Inhibition of SARS-CoV-2 Omicron BA.1 and BA.4 Variants After Fourth Vaccination or Tixagevimab and Cilgavimab Administration in Patients With Cancer.

This cohort study assesses the capacity of passive immunization and tixagevimab and cilgavimab to inhibit interaction between receptor-binding domains and angiotensin-converting enzyme 2 in patients with hemato-oncologic diseases.

Third dose of SARS-CoV-2 vaccination in hemato-oncological patients and health care workers: immune responses and adverse events - a retrospective cohort study.

BACKGROUND: Due to potentially immune-escaping virus variants and waning immunity, a third SARS-CoV-2 vaccination dose is increasingly recommended. However, data in patients with cancer are limited. PATIENTS AND METHODS: We measured anti-SARS-CoV-2 spike protein antibody levels after the third vaccination dose in 439 patients with cancer and 41 health care workers (HCW) at an academic centre in Austria and a rural community hospital in Italy. Adverse events were retrieved from questionnaires. RESULTS: Overall, 439 patients and 41 HCW were included. SARS-CoV-2 infections were observed in 62/439 (14.1%) patients before vaccination and in 5/439 (1.1%) patients after ≥1 dose. Longitudinal analysis revealed a decrease of antibody levels between 3 and 6 months after second vaccination in patients with solid tumours (p < 0.001) and haematological malignancies without anti-B cell therapies (p < 0.001). After the third dose, anti-S levels increased compared to the first/second dose. Patients receiving B cell-targeted agents had lower antibody levels than patients with haematological malignancies undergoing other treatments (p < 0.001) or patients with solid tumours (p < 0.001). Moreover, anti-S levels correlated with CD19+ (B cell) and CD56+ (NK cell) counts in peripheral blood. The most frequent adverse events after the third dose were local pain (75/160, 46.9%), fatigue (25/160, 15.6%) and fever/chills (16/160, 10.0%). Patients with cancer had lower anti-S levels than HCW (p = 0.015). CONCLUSIONS: This study in patients with cancer shows improved antibody levels after the third vaccination dose at an acceptable side-effect profile. Lower antibody levels than in controls underline the need for further follow-up studies and dedicated trials.

Mobility as a driver of severe acute respiratory syndrome coronavirus 2 in cancer patients during the second coronavirus disease 2019 pandemic wave.

We retrospectively analyzed the epidemiological characteristics of cancer patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and their correlations with publicly available mobility data. Between 19 October 2020 and 28 February 2021, 4754 patient visits were carried out, and 1454 treatments have been applied at the Haemato-Oncology Day Hospital Merano. Additional measures to prevent local SARS-CoV-2 transmission included a specific questionnaire for coronavirus disease 2019 (COVID-19) symptoms as well as a SARS-CoV-2 real-time polymerase-chain reaction (RT-PCR) 2 days prior to any intravenous or subcutaneous therapy. Community mobility was assessed through publicly available mobile phone tracking data from Google; 106/719 (14.7%) cancer patients have been tested positive for SARS-CoV-2 by PCR during the second wave compared to 5/640 (0.8%) within the first wave (P < .001); 66/106 (62%) had solid tumors, and 40/106 (38%) had hematological malignancies; 90/106 (85%) patients received ongoing antitumor therapies. Mortality rate of COVID-19 positive cancer patients (7/106; 6.6%) was higher compared to the overall population (731/46 421; 1.6%; P < .001). Strict control measures at our department led to a significantly lower test positivity rate compared to the general population, resulting in a reduction of 58.5% of new SARS-CoV-2 cases. Over time, infection rates and community mobility correlated in the first and second wave after initiating and lifting restrictions. Our findings underscore the importance of strict preventive control measures including testing and contact tracing in vulnerable subpopulations such as cancer patients, particularly if social restriction policies are being lifted. Smartphone-based mobility data may help to guide policy makers to prevent a vulnerable population like cancer patients from virus transmission.

Humoral Immune Response in Hematooncological Patients and Health Care Workers Who Received SARS-CoV-2 Vaccinations.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. Design, Setting, and Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Main Outcomes and Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). Conclusions and Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

Evaluating the longitudinal effectiveness of preventive measures against COVID-19 and seroprevalence of IgG antibodies to SARS-CoV-2 in cancer outpatients and healthcare workers.

BACKGROUND: It has been assumed that cancer patients, especially those undergoing chemotherapy, are at increased risk for infection and severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared to the general population. After the first alert message from the local healthcare service, a series of drastic measures were taken at our outpatient clinic to contain the spread of coronavirus disease 2019 (COVID-19). METHODS: In this retrospective study, all consecutive cancer outpatients completed a baseline SARS-CoV­2 test via real-time polymerase chain reaction (RT-PCR) from 15 March to 26 May 2020. In the later phase, after the peak of the pandemic, patients as well as healthcare workers were tested for anti-SARS-CoV­2 IgG antibodies. RESULTS: Between 15 March and 26 May 2020, 0.78% (N = 5/640) cancer patients tested positive for SARS-CoV­2 by RT-PCR. Between 22 June and 17 July 2020, anti-SARS-CoV­2 IgG antibodies were detected in 2 out of 250 (0.8%) cancer patients and 2 out of 36 (5.5%) healthcare workers. In only 1 out of 4 cancer patients with confirmed COVID-19 infection, could SARS-CoV­2 antibodies be detected. CONCLUSION: Our findings suggest that the majority of our patients and healthcare workers had not been infected with SARS-CoV­2 and rapidly implemented measures were effective. Maintenance of preventive measures should be continued until vaccines or specific treatments are available.

Infection rate and clinical management of cancer patients during the COVID-19 pandemic: experience from a tertiary care hospital in northern Italy.

BACKGROUND: Optimal management of patients with cancer during COVID-19 pandemic is still pending. METHODS: Our patients were advised to maintain their scheduled appointments, and planned cancer treatment was continued without unnecessary delays in an outpatient setting. Additional strict preventive infection measures were rapidly implemented at our outpatient department. When COVID-19 test became widely available, universal testing of healthcare workers and vigorous screening of all patients coming to our facility for COVID-19 infection were performed by SARS-CoV-2 real-time reverse transcription PCR on rhinopharyngeal swab. RESULTS: As of the data cut-off on 9 April 2020, a total of 156 oncology patients with a median age of 67 (range 26-86) years and 63 haematology patients (median age 69 years, range 23-89) were screened for COVID-19 during active cancer treatment. Prevalence (1.8%; 4/219) of COVID-19 in patients with cancer was significantly higher compared with a respective control group of asymptomatic counterparts (p=0.018). Outcomes of COVID-19 positive patients were good, with only one observed death due to progression of advanced metastatic disease. CONCLUSION: Our data indicate that continuation of anticancer treatment in epidemic areas during the COVID-19 pandemic seems to be safe and feasible, if adequate and strict preventive measures are vigorously and successfully carried out.

Clinical outcomes and prognostic factors in patients with multiple myeloma in South Tyrol: a retrospective single-center analysis.

High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) as well as the introduction of novel agents (NA) significantly improved survival for patients with multiple myeloma (MM). A total of 150 unselected newly diagnosed MM patients treated at our institution from 1998 to 2017 were retrospectively analyzed. Median age at diagnosis was 69 years (range 33-93 years) with a median follow-up of 48.6 months. The median overall survival (OS) for the entire cohort was 60.7 months (range 0.3-280.1). Patients who received frontline HD-ASCT (p < 0.01) or NA-based first-line treatment (p = 0.043) had a significantly better OS. According to the revised Myeloma Comorbidity Index (R-MCI), patients were defined as fit (36.5%), intermediate-fit (44.5%), or frail (19%) with a significant difference in OS between these categories (p < 0.01). Multivariate analysis revealed R-MCI as an independent prognostic factor for OS (p < 0.01). Presence of subclinical amyloid deposits (A+) was detected in 18 out of 66 patients (27.3%) and significantly correlated with a serum free light chain (sFLC) ratio ≥ 100 (p = 0.01) and bone marrow plasma cell infiltration > 60% (p = 0.04). Furthermore, patients with A+ had significantly worse OS compared with their counterparts (p = 0.048). Our results corroborate the efficacy of both early HD-ASCT and the use of new agents as initial therapy of MM patients in "real-world" daily clinical practice. The R-MCI is an easily applicable tool to stratify MM patients and may support treatment decisions. The prognostic value of subclinical amyloid deposition should be validated within prospective studies.

Feasibility of abiraterone acetate treatment in patients with metastatic castration-resistant prostate cancer and atrial fibrillation.

BACKGROUND: Abiraterone acetate (AA), a selective inhibitor of the CYP17 enzyme, demonstrated a significant improvement in the treatment of patients with metastatic castration-resistant prostate cancer. The risk of endocrine side effects, mainly an increased adrenal mineralocorticoid production, could limit its use in patients with atrial fibrillation. METHODS: We retrospectively reviewed the clinical records of 85 metastatic castration-resistant prostate cancer patients treated with AA at our institutions and identified six patients suffering from concomitant atrial fibrillation. RESULTS: In these six patients, the median duration of AA treatment was 11.5 months (range 4-22 months) with a biochemical response in three patients. No significant cardiac events were observed during the treatment. CONCLUSION: Our data suggest that AA may be safely administered in patients with atrial fibrillation.

Predominant expression of truncated EpCAM is associated with a more aggressive phenotype and predicts poor overall survival in colorectal cancer.

Regulated intramembrane proteolysis (RIP) has been shown to be an important mechanism for oncogenic activation of EpCAM through nuclear translocation of the intracellular domain EpICD. Recently, we identified two different membranous EpCAM variants namely EpCAM(MF) (full-length) and EpCAM(MT) (truncated) to be expressed in the majority of human epithelial tumors. The aim of our study was to evaluate the potential role of these two protein variants as additional prognostic biomarkers in colorectal cancer. In most studies only one antibody targeting the extracellular domain of EpCAM (EpEX) has been used, whereas in the present study additionally an antibody which detects the intracellular domain (EpICD) was applied to discriminate between different EpCAM variants. Using immunohistochemistry, we analyzed the expression of EpCAM(MF) and EpCAM(MT) variants in 640 patients with colorectal cancer and determined their correlations with other prognostic factors and clinical outcome. A statistically significant association was observed for EpCAM(MT) with advanced tumor stage (p < 0.001), histological grade (p = 0.01), vascular (p < 0.001) and marginal (p = 0.002) invasion. Survival analysis demonstrated reduced overall survival (p < 0.004) in patients with tumors expressing the EpCAM(MT) phenotype when compared to patients with tumors expressing the EpCAM(MF) variant. In conclusion, this study for the first time indicates that expression of EpCAM(MT) is associated with a more aggressive phenotype and predicts poor survival in patients with colorectal cancer.

Detection of soluble EpCAM (sEpCAM) in malignant ascites predicts poor overall survival in patients treated with catumaxomab.

EpCAM is an attractive target for cancer therapy and the EpCAM-specific antibody catumaxomab has been used for intraperitoneal treatment of EpCAM-positive cancer patients with malignant ascites. New prognostic markers are necessary to select patients that mostly benefit from catumaxomab. Recent data showed that soluble EpCAM (sEpCAM) is capable to block the effect of catumaxomab in vitro. This exploratory retrospective analysis was performed on archived ascites samples to evaluate the predictive role of sEpCAM in catumaxomab-treated patients. Sixty-six catumaxomab-treated patients with an available archived ascites sample were included in this study and tested for sEpCAM by sandwich ELISA. All probes were sampled before treatment start and all patients received at least one catumaxomab infusion. Overall survival, puncture-free survival and time to next puncture were compared between sEpCAM-positive and -negative patients. We detected sEpCAM in ascites samples of 9 patients (13.6%). These patients showed a significantly shorter overall survival. The prognostic significance of sEpCAM in ascites was particularly strong in patients with ovarian cancer. Puncture-free survival and time to next puncture were not significantly different between sEpCAM-positive and -negative patients. We propose sEpCAM in malignant ascites as a potential predictive marker in cancer patients treated with catumaxomab. Prospective studies with larger patients samples are urgently needed to confirm these findings and studies testing dose-intensified catumaxomab in patients with sEpCAM-positive ascites should be envisaged.

Soluble EpCAM levels in ascites correlate with positive cytology and neutralize catumaxomab activity in vitro.

BACKGROUND: EpCAM is highly expressed on membrane of epithelial tumor cells and has been detected as soluble/secreted (sEpCAM) in serum of cancer patients. In this study we established an ELISA for in vitro diagnostics to measure sEpCAM concentrations in ascites. Moreover, we evaluated the influence of sEpCAM levels on catumaxomab (antibody)--dependent cellular cytotoxicity (ADCC). METHODS: Ascites specimens from cancer patients with positive (C+, n = 49) and negative (C-, n = 22) cytology and ascites of patients with liver cirrhosis (LC, n = 31) were collected. All cell-free plasma samples were analyzed for sEpCAM levels with a sandwich ELISA system established and validated by a human recombinant EpCAM standard for measurements in ascites as biological matrix. In addition, we evaluated effects of different sEpCAM concentrations on catumaxomab-dependent cell-mediated cytotoxicity (ADCC) with human peripheral blood mononuclear cells (PBMNCs) and human tumor cells. RESULTS: Our ELISA showed a high specificity for secreted EpCAM as determined by control HEK293FT cell lines stably expressing intracellular (EpICD), extracellular (EpEX) and the full-length protein (EpCAM) as fusion proteins. The lower limit of quantification was 200 pg/mL and the linear quantification range up to 5,000 pg/mL in ascites as biological matrix. Significant levels of sEpCAM were found in 39% of C+, 14% of C- and 13% of LC ascites samples. Higher concentrations of sEpCAM were detectable in C+ (mean: 1,015 pg/mL) than in C- (mean: 449 pg/mL; p = 0.04) or LC (mean: 326 pg/mL; p = 0.01). Soluble EpCAM concentration of 1 ng/mL significantly inhibited ADCC of PBMNCs on EpCAM overexpressing target cells. CONCLUSION: Elevated concentrations of sEpCAM can be found in a subgroup of C+ and also in a small group of C- patients. We consider that sEpCAM levels in different tumor entities and individual patients should be evaluated prior to applying anti-EpCAM antibody-based cancer therapies, since sEpCAM neutralizes catumaxomab activity, making therapy less efficient.

Expression of EpCAM(MF) and EpCAM(MT) variants in human carcinomas.

AIMS: Regulated intramembrane proteolysis has been shown to be an important mechanism for oncogenic activation of epithelial cell adhesion molecule (EpCAM) through nuclear translocation of the intracellular domain EpICD. Recent studies have identified new membrane-bound EpCAM variants. To evaluate the prevalence of two membranous EpCAM variants in human tumours, we performed a large-scale expression analysis using specific antibodies against the extracellular domain EpEX (MOC-31 clone) and the intracellular domain EpICD (9-2 clone) of the EpCAM antigen by immunohistochemistry. MATERIAL AND METHODS: Two multi-tissue microarrays (TMA) series containing 1564 tissue samples each of 53 different histological tumour types were stained and compared. One TMA was stained for EpEX and one for EpICD. Membranous full-length EpCAM (EpCAM(MF)) expression in tissues was defined by the expression of EpEX and EpICD, while the truncated variant of EpCAM (EpCAM(MT)) was characterised by a significant loss of membranous EpICD expression compared with EpEX expression. RESULTS: We defined tumours with high EpCAM(MT) expression (ie, cancers of the endometrium and bladder), tumours with intermediate (ie, gastric, pancreatic, colorectal and oesophageal cancer) and tumours with low rates of expression of the EpCAM(MT) variant (ie, lung, ovarian, gallbladder, breast and prostate cancer). CONCLUSIONS: Our results indicate that loss of membranous EpICD expression is a common event in human epithelial carcinomas, arguing for the expression of different degrees of EpCAM(MF) and EpCAM(MT) variants across the most important tumour entities. Future studies evaluating the prognostic and predictive role of these variants in human malignancies, especially in patients treated with EpCAM-specific antibodies, are clearly warranted.

Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer.

AIMS: Epithelial cell adhesion molecule (EpCAM) is a widely used immunohistochemical marker for epithelial human malignancies. Antibodies to target EpCAM are usually directed against its ectodomain (EpEX), but do not detect the intracellular domain (EpICD). The aim of this study was to compare membranous EpEX versus EpICD expression by immunohistochemistry. METHODS AND RESULTS: Concurrent EpEX and EpICD expression was investigated retrospectively in cancerous and matched non-neoplastic tissue samples from patients with pancreatic adenocarcinoma. In total, 317 paired samples of pancreatic tissue from 88 patients were analysed and correlated with clinicopathological parameters. In non-cancerous tissue, a high concordance of membranous EpEX and EpICD expression was observed and defined as the expression of the full-length EpCAM (EpEX(+)/EpICD(+) phenotype, EpCAM(MF)), which was highly predominant. In contrast, while most tumour samples were EpEX positive, loss of membranous EpICD expression (EpEX(+)/EpICD(-) phenotype, EpCAM(MT)) was observed in one-third of cases, and these patients had a significantly shortened disease-free and overall survival. CONCLUSIONS: This study demonstrates for the first time that loss of membranous EpICD expression is a frequent event and predicts poor prognosis in patients with pancreatic cancer. Additional studies evaluating the predictive and prognostic value of the expression of different membranous EpCAM variants are warranted in epithelial cancers.

Low expression of junctional adhesion molecule A is associated with metastasis and poor survival in pancreatic cancer.

BACKGROUND: Characterized by its highly aggressive tumor biology, pancreatic cancer still remains a fatal diagnosis. The junctional adhesion molecule A (JAM-A) is a type I transmembrane glycoprotein, which recently has been shown to affect the prognosis of several human malignancies. METHODS: JAM-A antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumor tissue samples from a series (n = 186) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated by Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. RESULTS: Low expression of JAM-A was observed in 79 (42 %) of 186 pancreatic cancer specimens and was significantly associated with poor overall survival (P < 0.01). By univariate analysis, low expression of JAM-A was found to correlate with positive lymph node status (P = 0.02), the presence of distant metastasis (P = 0.05), and tumor grade (P = 0.04), suggesting it may be an important event involved in cancer progression. Furthermore, in the subgroup of patients with surgically resected pancreatic cancer, low expression of JAM-A significantly correlated with decreased progression-free survival (P < 0.01). Multivariate analysis revealed JAM-A to be an independent predictor of poor outcome. DISCUSSION: These findings suggest for the first time that low levels of JAM-A expression in pancreatic cancer are associated with poor clinical outcome. JAM-A may represents a target molecule for functional inactivation and serve as a novel biomarker of adverse prognosis in pancreatic cancer.

High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial.

BACKGROUND: Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown. DESIGN AND METHODS: Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114). RESULTS: The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014). CONCLUSIONS: Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262).

EpCAM expression in primary tumour tissues and metastases: an immunohistochemical analysis.

AIMS: Epithelial cell adhesion molecule (EpCAM) is a cell surface protein with oncogenic features that is expressed on healthy human epithelia and corresponding malignant tumours. EpCAM expression frequently correlates with more aggressive tumour behaviour and new EpCAM-specific therapeutic agents have recently been approved for clinical use in patients with cancer. However, no consensus exists on how and when to evaluate EpCAM expression in patients with cancer. MATERIAL AND METHODS: EpCAM expression was assessed by a well-established immunohistochemical staining protocol in 2291 primary tumour tissues and in 108 metastases using the EpCAM-specific antibody clone VU1D9. A total immunostaining score was calculated as the product of a proportion score and an intensity score. Four expression subgroups (no, weak, moderate and intense) were defined. As described previously, the term 'EpCAM overexpression' was reserved for tissues showing a total immunostaining score >4. RESULTS: EpCAM was highly expressed in most tumours of gastrointestinal origin and in some carcinomas of the genitourinary tract. However, hepatocellular carcinomas, clear cell renal cell cancer, urothelial cancer and squamous cell cancers were frequently EpCAM negative. EpCAM expression in breast cancer depended on the histological subtype; lobular histology usually showed no or weak expression. Most metastases were EpCAM positive and they frequently reflected the expression phenotype of the primary tumour. CONCLUSION: EpCAM expression was detected on adenocarcinomas of various primary sites. If EpCAM-specific antibodies are intended to be used in patients with cancer, we recommend prior immunohistochemical evaluation of EpCAM expression, particularly in patients with renal cell cancer, hepatocellular carcinoma, urothelial carcinoma, breast cancer and squamous cell carcinomas.

Effects of EpCAM overexpression on human breast cancer cell lines.

BACKGROUND: Recently, EpCAM has attracted major interest as a target for antibody- and vaccine-based cancer immunotherapies. In breast cancer, the EpCAM antigen is overexpressed in 30-40% of all cases and this increased expression correlates with poor prognosis. The use of EpCAM-specific monoclonal antibodies is a promising treatment approach in these patients. METHODS: In order to explore molecular changes following EpCAM overexpression, we investigated changes of the transcriptome upon EpCAM gene expression in commercially available human breast cancer cells lines Hs578T and MDA-MB-231. To assess cell proliferation, a tetrazolium salt based assay was performed. A TCF/LEF Reporter Kit was used to measure the transcriptional activity of the Wnt/ß-catenin pathway. To evaluate the accumulation of ß-catenin in the nucleus, a subcellular fractionation assay was performed. RESULTS: For the first time we could show that expression profiling data of EpCAM transfected cell lines Hs578TEpCAM and MDA-MB-231EpCAM indicate an association of EpCAM overexpression with the downregulation of the Wnt signaling inhibitors SFRP1 and TCF7L2. Confirmation of increased Wnt signaling was provided by a TCF/LEF reporter kit and by the finding of the nuclear accumulation of ß-catenin for MDA-MB-231 EpCAM but not Hs578T EpCAM cells. In Hs578T cells, an increase of proliferation and chemosensitivity to Docetaxel was associated with EpCAM overexpression. CONCLUSIONS: These data show a cell type dependent modification of Wnt signaling components after EpCAM overexpression in breast cancer cell lines, which results in marginal functional changes. Further investigations on the interaction of EpCAM with SFRP1 and TCF7L2 and on additional factors, which may be causal for changes upon EpCAM overexpression, will help to characterize unique molecular properties of EpCAM-positive breast cancer cells.

High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study.

BACKGROUND: Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib. DESIGN AND METHODS: In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated. RESULTS: Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014). CONCLUSIONS: This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogenetic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: NCT00327262).