The impact of HER2 phenotype of circulating tumor cells in metastatic breast cancer: a retrospective study in 107 patients

Background: In metastatic breast cancer (MBC), antigen profiles of metastatic tissue and primary tumor differ in up to 20 % of patients. Reassessment of predictive markers, including human epidermal growth factor receptor 2 (HER2) expression, might help to optimize MBC treatment. While tissue sampling is invasive and often difficult to repeat, circulating tumor cell (CTC) analysis requires only a blood sample and might provide an easy-to-repeat, real-time “liquid biopsy” approach. The present retrospective study was conducted to compare HER2 expression in primary tumors, metastatic tissue, and circulating tumor cells (CTCs) from MBC patients and to analyze the potential impact of HER2 overexpression by CTCs on progression-free (PFS) and overall survival (OS) in MBC. Methods: CTC-positive (five or more CTCs/7.5 mL blood; CellSearch®, Janssen Diagnostics) MBC patients starting a new line of systemic treatment were eligible for the study. HER2 status of CTCs was determined by immunofluorescence (CellSearch®). HER2 status of primary (PRIM) and metastatic (MET) tumor tissue was determined by immunohistochemistry. Data were analyzed using descriptive statistics and Kaplan–Meier plots. Results: One hundred seven patients (median age (range) 57 (33–81) years) were included. 100/107 (93 %) patients were followed-up for a median [95 % confidence interval (CI)] of 28.5 [25.1–40.1] months. Of 37/107 (35 %) CTC-HER2-positive patients only 10 (27 %) were PRIM-HER2-positive. 6/46 (13 %) patients were MET-HER2-positive; only 2/10 (20 %) CTC-HER2-positive patients were MET-HER2-positive. Overall accuracy between CTC-HER2 expression and PRIM-HER2 and MET-HER2 status was 69 % and 74 %, respectively. Kaplan–Meier plots of PFS and OS by CTC-HER2 status revealed significantly longer median [95 % CI] PFS of CTC-HER2-positive versus CTC-HER2-negative patients (7.4 [4.7–13.7] versus 4.34 [3.5–5.9] months; p = 0.035). CTC-HER2-positive status showed no significant difference for OS (13.7 [7.7–30.0] versus 8.7 [5.9–15.3] months; p = 0.287). Conclusions: HER2 status can change during the course of breast cancer. CTC phenotyping may serve as an easy-to-perform “liquid biopsy” to reevaluate HER2 status and potentially guide treatment decisions. Further, prospective studies are needed

ClinOmicsTrailbc: a visual analytics tool for breast cancer treatment stratification

Motivation: Breast cancer is the second leading cause of cancer death among women. Tumors, even of the same histopathological subtype, exhibit a high genotypic diversity that impedes therapy stratification and that hence must be accounted for in the treatment decision-making process. Results: Here, we present ClinOmicsTrailbc, a comprehensive visual analytics tool for breast cancer decision support that provides a holistic assessment of standard-of-care targeted drugs, candidates for drug repositioning and immunotherapeutic approaches. To this end, our tool analyzes and visualizes clinical markers and (epi-)genomics and transcriptomics datasets to identify and evaluate the tumor’s main driver mutations, the tumor mutational burden, activity patterns of core cancerrelevant pathways, drug-specific biomarkers, the status of molecular drug targets and pharmacogenomic influences. In order to demonstrate ClinOmicsTrailbc’s rich functionality, we present three case studies highlighting various ways in which ClinOmicsTrailbc can support breast cancer precision medicine. ClinOmicsTrailbc is a powerful integrated visual analytics tool for breast cancer research in general and for therapy stratification in particular, assisting oncologists to find the best possible treatment options for their breast cancer patients based on actionable, evidence-based results. Availability and implementation: ClinOmicsTrailbc can be freely accessed at https://clinomicstrail. bioinf.uni-sb.de

MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

OBJECTIVE: To evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival. PATIENTS AND METHODS: We conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong). RESULTS: Expression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P<.001 for both). In HGSOC, strong MyD88 expression was modestly associated with shortened overall survival (hazard ratio [HR], 1.13; 95% CI, 1.01-1.26; P=.04) but was also associated with advanced stage (P<.001). The expression of TLR4 was not associated with survival. In low-grade serous ovarian cancer (LGSOC), strong expression of both MyD88 and TLR4 was associated with favorable survival (HR [95% CI], 0.49 [0.29-0.84] and 0.44 [0.21-0.89], respectively; P=.009 and P=.02, respectively). CONCLUSION: Results are consistent with an association between strong MyD88 staining and advanced stage and poorer survival in HGSOC and demonstrate correlation between strong MyD88 and TLR4 staining and improved survival in LGSOC, highlighting the biological differences between the 2 serous histotypes

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Abstract: Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

Abstract: Background: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Methods: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Results: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). Conclusions: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes

An Activity Tracker–Guided Physical Activity Program for Patients Undergoing Radiotherapy: Protocol for a Prospective Phase III Trial (OnkoFit I and II Trials)

BackgroundThe positive impact that physical activity has on patients with cancer has been shown in several studies over recent years. However, supervised physical activity programs have several limitations, including costs and availability. Therefore, our study proposes a novel approach for the implementation of a patient-executed, activity tracker–guided exercise program to bridge this gap. ObjectiveOur trial aims to investigate the impact that an activity tracker–guided, patient-executed exercise program for patients undergoing radiotherapy has on cancer-related fatigue, health-related quality of life, and preoperative health status. MethodsPatients receiving postoperative radiotherapy for breast cancer (OnkoFit I trial) or neoadjuvant, definitive, or postoperative treatment for other types of solid tumors (OnkoFit II trial) will be randomized (1:1:1) into 3-arm studies. Target accrual is 201 patients in each trial (50 patients per year). After providing informed consent, patients will be randomized into a standard care arm (arm A) or 1 of 2 interventional arms (arms B and C). Patients in arms B and C will wear an activity tracker and record their daily step count in a diary. Patients in arm C will receive personalized weekly targets for their physical activity. No further instructions will be given to patients in arm B. The target daily step goals for patients in arm C will be adjusted weekly and will be increased by 10% of the average daily step count of the past week until they reach a maximum of 6000 steps per day. Patients in arm A will not be provided with an activity tracker. The primary end point of the OnkoFit I trial is cancer-related fatigue at 3 months after the completion of radiotherapy. This will be measured by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. For the OnkoFit II trial, the primary end point is the overall quality of life, which will be assessed with the Functional Assessment of Cancer Therapy-General sum score at 6 months after treatment to allow for recovery after possible surgery. In parallel, blood samples from before, during, and after treatment will be collected in order to assess inflammatory markers. ResultsRecruitment for both trials started on August 1, 2020, and to date, 49 and 12 patients have been included in the OnkoFit I and OnkoFit II trials, respectively. Both trials were approved by the institutional review board prior to their initiation. ConclusionsThe OnkoFit trials test an innovative, personalized approach for the implementation of an activity tracker–guided training program for patients with cancer during radiotherapy. The program requires only a limited amount of resources. Trial RegistrationClinicalTrials.gov NCT04506476; https://clinicaltrials.gov/ct2/show/NCT04506476. ClinicalTrials.gov NCT04517019; https://clinicaltrials.gov/ct2/show/NCT04517019. International Registered Report Identifier (IRRID)DERR1-10.2196/2852

Characteristics, Treatment Patterns and Survival of International Federation of Gynecology and Obstetrics Stage IV Epithelial Ovarian Cancer—A Population-Based Study

Background: The aim of the present study was to describe an unselected population of patients with diagnosis of FIGO stage IV OC. Methods: Data from 1183 patients were available for analysis. Results: The majority of patients (962/1183, 81.3%) received cancer-directed treatment. The median follow-up time was 3.8 years, and the median overall survival duration was 1.9 years. Notably, patients >80 years had a low overall survival rate (HR of age >80 years vs. ≤50 years was 3.81, 95%-CI [2.76, 5.27], p p p = 0.007 vs. systemic treatment only. After adjustment for age and histology, survival differences between treatment schemes were smaller (HR 0.81, 95%-CI [0.66, 1.00], p = 0.12). Conclusions: In this cohort of patients with FIGO stage IV OC, more than 80% of the patients received cancer-directed treatment. Age and high-grade serous histology were determinants for survival. The highest overall survival rate was observed in patients who underwent surgery followed by systemic treatment