Rhomboid intramembrane protease RHBDL4 triggers ER-export and non-canonical secretion of membrane-anchored TGFα

Rhomboid intramembrane proteases are the enzymes that release active epidermal growth factor receptor (EGFR) ligands in Drosophila and C. elegans, but little is known about their functions in mammals. Here we show that the mammalian rhomboid protease RHBDL4 (also known as Rhbdd1) promotes trafficking of several membrane proteins, including the EGFR ligand TGFα, from the endoplasmic reticulum (ER) to the Golgi apparatus, thereby triggering their secretion by extracellular microvesicles. Our data also demonstrate that RHBDL4-dependent trafficking control is regulated by G-protein coupled receptors, suggesting a role for this rhomboid protease in pathological conditions, including EGFR signaling. We propose that RHBDL4 reorganizes trafficking events within the early secretory pathway in response to GPCR signaling. Our work identifies RHBDL4 as a rheostat that tunes secretion dynamics and abundance of specific membrane protein cargoes.Baden-Württemberg Stiftung; Network of Aging Research (NAR, University of Heidelberg); Deutsche Forschungsgemeinschaft grant: (SFB 1036, TP 12); EMBO Installation Grant number: (2329); Ministry of Education, Youth and Sports of the Czech Republic projects: (LK11206, LO1302); Medical Research Council programme number: (U105178780); Boehringer-Ingelheim

Initial clinical results with a fusion prototype for mammography and three-dimensional ultrasound with a standard mammography system and a standard ultrasound probe

Background Combinations *Equal contributors. of different imaging techniques in fusion devices appear to be associated with improvements in diagnostic assessment. Purpose The aim of this study was to test the feasibility of using an automated standard three-dimensional (3D) ultrasound (US) device fused with standard mammography for the first time in breast cancer patients. Material and Methods Digital mammograms and 3D automated US images were obtained in 23 patients with highly suspicious breast lesions. A recently developed fusion machine consisting of an ABVS 3D US transducer from an Acuson S2000 machine and a conventional Mammomat Inspiration device (both Siemens Healthcare GmbH, Erlangen, Germany) were used for the purpose. The feasibility of the examinations, imaging coverage, and patients' experience of the procedure were examined. Results In 15 out of 19 patients, the region of interest (ROI) with the tumor marked in the mammogram was visible on US. The examination was experienced positively by the patients, with no unexpected pain or injury. The examination was time-saving and well tolerated. Conclusion In conclusion, we have shown initial clinical feasibility of an US/radiography fusion prototype with good localization and evaluation of the ROIs. The combined examination was well tolerated. The simultaneous evaluation with mammography and US imaging may be able to improve detection and reduce examiner-related variability

HLA-G and HLA-F protein isoform expression in breast cancer patients receiving neoadjuvant treatment

The immunosuppressive human leukocyte antigens HLA-G and HLA-F are expressed on trophoblast and malignant cells. Four membrane-bound and three soluble HLA-G protein isoforms have been described, which have different immunosuppressive potentials. HLA-F has three transcript variants, resulting in three different protein isoforms. The aim of this study was to evaluate the prognostic and predictive value of HLA-G and HLA-F protein isoform expression patterns in patients with breast cancer. Core biopsies were taken at diagnosis in patients with HER2+ (n = 28), luminal B-like (n = 49) and triple-negative (n = 38) breast cancers who received neoadjuvant chemotherapy. Expression levels of HLA-F and -G were correlated with the pathological complete response (pCR). Protein expression was determined by Western blot analysis, using two antibodies for each HLA, specific for different isoforms. The protein expression of HLA isoforms did not significantly differ between breast cancer subtypes. However, some initial indications were found for an association between the soluble HLA-G6 protein isoform and pCR in HER2+ breast cancer. The study provides preliminary evidence for the evaluation of HLA-G isoform expression, in particular HLA-G6, as a possible new marker for pCR in HER2+ breast cancer

Analysis of motives and patient satisfaction in oncological second opinions provided by a certified university breast and gynecological cancer center

Abstract Purpose Second opinions in oncology are becoming increasingly important in an era of more complex treatments and a growing demand for information by patients. Therefore, we analyzed their effects and influencing factors like patients’ motives, subjective extent of information and satisfaction with communications. Methods This prospective study evaluated second opinions for patients with breast cancer or gynecological malignancy. The patients received a questionnaire before and two months after, which inquired expectations, reasons, and satisfaction with the second opinion and the attending physicians. Results A total of 164 patients were included and the majority had breast cancer (75.0%). Receiving the second opinion made 89.7% feel better informed, their need for information decreased (from 75.3% to 39.2%, P < 0.0001), and satisfaction with doctor–patient communications increased (from 61.9 to 91.8%, P = 0.0002). There were various reasons for requesting a second opinion, e.g., the extremely stressful situation of a cancer diagnosis, hope for change in the treatment recommendation or dissatisfaction with the initial physicians. Conclusions Second opinions can lead to significantly greater patient satisfaction, meeting the need for information and leading to better management of patients in the extremely stressful situation of a cancer diagnosis. Doctor–patient communications play a key role

RANKL and OPG and their influence on breast volume changes during pregnancy in healthy women

Breast cancer risk is reduced by number of pregnancies and breastfeeding duration, however studies of breast changes during or after pregnancy are rare. Breast volume changes – although not linked to breast cancer risk – might be an interesting phenotype in this context for correlative studies, as changes of breast volume vary between pregnant women. Serum receptor activator of nuclear factor kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG) were measured prospectively before gestational week 12, and three-dimensional breast volume assessments were performed. A linear regression model including breast volume at the start of pregnancy, RANKL, OPG, and other factors was used to predict breast volume at term. The mean breast volume was 413 mL at gestational week 12, increasing by a mean of 99 mL up to gestational week 40. In addition to body mass index and breast volume at the beginning of pregnancy, RANKL and OPG appeared to influence breast volume with a mean increase by 32 mL (P = 0.04) and a mean reduction by 27 mL (P = 0.04), respectively. Linking the RANKL/RANK/OPG pathway with breast volume changes supports further studies aiming at analysing breast changes during pregnancy with regard to breast cancer risk

Assessment of the additional clinical potential of X-ray dark-field imaging for breast cancer in a preclinical setup

Background: Mammography can identify calcifications up to 50–100 μm in size as a surrogate parameter for breast cancer or ductal carcinoma in situ (DCIS). Microcalcifications measuring <50 µm are also associated with breast cancer or DCIS and are frequently not detected on mammography, although they can be detected with dark-field imaging. This study examined whether additional breast examination using X-ray dark-field imaging can increase the detection rate of calcifications. Advances in knowledge:  (1) evaluation of additional modality of breast imaging;  (2) specific evaluation of breast calcifications. Implications for patient care: the addition of X-ray dark-field imaging to conventional mammography could detect additional calcifications. Methods: Talbot–Lau X-ray phase–contrast imaging and X-ray dark-field imaging were used to acquire images of breast specimens. The radiation dosage with the technique is comparable with conventional mammography. Three X-ray gratings with periods of 5–10 µm between the X-ray tube and the flat-panel detector provide three different images in a single sequence: the conventional attenuation image, differential phase image, and dark-field image. The images were read by radiologists. Radiological findings were marked and examined pathologically. The results were described in a descriptive manner. Results: A total of 81 breast specimens were investigated with the two methods; 199 significant structures were processed pathologically, consisting of 123 benign and 76 malignant lesions (DCIS or invasive breast cancer). X-ray dark-field imaging identified 15 additional histologically confirmed carcinoma lesions that were visible but not declared suspicious on digital mammography alone. Another four malignant lesions that were not visible on mammography were exclusively detected with X-ray dark-field imaging. Conclusions: Adding X-ray dark-field imaging to digital mammography increases the detection rate for breast cancer and DCIS associated lesions with micrometer-sized calcifications. The use of X-ray dark-field imaging may be able to provide more accurate and detailed radiological classification of suspicious breast lesions. Adding X-ray dark-field imaging to mammography may be able to increase the detection rate and improve preoperative planning in deciding between mastectomy or breast-conserving therapy, particularly in patients with invasive lobular breast cancer

Molecular Subtyping of Invasive Breast Cancer Using a PAM50-Based Multigene Expression Test-Comparison with Molecular-Like Subtyping by Tumor Grade/Immunohistochemistry and Influence on Oncologist’s Decision on Systemic Therapy in a Real-World Setting

In intermediate risk hormone receptor (HR) positive, HER2 negative breast cancer (BC), the decision regarding adjuvant chemotherapy might be facilitated by multigene expression tests. In all, 142 intermediate risk BCs were investigated using the PAM50-based multigene expression test Prosigna® in a prospective multicentric study. In 119/142 cases, Prosigna® molecular subtyping was compared with local and two central (C1 and C6) molecular-like subtypes relying on both immunohistochemistry (IHC; HRs, HER2, Ki-67) and IHC + tumor grade (IHC+G) subtyping. According to local IHC, 35.4% were Luminal A-like and 64.6% Luminal B-like subtypes (local IHC+G subtype: 31.9% Luminal A-like; 68.1% Luminal B-like). In contrast to local and C1 subtyping, C6 classified >2/3 of cases as Luminal A-like. Pairwise agreement between Prosigna® subtyping and molecular-like subtypes was fair to moderate depending on molecular-like subtyping method and center. The best agreement was observed between Prosigna® (53.8% Luminal A; 44.5% Luminal B) and C1 surrogate subtyping (Cohen’s kappa = 0.455). Adjuvant chemotherapy was suggested to 44.2% and 88.6% of Prosigna® Luminal A and Luminal B cases, respectively. Out of all Luminal A-like cases (locally IHC/IHC+G subtyping), adjuvant chemotherapy was recommended if Prosigna® testing classified as Prosigna® Luminal A at high / intermediate risk or upgraded to Prosigna® Luminal B

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2-positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype ‘lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach

Cost effectiveness of bilateral risk-reducing mastectomy and salpingo-oophorectomy

Background Growing demand for risk-reducing surgery in individuals with inherited susceptibility to cancer leads to the question whether these procedures are cost effective for the executing hospitals. This study compared the clinical costs for bilateral risk-reducing mastectomy (BRRM) with and without different types of reconstruction, risk-reducing salpingo-oophorectomy (RRSO), and their combinations with corresponding reimbursements in the statutory health-care system in Germany. Patients and methods Real total costs of care for BRRM with and without reconstruction, RRSO, and their combinations were calculated as the sum of all personnel and technical costs. These costs calculated in a German University hospital were compared with the sum of all reimbursements in the German DRG-based health-care system. Results While sole RRSO, BRRM without reconstruction, and BRRM with secondary DIEP (deep inferior epigastric perforator)—reconstruction still result in a small benefit, we even found shortfalls for the hospital with all other prophylactic operations under consideration. The calculated deficits were especially high for BRRM with implant-based breast reconstruction and for combined operations when the risk reduction is achieved with a minimum of separate operations. Conclusions Risk-reducing surgery in BRCA-mutation carriers is frequently not cost-covering for the executing hospitals in the German health-care system. Thus, appropriate concepts are required to ensure a nationwide care