Brustkrebs: Auf dem Weg zu einer personalisierten Therapie : molekulare Subtypen und "Wirtsfaktoren" entscheiden über Prognose und Therapie-Erfolg

Brustkrebs ist die häufigste Krebserkrankung und Todesursache bei Frauen. Die Forschung der letzten Jahrzehnte hat gezeigt, dass es sich dabei nicht um eine einzelne, immer gleich verlaufende Erkrankung handelt. Vielmehr geht man heute davon aus, dass Brustkrebs eine heterogene Erkrankung mit verschiedenen Subtypen darstellt. Sie lassen sich klinisch und molekular deutlich von einander unterscheiden. Wichtiges Ziel der modernen Forschung und ihrer Methoden ist daher die Entwicklung einer individuellen Therapie für jede einzelne Patientin

Antibiotic Use During Pregnancy and Childbirth: Prospective Observational Study on Prevalence, Indications, and Prescribing Patterns in a German Tertiary Center

Introduction Antibiotics are powerful drugs to prevent and treat perinatal infections. Overuse of antibiotics leads to antibiotic resistance, has potential side effects and influences the maternal and neonatal microbiome. Patients and Methods We performed a prospective observational study on the prevalence, indications, and prescribing patterns of antibiotics during pregnancy and childbirth. We included women who had given birth after 23+0 weeks of gestation at a single tertiary center in Germany from January 2020 to March 2021. Descriptive statistics and binomial regression were performed to analyze the factors influencing the prescription of antibiotics. Results We included 522 postpartum women into our study. 337 (64.6%) were exposed to antibiotics during pregnancy and/or childbirth. 115 women received antibiotics during pregnancy, 291 during birth. Most antibiotics during pregnancy were prescribed for urinary tract infections (UTIs) (56.0%). Most prescriptions were issued by obstetrics and gynecology physicians (65.8%), followed by hospitals (16.7%) and family medicine physicians (8.8%). Most antibiotics during childbirth were given for a cesarean section (64.3%), followed by preterm rupture of membranes (41.2%). 95.3% of women who had a preterm birth were exposed to antibiotics. In logistic regression models, lower gestational age at birth, higher maternal body-mass-index and smoking were independently associated with antibiotic use during pregnancy and childbirth. Conclusion We found a high rate of antibiotic exposure during pregnancy and childbirth. Our results imply an urgent need for antibiotic stewardship programs in perinatal medicine as well as further research on the effects of perinatal antibiotic exposure on microbiome development and childhood health. // Einleitung Antibiotika sind potente Medikamente, die verschrieben werden, um perinatale Infektionen zu verhindern oder zu behandeln. Der übermäßige Einsatz von Antibiotika führt zur Antibiotikaresistenz, ist potenziell mit Nebenwirkungen behaftet und hat zudem Auswirkungen auf das mütterliche und neonatale Mikrobiom. Patientinnen und Methoden Wir führten eine prospektive Beobachtungsstudie durch, um die Prävalenz, die Indikationen und die Verschreibungsmuster für Antibiotika während der Schwangerschaft und der Geburt zu untersuchen. Eingeschlossen wurden Frauen, die nach 23+0 Schwangerschaftswochen zwischen Januar 2020 and März 2021 in einem deutschen universitären Perinatalzentrum Level I entbanden. Es wurden eine deskriptive statistische Analyse sowie binomiale Regressionsanalysen durchgeführt, um Faktoren, welche die Verschreibung von Antibiotika beeinflussen, zu identifizieren. Ergebnisse Insgesamt wurden 522 Frauen nach der Entbindung eingeschlossen. 337 (64,6%) erhielten Antibiotika während der Schwangerschaft und/oder der Geburt. 115 Frauen erhielten Antibiotika während der Schwangerschaft und 291 Frauen erhielten sie während der Geburt. Die meisten Antibiotika wurden während der Schwangerschaft zur Behandlung von Harnwegsinfektionen verschrieben (56,0%). Die meisten Verschreibungen wurden von Frauenärzten ausgestellt (65,8%), gefolgt von Krankenhäusern (16,7%) und Hausärzten (8,8%). Die meisten während der Geburt verabreichten Antibiotika wurden wegen eines Kaiserschnitts (64,3%) verschrieben; an zweiter Stelle war die Verschreibung wegen vorzeitigen Blasensprungs (41,2%). 95,3% der Frauen, die eine Frühgeburt hatten, wurden mit Antibiotika behandelt. In den Regressionsmodellen war ein niedriges Gestationsalter bei der Entbindung, ein hoher mütterlicher Body-Mass-Index und Rauchen unabhängig voneinander mit dem Einsatz von Antibiotika während der Schwangerschaft und der Geburt assoziiert. Schlussfolgerung Unsere Studie zeigt eine hohe Antibiotikaexposition von Frauen während Schwangerschaft und Geburt. Die Ergebnisse weisen darauf hin, dass ein Antibiotic-Stewardship-Programm in der Perinatalmedizin dringend nötig ist. Weitere Studien zu den Auswirkungen einer perinatalen Antibiotikaexposition auf die frühe Entwicklung des menschlichen Mikrobioms sowie auf die Gesundheit von Kindern werden benötigt

Does Maternal Underweight Prior to Conception Influence Pregnancy Risks and Outcome?

While obesity in pregnancy and pregnancy outcome in obese women are subjects of diverse research in recent publications, it is remarkable that the data for pregnancy outcome in pre-conceptional underweight mothers is extremely limited. Apart from an increasing prevalence of obesity, however, the prevalence for underweight in distinct sub-groups of mothers is also increasing. In contrary to obesity, less people are affected by underweight in Europe. The World Health Organization (WHO) classifies human weight into different categories (1). A body mass index (BMI) less than 18.5 kg/m 2 is defined as underweight. In Germany, the incidence of underweight in women is low with a nationwide prevalence of 3% (2). Especially in young women in certain social groups, an anorectic model-like weight is the ideal of beauty and a lot of cases of underweight in women of childbearing age are due to eating disorders (3). The lifetime incidence of eating disorders in young women of childbearing age is 5.2-6.5 % (4). While obesity is a frequently encountered problem in pregnant women with multiple complications during pregnancy and delivery (5-16), data on pregnant women with underweight or anorexia are scarce Because of hormonal disorders due to anorexia, underweight women often have menstrual irregularities leading to amenorrhea and infertility. Disorders in hypothalamic-hypophysis functions result in hypogonadotrope anovulatory cycle

T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers

Introduction: Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor. Methods: Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed. Results: A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy. Conclusions: Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis

Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy. Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years. Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results. Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy

Homogeneous Datasets of Triple Negative Breast Cancers Enable the Identification of Novel Prognostic and Predictive Signatures

Background: Current prognostic gene signatures for breast cancer mainly reflect proliferation status and have limited value in triple-negative (TNBC) cancers. The identification of prognostic signatures from TNBC cohorts was limited in the past due to small sample sizes. Methodology/Principal Findings: We assembled all currently publically available TNBC gene expression datasets generated on Affymetrix gene chips. Inter-laboratory variation was minimized by filtering methods for both samples and genes. Supervised analysis was performed to identify prognostic signatures from 394 cases which were subsequently tested on an independent validation cohort (n = 261 cases). Conclusions/Significance: Using two distinct false discovery rate thresholds, 25% and <3.5%, a larger (n = 264 probesets) and a smaller (n = 26 probesets) prognostic gene sets were identified and used as prognostic predictors. Most of these genes were positively associated with poor prognosis and correlated to metagenes for inflammation and angiogenesis. No correlation to other previously published prognostic signatures (recurrence score, genomic grade index, 70-gene signature, wound response signature, 7-gene immune response module, stroma derived prognostic predictor, and a medullary like signature) was observed. In multivariate analyses in the validation cohort the two signatures showed hazard ratios of 4.03 (95% confidence interval [CI] 1.71–9.48; P = 0.001) and 4.08 (95% CI 1.79–9.28; P = 0.001), respectively. The 10-year event-free survival was 70% for the good risk and 20% for the high risk group. The 26-gene signatures had modest predictive value (AUC = 0.588) to predict response to neoadjuvant chemotherapy, however, the combination of a B-cell metagene with the prognostic signatures increased its response predictive value. We identified a 264-gene prognostic signature for TNBC which is unrelated to previously known prognostic signatures

AGO Recommendations for the surgical therapy of breast cancer: update 2022

The recommendations of the AGO Breast Committee on the surgical therapy of breast cancer were last updated in March 2022 (www.ago-online.de). Since surgical therapy is one of several partial steps in the treatment of breast cancer, extensive diagnostic and oncological expertise of a breast surgeon and good interdisciplinary cooperation with diagnostic radiologists is of great importance. The most important changes concern localization techniques, resection margins, axillary management in the neoadjuvant setting and the evaluation of the meshes in reconstructive surgery. Based on meta-analyses of randomized studies, the level of recommendation of an intraoperative breast ultrasound for the localization of non-palpable lesions was elevated to “++”. Thus, the technique is considered to be equivalent to wire localization, provided that it is a lesion which can be well represented by sonography, the surgeon has extensive experience in breast ultrasound and has access to a suitable ultrasound device during the operation. In invasive breast cancer, the aim is to reach negative resection margins (“no tumor on ink”), regardless of whether an extensive intraductal component is present or not. Oncoplastic operations can also replace a mastectomy in selected cases due to the large number of existing techniques, and are equivalent to segmental resection in terms of oncological safety at comparable rates of complications. Sentinel node excision is recommended for patients with cN0 status receiving neoadjuvant chemotherapy after completion of chemotherapy. Minimally invasive biopsy is recommended for initially suspect lymph nodes. After neoadjuvant chemotherapy, patients with initially 1 – 3 suspicious lymph nodes and a good response (ycN0) can receive the targeted axillary dissection and the axillary dissection as equivalent options

AGO recommendations for the surgical therapy of the axilla after neoadjuvant chemotherapy: 2021 Update

For many decades, the standard procedure to treat breast cancer included complete dissection of the axillary lymph nodes. The aim was to determine histological node status, which was then used as the basis for adjuvant therapy, and to ensure locoregional tumour control. In addition to the debate on how to optimise the therapeutic strategies of systemic treatment and radiotherapy, the current discussion focuses on improving surgical procedures to treat breast cancer. As neoadjuvant chemotherapy is becoming increasingly important, the surgical procedures used to treat breast cancer, whether they are breast surgery or axillary dissection, are changing. Based on the currently available data, carrying out SLNE prior to neoadjuvant chemotherapy is not recommended. In contrast, surgical axillary management after neoadjuvant chemotherapy is considered the procedure of choice for axillary staging and can range from SLNE to TAD and ALND. To reduce the rate of false negatives during surgical staging of the axilla in pN+(CNB) stage before NACT and ycN0 after NACT, targeted axillary dissection (TAD), the removal of > 2 SLNs (SLNE, no untargeted axillary sampling), immunohistochemistry to detect isolated tumour cells and micro-metastases, and marking positive lymph nodes before NACT should be the standard approach. This most recent update on surgical axillary management describes the significance of isolated tumour cells and micro-metastasis after neoadjuvant chemotherapy and the clinical consequences of low volume residual disease diagnosed using SLNE and TAD and provides an overview of this year's AGO recommendations for surgical management of the axilla during primary surgery and in relation to neoadjuvant chemotherapy

A clinically relevant gene signature in triple negative and basal-like breast cancer

Introduction: Current prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease. Methods: We assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables. Results: Seventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables. Conclusions: We describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease