 year of decongestive lymphatic therapy (DLT) ranged between €799 (= USD$1126.60) and USD$3165. CONCLUSION: This systematic review revealed that BCRL imposes a substantial economic burden on patients and society. However, more standardized high-quality health economic analyses among this field are required. Recent economic analyses related to BCRL treatment in Europe, Asia, Africa and South America are lacking. Worldwide, further scrutiny of the economic impact of DLT for BCRL in clinical settings is needed. CLINICAL TRIAL REGISTRATION NUMBER: The review makes part of a double-blind, multi-center, randomized controlled trial (EFforT-BCRL trial), which is registered in clinicaltrials.gov (NCT02609724). CME reference S58689, EudraCT Number 2015-004822-33.

Physical activity level and age contribute to functioning problems in patients with breast cancer-related lymphedema: a multicentre cross-sectional study.

PURPOSE: Breast cancer survivors face a high risk of developing breast cancer-related lymphedema (BCRL). Besides physical symptoms such as swelling, BCRL can have a psychosocial impact and lead to problems in daily functioning. Understanding contributing variables to problems in functioning yields possibilities to improve treatment modalities and consequently patients' quality of life. Therefore, the aim of this study was to explore the association between patient-, lymphedema-, and cancer treatment-related variables with problems in functioning in patients with BCRL. METHODS: A cross-sectional study was performed in 185 patients with BCRL. Problems in daily functioning (dependent variable) were evaluated with the Lymph-ICF-UL questionnaire. Following independent variables were analysed by bi-variate and multivariable analyses, including a stepwise regression analysis: patient-related variables (age, BMI, physical activity level, education), lymphedema-related variables (excessive arm volume, duration of lymphedema, total pitting score, presence of hand edema, hardness of the tissue, lymphedema stage), and cancer treatment-related variables (type of surgery, surgery at the dominant side, radiotherapy, chemotherapy, hormone therapy, immunotherapy, TNM-classification). RESULTS: The Lymph-ICF-UL mean total score was 38% (± 21), representing a moderate amount of problems in general functioning. Multivariable regression analyses revealed that lower physical activity level and lower age are contributing factors to more problems in daily functioning. Stepwise regression analysis indicated that up to 8% of the variance in problems in functioning could be explained by physical activity level and age of patients with BCRL. CONCLUSION: Especially patients with low physical activity level and younger patients experience more problems in functioning. For the determination of certain causal interactions, future longitudinal studies including other independent variables that might explain a higher amount of problems in functioning in this population, are warranted. TRIAL REGISTRATION: The study makes part of a double-blind, multi-center, randomized controlled trial (EFforT-BCRL trial), which is registered in clinicaltrials.gov (NCT02609724). CME reference S58689, EudraCT Number 2015-004822-33.

What is the best method to determine excessive arm volume in patients with breast cancer-related lymphoedema in clinical practice? Reliability, time efficiency and clinical feasibility of five different methods.

OBJECTIVE: To investigate the reliability, time efficiency and clinical feasibility of five commonly used methods for assessing excessive arm volume in patients with breast cancer-related lymphoedema (BCRL). DESIGN: Cross-sectional study. SETTING: University Hospitals Leuven, Belgium. SUBJECTS: 30 participants with unilateral BCRL. METHODS: Excessive arm volume was determined by five different methods: traditional volumetry with overflow, volumetry without overflow, inverse volumetry, optoelectronic volumetry and calculated volume based on circumference measurements. To investigate intra- and inter-rater reliability, measurements were performed twice by the same assessor and once by a different assessor. Intraclass correlation coefficients (ICCs), standard errors of the measurement (SEMs) and systematic changes between the means were calculated. To determine time efficiency, the mean setup time, execution time and total time were examined for each method. Furthermore, 12 limitations regarding clinical feasibility were listed and scored for each method. Finally, an overall ranking score was determined between the methods. RESULTS: Mean age was 65 (±8) years and mean body mass index was 28 (±4) kg/m2. Intra- and inter-rater reliability ranged between strong and very strong. Calculated arm volume based on circumferences (mean excessive arm volume: assessor A: 477 (±367) mL; assessor B: 470 (±367) mL; assessor A (second time): 493 (±362) mL) showed the highest intra- and inter-rater ICCs of .987 and .984, respectively. Optoelectronic volumetry was the fastest method, representing a mean total time of 1 minute and 43 (±26) seconds for performing a bilateral measurement. The least limitations were reported on the calculated volume based on the circumference method (3 out of 12 limitations). CONCLUSION: Calculated volume based on arm circumferences is the best measurement method for evaluating excessive arm volume over time in terms of reliability, low error rate, low cost, few limitations and the time spent.

Oncological safety of autologous breast reconstruction after mastectomy for invasive breast cancer.

BACKGROUND: The number of patients requesting autologous breast reconstruction (ABR) after mastectomy for breast cancer has increased over the past decades. However, concern has been expressed about the oncological safety of ABR. The aim of our study was to assess the effect of ABR on distant relapse. METHODS: In this retrospective cohort study, data was analysed from patients who underwent mastectomy for invasive breast cancer in University Hospitals Leuven between 2000 and 2011. In total, 2326 consecutive patients were included, 485 who underwent mastectomy with ABR and 1841 who underwent mastectomy alone. The risk of relapse in both groups was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. ABR was considered as a time-dependent variable. Additionally, the evolution of the risk over follow-up time was calculated. RESULTS: With a median follow-up of 68 months, 8% of patients in the reconstruction group developed distant metastases compared to 15% in the mastectomy alone group (univariate HR 0.70, 95% CI 0.50-0.97, p = 0.0323). However, after adjustment for potential confounding factors in a Cox multivariable analysis, the risk of distant relapse was no longer significantly different between groups (multivariate HR 0.82, 95% CI 0.55-1.22, p = 0.3301). Moreover, the risk of metastasis after reconstruction was not time-dependent. CONCLUSIONS: These findings suggest that there is no effect of ABR on distant relapse rate and thus that ABR is an oncological safe procedure. The rate of local recurrence was too low to make any significant conclusions.

Effectiveness of Botulinum Toxin A for Persistent Upper Limb Pain After Breast Cancer Treatment: A Double-Blinded Randomized Controlled Trial.

OBJECTIVE: To investigate the effect of a single botulinum toxin A (BTX-A) infiltration in the pectoralis major muscle in addition to a standard physical therapy program for treatment of persistent upper limb pain in breast cancer survivors. DESIGN: Double-blinded (patient and assessor) randomized controlled trial. SETTING: A university hospital. PARTICIPANTS: Breast cancer patients (N=50) with pain. INTERVENTION: The intervention group received a single BTX-A infiltration. The control group received a placebo (saline) infiltration. Within 1 week after the infiltration, all patients attended an individual physical therapy program (12 sessions) during the first 3 months and a home exercise program up to 6 months after infiltration. MAIN OUTCOME MEASURES: The primary outcome was change in pain intensity at the upper limb (visual analog scale, 0-100) after 3 months. Secondary outcomes were prevalence rate of pain, pressure hypersensitivity, pain quality, shoulder function, and quality of life. Measures were taken before the intervention and at 1, 3, and 6 months' follow-up. RESULTS: No significant difference in change in pain intensity after 3 months was found (mean difference in change, 3/100; 95% confidence interval [CI], -13 to 19). From baseline up to 6 months, a significantly different change in upper limb pain intensity was found between groups in favor of the intervention group (mean difference in change, 16/100; 95% CI, 1-31). CONCLUSIONS: A single BTX-A infiltration in combination with an individual physical therapy program significantly decreased pain intensity at the upper limb in breast cancer survivors up to 6 months. However, the effect size was not clinically relevant, and no other beneficial effects were found.

Serum methylmalonic acid concentrations at breast cancer diagnosis significantly correlate with clinical frailty.

Methylmalonic acid (MMA), a by-product of propionate metabolism, is known to increase with age. This study investigates the potential of serum MMA concentrations as a biomarker for age-related clinical frailty in older patients with breast cancer. One hundred nineteen patients ≥ 70 years old with early-stage breast cancer were included (median age 76 years). G8 screening, full geriatric assessment, clinical parameters (i.e., estimated glomerular filtration rate (eGFR) and body mass index (BMI)), and serum sample collection were collected at breast cancer diagnosis before any therapy was administered. MMA concentrations were measured via liquid chromatography with tandem mass spectrometry. MMA concentrations significantly increased with age and eGFR (all P < 0.001) in this older population. The group with an abnormal G8 (≤ 14, 51% of patients) had significantly higher MMA levels than the group with normal G8 (> 14, 49%): 260 nmol/L vs. 188 nmol/L, respectively (P = 0.0004), even after correcting for age and eGFR (P = 0.001). Furthermore, in the detailed assessment, MMA concentrations correlated most with mobility (Eastern Cooperative Oncology Group (ECOG) Performance Status and Activities of Daily Living (ADL) tools, all P ≤ 0.02), comorbidity (Charlson Comorbidity Index (CCI) tool, P = 0.005), and polypharmacy (P < 0.001), whereas no significant associations were noted for instrumental ADL (IADL), Mini-Mental State Examination (MMSE), Geriatric Depression Scale-15 (GDS15), Mini Nutritional Assessment-Short Form (MNA-SF), and pain (all P > 0.1). In addition, our results showed that higher MMA levels correlate with poor overall survival in breast cancer patients (P = 0.003). Elevated serum MMA concentrations at initial diagnosis are significantly associated, not only with age but also independently with clinical frailty, suggesting a possible influence of MMA on clinical frailty in older patients with early-stage breast cancer.

Metastases of primary mixed no-special type and lobular breast cancer display an exclusive lobular histology.

Primary tumors with a mixed invasive breast carcinoma of no-special type (IBC-NST) and invasive lobular cancer (ILC) histology are present in approximately five percent of all patients with breast cancer and are understudied at the metastatic level. Here, we characterized the histology of metastases from two patients with primary mixed IBC-NST/ILC from the postmortem tissue donation program UPTIDER (NCT04531696). The 14 and 43 metastatic lesions collected at autopsy had morphological features and E-cadherin staining patterns consistent with pure ILC. While our findings still require further validation, they may challenge current clinical practice and imaging modalities used in these patients.

Treatment Response, Tumor Infiltrating Lymphocytes and Clinical Outcomes in Inflammatory Breast Cancer-Treated with Neoadjuvant Systemic Therapy.

Inflammatory breast cancer (IBC) is a rare (1%-5%), aggressive form of breast cancer, accounting for approximately 10% of breast cancer mortality. In the localized setting, standard of care is neoadjuvant chemotherapy (NACT) ± anti-HER2 therapy, followed by surgery. Here we investigated associations between clinicopathologic variables, stromal tumor-infiltrating lymphocytes (sTIL), and pathologic complete response (pCR), and the prognostic value of pCR. We included 494 localized patients with IBC treated with NACT from October 1996 to October 2021 in eight European hospitals. Standard clinicopathologic variables were collected and central pathologic review was performed, including sTIL. Associations were assessed using Firth logistic regression models. Cox regressions were used to evaluate the role of pCR and residual cancer burden (RCB) on disease-free survival (DFS), distant recurrence-free survival (DRFS), and overall survival (OS). Distribution according to receptor status was as follows: 26.4% estrogen receptor negative (ER-)/HER2-; 22.0% ER-/HER2+; 37.4% ER+/HER2-, and 14.1% ER+/HER2+. Overall pCR rate was 26.3%, being highest in the HER2+ groups (45.9% for ER-/HER2+ and 42.9% for ER+/HER2+). sTILs were low (median: 5.3%), being highest in the ER-/HER2- group (median: 10%). High tumor grade, ER negativity, HER2 positivity, higher sTILs, and taxane-based NACT were significantly associated with pCR. pCR was associated with improved DFS, DRFS, and OS in multivariable analyses. RCB score in patients not achieving pCR was independently associated with survival. In conclusion, sTILs were low in IBC, but were predictive of pCR. Both pCR and RCB have an independent prognostic role in IBC treated with NACT. SIGNIFICANCE: IBC is a rare, but very aggressive type of breast cancer. The prognostic role of pCR after systemic therapy and the predictive value of sTILs for pCR are well established in the general breast cancer population; however, only limited information is available in IBC. We assembled the largest retrospective IBC series so far and demonstrated that sTIL is predictive of pCR. We emphasize that reaching pCR remains of utmost importance in IBC.

Rapid autopsies to enhance metastatic research: the UPTIDER post-mortem tissue donation program.

Research on metastatic cancer has been hampered by limited sample availability. Here we present the breast cancer post-mortem tissue donation program UPTIDER and show how it enabled sampling of a median of 31 (range: 5-90) metastases and 5-8 liquids per patient from its first 20 patients. In a dedicated experiment, we show the mild impact of increasing time after death on RNA quality, transcriptional profiles and immunohistochemical staining in tumor tissue samples. We show that this impact can be counteracted by organ cooling. We successfully generated ex vivo models from tissue and liquid biopsies from distinct histological subtypes of breast cancer. We anticipate these and future findings of UPTIDER to elucidate mechanisms of disease progression and treatment resistance and to provide tools for the exploration of precision medicine strategies in the metastatic setting.

Angiotensin-converting enzyme inhibition and food restriction restore delayed preconditioning in diabetic mice.

BACKGROUND: Classical and delayed preconditioning are powerful endogenous protection mechanisms against ischemia-reperfusion damage. However, it is still uncertain whether delayed preconditioning can effectively salvage myocardium in patients with co-morbidities, such as diabetes and the metabolic syndrome. We investigated delayed preconditioning in mice models of type II diabetes and the metabolic syndrome and investigated interventions to optimize the preconditioning potential. METHODS: Hypoxic preconditioning was induced in C57Bl6-mice (WT), leptin deficient ob/ob (model for type II diabetes) and double knock-out (DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome). Twenty-four hours later, 30 min of regional ischemia was followed by 60 min reperfusion. Left ventricular contractility and infarct size were studied. The effect of 12 weeks food restriction or angiotensin-converting enzyme inhibition (ACE-I) on this was investigated. Differences between groups were analyzed for statistical significance by student's t-test or one-way ANOVA followed by a Fisher's LSD post hoc test. Factorial ANOVA was used to determine the interaction term between preconditioning and treatments, followed by a Fisher's LSD post hoc test. Two-way ANOVA was used to determine the relationship between infarct size and contractility (PRSW). A value of p<0.05 was considered significant. RESULTS: Left ventricular contractility is reduced in ob/ob compared with WT and even further reduced in DKO. ACE-I improved contractility in ob/ob and DKO mice. After ischemia/reperfusion without preconditioning, infarct size was larger in DKO and ob/ob versus WT. Hypoxic preconditioning induced a strong protection in WT and a partial protection in ob/ob mice. The preconditioning potential was lost in DKO. Twelve weeks of food restriction or ACE-I restored the preconditioning potential in DKO and improved it in ob/ob. CONCLUSION: Delayed preconditioning is restored by food restriction and ACE-I in case of type II diabetes and the metabolic syndrome.