How VEGF-A and its splice variants affect breast cancer development – clinical implications

Background: Altered expression levels and structural variations in the vascular endothelial growth factor (VEGF) have been found to play important roles in cancer development and to be associated with the overall survival and therapy response of cancer patients. Particularly VEGF-A and its splice variants have been found to affect physiological and pathological angiogenic processes, including tumor angiogenesis, correlating with tumor progression, mostly caused by overexpression. This review focuses on the expression and impact of VEGF-A splice variants under physiologic conditions and in tumors and, in particular, the distribution and role of isoform VEGF(165)b in breast cancer. Conclusions and perspectives: Many publications already highlighted the importance of VEGF-A and its splice variants in tumor therapy, especially in breast cancer, which are summarized in this review. Furthermore, we were able to demonstrate that cytoplasmatic VEGFA/(165)b expression is higher in invasive breast cancer tumor cells than in normal tissues or stroma. These examples show that the detection of VEGF splice variants can be performed also on the protein level in formalin fixed tissues. Although no quantitative conclusions can be drawn, these results may be the starting point for further studies at a quantitative level, which can be a major step towards the design of targeted antibody-based (breast) cancer therapies

VEGF-A165b levels are reduced in breast cancer patients at primary diagnosis but increase after completion of cancer treatment

The antiangiogenic splice variant VEGF-A165b is downregulated in a variety of cancer entities, but little is known so far about circulating plasma levels. The present analysis addresses this question and examines circulating VEGF-A/VEGF-A165b levels in a collective of female high-risk breast cancer patients over the course of treatment. Within the SUCCES-A trial 205 patients were recruited after having received primary breast surgery. Using ELISA VEGF-A/VEGF-A165b concentrations were determined and correlated to clinical characteristics (1) before adjuvant chemotherapy, (2) four weeks and (3) two years after therapy and compared to healthy controls (n = 107). VEGF(165b) levels were significantly elevated after completion of chemotherapy. Within the breast cancer cohort, VEGF-A165b levels increased two years after completion of chemotherapy. VEGF-A plasma concentrations were significantly elevated in the breast cancer cohort at all examined time points and decreased after treatment. VEGF-A levels two years after chemotherapy correlated with increased cancer related mortality, no such correlation could be found between VEGF-A165b and the examined clinical characteristics. Compared to controls, VEGF-A/VEGF-A165b ratios were decreased in patients before and after chemotherapy. Our data suggests that circulating VEGF-A165b is significantly reduced in women with primary breast cancer at time of diagnosis;furthermore, levels change during adjuvant treatment

LDOC1 as negative prognostic marker for vulvar cancer patients

So far, studies about targeted therapies and predictive biomarkers for vulva carcinomas are rare. The leucine zipper downregulated in cancer 1 gene (LDOC1) has been identified in various carcinomas as a tumor-relevant protein influencing patients’ survival and prognosis. Due to the lack of information about LDOC1 and its exact functionality, this study focuses on the expression of LDOC1 in vulvar carcinoma cells and its surrounding immune cells as well as its correlation to clinicopathological characteristics and prognosis. Additionally, a possible regulation of LDOC1 in vulvar cancer cell lines via the NF-κB signaling pathway was analyzed. Vulvar carcinoma sections of 157 patients were immunohistochemically stained and examined regarding LDOC1 expression by using the immunoreactive score (IRS). To characterize LDOC1-positively stained immune cell subpopulations, immunofluorescence double staining was performed. The effect of the NF-κB inhibitor C-DIM 12 (3,3′-[(4-chlorophenyl)methylene]bis[1 H-indole]) on vulvar cancer cell lines A431 and SW 954 was measured according to MTT and BrdU assays. Baseline expression levels of LDOC1 in the vulvar cancer cell lines A431 and SW 954 was analyzed by real-time PCR. LDOC1 was expressed by about 90% of the cancer cells in the cytoplasm and about half of the cells in the nucleus. Cytoplasmatic expression of LDOC1 was associated with decreased ten-year overall survival of the patient, whereas nuclear staining showed a negative association with disease-free survival. Infiltrating immune cells were mainly macrophages followed by regulatory T cells. Incubation with C-DIM 12 decreased the cell viability and proliferation of vulvar cancer cell line A431, but not of cell line SW 954. LDOC1 expression on mRNA level was twice as high in the cell line A431 compared to the cell line SW 954. Overexpression of LDOC1 was associated with unfavorable overall and disease-free survival. Tumor growth could be inhibited by C-DIM 12 in vitro if the expressed LDOC1 level was high enough

ASO Author Reflections: An Alternative to Sentinel-Node Biopsy? Preoperative Sonographic Prediction of Limited Axillary Disease in Breast Cancer Patients Meeting the Z0011 Criteria

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Preoperative Sonographic Prediction of Limited Axillary Disease in Patients with Primary Breast Cancer Meeting the Z0011 Criteria: an Alternative to Sentinel Node Biopsy?

Purpose To assess the accuracy of preoperative sonographic staging for prediction of limited axillary disease (LAD, one or two metastatic lymph nodes) and to identify factors associated with high prediction–pathology concordance in patients with early-stage breast cancer meeting the Z0011 criteria. Materials and Methods Patients treated between January 2015 and January 2020 were included in this retrospective, multicentric analysis of prospectively acquired service databases. The accuracy of LAD prediction was assessed separately for patients with one and two suspicious lymph nodes on preoperative sonography. Test validity outcomes for LAD prediction were calculated for both groups, and a multivariate model was used to identify factors associated with high accuracy of LAD prediction. Results Of 2059 enrolled patients, 1513 underwent sentinel node biopsy, 436 primary and 110 secondary axillary dissection. For LAD prediction in patients with one suspicious lymph node on preoperative ultrasound, sensitivity was 92% (95% CI 87–95%), negative predictive value (NPV) was 92% (95% CI 87–95%), and the false-negative rate (FNR) was 8% (95% CI 5–13%). For patients with two preoperatively suspicious nodes, the sensitivity, NPV, and FNR were 89% (95% CI 84–93%), 73% (62–83%), and 11% (95% CI 7–16%), respectively. On multivariate analysis, the number of suspicious lymph nodes was associated inversely with correct LAD prediction ([OR 0.01 (95% CI 0.01–0.93), p ≤ 0.01]. Conclusions Sonographic axillary staging in patients with one metastatic lymph node predicted by preoperative ultrasound showed high accuracy and a false-negative rate comparable to sentinel node biopsy for prediction of limited axillary disease

PRO B: evaluating the effect of an alarm-based patient-reported outcome monitoring compared with usual care in metastatic breast cancer patients—study protocol for a randomised controlled trial

Background: Despite the progress of research and treatment for breast cancer, still up to 30% of the patients afflicted will develop distant disease. Elongation of survival and maintaining the quality of life (QoL) become pivotal issues guiding the treatment decisions. One possible approach to optimise survival and QoL is the use of patient-reported outcomes (PROs) to timely identify acute disease-related burden. We present the protocol of a trial that investigates the effect of real-time PRO data captured with electronic mobile devices on QoL in female breast cancer patients with metastatic disease. Methods: This study is a randomised, controlled trial with 1:1 randomisation between two arms. A total of 1000 patients will be recruited in 40 selected breast cancer centres. Patients in the intervention arm receive a weekly request via an app to complete the PRO survey. Symptoms will be assessed by study-specific optimised short forms based on the EORTC QLQ-C30 domains using items from the EORTC CAT item banks. In case of deteriorating PRO scores, an alarm is sent to the treating study centre as well as to the PRO B study office. Following the alarm, the treating breast cancer centre is required to contact the patient to inquire about the reported symptoms and to intervene, if necessary. The intervention is not specified and depends on the clinical need determined by the treating physician. Patients in the control arm are prompted by the app every 3 months to participate in the PRO survey, but their response will not trigger an alarm. The primary outcome is the fatigue level 6 months after enrolment. Secondary endpoints include among others hospitalisations, use of rescue services and overall QoL. Discussion: Within the PRO B intervention group, we expect lower fatigue levels 6 months after intervention start, higher levels of QoL, less unplanned hospitalisations and less emergency room visits compared to controls. In case of positive results, our approach would allow a fast and easy transfer into clinical practice due to the use of the already nationwide existing IT infrastructure of the German Cancer Society and the independent certification institute OnkoZert

RESPONDER – diagnosis of pathological complete response by vacuum-assisted biopsy after neoadjuvant chemotherapy in breast Cancer - a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial

Background: Neoadjuvant chemotherapy (NACT) is a standard approach of the multidisciplinary treatment of breast cancer. Depending on the biological subtype a pathological complete response in the breast (bpCR) can be achieved in up to 60% of the patients. However, only limited accuracy can be reached when using imaging for prediction of bpCR prior to surgery. Due to this diagnostic uncertainty, surgery after NACT is considered to be obligatory for all patients in order to either completely remove residual disease or to diagnose a bpCR histologically. The purpose of this trial is to evaluate the accuracy of a vacuum-assisted biopsy (VAB) to diagnose a bpCR after NACT prior to surgery. Methods: This study is a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial. The study will take place at 21 trial sites in Germany. Six hundred female patients with breast cancer after completed NACT showing at least a partial response to NACT treatment will be enrolled. A vacuum-assisted biopsy (VAB) guided either by ultrasound or mammography will be performed followed by histopathological evaluation of the VAB specimen before standard, guideline-adherent breast surgery. The study is designed to prove that the false negative rate of the VAB is below 10%. Discussion: As a bpCR is becoming a more frequent result after NACT, the question arises whether breast surgery is therapeutically necessary in such cases. To study this subject further, it will be crucial to develop a reliable test to diagnose a bpCR without surgery. During the study we anticipate possible problems in patient recruitment as the VAB intervention does not provide participating patients with any personal benefit. Hence, a proficient informed consent discussion with the patient and a detailed explanation of the study aim will be crucial for patient recruitment. Another critical issue is the histopathological VAB evaluation of a non-tumorous specimen as this may have been taken either from the former tumor region (bpCR) or outside of the (former) tumor region (non-representative VAB, sampling error). Trial registration: The trial has been registered at clinicaltrials.gov with the identifier NCT02948764 on October 28, 2016 and at the German Clinical Trials Register ( DRKS00011761 ) on February 20, 2017. The date of enrolment of the first participant to the trial was on March 8, 2017

Patientinnenzentrierte Behandlung des Mammakarzinoms

In den Ausführungen konnte gezeigt werden, dass sich die Behandlung des Mammakarzinoms in den vergangenen 50 Jahren radikal verändert hat. Neben den operativen Veränderungen im Sinne einer zunehmenden Reduktion des Eingriffes haben sich gleichzeitig, vor allem bedingt durch medikamentöse Therapiemöglichkeiten, die Heilungschancen bei Brustkrebs im Frühstadium stark verbessert. Auch in der metastasierten Situation hat sich das Überleben deutlich verlängert. Die Hoffnung ist, dass diese Entwicklung weiter anhält. Trotz oder auch aufgrund der zunehmenden Reduktion des operativen Vorgehens verbunden mit immer komplexeren individualisierten Therapiemöglichkeiten ist die Zahl an Mammakarzinom-Behandlungsoptionen exponentiell gestiegen. Dies bedeutet gleichzeitig, dass sowohl das medizinische Personal wie auch die betroffene Patientin mit deutlich komplexeren Entscheidungsprozessen konfrontiert werden, für die es neue Beurteilungskriterien braucht. Diese Beurteilungskriterien sind nötig, um die kurz-, mittel- und langfristigen Folgen für die Patientin objektiv aufzeigen zu können. Die Nutzung von PROs bildet das Bindeglied zwischen einer modernen patient*innen- zentrierten medikamentösen/chirurgischen Therapie und den Wünschen, Vorstellungen und Wertvorstellungen der betroffenen Patientin. PROs können als patient*innen- zentriertes Symptommonitoring während der Therapie genutzt werden. PRO-Langzeit- daten können Therapieentscheidungen unterstützen und in der Nachsorge als Monitoring genutzt werden. Die Nutzung von PROs hat möglicherweise auch einen positiven Einfluss auf das Überleben von Mammakarzinom-Patientinnen. Ob sich die Ergebnisse von Basch und Denis zum intensivierten Symptommonitoring auch bei der Mammakarzinom-Erkrankung bestätigen, wird die PRO B Studie zeigen

ASO Author Reflections: Non-radioactive Sentinel Node Localization with Superparamagnetic Iron Oxide in Clinically Node-Negative Breast Cancer Patients: A Possibility for Improvement of the Care Pathway

Background!#!Sentinel lymph node biopsy after technetium-99 (Tc!##!Methods!#!This study compared 59 patients who underwent breast cancer surgery including sentinel lymph node biopsy. Based on the surgeon's choice, 29 patients were treated with Tc!##!Results!#!The mean time spent on the preoperative breast cancer care pathway was significantly shorter for the Magtrace group (5.4 ± 1.3 min) than for the Tc!##!Conclusions!#!Magtrace localization shortened the preoperative care pathway and did not affect surgical time or reimbursement. Once established, it could allow for cost reduction and improve patient comfort

Intraoperative indocyanine green fluorescence imaging in breast surgery

Background: Since postoperative complications after reconstructive breast surgery are often related to drastic increases of patient suffering and treatment costs, several devices were developed in order to avoid them. In this respect, the intraoperative fluorescence angiography with indocyanine green (ICG) provides promising results by detecting ischemic skin intraoperatively. Methods: Women who underwent reconstructive breast surgery at the breast center at Charité between April and December 2017 were included in the analysis. General patient characteristics, medical history, type of surgery, as well as postoperative parameters, complications and patient reported outcomes were compared between patients operated using ICG fluorescence angiography and conventionally operated patients. Results: Among 68 patients with breast reconstruction 36 (52.9%) were operated with the ICG angiography device and 32 (47.1%) without. No significant differences regarding patient demographics, medical history, and surgical procedure were found. Wound healing disorders occurred in 11.1% of the ICG group and in 9.4% of the control group. About 11% of both groups developed major complications which required revision surgery. Complication rates and patient reported outcome did not differ significantly. Across both groups, only the risk factor resection weight (≥ 500 g) was significantly associated with wound healing disorders (RR = 6.80; 95%CI 1.93–23.81; p = 0.022)